Comparative Immunomodulatory Activity of Nigella sativa L. Preparations on Proinflammatory Mediators: A Focus on Asthma

Introduction: A range of traditional and commercial preparations of NS is frequently used in the treatment of several inflammatory diseases. Often, these preparations have poor preclinical characterization that may lead to variable pharmacological effects.Objective: To assess the in vitro effects of different chemically defined preparations of NS on some asthma-related mediators of inflammation.Methods: Different NS preparations were obtained by either seed extraction with a spectrum of solvents ranging from lipophilic to hydrophilic, or commercial products were collected. The TQ concentration of NS was analyzed by HPLC. Immunomodulatory activity was assessed by the release of mediators (IL-2, IL-6, PGE2) in primary human T-lymphocytes, monocytes, and A549 human lung epithelial cells.Results: Ten distinct NS preparations showed variability in TQ concentration, being highest in the oily preparations extract-7 (2.4% w/w), followed by extract-10 (0.7%w/w). Similarly, the release of mediators was varied, being greatest in extract-7 and 10 via significantly (<0.05) suppressing IL-2, IL-6, and PGE2 in T-lymphocytes as well as IL-6 and PGE2 in monocytes. Also, PGE2 release in A549 cells was significantly enhanced by both extracts.Conclusion: The TQ concentration and in vitro activity were variable among the different NS preparations. TQ-rich oily NS preparations produced potent favorable immunomodulation in asthma inflammation and can be used in future studies

Anti-Proliferative, Cytotoxic and Antioxidant Properties of the Methanolic Extracts of Five Saudi Arabian Flora with Folkloric Medicinal Use: Aizoon canariense, Citrullus colocynthis, Maerua crassifolia, Rhazya stricta and Tribulus macropterus

Saudi Arabian flora have a history of use as folklore remedies, although such properties have yet to be explored rigorously, and the safety of such remedies should be assessed. This study determined the anti-proliferative, cytotoxic, and antioxidant properties of extracts of the following five plants indigenous to Saudi Arabia: Aizoon canariense, Citrullus colocynthis, Maerua crassifolia, Rhazya stricta, and Tribulus macropterus. The aerial parts of the five plants were collected from various locations of the western and northern regions of Saudi Arabia and used to prepare methanolic extracts. Three approaches were used to determine the proliferation and cytotoxicity effects using HaCaT cells: MTT, FACS, and confocal microscopy. Meanwhile, two approaches were used to study the antioxidant potential: DPPH (acellular) and RosGlo (cellular, using HaCaT cells). C. colocynthis possessed anti-proliferative activity against HaCaT cells, showing a significant decrease in cell proliferation from 24 h onwards, while R. stricta showed significant inhibition of cell growth at 120 and 168 h. The IC50 values were determined for both plant extracts for C. colocynthis, with 17.32 and 16.91 µg/mL after five and seven days of treatment, respectively, and for R. stricta, with 175 and 105.3 µg/mL after five and seven days of treatment. R. stricta and M. crassifolia exhibited the highest capacities for scavenging the DPPH radical with IC50 values of 335 and 448 µg/mL, respectively. The subsequent ROS-Glo H2O2 assay confirmed these findings. The R. stricta and M. crassifolia extracts showed potent antioxidant activity in both acellular and cellular models. The C. colocynthis extract also demonstrated significant anti-proliferation and cytotoxic activity, as did the R. stricta extract. These properties support their usage in folk medicine and also indicate a further potential for development for holistic medicinal use or as sources of new active compounds

Nigella Sativa Supplementation Accelerates Recovery from Mild COVID-19: First Randomized Controlled Clinical Trial (RCT)

Background Effective treatment for patients with the novel Coronavirus Disease (COVID-19) is desperately needed and is under rigorous research. Nigella sativa oil (NSO), a herbal medicine, that has a documented wide antiviral and immunomodulatory activities offering a therapeutic potential for COVID-19. Methods Adult symptomatic patients with mild COVID-19 were recruited between May and August 2020 from King Abdulaziz University Hospital in Jeddah, Saudi Arabia. They were randomly assigned to receive supplementation with oral capsules of NSO (MARNYS® Cuminmar 500 mg twice daily for 10 days) plus standard of care or standard of care medications alone. The primary endpoint was the proportion of patients recovered (free of symptoms for 3 days) within 14 days after randomization. This trial was registered with clinicaltrials.gov, NCT04401202. Findings A total of 94 patients were enrolled. Their mean age was 35 (SD=11) years old and 57% of them were male. There were 47 patients in the treatment group (NSO) and 47 patients in the control group. The proportion of patients recovered in the treatment group was significantly higher than the control group, 37 (79%) versus 21 (45%) (p=0.001). Additionally, there was a significant difference in the average recovery time among both groups, 9 (SD=3) versus 11 (SD=3) days (p=0.003). Furthermore, 2 patients from the control group required hospitalization within the study period versus none in the treatment group. Adverse events were reported in 3 patients of NSO recipients as gastrointestinal symptoms. Conclusions In this RCT of adult patients with mild COVID-19, NSO was associated with a significant increase in the likelihood of recovery and a decrease in the likelihood of hospitalization. To our knowledge, this is the first RCT that shows potential therapeutic benefits of NSO in patients with COVID-19 which requires further confirmation with larger double-blinded RCTs

Deciphering Molecular Aspects of Potential <i>α</i>-Glucosidase Inhibitors within <i>Aspergillus terreus</i>: A Computational Odyssey of Molecular Docking-Coupled Dynamics Simulations and Pharmacokinetic Profiling

Hyperglycemia, as a hallmark of the metabolic malady diabetes mellitus, has been an overwhelming healthcare burden owing to its high rates of comorbidity and mortality, as well as prospective complications affecting different body organs. Available therapeutic agents, with α-glucosidase inhibitors as one of their cornerstone arsenal, control stages of broad glycemia while showing definitive characteristics related to their low clinical efficiency and off-target complications. This has propelled the academia and industrial section into discovering novel and safer candidates. Herein, we provided a thorough computational exploration of identifying candidates from the marine-derived Aspergillus terreus isolates. Combined structural- and ligand-based approaches using a chemical library of 275 metabolites were adopted for pinpointing promising α-glucosidase inhibitors, as well as providing guiding insights for further lead optimization and development. Structure-based virtual screening through escalating precision molecular docking protocol at the α-glucosidase canonical pocket identified 11 promising top-docked hits, with several being superior to the market drug reference, acarbose. Comprehensive ligand-based investigations of these hits’ pharmacokinetics ADME profiles, physiochemical characterizations, and obedience to the gold standard Lipinski’s rule of five, as well as toxicity and mutagenicity profiling, proceeded. Under explicit conditions, a molecular dynamics simulation identified the top-stable metabolites: butyrolactone VI (SK-44), aspulvinone E (SK-55), butyrolactone I 4′’’’-sulfate (SK-72), and terrelumamide B (SK-173). They depicted the highest free binding energies and steadiest thermodynamic behavior. Moreover, great structural insights have been revealed, including the advent of an aromatic scaffold-based interaction for ligand–target complex stability. The significance of introducing balanced hydrophobic/polar moieties, like triazole and other bioisosteres of carboxylic acid, has been highlighted across docking, ADME/Tox profiling, and molecular dynamics studies for maximizing binding interactions while assuring safety and optimal pharmacokinetics for targeting the intestinal-localized α-glucosidase enzyme. Overall, this study provided valuable starting points for developing new α-glucosidase inhibitors based on nature-derived unique scaffolds, as well as guidance for prospective lead optimization and development within future pre-clinical and clinical investigations

Terretonin as a New Protective Agent against Sepsis-Induced Acute Lung Injury: Impact on SIRT1/Nrf2/NF-&kappa;Bp65/NLRP3 Signaling

Endophytic fungi are proving to be an excellent source of chemical entities with unique structures and varied bioactivities. Terretonin (TE) and its structurally related derivatives are a class of meroterpenoids, possessing the same unique tetracyclic core skeleton, which have been reported from the Aspergillus genus. This study was carried out to assess the potential protective effects of TE separated from the endophytic fungus A. terreus against LPS (lipopolysaccharide)-induced ALI (acute lung injury) in mice. The results revealed that TE alleviated pulmonary edema as it lowered both the W/D lung ratio and protein content. The inflammatory response represented by inflammatory cell infiltration into the lung tissues was greatly repressed by TE. That was supported by the improved histopathological results and also by the reduced level of myeloperoxidase in the lung. TE showed a potent antioxidant activity as it attenuated lipid peroxidative markers (malondialdehyde, 4-hydroxynonenal, and protein carbonyl) and enhanced endogenous antioxidants (reduced glutathione, superoxide dismutase, and catalase) in lung tissues. Similarly, TE increased the mRNA expression of SIRT1, Nrf2, and its genes (HO-1, NQO1, and GCLm). On the other hand, TE restrained the activation of NF-&kappa;B (nuclear factor-&kappa;B) in the lung. Consequently, TE depressed the pro-inflammatory cytokines: nitric oxide (NOx), TNF-&alpha; (tumor necrosis factor-&alpha;), and interleukins (IL-6 and -1&beta;). Additionally, TE inhibited NLRP3 signaling and interrupted apoptosis by decreasing the levels of proapoptotic markers (Bax and caspase-3) and increasing the level of an anti-apoptotic marker (Bcl-2). In conclusion, TE had a remarkable protective potential on LPS-induced lung damage via antioxidant and anti-inflammatory mechanisms. This finding encourages further investigations on this promising candidate

Meleagrin Isolated from the Red Sea Fungus Penicillium chrysogenum Protects against Bleomycin-Induced Pulmonary Fibrosis in Mice

The Red Sea marine fungus Penicillium chrysogenum (Family: Ascomycota) comprises a panel of chemically diverse natural metabolites. A meleagrin alkaloid was isolated from deep-sediment-derived P. chrysogenum Strain S003 and has been reported to exert antibacterial and cytotoxic activities. The present study aimed to explore the therapeutic potential of meleagrin on pulmonary fibrosis. Lung fibrosis was induced in mice by a single intratracheal instillation of 2.5 mg/kg bleomycin. Mice were given 5 mg/kg meleagrin daily either for 3 weeks after bleomycin administration in the treatment group or 2 weeks before and 3 weeks after bleomycin administration in the protection group. Bleomycin triggered excessive ROS production, inflammatory infiltration, collagen overproduction and fibrosis. Bleomycin-induced pulmonary fibrosis was attenuated by meleagrin. Meleagrin was noted to restore the oxidant&ndash;antioxidant balance, as evidenced by lower MDA contents and higher levels of SOD and catalase activities and GSH content compared to the bleomycin group. Meleagrin also activated the Nrf2/HO-1 antioxidant signaling pathway and inhibited TLR4 and NF-&kappa;B gene expression, with a subsequent decreased release of pro-inflammatory cytokines (TNF-&alpha;, IL-6 and IFN-&gamma;). Additionally, meleagrin inhibited bleomycin-induced apoptosis by abating the activities of pro-apoptotic proteins Bax and caspase-3 while elevating Bcl2. Furthermore, it suppressed the gene expression of &alpha;-SMA, TGF-&beta;1, Smad-2, type I collagen and MMP-9, with a concomitant decrease in the protein levels of TGF-&beta;1, &alpha;-SMA, phosphorylated Smad-2, MMP-9, elastin and fibronectin. This study revealed that meleagrin&rsquo;s protective effects against bleomycin-induced pulmonary fibrosis are attributed to its antioxidant, anti-inflammatory, anti-apoptotic and antifibrotic properties. Notably, the use of meleagrin as a protective agent against bleomycin-induced lung fibrosis was more efficient than its use as a treatment agent

Metabolic Profiling, Chemical Composition, Antioxidant Capacity, and In Vivo Hepato- and Nephroprotective Effects of Sonchus cornutus in Mice Exposed to Cisplatin

Sonchus cornutus (Asteraceae) is a wild. edible plant that represents a plentiful source of polyphenolic compounds. For the first time, the metabolic analysis profiling demonstrated the presence of anthocyanidin glycosides, coumarins, flavonoids and their corresponding glycosides, and phenolic acids. The total phenolic compounds were determined to be 206.28 &plusmn; 14.64 mg gallic acid equivalent/gm, while flavonoids were determined to be 45.56 &plusmn; 1.78 mg quercetin equivalent/gm. The crude extract of S. cornutus exhibited a significant 1,1-diphenyl-2-picrylhydrazyl free radical scavenging effect with half-maximal inhibitory concentration (IC50) of 16.10 &plusmn; 2.14 &micro;g/mL compared to ascorbic acid as a standard (10.64 &plusmn; 0.82 &micro;g/mL). In vitro total antioxidant capacity and ferric reducing power capacity assays revealed a promising reducing potential of S. cornutus extract. Therefore, the possible protective effects of S. cornutus against hepatic and renal toxicity induced by cisplatin in experimental mice were investigated. S. cornutus significantly ameliorated the cisplatin-induced disturbances in liver and kidney functions and oxidative stress, decreased MDA, ROS, and NO levels, and restored CAT and SOD activities. Besides, it reversed cisplatin-driven upregulation in inflammatory markers, including iNOS, IL-6, and IL-1&beta; levels and NF-&kappa;B and TNF-&alpha; expression, and elevated anti-inflammatory IL-10 levels and Nrf2 expression. Additionally, the extract mitigated cisplatin alteration in apoptotic (Bax and caspase-3) and anti-apoptotic (Bcl-2) proteins. Interestingly, hepatic, and renal histopathology revealed the protective impacts of S. cornutus against cisplatin-induced pathological changes. Our findings guarantee a protective effect of S. cornutus against cisplatin-induced hepatic and renal damage via modulating oxidative stress, inflammation, and apoptotic pathways