Search

A new xanthone glycoside, 1,3,5,6-tetrahydroxyxanthone-C-4-β-d-glucopyranoside was isolated from the methanol extract of

The large-scale dissemination of coronavirus disease-2019 (COVID-19) and its serious complications have pledged the scientific research communities to uncover the pathogenesis mechanisms of its etiologic agent, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Methods of unveiling such mechanisms are rooted in understanding the viral agent’s interactions with the immune system, including its ability to activate macrophages, due to their suggested role in prolonged inflammatory phases and adverse immune responses. The objective of this study is to test the effect of SARS-CoV-2-free proteins on the metabolic and immune responses of macrophages. We hypothesized that SARS-CoV-2 proteins shed during the infection cycle may dynamically induce metabolic and immunologic alterations with an inflammatory impact on the infected host cells. It is imperative to delineate such alterations in the context of macrophages to gain insight into the pathogenesis of these highly infectious viruses and their associated complications and thus, expedite the vaccine and drug therapy advent in combat of viral infections. Human monocyte-derived macrophages were treated with SARS-CoV-2-free proteins at different concentrations. The phenotypic and metabolic alterations in macrophages were investigated and the subsequent metabolic pathways were analyzed. The obtained results indicated that SARS-CoV-2-free proteins induced concentration-dependent alterations in the metabolic and phenotypic profiles of macrophages. Several metabolic pathways were enriched following treatment, including vitamin K, propanoate, and the Warburg effect. These results indicate significant adverse effects driven by residual viral proteins that may hence be considered determinants of viral pathogenesis. These findings provide important insight as to the impact of SARS-CoV-2-free residual proteins on the host cells and suggest a potential new method of management during the infection and prior to vaccination.

Tephrosia is widely distributed throughout tropical, subtropical, and arid regions. This genus is known for several biological activities, including its anti-Candida activity, which is mainly attributed to prenylated flavonoids. The biological activities of most Tephrosia species have been studied, except T. apollinea. This study was conducted to investigate the underlying anti-Candida activity of T. apollinea, wildly grown in the United Arab Emirates (UAE). The T. apollinea plant was collected, dried, and the leaves were separated. The leaves were ground and extracted. The dried extract was subjected to successive chromatography to identify unique phytochemicals with a special pharmacological activity. The activity of the compound was validated by homology modeling and molecular docking studies. A novel steroidal compound (ergosta-6, 8(14), 22, 24(28)-tetraen-3-one) was isolated and named TNS. In silico target identification of TNS revealed a high structural similarity with the Candida 14-α-demethylase enzyme substrate. The compound exhibited a significant anti-Candida activity, specifically against the multi-drug-resistant Candida auris at MIC50, 16 times less than the previously reported prenylated flavonoids and 5 times less than the methanol extract of the plant. These findings were supported by homology modeling and molecular docking studies. TNS may represent a new class of Candida 14-α-demethylase inhibitors.

Terrein is a bioactive marine secondary metabolite isolated from the fungal strain of Penicillium species SF-7181 and Aspergillus terreus. Previous studies showed that terrein possesses cytotoxic properties attributed to interrupting various molecular pathways, such as nuclear factor kappa B (NF-kB). Gemcitabine (GCB) is an anticancer drug commonly used to treat colorectal cancer; however, it suffers from tumor cell resistance and subsequently treatment failure. In this study, the potential anticancer properties of terrein as well as its chemomodulatory effect on GCB are assessed against various colorectal cancer cell lines (SW620, HT29 and HCT116) under normoxic and hypoxic (pO2 ≤ 1%) conditions. The antiproliferative effects of terrein, GCB and their equitoxic combination were evaluated using sulforhodamine-B assay. In SW620, terrein had IC50’s of 66.89±8.5 µM and 73.4±1.3 µM as single treatment, and the IC50’s of GCB in combination treatment were 0.27± 0.01 µM and 0.24±0.04 µM, under hypoxic and normoxic conditions, respectively. In HT29, terrein had IC50’s of 85.5±4.4 µM and 49.6±11.4 µM, and the IC50’s of GCB in combination treatment were 3.2±0.08 µM and 0.27±0.005 µM, under hypoxic and normoxic conditions, respectively. In HCT116, terrein had IC50’s of 21.6±2.891 µM and 74.76±0.97 µM, and the IC50’s of GCB in combination treatment were 0.23±0.03 µM and 0.23±0.005 µM, under hypoxic and normoxic conditions, respectively. In both SW620 and HCT116, terrein exhibited a preferential antitumor effect in hypoxic conditions; however, the opposite was observed in HT29. Upon further analysis via flow cytometry after annexin-V/FITC and PI staining, GCB and its combination treatment with terrein were found to induce necrosis in all cell lines under investigation. In addition, terrein was found to significantly induce significant S-phase cell arrest compared to GCB treatment alone using DNA content cytometry assay coupled with PI staining. Currently, we are studying the expression of multiple cyclins/CDK’s involved in the different cell cycle phases for further understanding of the detailed mechanism of action. Using flowcytometry assessment after staining with acridine orange, terrein suppressed autophagy compared to control cells as well as GCB treatment. NMR metabolomic analysis revealed that the change in oxygen levels significantly affected extracellular amino acid metabolite profiling such as leucin, which increased significantly due to hypoxia; while tyrosine decreased significantly in response to hypoxic environment. Currently, the gene expression profiling corresponding to these amino acids metabolomic changes are undergoing. Therefore, oxygen concentration plays a vital role in the intratumoral amino acid metabolism in response to terrein, GCB and their combination within colorectal cancer cells. Citation Format: Reham K. Abu Hijjleh, Dalia Y. Al Saeedy, Naglaa S. Ashmawy, Ahmed Gouda, Sameh S. Elhady, Ahmed M. Al-Abd. The potential chemo-modulatory effect of the marine-derived secondary metabolite terrein on the anticancer properties of gemcitabine in colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1065.

The current pandemic caused by SARS-CoV2 and named COVID-19 urgent the need for novel lead antiviral drugs. Recently, United States Food and Drug Administration (FDA) approved the use of remdesivir as anti-SARS-CoV-2. Remdesivir is a natural product-inspired nucleoside analogue with significant broad-spectrum antiviral activity. Nucleosides analogues from marine sponge including spongouridine and spongothymidine have been used as lead for the evolutionary synthesis of various antiviral drugs such as vidarabine and cytarabine. Furthermore, the marine sponge is a rich source of compounds with unique activities. Marine sponge produces classes of compounds that can inhibit the viral cysteine protease (Mpro) such as esculetin and ilimaquinone and human serine protease (TMPRSS2) such as pseudotheonamide C and D and aeruginosin 98B. Additionally, sponge-derived compounds such as dihydrogracilin A and avarol showed immunomodulatory activity that can target the cytokines storm. Here, we reviewed the potential use of sponge-derived compounds as promising therapeutics against SARS-CoV-2. Despite the reported antiviral activity of isolated marine metabolites, structural modifications showed the importance in targeting and efficacy. On that basis, we are proposing a novel structure with bifunctional scaffolds and dual pharmacophores that can be superiorly employed in SARS-CoV-2 infection.

Flavonoids are a class of phenolic natural products, well-identified in traditional and modern medicines in the treatment of several diseases including viral infection. Flavonoids showed potential inhibitory activity against coronaviruses including the current pandemic outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and designated as COVID-19. Here, we have collected all data related to the potential inhibitory mechanisms of flavonoids against SARS-CoV-2 infection and their significant immunomodulatory activities. The data were mapped and compared to elect major flavonoids with a promising role in the current pandemic. Further, we have linked the global existence of flavonoids in medicinal plants and their role in protection against COVID-19. Computational analysis predicted that flavonoids can exhibit potential inhibitory activity against SARS-CoV-2 by binding to essential viral targets required in virus entry and/ or replication. Flavonoids also showed excellent immunomodulatory and anti-inflammatory activities including the inhibition of various inflammatory cytokines. Further, flavonoids showed significant ability to reduce the exacerbation of COVID-19 in the case of obesity via promoting lipids metabolism. Moreover, flavonoids exhibit a high safety profile, suitable bioavailability, and no significant adverse effects. For instance, plants rich in flavonoids are globally distributed and can offer great protection from COVID-19. The data described in this study strongly highlighted that flavonoids particularly quercetin and luteolin can exhibit promising multi-target activity against SARS-CoV-2, which promote their use in the current and expected future outbreaks. Therefore, a regimen of flavonoid-rich plants can be recommended to supplement a sufficient amount of flavonoids for the protection and treatment from SARS-CoV-2 infection.

The plant genus Polyscias (family Araliaceae) comprises about 116 species that are widely used for ornamental purposes and some, bear potential medicinal value. Polyscias species are represented as perennial shrubs and are commonly cultivated in southeastern Asia and the Pacific region. Studies on species of this genus have provided essential data regarding the chemical composition and pharmacological activities of Polyscias extracts and isolated secondary metabolites. Phytochemical investigations of Polyscias species revealed the isolation of about 97 chemical compounds from various chemical classes, including saponins as major constituents. Biological studies demonstrated that Polyscias extracts and their bioactive compounds possess antibacterial, antifungal, cytotoxic, immuno-stimulant, wound healing and anti-asthmatic activities. Bearing potential value for drug discovery, regardless of the presented data, further studies are required to investigate other Polyscias species, to assess the biological activities of their extracts as well as the isolated chemical compounds and to identify the suggested underlying mechanisms of action for their pharmacological activities.

Phytochemical investigation of Polyscias guilfoylei leaves extract (PGE) led to the isolation of nine compounds, that is, ent-labda-8(17),13-diene-15,18-diol (1), stigmasterol (2), spinasterol (3), N-(1,3-dihydroxyoctadecan-2-yl) palmitamide (4), panaxydiol (5), 3-O-β-d-glucopyranosylstigmasta-5,22-diene-3-β-ol (6), (8Z)-2-(2 hydroxypentacosanoylamino) octadeca-8-ene-1,3,4-triol (7), 4-hydroxybenzoic acid (8), and tamarixetin 3,7-di-O-α-L-rhamnopyranoside (9). Compound 4 is reported in this study for the first time in nature whereas compound 9 is reported for the second time. Structural elucidation of the compounds was carried out using Nuclear Magnetic Resonance and Electrospray Ionization coupled with Mass Spectrometry spectroscopic analyses. PGE and compounds 4 and 9 exhibited weak cytotoxicity against both MCF-7 and HCT-116 cell lines using 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide assay. The antimicrobial activity of PGE and compounds 4 and 9 was evaluated using the agar diffusion method. Escherichia coli was the most susceptible Gram-negative bacteria toward PGE with a minimum inhibitory concentration value of 9.76 μg/mL, whereas compounds 4 and 9 did not show any antimicrobial activity. Compound 4 exhibited promising inhibition of histamine release using U937 human monocytes with an IC50 value of 38.65 μg/mL.