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BMC Complementary Medicine and Therapies Jul 2021Degenerative kidney diseases are mostly associated with oxidative stress. Natural products are considered as the antioxidants enrich food that can restrict the progress...
BACKGROUND
Degenerative kidney diseases are mostly associated with oxidative stress. Natural products are considered as the antioxidants enrich food that can restrict the progress of oxidative stress induced disorders. Therefore, the present study was aimed to evaluate the renal protective effect of Ajuga parviflora leaf extract in carbon tetrachloride intoxicated rats.
METHODS
The hydromethanolic extract of A. parviflora leaves was obtained by extracting twice in 60% methanol. The principal bioactive constituents were detected by LC/MS analysis. Toxicity of plant extract was assessed using brine shrimp lethal toxicity test and acute toxicity model on healthy Sprague-Dawley male rats. Nephroprotective effects of plant extract were also evaluated on rats by inducing CCl renal toxicity in comparison with positive control and naïve groups. The dose of A. parviflora administered to animal was 100, 200 and 300 mg/kg. All administrations were given orally on an alternate day basis for 30 days. Urine and serum biomarkers were analyzed, along with antioxidant enzymes. Finally, the DNA damages, lipid peroxides, hydrogen peroxides and nitrites were assessed in rat's renal tissue. The histopathology alterations in renal tissues were further studied for kidney damages.
RESULTS
The LC/MS analysis confirmed the presence of different important pharmacological compounds in A. parviflora methanolic leaf extract. The key bioactive compounds include pyocyanin, zonisamide, D Saccharic acid, altretamine, carbocyclic thromboxane A2, Sinapyl alcohol, and vitamin C. The important polypeptides identified include Lys-Tyr-Lys, His-His-Lys, Met-Asp-Arg, Phe-Val-Arg, and PyroGlu-Val-Arg. The LD of A. parviflora was found to be > 1000 μg/mL. A. parviflora administration significantly subsides CCl toxicity in rats, reduced the elevated level of RBCs, pus and epithelial cells. The abnormal elevated level of specific gravity, creatinine, urobilinogen, urea and albumin were also reduced to normal physiological level. The reduced urinary protein and pH were also normalized. The serum urobilinogen, urea and total bilirubin levels were also reversed to normal levels while the diminished albumin and total protein levels also came to normal. The important phase I and II enzyme levels were also reversed in A. parviflora administered rats. The HO, thiobarbituric acid reactive substance (TBARS) and nitrite levels were significantly decreased. Furthermore, the damaged DNA and histopathological changes in CCl exposed rats were also highly significantly reversed after the administration of A. parviflora. All effects were significant (P < 0.05) and highly significant (P < 0.005) at 100 and 300 mg/kg respectively.
CONCLUSION
The restored urine and serum profile of various parameters to normal physiological levels suggests that the A. parviflora has potential antioxidant and repairing potential in renal disorders.
Topics: Acute Kidney Injury; Ajuga; Animals; Antioxidants; Carbon Tetrachloride; Phytochemicals; Plant Extracts; Rats; Rats, Sprague-Dawley
PubMed: 34253216
DOI: 10.1186/s12906-021-03360-9 -
Heliyon May 2023A new library of 1,2,3-triazole-incorporated 1,3,4-oxadiazole-triazine derivatives (9a-j) was designed, synthesized, and tested in vitro for anticancer activity against...
A new library of 1,2,3-triazole-incorporated 1,3,4-oxadiazole-triazine derivatives (9a-j) was designed, synthesized, and tested in vitro for anticancer activity against PC3 and DU-145 (prostate cancer), A549 (lung cancer), and MCF-7 (breast cancer) cancer cell lines using the MTT assay with etoposide as the control drug. The compounds exhibited remarkable anticancer activity, with IC50 values ranging from 0.16 ± 0.083 μM to 11.8 ± 7.46 μM, whereas the positive control ranged from 1.97 0.45 μM to 3.08 0.135 μM. Compound 9 d with a 4-pyridyl moiety shown exceptional anticancer activity against PC3, A549, MCF-7, and DU-145 cell lines, with IC50 values of 0.17 ± 0.063 μM, 0.19 ± 0.075 μM, 0.51 ± 0.083 μM, and 0.16 ± 0.083 μM, respectively.
PubMed: 37206039
DOI: 10.1016/j.heliyon.2023.e15935 -
Chemistry, An Asian Journal Jan 2023The dimethylamino functionality has significant importance in industrially relevant molecules and methodologies to install these efficiently are highly desirable. We...
The dimethylamino functionality has significant importance in industrially relevant molecules and methodologies to install these efficiently are highly desirable. We report herein a highly efficient, room-temperature dimethylamination of chloroheteroarenes performed via the in-situ generation of dimethylamine using N,N-dimethylformamide (DMF) as precursor wiith a large substrate scope that includes various heteroarenes, purines as well as commercially relevant drugs such as altretamine, ampyzine and puromycin precursor.
Topics: Temperature; Dimethylformamide; Catalysis
PubMed: 36355632
DOI: 10.1002/asia.202201006 -
ELife Jun 2019Microbes are nature's chemists, capable of producing and metabolizing a diverse array of compounds. In the human gut, microbial biochemistry can be beneficial, for...
Microbes are nature's chemists, capable of producing and metabolizing a diverse array of compounds. In the human gut, microbial biochemistry can be beneficial, for example vitamin production and complex carbohydrate breakdown; or detrimental, such as the reactivation of an inactive drug metabolite leading to patient toxicity. Identifying clinically relevant microbiome metabolism requires linking microbial biochemistry and ecology with patient outcomes. Here we present MicrobeFDT, a resource which clusters chemically similar drug and food compounds and links these compounds to microbial enzymes and known toxicities. We demonstrate that compound structural similarity can serve as a proxy for toxicity, enzyme sharing, and coarse-grained functional similarity. MicrobeFDT allows users to flexibly interrogate microbial metabolism, compounds of interest, and toxicity profiles to generate novel hypotheses of microbe-diet-drug-phenotype interactions that influence patient outcomes. We validate one such hypothesis experimentally, using MicrobeFDT to reveal unrecognized gut microbiome metabolism of the ovarian cancer drug altretamine.
Topics: Altretamine; Bacteria; Biotransformation; Carbohydrate Metabolism; Diet; Food; Gastrointestinal Microbiome; Gastrointestinal Tract; Host Microbial Interactions; Humans; Molecular Structure; Pharmaceutical Preparations
PubMed: 31184303
DOI: 10.7554/eLife.42866 -
Bioorganic Chemistry Dec 2023There is an increasing interest in halting CRC by combining ferroptosis with other forms of tumor cell death. However, ferroptosis induction is seldom studied in tandem...
Battling colorectal cancer via s-triazine-based MMP-10/13 inhibitors armed with electrophilic warheads for concomitant ferroptosis induction; the first-in-class dual-acting agents.
There is an increasing interest in halting CRC by combining ferroptosis with other forms of tumor cell death. However, ferroptosis induction is seldom studied in tandem with inhibiting MMPs. A combination that is expected to enhance the therapeutic outcome based on mechanistic ferroptosis studies highlighting the interplay with MMPs, especially MMP-13 associated with CRC metastasis and poor prognosis. Herein, we report new hybrid triazines capable of simultaneous MMP-10/13 inhibition and ferroptosis induction bridging the gap between their anticancer potentials. The MMP-10/13 inhibitory component of the scaffold was based on the non-hydroxamate model inhibitors. s-Triazine was rationalized as the core inspired by altretamine, an FDA-approved ferroptosis inducer. The ferroptosis pharmacophores were then installed as Michael acceptors via triazole-based spacers. The electrophilic reactivity was tuned by incorporating cyano and/or substituted phenyl groups influencing their electronic and steric properties and enriching the SAR study. Initial screening revealed the outstanding cytotoxicity profiles of the nitrophenyl-tethered chalcone 5e and the cyanoacrylohydrazides bearing p-fluorophenyl 9b and p-bromophenyl 9d appendages. 9b and 9d surpassed NNGH against MMP-10 and -13, especially 9d (IC = 0.16 μM). Ferroptosis studies proved that 9d depleted GSH in HCT-116 cells by a relative fold decrement of 0.81 with modest direct GPX4 inhibition, thus inducing lipid peroxidation, the hallmark of ferroptosis, by 1.32 relative fold increment. Docking presumed that 9d could bind to the MMP-10 S1' pocket and active site His221, extend through the MMP-13 hydrophobic pocket, and interact covalently with the GPX4 catalytic selenocysteine. 9d complexed with ferrous oxide nanoparticles was 7.5 folds more cytotoxic than its free precursor against HCT-116 cells. The complex-induced intracellular iron overload, depleted GSH with a relative fold decrement of 0.12, consequently triggering lipid peroxidation and ferroptosis by a 3.94 relative fold increment. Collectively, 9d could be a lead for tuning MMPs selectivity and ferroptosis induction potential to maximize the benefit of such a combination.
Topics: Humans; Ferroptosis; Matrix Metalloproteinase 13; Matrix Metalloproteinase 10; Triazines; Colorectal Neoplasms
PubMed: 37703744
DOI: 10.1016/j.bioorg.2023.106839 -
Cell Jul 2015Genome-wide identification of the mechanism of action (MoA) of small-molecule compounds characterizing their targets, effectors, and activity modulators represents a...
Genome-wide identification of the mechanism of action (MoA) of small-molecule compounds characterizing their targets, effectors, and activity modulators represents a highly relevant yet elusive goal, with critical implications for assessment of compound efficacy and toxicity. Current approaches are labor intensive and mostly limited to elucidating high-affinity binding target proteins. We introduce a regulatory network-based approach that elucidates genome-wide MoA proteins based on the assessment of the global dysregulation of their molecular interactions following compound perturbation. Analysis of cellular perturbation profiles identified established MoA proteins for 70% of the tested compounds and elucidated novel proteins that were experimentally validated. Finally, unknown-MoA compound analysis revealed altretamine, an anticancer drug, as an inhibitor of glutathione peroxidase 4 lipid repair activity, which was experimentally confirmed, thus revealing unexpected similarity to the activity of sulfasalazine. This suggests that regulatory network analysis can provide valuable mechanistic insight into the elucidation of small-molecule MoA and compound similarity.
Topics: Algorithms; Antineoplastic Agents; Epistasis, Genetic; Genome-Wide Association Study; Molecular Targeted Therapy; Neoplasms; Small Molecule Libraries
PubMed: 26186195
DOI: 10.1016/j.cell.2015.05.056 -
Journal of Animal Physiology and Animal... May 2020The Zi goose is native to North-east China and is noted for its high egg production. Alpha enolase (ENO1) is a glycolytic enzyme which functions as a plasminogen...
The Zi goose is native to North-east China and is noted for its high egg production. Alpha enolase (ENO1) is a glycolytic enzyme which functions as a plasminogen receptor in follicular granulosa cells (FGCs), with several studies showing that FGCs can support follicular development. By transfecting the ENO1 interfering plasmid (shRNA) into FGCs, ENO1 expression in these cells was downregulated, suggesting the successful knock-down of ENO1 in these cells. In this knock-down model, we detected 13 metabolites from FGCs using LC/MS. When compared with the non-coding shRNA (NC) group, the lower level metabolites were (R)-(+)-citronellic acid, altretamine, 3-hydroxycaproic acid, heptadecanoic acid, cholecalciferol vitamin D3, indole, benzoic acid, capric acid, caffeic acid, azelaic acid, 3,4-dihydroxyhydrocinnamic acid and cholic acid, while oleic acid was detected at high levels. To further examine the results of metabolomics, six key metabolites were verified by gas chromatography-mass spectrometry (GC-MS). We found that vitamin D3, indole, benzoic acid, capric acid and cholic acid were significantly downregulated in the shRNA group, while oleic acid was significantly upregulated. This observation was consistent with the metabolomics data. Through these studies, we found that decreased ENO1 levels altered certain metabolite levels in FGCs.
Topics: Animals; Cells, Cultured; DNA-Binding Proteins; Female; Geese; Gene Expression Regulation, Enzymologic; Granulosa Cells; Humans; Metabolic Networks and Pathways; Phosphopyruvate Hydratase; Principal Component Analysis; RNA Interference; RNA, Small Interfering; Tumor Suppressor Proteins
PubMed: 31821655
DOI: 10.1111/jpn.13254