Combination of Callyspongia sp. and stem cells for wound repair and skin regeneration: in vivo and in silico evidences.

Delayed healing of chronic wounds results in amputation and mortality rates in serious cases. The present study examines the merged wound-restorative efficacy of injectable bone marrow-derived mesenchymal stem cells (BMMSCs) and topical Callyspongia sp. extract in immunocompromised rats. HR-LC-MS analysis of Callyspongia sp. extract tentatively identified twenty-nine compounds (1-29) and highlighted its richness in fatty acids and terpenoids, known for their wound regenerating efficacies. The wound closure was greatly prominent in the BMMSCs/Callyspongia sp. group in contrast to the control group (p < 0.001). The RT-PCR gene expression emphasized these results by attenuating the oxidative, inflammatory, and immunity markers, further confirmed by histopathological findings. Additionally, in silico modeling was particularly targeting matrix metalloproteinase-9 (MMP9), a key player in wound healing processes. Computational analysis revealed that compounds 18 and 19 potentially modulate MMP9 activity. The combination of BMMSCs and topical Callyspongia sp. extract holds a promise for regenerative therapy constituting a drastic advance in the wound cure of immunocompromised patients, eventually further safety assessments and clinical trials are required.

Cytotoxic metabolites from Sinularia levi supported by network pharmacology.

The in-vitro anti-proliferative evaluation of Sinularia levi total extract against three cell lines revealed its potent effect against Caco-2 cell line with IC50 3.3 µg/mL, followed by MCF-7 and HepG-2 with IC50 6.4 µg/mL and 8.5 µg/mL, respectively, in comparison to doxorubicin. Metabolic profiling of S. levi total extract using liquid chromatography coupled with high-resolution electrospray ionization mass spectrometry (LC-HR-ESI-MS) revealed the presence of phytoconstituents clusters consisting mainly of steroids and terpenoids (1-20), together with five metabolites 21-25, which were additionally isolated and identified through the phytochemical investigation of S. levi total extract through various chromatographic and spectroscopic techniques. The isolated metabolites included one sesquiterpene, two steroids and two diterpenes, among which compounds prostantherol (21) and 12-hydroperoxylsarcoph-10-ene (25) were reported for the first time in Sinularia genus. The cytotoxic potential evaluation of the isolated compounds revealed variable cytotoxic effects against the three tested cell lines. Compound 25 was the most potent with IC50 value of 2.13 ± 0.09, 3.54 ± 0.07 and 5.67 ± 0.08 µg/mL against HepG-2, MCF-7 and Caco-2, respectively, followed by gorgosterol (23) and sarcophine (24). Additionally, network analysis showed that cyclin-dependent kinase 1 (CDK1) was encountered in the mechanism of action of the three cancer types. Molecular docking analysis revealed that CDK1 inhibition could possibly be the reason for the cytotoxic potential.

Apium extract alleviates indomethacin-induced gastric ulcers in rats via modulating the VEGF and IK-κB/NF-κB p65 signaling pathway: insights from in silico and in vivo investigations.

BACKGROUND: Gastric ulcers represent a worldwide health problem, characterized by erosions that affect the mucous membrane of the stomach and may even reach the muscular layer, leading to serious complications. Numerous natural products have been assessed as anti-ulcerogenic agents, and have been considered as new approaches for treatment or prevention of gastric ulcers. The present research investigated the preventive benefits of Apium graveolens L. (Apiaceae), known as celery, seed extract towards indomethacin-induced ulceration of the stomach in rats. METHODS: Metabolomic profiling, employing liquid chromatography coupled to high-resolution electrospray ionization mass spectrometry (LC-HR-ESI-MS), was implemented with the aim of investigating the chemical profile of the seeds. Histopathological analysis of gastric tissues, as well as assessment of numerous inflammatory cytokines and oxidative stress indicators, confirmed the in vivo evaluation. RESULTS: The prior treatment with A. graveolens seed extract resulted in a substantial reduction in the ulcer index when compared to the indomethacin group, indicating an improvement in stomach mucosal injury. Moreover, the gastroprotective effect was demonstrated through examination of the oxidative stress biomarkers which was significantly attenuated upon pre-treatment with A. graveolens seed extract. Vascular endothelial growth factor (VEGF), a fundamental angiogenic factor that stimulates angiogenesis, was markedly inhibited by indomethacin. A. graveolens seed extract restored this diminished level of VEGF. The dramatic reductions in NF-κB protein levels indicate a considerable attenuation of the indomethacin-induced IKκB/NF-κB p65 signaling cascade. These activities were also correlated to the tentatively featured secondary metabolites including, phenolic acids, coumarins and flavonoids, previously evidenced to exert potent anti-inflammatory and antioxidant activities. According to our network pharmacology study, the identified metabolites annotated 379 unique genes, among which only 17 genes were related to gastric ulcer. The PTGS2, MMP2 and PTGS1 were the top annotated genes related to gastric ulcer. The top biological pathway was the VEGF signaling pathway. CONCLUSION: A. graveolens seed extract possesses significant anti-ulcer activity, similar to famotidine, against gastric lesions induced by indomethacin in rats. It is worth highlighting that the extract overcomes the negative effects of conventional chemical anti-secretory drugs because it does not lower stomach acidity.

Paralemnalia thyrsoides-associated fungi: phylogenetic diversity, cytotoxic potential, metabolomic profiling and docking analysis.

BACKGROUND: Cancer continues to be one of the biggest causes of death that affects human health. Chemical resistance is still a problem in conventional cancer treatments. Fortunately, numerous natural compounds originating from different microbes, including fungi, possess cytotoxic characteristics that are now well known. This study aims to investigate the anticancer prospects of five fungal strains that were cultivated and isolated from the Red Sea soft coral Paralemnalia thyrsoides. The in vitro cytotoxic potential of the ethyl acetate extracts of the different five isolates were evaluated using MTS assay against four cancer cell lines; A549, CT-26, MDA-MB-231, and U87. Metabolomics profiling of the different extracts using LC-HR-ESI-MS, besides molecular docking studies for the dereplicated compounds were performed to unveil the chemical profile and the cytotoxic mechanism of the soft coral associated fungi. RESULTS: The five isolated fungal strains were identified as Penicillium griseofulvum (RD1), Cladosporium sphaerospermum (RD2), Cladosporium liminiforme (RD3), Penicillium chrysogenum (RD4), and Epicoccum nigrum (RD5). The in vitro study showed that the ethyl acetate extract of RD4 exhibited the strongest cytotoxic potency against three cancer cell lines A549, CT-26 and MDA-MB-231 with IC50 values of 1.45 ± 8.54, 1.58 ± 6.55 and 1.39 ± 2.0 µg/mL, respectively, also, RD3 revealed selective cytotoxic potency against A549 with IC50 value of 6.99 ± 3.47 µg/mL. Docking study of 32 compounds dereplicated from the metabolomics profiling demonstrated a promising binding conformation with EGFR tyrosine kinase that resembled its co-crystallized ligand albeit with better binding energy score. CONCLUSION: Our results highlight the importance of soft coral-associated fungi as a promising source for anticancer metabolites for future drug discovery.

A Review: Pharmacological Activity and Phytochemical Profile of Abelmoschus esculentus (2010-2022).

Abelmoschus esculentus L. Moench (okra) which belongs to the family Malvaceae is a commonly consumed vegetable that consists of the seed component which is rich in polyphenolic compounds. The aim of this study is to highlight the chemical and biological diversity of A. esculentus. This plant contains many vitamins, minerals, proteins and carbohydrates in addition to flavonoids, terpenes, phenolic compounds and sterols. These variations in the chemical composition resulted in different therapeutic activities including antidiabetic, hypolipidemic, antioxidant, antimicrobial, anticancer, wound healing, hepatoprotective, immunomodulator, neuroprotective, and gastroprotective activities in addition to cardioprotective activity.

Pharmacological and phytochemical biodiversity of Corchorus olitorius.

Corchorus olitorius L. is a nutritious green leafy vegetable that is eaten as a viscous soup in African and Middle Eastern cultures. The purpose of this review is to highlight the nutritional and nutraceutical potential of this plant. The leaves of C. olitorius are rich providers of minerals as calcium and iron in addition to vitamins B1, B2, folic acid C and E. The leaves contain numerous compounds having several biological effects including antidiabetic and antioxidant properties. Besides, the leaves comprise other phytochemicals such as cardiac glycosides, terpenes, flavonoids, fatty acids, hydrocarbons and phenolics. Various extracts of C. olitorius were shown to exhibit antioxidant, anti-inflammatory, hepatoprotective, antihyperlipidemic, immunostimulant, antitumor, antimicrobial, antidiabetic, analgesic, wound-healing properties and cardioprotective activities.

Cichoriin, a Biocoumarin, Mitigates Oxidative Stress and Associated Adverse Dysfunctions on High-Fat Diet-Induced Obesity in Rats.

Metabolic dysfunctions linked to obesity carry the risk of co-morbidities such as diabetes, hepatorenal, and cardiovascular diseases. Coumarins are believed to display several biological effects on diverse adverse health conditions. This study was conducted to uncover the impact of cichoriin on high-fat diet (HFD)-induced obese rats. Methods: Obesity was induced in twenty rats by exposure to an HFD for six weeks. The rats were randomly divided into five groups; group I comprised five healthy rats and was considered the control one. On the other hand, the HFD-induced rats were divided into the following (five per each group): group II (the HFD group), groups III (cichoriin 50 mg/kg) and IV (cichoriin 100 mg/kg) as the treatment groups, and group V received atorvastatin (10 mg/kg) (as a standard). Triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), alanine transaminase (ALT), aspartate transaminase (AST), creatine kinase MB (CK-MB), urea, creatinine, the hepatic and renal malondialdehyde (MDA) as well as reduced glutathione (GSH) levels were assessed. Histopathological analysis of the heart, kidney, and liver tissues was investigated. mRNA and protein expressions of the peroxisome proliferator-activated receptor gamma (PPAR-γ) were estimated. Results: The administration of cichoriin alleviated HFD-induced metabolic dysfunctions and improved the histopathological characteristics of the heart, kidney, and liver. Additionally, the treatment improved the lipid profile and hepatic and renal functions, as well as the oxidative balance state. Cichoriin demonstrated an upregulation of the mRNA and protein expressions of PPAR-γ. Taken together, these findings are the first report on the beneficial role of cichoriin in alleviating adverse metabolic effects in HFD-induced obesity and adapting it into an innovative obesity management strategy.

Mechanistic Insights into the Ameliorative Effect of Cichoriin on Diabetic Rats-Assisted with an In Silico Approach.

Type 2 diabetes mellitus is considered to be a substantial socioeconomic burden worldwide on both patients and governments. Coumarins are biomolecules with a diversity of biological activities. The current investigation aimed to explore the ameliorative effects of cichoriin, which is a type of coumarin, on high-fat diet/streptozotocin (HFD/STZ)-induced diabetic rats. METHODS: Rats were allocated into five groups. Group I was considered as the control group, while the other groups were HFD/STZ-induced diabetic rats. Group II was assigned as the diabetic control. Groups III and IV were treated with cichoriin (50 or 100 mg/kg, respectively). Group V received glibenclamide (5 mg/kg) (as a positive control). The blood glucose (BG), serum insulin, triglycerides (TG), total cholesterol (TC), total antioxidant capacity (TAC), catalase, hepatic superoxide dismutase (SOD) and content of malondialdehyde (MDA) were assessed. Histopathological and immunohistochemistry analysis of pancreatic tissue were performed. mRNA and protein expressions of GLUT4, AMPK, and PI3K were estimated. RESULTS: Cichoriin treatment ameliorated HFD/STZ-induced diabetic conditions and mitigated the histopathological characteristics of the pancreas, as well as increasing pancreatic insulin expression. This decreased the levels of BG, TG, TC, and MDA and improved the TAC, catalase and SOD contents. Cichoriin demonstrated upregulation of mRNA and protein expressions of GLUT4, AMPK, and PI3K. The in silico binding of cichoriin with GLUT4, AMPK, and PI3K supported the possible current activities. CONCLUSION: Collectively, this work highlighted the potential role of cichoriin in mitigating HFD/STZ-induced diabetic conditions and showed it to be a valuable product.

Brassica oleracea L. var. botrytis Leaf Extract Alleviates Gentamicin-Induced Hepatorenal Injury in Rats-Possible Modulation of IL-1ß and NF-κB Activity Assisted with Computational Approach.

BACKGROUND: Recently, crop byproducts are considered a hot topic and can be converted into beneficial products. Cauliflower is well-known for its protective effects against oxidative stress-induced damage. The current study aimed to investigate the chemical profile and the ameliorative effects of cauliflower leaf extract (CL) on gentamicin-induced renal and hepatic injuries in rats. METHODS: Cauliflower leaf was extracted with methanol to give the total methanol extract (TME) followed by the determination of total phenolic contents (TPC). Rats were divided into five groups; Group I was assigned as the control group, while the other groups were injected with gentamicin for ten days. Group II was given distilled water. Rats in groups III and IV were treated with oral CL (200 mg/kg and 400 mg/kg, respectively). Group V received L-cysteine (as a positive control). The functions of the kidneys and liver; oxidative stress and morphological and apoptotic changes of renal and hepatic tissues were assessed. RESULTS: The TME was subjected to chromatographic techniques to yield ferulic acid, vanillic acid, p-coumaric acid and quercetin. TPC was 72.31 mg GAE/g of dried extract. CL treatment dose-dependently ameliorated gentamicin-induced impaired kidney and liver functions and improved the histopathological appearance of both organs. It also reduced gentamicin-induced oxidative stress. CL demonstrated downregulation of mRNA and protein expressions of IL-1ß and NF-κB compared to nontreated rats. In silico interaction of the isolated compounds with amino acid residues of IL-1ß and NF-κB might explain the current findings. CONCLUSION: Taken together, this study raises the waste-to-wealth potential of cauliflower to mitigate gentamicin-induced hepatorenal injury and convert the waste agromaterials into valuable products.

Ameliorative Effect of Ocimum forskolei Benth on Diabetic, Apoptotic, and Adipogenic Biomarkers of Diabetic Rats and 3T3-L1 Fibroblasts Assisted by In Silico Approach.

Diabetes mellitus (DM) is a complicated condition that is accompanied by a plethora of metabolic symptoms, including disturbed serum glucose and lipid profiles. Several herbs are reputed as traditional medicine to improve DM. The current study was designed to explore the chemical composition and possible ameliorative effects of Ocimum forskolei on blood glucose and lipid profile in high-fat diet/streptozotocin-induced diabetic rats and in 3T3-L1 cell lines as a first report of its bioactivity. Histopathological study of pancreatic and adipose tissues was performed in control and treatment groups, along with quantification of glucose and lipid profiles and the assessment of NF-κB, cleaved caspase-3, BAX, and BCL2 markers in rat pancreatic tissue. Glucose uptake, adipogenic markers, DGAT1, CEBP/α, and PPARγ levels were evaluated in the 3T3-L1 cell line. Hesperidin was isolated from total methanol extract (TME). TME and hesperidin significantly controlled the glucose and lipid profile in DM rats. Glibenclamide was used as a positive control. Histopathological assessment showed that TME and hesperidin averted necrosis and infiltration in pancreatic tissues, and led to a substantial improvement in the cellular structure of adipose tissue. TME and hesperidin distinctly diminished the mRNA and protein expression of NF-κB, cleaved caspase-3, and BAX, and increased BCL2 expression (reflecting its protective and antiapoptotic actions). Interestingly, TME and hesperidin reduced glucose uptake and oxidative lipid accumulation in the 3T3-L1 cell line. TME and hesperidin reduced DGAT1, CEBP/α, and PPARγ mRNA and protein expression in 3T3-L1 cells. Moreover, docking studies supported the results via deep interaction of hesperidin with the tested biomarkers. Taken together, the current study demonstrates Ocimum forskolei and hesperidin as possible candidates for treating diabetes mellitus.

The endophytic Aspergillus strains: A bountiful source of natural products.

Fungi that invade plant inner tissues without inducing disease symptoms are known as fungal endophytes. They represent a promising and tremendous reservoir of natural products with valuable biological potentials for application in medicine, agriculture and industry. Among the numerous existing endophytic fungi, Aspergillus strains constitute one of the most prolific sources of secondary metabolites with diverse chemical classes and interesting biological activities. This review covers the literature of the year 2020, reporting the isolation of 202 compounds obtained from more than 10 different endophytic Aspergillus species associated with different host plants. Analysis and interpretation of the collected data revealed that chemical investigation of endophytes belonging to the genus Aspergillus may greatly contribute to the discovery of potential drug leads. The isolated metabolites were chemically various and exhibited diverse biological activities such as antibacterial, anti-cancer, anti-plasmodial, anti-inflammatory, antioxidant, immunosuppressive and antifungal activities. Moreover, adoption of advanced technology in molecular biology together with modern chemical tools is anticipated to improve the discovery of new biopharmaceuticals from this valuable microbial world in the future.

Identifying the specific-targeted marine cerebrosides against SARS-CoV-2: an integrated computational approach.

Cerebrosides are a group of metabolites belonging to the glycosphingolipids class of natural products. So far, 167 cerebrosides, compounds 1-167, have been isolated from diverse marine organisms or microorganisms. The as yet smaller number of compounds that have been studied more in depth proves a potential against challenging diseases, such as cancer, a range of viral and bacterial diseases, as well as inflammation. This review provides a comprehensive summary on this so far under-explored class of compounds, their chemical structures, bioactivities, and their marine sources, with a full coverage to the end of 2020. Today, the global pandemic concern, COVID-19, has claimed millions of death cases around the world, making the development of anti-SARS-CoV-2 drugs urgently needed for such a battle. Accordingly, selected examples from all subclasses of cerebrosides were virtually screened for potential inhibition of SARS-CoV-2 proteins that are crucially involved in the viral-host interaction, viral replication, or in disease progression. The results highlight five cerebrosides that could preferentially bind to the hACE2 protein, with binding scores between -7.1 and -7.6 kcal mol-1 and with the docking poses determined underneath the first α1-helix of the protein. Moreover, the molecular interaction determined by molecular dynamic (MD) simulation revealed that renieroside C1 (60) is more conveniently involved in key hydrophobic interactions with the best stability, least deviation, least ΔG (-6.9 kcal mol-1) and an RMSD value of 3.6 Å. Thus, the structural insights assure better binding affinity and favorable molecular interaction of renieroside C1 (60) towards the hACE2 protein, which plays a crucial role in the biology and pathogenesis of SARS-CoV-2.

The metabolomic analysis of five Mentha species: cytotoxicity, anti-Helicobacter assessment, and the development of polymeric micelles for enhancing the anti-Helicobacter activity.

Mentha species are medicinally used worldwide and remain attractive for research due to the diversity of their phytoconstituents and large therapeutic indices for various ailments. This study used the metabolomics examination of five Mentha species (M. suaveolens, M. sylvestris, M. piperita, M. longifolia, and M. viridis) to justify their cytotoxicity and their anti-Helicobacter effects. The activities of species were correlated with their phytochemical profiles by orthogonal partial least square discriminant analysis (OPLS-DA). Tentatively characterized phytoconstituents using liquid chromatography high-resolution electrospray ionization mass spectrometry (LC-HR-ESI-MS) included 49 compounds: 14 flavonoids, 10 caffeic acid esters, 7 phenolic acids, and other constituents. M. piperita showed the highest cytotoxicity to HepG2 (human hepatoma), MCF-7 (human breast adenocarcinoma), and CACO2 (human colon adenocarcinoma) cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. OPLS-DA and dereplication studies predicted that the cytotoxic activity was related to benzyl glucopyranoside-sulfate, a lignin glycoside. Furthermore, M. viridis was effective in suppressing the growth of Helicobacter pylori at a concentration of 50 mg mL-1. OPLS-DA predicted that this activity was related to a dihydroxytrimethoxyflavone. M. viridis extract was formulated with Pluronic® F127 to develop polymeric micelles as a nanocarrier that enhanced the anti-Helicobacter activity of the extract and provided minimum inhibitory concentrations and minimum bactericidal concentrations of 6.5 and 50 mg mL-1, respectively. This activity was also correlated to tentatively identified constituents, including rosmarinic acid, catechins, carvone, and piperitone oxide.

Correction: The metabolomic analysis of five Mentha species: cytotoxicity, anti-Helicobacter assessment, and the development of polymeric micelles for enhancing the anti-Helicobacter activity.

[This corrects the article DOI: 10.1039/D0RA09334C.].

Natural Products Repertoire of the Red Sea.

Marine natural products have achieved great success as an important source of new lead compounds for drug discovery. The Red Sea provides enormous diversity on the biological scale in all domains of life including micro- and macro-organisms. In this review, which covers the literature to the end of 2019, we summarize the diversity of bioactive secondary metabolites derived from Red Sea micro- and macro-organisms, and discuss their biological potential whenever applicable. Moreover, the diversity of the Red Sea organisms is highlighted as well as their genomic potential. This review is a comprehensive study that compares the natural products recovered from the Red Sea in terms of ecological role and pharmacological activities.

Tanzawaic acid derivatives from freshwater sediment-derived fungus Penicillium sp.

Chemical investigation of a freshwater sediment-derived fungus, Penicillium sp. (S1a1), led to the isolation of three new tanzawaic acid derivatives, including penitanzchroman (1), tanzawaic acids Y (2) and Z (3), along with six known tanzawaic acid analogues (4-9), three known isochromans (10-12) and two known benzoquinones (13 and 14). The structures of the new compounds were established based on high-resolution mass spectrometry, and detailed analysis of one- and two-dimensional NMR spectroscopy. The relative configuration of the new compounds was assigned on the basis of NMR spectroscopic data including ROESY spectra. The absolute configuration was determined based on the specific optical rotation, in addition to biogenetic considerations in comparison with related co-isolated known metabolites. Penitanzchroman (1) constitutes a hitherto unprecedented skeleton, formed of tanzawaic acid A (5) and (3S)-6-hydroxy-8-methoxy-3,5-dimethylisochroman (10) linked by a CC bond. Moreover, all compounds were evaluated for their antibacterial and cytotoxic activities.