Testicular Caspase-3 and β-Catenin Regulators Predicted via Comparative Metabolomics and Docking Studies

Hifnawy, Mohamed S.; Aboseada, Mahmoud A.; Hassan, Hossam M.; AboulMagd, Asmaa M.; Tohamy, Adel F.; Abdel-Kawi, Samraa Hussein; Rateb, Mostafa E.; Naggar, El Moataz Bellah El; Liu, Miaomiao; Quinn, Ronald J.; Alhadrami, Hani A.; Abdelmohsen, Usama Ramadan

doi:10.3390/metabo10010031

Cited by 16 publications

(12 citation statements)

References 86 publications

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“…Regarding dechlorogriseofulvin (5), we could not find any previous studies dealing with its possible anti-plasmodial activity. Furthermore, we were able to characterize aromatic ester derivatives namely benzyl benzoate ( 6), 4-hydroxy benzyl benzoate (7) and benzyl anisate (8), which were also linked to the extract's anti-plasmodial effect. Compound ( 6) was reported as a major component in Cinnamomum zeylanicum 19 and shown to exert a potent scabicidal activity 20 .…”

Section: Data Interpretation and Multivariate Analysis (Mva)mentioning

confidence: 99%

“…Regarding compounds (6-8), they were probably inactive as kinase inhibitors (Pa: 0.03-0.1) and had weak antimalarial activity (Pa: 0.25-0.3). To validate our MVA and PASS predictions, we selected representatives from compounds (1)(2)(3)(4)(5)(6)(7)(8) for in vitro anti-plasmodial testing. Interestingly, compounds 1 and 2 showed potent inhibitory activity with IC 50 values of 0.9 and 1.9 µM, respectively.…”

Section: In Silico Predictions and In-vitro Validationmentioning

confidence: 99%

“…Biological activity predictions using (PASS) software. The neural network-based software Prediction of Activity Spectra for Substances (PASS) 29 (www.way2d rug.com) was used for further prioritization of the antimalarial activity of the suggested compounds (1)(2)(3)(4)(5)(6)(7)(8). This software can predict > 4000 types of pharmacological and toxicological activities including their mechanism of action, with approximately 85% as acceptable precision, depending on the submitted compound structures that were subsequently screened utilizing the structure-activity relationship database (SARBase).…”

Section: In Vitro Anti-plasmodial Activitymentioning

confidence: 99%

“…Metabolomics has become an emerging strategy that can be utilized for the comprehensive characterization of complex crude extracts along with targeting marker metabolites that can be associated with certain biological activities before commencing time-consuming purification procedures [5][6][7] . The combination of suitable analytical tools (e.g.…”

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confidence: 99%

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A metabolomic approach to target antimalarial metabolites in the Artemisia annua fungal endophytes

Alhadrami

Sayed

El-Gendy

et al. 2021

Sci Rep

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Fungal endophytes are a major source of anti-infective agents and other medically relevant compounds. However, their classical blinded-chemical investigation is a challenging process due to their highly complex chemical makeup. Thus, utilizing cheminformatics tools such as metabolomics and computer-aided modelling is of great help deal with such complexity and select the most probable bioactive candidates. In the present study, we have explored the fungal endophytes associated with the well-known antimalarial medicinal plant Artemisia annua for their production of further antimalarial agents. Based on the preliminary antimalarial screening of these endophytes and using LC-HRMS-based metabolomics and multivariate analyses, we suggested different potentially active metabolites (compounds 1–8). Further in silico investigation using the neural-network-based prediction software PASS led to the selection of a group of quinone derivatives (compounds 1–5) as the most possible active hits. Subsequent in vitro validation revealed emodin (1) and physcion (2) to be potent antimalarial candidates with IC50 values of 0.9 and 1.9 µM, respectively. Our approach in the present investigation therefore can be applied as a preliminary evaluation step in the natural products drug discovery, which in turn can facilitate the isolation of selected metabolites notably the biologically active ones.

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Section: Data Interpretation and Multivariate Analysis (Mva)mentioning

confidence: 99%

Section: In Silico Predictions and In-vitro Validationmentioning

confidence: 99%

Section: In Vitro Anti-plasmodial Activitymentioning

confidence: 99%

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confidence: 99%

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A metabolomic approach to target antimalarial metabolites in the Artemisia annua fungal endophytes

Alhadrami

Sayed

El-Gendy

et al. 2021

Sci Rep

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“…Marine environments have proven to be an important source of unique chemical entities with a wide range of biological activities [1][2][3][4][5][6]. Owing to its biodiversity and seasonal variations in air and water temperatures, the Red Sea is one of the most important areas for marine research.…”

Section: Introductionmentioning

confidence: 99%

New Cytotoxic Natural Products from the Red Sea Sponge Stylissa carteri

et al. 2020

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Bioactivity-guided isolation supported by LC-HRESIMS metabolic profiling led to the isolation of two new compounds, a ceramide, stylissamide A (1), and a cerebroside, stylissoside A (2), from the methanol extract of the Red Sea sponge Stylissa carteri. Structure elucidation was achieved using spectroscopic techniques, including 1D and 2D NMR and HRMS. The bioactive extract’s metabolomic profiling showed the existence of various secondary metabolites, mainly oleanane-type saponins, phenolic diterpenes, and lupane triterpenes. The in vitro cytotoxic activity of the isolated compounds was tested against two human cancer cell lines, MCF-7 and HepG2. Both compounds, 1 and 2, displayed strong cytotoxicity against the MCF-7 cell line, with IC50 values at 21.1 ± 0.17 µM and 27.5 ± 0.18 µM, respectively. They likewise showed a promising activity against HepG2 with IC50 at 36.8 ± 0.16 µM for 1 and IC50 30.5 ± 0.23 µM for 2 compared to the standard drug cisplatin. Molecular docking experiments showed that 1 and 2 displayed high affinity to the SET protein and to inhibitor 2 of protein phosphatase 2A (I2PP2A), which could be a possible mechanism for their cytotoxic activity. This paper spreads light on the role of these metabolites in holding fouling organisms away from the outer surface of the sponge, and the potential use of these defensive molecules in the production of novel anticancer agents.

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Galantamine mitigates testicular injury and disturbed spermatogenesis in adjuvant arthritic rats via modulating apoptosis, inflammatory signals, and IL-6/JAK/STAT3/SOCS3 signaling

et al. 2023

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Rheumatoid arthritis (RA) affects the joints and the endocrine system via persistent immune system activation. RA patients have a higher frequency of testicular dysfunction, impotence, and decreased libido. This investigation aimed to evaluate the efficacy of galantamine (GAL) on testicular injury secondary to RA. Rats were allocated into four groups: control, GAL (2 mg/kg/day, p.o), CFA (0.3 mg/kg, s.c), and CFA + GAL. Testicular injury indicators, such as testosterone level, sperm count, and gonadosomatic index, were evaluated. Inflammatory indicators, such as interleukin-6 (IL-6), p-Nuclear factor kappa B (NF-κB p65), and anti-inflammatory cytokine interleukin-10 (IL-10), were assessed. Cleaved caspase-3 expression was immunohistochemically investigated. Protein expressions of Janus kinase (JAK), signal transducers and activators of transcription (STAT3), and Suppressors of Cytokine Signaling 3 (SOCS3) were examined by Western blot analysis. Results show that serum testosterone, sperm count, and gonadosomatic index were increased significantly by GAL. Additionally, GAL significantly diminished testicular IL-6 while improved IL-10 expression relative to CFA group. Furthermore, GAL attenuated testicular histopathological abnormalities by CFA and downregulated cleaved caspase-3 and NF-κB p65 expressions. It also downregulated JAK/STAT3 cascade with SOCS3 upregulation. In conclusion, GAL has potential protective effects on testicular damage secondary to RA via counteracting testicular inflammation, apoptosis, and inhibiting IL-6/JAK/STAT3/SOCS3 signaling. Graphical abstract

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Testicular Caspase-3 and β-Catenin Regulators Predicted via Comparative Metabolomics and Docking Studies

Cited by 16 publications

References 86 publications

A metabolomic approach to target antimalarial metabolites in the Artemisia annua fungal endophytes

A metabolomic approach to target antimalarial metabolites in the Artemisia annua fungal endophytes

New Cytotoxic Natural Products from the Red Sea Sponge Stylissa carteri

Galantamine mitigates testicular injury and disturbed spermatogenesis in adjuvant arthritic rats via modulating apoptosis, inflammatory signals, and IL-6/JAK/STAT3/SOCS3 signaling

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