Dactylospongia elegans-A Promising Drug Source: Metabolites, Bioactivities, Biosynthesis, Synthesis, and Structural-Activity Relationship.

Marine environment has been identified as a huge reservoir of novel biometabolites that are beneficial for medical treatments, as well as improving human health and well-being. Sponges have been highlighted as one of the most interesting phyla as new metabolites producers. Dactylospongia elegans Thiele (Thorectidae) is a wealth pool of various classes of sesquiterpenes, including hydroquinones, quinones, and tetronic acid derivatives. These metabolites possessed a wide array of potent bioactivities such as antitumor, cytotoxicity, antibacterial, and anti-inflammatory. In the current work, the reported metabolites from D. elegans have been reviewed, including their bioactivities, biosynthesis, and synthesis, as well as the structural-activity relationship studies. Reviewing the reported studies revealed that these metabolites could contribute to new drug discovery, however, further mechanistic and in vivo studies of these metabolites are needed.

Genus Smenospongia: Untapped Treasure of Biometabolites-Biosynthesis, Synthesis, and Bioactivities.

Marine sponges continue to attract remarkable attention as one of the richest pools of bioactive metabolites in the marine environment. The genus Smenospongia (order Dictyoceratida, family Thorectidae) sponges can produce diverse classes of metabolites with unique and unusual chemical skeletons, including terpenoids (sesqui-, di-, and sesterterpenoids), indole alkaloids, aplysinopsins, bisspiroimidazolidinones, chromenes, γ-pyrones, phenyl alkenes, naphthoquinones, and polyketides that possessed diversified bioactivities. This review provided an overview of the reported metabolites from Smenospongia sponges, including their biosynthesis, synthesis, and bioactivities in the period from 1980 to June 2022. The structural characteristics and diverse bioactivities of these metabolites could attract a great deal of attention from natural-product chemists and pharmaceuticals seeking to develop these metabolites into medicine for the treatment and prevention of certain health concerns.

In Vitro Anti-Inflammatory Activity of Cotula anthemoides Essential Oil and In Silico Molecular Docking of Its Bioactives.

The genus Cotula (Asteraceae) comprises about 80 species, amongst them Cotula anthemoides L. It is a wild plant growing in Egypt that possesses many traditional uses as a headache, colic, and chest cold remedy. In our study, the chemical composition of C. anthemoides essential oils was analyzed using GC-MS spectroscopy. Sixteen components of leave and stem oils and thirteen components of flower oils were characterized. The main components in both essential oil parts were camphor (88.79% and 86.45%) and trans-thujone (5.14% and 10.40%) in the leaves and stems and the flowers, respectively. The anti-inflammatory activity of the oils in lipopolysaccharide-stimulated RAW 264.7 macrophage cells was evaluated. The flower oil showed its predominant effect in the amelioration of proinflammatory cytokines and tumor necrosis factor-α, as well as cyclooxygenase-2. The bornyl acetate showed the highest affinity for the cyclooxygenase-2 receptor, while compound cis-p-menth-2-ene-1-ol had the best affinity for the tumor necrosis factor receptor, according to the results of molecular docking. In addition, the molecule cis-ß-farnesene showed promising dual affinity for both studied receptors. Our findings show that essential oils from C. anthemoides have anti-inflammatory properties through their control over the generation of inflammatory mediators. These findings suggest that C. anthemoides essential oils could lead to the discovery of novel sources of anti-inflammatory treatments.

Red Sea Sponge Callyspongia siphonella Extract Induced Growth Inhibition and Apoptosis in Breast MCF-7 and Hepatic HepG-2 Cancer Cell Lines in 2D and 3D Cell Cultures.

Introduction: The increasing incidence of cancer diseases necessitates the urgent exploration of new bioactive compounds. One of the trends in drug discovery is marine sponges which is gaining significant support due to the abundant production of natural pharmaceutical compounds obtained from marine ecosystems. This study evaluates the anticancer properties of an organic extract from the Red Sea sponge Callyspongia siphonella (C. siphonella) on HepG-2 and MCF-7 cancer cell lines. Methods: C. siphonella was collected, freeze-dried, and extracted using a methanol-dichloromethane mixture. The extract was analyzed via Liquid Chromatography-Mass Spectrometry. Cytotoxic effects were assessed through cell viability assays, apoptosis detection, cell cycle analysis, mitochondrial membrane potential assays, scratch-wound healing assays, and 3D cell culture assays. Results: Fifteen compounds were identified in the C. siphonella extract. The extract showed moderate cytotoxicity against MCF-7 and HepG-2 cells, with IC50 values of 35.6 ± 6.9 µg/mL and 64.4 ± 8 µg/mL, respectively, after 48 hours of treatment. It induced cell cycle arrest at the G2/M phase in MCF-7 cells and the S phase in HepG-2 cells. Apoptosis increased significantly in both cell lines, accompanied by reduced mitochondrial membrane potential. The extract inhibited cell migration, with notable reductions after 24 and 48 hours. In 3D cell cultures, the extract had IC50 values of 5.1 ± 2 µg/mL for MCF-7 and 166.4 ± 27 µg/mL for HepG-2 after 7 days of treatment, showing greater potency in MCF-7 spheres compared to HepG-2 spheres. Discussion and Conclusion: The anticancer activity is attributed to the bioactive compounds. The C. siphonella extract's ability to induce apoptosis, disrupt mitochondrial membrane potential, and arrest the cell cycle highlights its potential as a novel anticancer agent. Additional research is required to investigate the underlying mechanism by which this extract functions as a highly effective anticancer agent.

Evaluation of Cytotoxicity of the Methanolic Extract of Red Sea Marine Sponge Xestospongia Testudinaria and Its Related Compounds Against MCF-7 Human Breast Cancer Cells.

Background: Breast cancer is a leading cause of death and one of the most common fatal medical conditions in the world. Chemical compounds of various types have been identified in the Red Sea marine sponge Xestospongia testudinaria, including sterol esters, sterols, indole alkaloids, and brominated polyunsaturated fatty acids. These compounds have demonstrated promising biological features, which in cludes anti-inflammatory, cancer preventive, and antioxidant capacities. Methods: The cytotoxic potential of Xestospongia testudinaria was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and morphological alterations in MCF-7 cell line. Furthermore, the flow cytometry was also utilized to assess apoptosis and identify changes in the cell cycle; besides, cell migration was assessed by scratch wound-healing assay. Results: A significant dose-dependent decrease in the percentage of MCF-7 cell viability was observed with IC50 39.8 ug/mL. Functional studies were performed on MCF-7 to show that Xestospongia testudinaria raises apoptotic cell death and induces growth arrest at the G1/G0 while inhibiting cell migration in scratch assay. Conclusion: These results demonstrated that Xestospongia testudinaria extract has an inhibitory effect on breast cancer cells proliferation, migration and induce apoptosis. Thus, it holds great promise as a potential treatment for breast cancer.

Acetyl barlerin from Barleria trispinosa induces chemopreventive NQO1 and attenuates LPS-induced inflammation: in vitro and molecular dynamic studies.

Extraction and fractionation of Barleria trispinosa growing in Saudi Arabia yielded four iridoid compounds identified by spectroscopic techniques as acetylbarlerin (1), barlerin (2), shanzhiside methyl ester (3) and 6-⍺-L-rhamnopyranosyl-8-O-acetylshanzihiside methyl ester (4). Preliminary experiments confirmed that compound 1 acts as an inducer of chemopreventive NAD(P)H:Quinone oxidoreductase 1 (NQO1) enzymatic activity in a murine hepatoma (Hepa1c1c7) chemoprevention model. It also demonstrated the ability to inhibit the lipopolysaccharides (LPS)-induced nitric oxide (NO) production in the RAW264.7 macrophage model. Western blotting revealed the ability of compound 1 to up-regulate the protein expression of the NQO1 marker. Furthermore, compound 1 elicited NO suppression in RAW264.7 macrophages by inhibiting iNOS protein expression. Molecular docking and molecular simulation studies of 1 supported its experimental results as an inhibitor of the nuclear factor erythroid 2-Kelch-like ECH-associated protein 1 (Nrf2-KEAP1) complex, resulting in Nrf2-mediated induction of chemopreventive NQO1.Communicated by Ramaswamy H. Sarma.

Ethnobotanical Uses, Phytochemical Composition, Biosynthesis, and Pharmacological Activities of Carpesium abrotanoides L. (Asteraceae).

Carpesium abrotanoides L. (Asteraceae) is a medicinal plant with immense therapeutic importance and bioactivities. It is commonly encountered in various Asian regions. It has numerous ethnomedicinal uses for curing diverse ailments such as toothache, stomach ulcer, boils, tonsillitis, bronchitis, bacterial infection, bruises, swelling, virus infection, fever, and amygdalitis, as well as an anthelmintic versus round-, tape-, hook-, and pinworms. Different classes of phytoconstituents such as sesquiterpenes, sesquiterpene dimers, monoterpenes, and nitrogenous compounds have been reported from this plant. These phytoconstituents have proved to possess anti-inflammatory, cytotoxic, antimicrobial, and insecticidal capacities. The present review aims to summarize all published data on C. abrotanoides including traditional uses, phytoconstituents, bioactivities, and toxicological aspects, as well as the synthesis and biosynthesis of its metabolites through an extensive survey on various databases and various publishers. These reported data could draw the attention of various natural-metabolite-interested researchers and medicinal chemists towards the development of this plant and/or its metabolites into medicine for the prevention and treatment of certain illnesses. Despite the diverse traditional uses of C. abrotanoides, there is a need for scientific evidence to support these claims. Clinical trials are also required to further assure these data and validate this plant utilization in treating several diseases.

Fungal Naphthalenones; Promising Metabolites for Drug Discovery: Structures, Biosynthesis, Sources, and Pharmacological Potential.

Fungi are well-known for their abundant supply of metabolites with unrivaled structure and promising bioactivities. Naphthalenones are among these fungal metabolites, that are biosynthesized through the 1,8-dihydroxy-naphthalene polyketide pathway. They revealed a wide spectrum of bioactivities, including phytotoxic, neuro-protective, cytotoxic, antiviral, nematocidal, antimycobacterial, antimalarial, antimicrobial, and anti-inflammatory. The current review emphasizes the reported naphthalenone derivatives produced by various fungal species, including their sources, structures, biosynthesis, and bioactivities in the period from 1972 to 2021. Overall, more than 167 references with 159 metabolites are listed.

Prophylactic Anti-Osteoporotic Effect of Matricaria chamomilla L. Flower Using Steroid-Induced Osteoporosis in Rat Model and Molecular Modelling Approaches.

The anti-osteoporotic activity of ethanol extract from the Matricaria chamomilla L. flower was evaluated using steroid-induced osteoporosis in a rat model for the first time. Biochemical parameters such as serum calcium, phosphate, magnesium, creatinine, and alkaline phosphatase were assessed. At a 400 mg/kg body weight dose, the extract showed 54.01% and 27.73% reduction in serum calcium and phosphate ions serum levels, respectively. Meanwhile, it showed a 20% elevation in serum magnesium level, compared to the steroid-treated group. It also showed a significant decrease in creatinine and alkaline phosphatase levels, by 29.41% and 27.83%, respectively. The obtained results were further supported by biomechanical analyses, which revealed that a 400 mg/kg body weight dose of the flower extract increased bone strength and thickness. At the same time, it does not affect the bone length, compared to the diseased group. Histopathological examination revealed that the extract showed a significant increase in trabecular thickness, and it had restored the architecture of the cortical and trabecular structure with well-organized bone matrix. The possible inhibitory effect of the major phenolic compounds identified from the plant extract on cathepsin K was investigated using molecular docking. Rutin (4) had the best-fitting score within the active site, as evidenced by the free binding energy, (∆G = -54.19 Kcal/mol). ADMET/TOPKAT revealed that the examined compounds had variable pharmacodynamics and pharmacokinetic properties that could be improved to enhance the bioavailability during incorporation in various dosage forms. Thus, it can be concluded that this plant extract showed potential therapeutic benefits for osteoporosis.

Ecdysteroids as Potent Enzyme Inhibitors and Verification of Their Activity Using In Vitro and In Silico Docking Studies.

Ecdysteroids represent arthropods' steroidal hormones, and they exist in about 5-6% of plant species. In this study, the enzyme inhibitory activity of 20 ecdysteroids was assessed for the first time via determining their inhibition versus acetylcholinesterase, butyrylcholinesterase, tyrosinase, as well as α-amylase enzymes. Furthermore, 20-Hydroxyecdysone-2,3,22-tri-O-acetate (4) showed the highest inhibition of acetylcholinesterase and butyrylcholinesterase with values of 5.56 and 4.76 mg GALAE/g, respectively. All ecdysteroids displayed tyrosinase inhibitory effects, whereas the most potent was viticosterone E (7) with 78.88 mg KAE/g. Most ecdysteroids had similar amylase inhibitory properties; meanwhile, the best α-amylase inhibitory potential was observed with viticosterone E-diacetonide (18) (0.35 mmol ACAE/g). Most of the tested compounds showed tyrosinase inhibitory potential; therefore, they were exposed to molecular docking evaluation using the tyrosinase enzyme. Viticosterone E (7) showed the best ranking score with a docking score of -5.716 Kcal/mol and made three separate H-bonds with Gly281, Asn81, and His85. From ADMET /TOPKAT in silico evaluation, it was obvious that most of the compounds displayed reasonable pharmacodynamic and pharmacokinetic properties; however, their toxicity should be carefully monitored by adjusting their doses while investigating their activity after incorporation into dosage forms. Principal component analysis (PCA) based upon the in vitro and in silico data was carried out to visualize the differences between the tested compounds better. PCA score plot successfully classifies the compounds into four main clusters that, in turn, reflects the similarities and differences among the clustered compounds with respect to their biological, pharmacokinetic, and pharmacodynamic properties that are mainly influenced by the similarity in the chemical structure. Thus, ecdysteroids can act as effective drug entities for alleviating several disorders owing to their enzyme inhibitory potential.

In Vivo Evaluation of the Anti-Schistosomal Potential of Ginger-Loaded Chitosan Nanoparticles on Schistosoma mansoni: Histopathological, Ultrastructural, and Immunological Changes.

Chemotherapy is the most widely advocated method of Schistosome control. However, repeated chemotherapy leads to the emergence of drug-resistant Schistosoma strains. Therefore, efforts to find alternative drugs, especially those of natural origin, have risen globally. Nanoparticles (NPs) have received special interest as efficient drug delivery systems. This work aimed to investigate the anti-schistosomal potential of Zingiber officinale (ginger, Zingiberaceae)-loaded chitosan nanoparticles (GCsNPs) on Schistosoma mansoni experimentally infected mice that were exposed to 80 ± 10 cercariae/mouse. The study groups are: (G1) negative control; (G2) positive control; (G3) praziquantel in a dose of 500 mg/kg/day for two consecutive days; (G4) ginger in a dose of 500 mg/kg treated; (G5) chitosan nanoparticles in a dose 3 mg/kg (G6) GCsNPs in a dose 250 mg/kg; and (G7) GCsNPs in a dose 500 mg/kg. The anti-schistosome potential was assessed using histopathological scanning electron microscopically and immunological parameters. The results showed that there was a significant decrease in cellular granuloma count (p < 0.05) and granuloma diameter (p < 0.001) in all infected treated mice groups, in comparison to the infected non-treated group with the highest reduction in both G3 and G7. SEM of S. mansoni adult worm recovered from G3 showed mild edema of oral and ventral suckers with some peeling and blebs around them, while that recovered from G7 showed abnormal oedematous oral and retracted ventral sucker, edema of the tegument, rupture of many tubercles with vacuolation and complete loss of spines. All infected treated mice groups, in comparison to positive control G2, showed a significant reduction in IL-4, IL-10, and TNF-α levels (p-value < 0.001), especially groups G6 and G7 (p-value < 0.05); both G6 and G7 values were nearer to the normal that indicated recovery of the liver tissue.

Evaluation of the Antihyperglycemic and Antihyperlipidemic Activity of Saussurea hypoleuca Root in Alloxan-Induced Diabetes in Rat Model and Correlation to Its Major Secondary Metabolites.

Saussurea hypoleuca belongs to the family Asteraceae, which has previously shown hepatoprotective, anticancer, and antioxidant activity. This study aimed to evaluate the antihyperglycemic and antihyperlipidemic activity of its root methanol extract and various fractions for the first time. This was performed using alloxan-induced diabetes in the rat model for both short, and long-term periods using different administration doses. Different biochemical parameters were studied and further consolidated by histopathological examination and in silico molecular modeling. The results showed that in the long-term study, at a dose of 400 mg/kg b.wt, the ethyl acetate fraction caused a pronounced reduction in fasting blood glucose level (FBG) and glycated hemoglobin (HbA1c) by 77.2% and 36.8%, respectively, compared to the diabetic group. This was confirmed by the histopathological examination of the animals' pancreatic sections. The ethyl acetate fraction also showed a reduction in total cholesterol (TC), total glycerides (TG), and low-density lipoprotein cholesterol (LDL-C) levels. It improved kidney and liver functions, causing a reduction in aspartate aminotransferase (AST), alkaline phosphatase (ALP), alanine transaminase (ALT), urea, and creatinine levels. This is mainly attributed to its richness in secondary metabolites. Molecular docking showed that all the tested compounds showed certain inhibitory potential towards human α-glucosidase (HAG) and ATP citrate lyase (ACL). Thus, Saussurea hypoleuca roots can help in the management of hyperglycemia, hyperlipidemia, and hepatic and kidney dysfunction.

Bio-Guided Isolation of SARS-CoV-2 Main Protease Inhibitors from Medicinal Plants: In Vitro Assay and Molecular Dynamics.

Since the emergence of the pandemic of the coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the discovery of antiviral phytoconstituents from medicinal plants against SARS-CoV-2 has been comprehensively researched. In this study, thirty-three plants belonging to seventeen different families used traditionally in Saudi Arabia were tested in vitro for their ability to inhibit the SARS-CoV-2 main protease (MPRO). Major constituents of the bio-active extracts were isolated and tested for their inhibition potential against this enzyme; in addition, their antiviral activity against the SARS-CoV-2 Egyptian strain was assessed. Further, the thermodynamic stability of the best active compounds was studied through focused comparative insights for the active metabolites regarding ligand-target binding characteristics at the molecular level. Additionally, the obtained computational findings provided useful directions for future drug optimization and development. The results revealed that Psiadia punctulata, Aframomum melegueta, and Nigella sativa extracts showed a high percentage of inhibition of 66.4, 58.7, and 31.5%, against SARS-CoV-2 MPRO, respectively. The major isolated constituents of these plants were identified as gardenins A and B (from P. punctulata), 6-gingerol and 6-paradol (from A. melegueta), and thymoquinone (from N. sativa). These compounds are the first to be tested invitro against SARS-CoV-2 MPRO. Among the isolated compounds, only thymoquinone (THY), gardenin A (GDA), 6-gingerol (GNG), and 6-paradol (PAD) inhibited the SARS-CoV-2 MPRO enzyme with inhibition percentages of 63.21, 73.80, 65.2, and 71.8%, respectively. In vitro assessment of SARS-CoV-2 (hCoV-19/Egypt/NRC-03/2020 (accession number on GSAID: EPI_ISL_430820) revealed a strong-to-low antiviral activity of the isolated compounds. THY showed relatively high cytotoxicity and was anti-SARS-CoV-2, while PAD demonstrated a cytotoxic effect on the tested VERO cells with a selectivity index of CC50/IC50 = 1.33 and CC50/IC50 = 0.6, respectively. Moreover, GNG had moderate activity at non-cytotoxic concentrations in vitro with a selectivity index of CC50/IC50 = 101.3/43.45 = 2.3. Meanwhile, GDA showed weak activity with a selectivity index of CC50/IC50 = 246.5/83.77 = 2.9. The thermodynamic stability of top-active compounds revealed preferential stability and SARS-CoV-2 MPRO binding affinity for PAD through molecular-docking-coupled molecular dynamics simulation. The obtained results suggest the treating potential of these plants and/or their active metabolites for COVID-19. However, further in-vivo and clinical investigations are required to establish the potential preventive and treatment effectiveness of these plants and/or their bio-active compounds in COVID-19.

The Polarized Redistribution of the Contractile Vacuole to the Rear of the Cell is Critical for Streaming and is Regulated by PI(4,5)P2-Mediated Exocytosis.

Dictyostelium discoideum amoebae align in a head to tail manner during the process of streaming during fruiting body formation. The chemoattractant cAMP is the chemoattractant regulating cell migration during this process and is released from the rear of cells. The process by which this cAMP release occurs has eluded investigators for many decades, but new findings suggest that this release can occur through expulsion during contractile vacuole (CV) ejection. The CV is an organelle that performs several functions inside the cell including the regulation of osmolarity, and discharges its content via exocytosis. The CV localizes to the rear of the cell and appears to be part of the polarity network, with the localization under the influence of the plasma membrane (PM) lipids, including the phosphoinositides (PIs), among those is PI(4,5)P2, the most abundant PI on the PM. Research on D. discoideum and neutrophils have shown that PI(4,5)P2 is enriched at the rear of migrating cells. In several systems, it has been shown that the essential regulator of exocytosis is through the exocyst complex, mediated in part by PI(4,5)P2-binding. This review features the role of the CV complex in D. discoideum signaling with a focus on the role of PI(4,5)P2 in regulating CV exocytosis and localization. Many of the regulators of these processes are conserved during evolution, so the mechanisms controlling exocytosis and membrane trafficking in D. discoideum and mammalian cells will be discussed, highlighting their important functions in membrane trafficking and signaling in health and disease.