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.

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.

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.

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.