The genus Calophyllum from the family Calophyllaceae has been extensively investigated in the past due to its rich source of bioactive phenolics such as coumarins, chromanones, and xanthones. In this ...study, phytochemical investigation on the stem bark of Calophyllum havilandii has afforded a new 4‐propyldihydrocoumarin derivative, havilarin (1) together with calolongic acid (2), caloteysmannic acid (3), isocalolongic acid (4), euxanthone (5), and β‐sitosterol (6). The chemical structure of compound 1 was elucidated and established based on detailed spectroscopic techniques, including MS, IR, UV, 1D and 2D NMR. The results of anti‐bacillus study indicated that the chloroform extract showed promising activities with MIC value ranging between 0.5 to 1 μg/mL on selected bacillus strains. Besides, the plant extracts and compounds 1–4 were assessed for their cytotoxicity potential on HL‐7702 cell line. All the tested plant extracts and respective chemical constituents displayed non‐cytotoxic activity on HL‐7702 cell line.
The present research work describes the synthesis of new series of nicotinonitrile (
2
) and furo2,3-
b
pyridine (
3
) heterocycles bearing thiophene substituent. The nicotinonitrile derivatives were ...prepared from the corresponding 3-cyano-(2
H
)-pyridones (
1a–f
) in excellent yields. The ring cyclization of the nicotinonitrile derivatives (
2a–f
) in the presence of sodium methoxide provided the furo2,3-
b
pyridines (
3a–f
) in moderate to good yields. All the newly synthesized compounds were characterized by extensive NMR analysis data, including 1D-NMR experiments (
1
H and
13
C) and 2D-NMR experiments (COSY, HMBC, HSQC), as well as HRESIMS data. All the final products were subjected for cytotoxic activity against five different tumour cell lines including HeLa (cervical), DU145 (prostate), HepG2 (liver), MDA-MB-231 (breast-ER negative) and MCF7 (breast-ER positive), in addition to HSF1184 (normal human fibroblast) using the MTT assay. Compounds
2d
and
3e
were found to exhibit promising cytotoxicity with IC
50
of < 20 µM against all different tested tumour cell lines. In addition, these compounds showed high selectivity (40–287 folds) for tumour cells over normal cells.
Graphical abstract
Due to the recent emergence of drug-resistance of antidiabetic drugs and increase in the number of diabetes cases around the world, the search for and discovery of more effective α-amylase inhibitors ...is of great interest. In the present study, a new series of eighteen ortho-carboxamidostilbene derivatives were synthesized via Heck coupling reaction. The structures of the synthesized compounds were identified by various spectroscopic techniques, including HRMS, FTIR and 1D-NMR. In addition, the compounds were evaluated in vitro for their potential α-amylase inhibitory potency using acarbose as the reference drug. Compounds 5e, 5f and 6e showed remarkably moderate to good inhibitory activity with IC50 values ranging from 13.3 − 28.2 µM. These compounds showed the potent IC50 values compared to the reference drug acarbose (IC50 = 30.2 ± 0.1). The in-silico molecular docking studies revealed that the binding interactions of the most active ortho-carboxamidostilbene derivatives (5e and 6e) with binding energies of -8.7 ± 0.0 and -8.6 ± 0.2 kcal/mol. Based on the structure-activity relationship (SAR) analysis, it was established that variations in the inhibitory activities of α-amylase enzymes were attributed to distinct types of substituents at the amide group of aryl ring A, and the number and position of methoxy groups attached to aryl ring B. These findings highlight α-amylase inhibitory properties of ortho-carboxamidostilbene-containing cyclohexyl and benzyl moieties, serving as potential lead compounds in antidiabetic drug development for the treatment of type II diabetes mellitus.
This study aimed at recovery of thermostable lipase from
Escherichia coli
BL21 using porous glass beads grafted with polyethylene glycol (PEG) in aqueous impregnated resins system (AIRS). The ...influencing parameters such as concentration and pH of extraction solution, concentration of NaCl, size of the beads, and pH of the desorption solution on the partition behaviour of lipase were evaluated. Smaller adsorbent (4 mm) had a 65.5% of recovery yield with approximately two-fold higher purification factor compared to that obtained with the larger adsorbent. Recombinant lipase was purified successfully using AIRS with a purification factor of 7.6 and yield of 78.4% under optimum conditions of 18% (w/w) PEG 4000, 10% (w/w) of potassium citrate at pH 9 with 3% (w/w) of NaCl. Optimum desorption was obtained with 4.0 mm of porous glass beads at pH 9.
Altered mitochondrial DNA (mtDNA) is the most common denominator to numerous metabolic diseases. The present study sought to investigate the correlation between mtDNA content in lymphocytes and ...associated clinical risk factors for impaired fasting glucose (IFG). We included 23 healthy control and 42 IFG participants in this cross-sectional study. The measurements of mtDNA content in lymphocytes and pro-inflammatory markers derived from both normal and diseased individuals were quantified. Spearman partial correlation and multivariate statistical analyses were employed to evaluate the association between mtDNA content and other metabolic covariates in IFG. Reduced mtDNA content was observed in the IFG group with microvascular complications than those without complications. The IFG patients with lowest median of mtDNA content had considerably elevated hyperglycemia, insulin resistance and inflammation. The adjusted partial correlation analysis showed that mtDNA content was positively correlated with HDL-cholesterol and IL-10 (
P
< 0.005 for all). Further, multiple linear regression analyses verified that reduced mtDNA content in lymphocytes was independently associated with HOMA-IR (
β
= 0.027,
P
= 0.003), HbA1c (
β
= 0.652,
P
= 0.002), HDL-cholesterol (
β
= − 1.056,
P
= 0.021), IL-6 (
β
= 0.423,
P
= 0.002), IL-10 (
β
= − 1.234,
P
= 0.043) and TNF-α (
β
= 0.542,
P
< 0.001) after adjustment for confounding factors. Our data show that reduced mtDNA content in lymphocytes was associated with insulin resistance and inflammation in individuals with IFG.
The current study focused on the metabolic effects of LTB4 on endothelial and mitochondrial functions in human aortic endothelial cells (HAECs). LTB4 treatment in a dose-dependent manner augmented ...the degree of mitochondrial superoxide generation in HAECs. Such impairments in mitochondrial integrity and dynamics by increased dynamin-related protein-1 (Drp1) and fission-1 (Fis1) protein expression but, reduced mitofusin (Mfn)-1 protein expression was noticed in HAECs. Furthermore, LTB4 considerably augmented the expression of Cytochrome C and Bax, but diminished the expression of Bcl-2, thus promoting endothelial apoptosis and inflammation. Additionally, LTB4 treatment resulted in the suppression of phosphatidyl inositol 3- kinase (PI3K)/Akt signaling. Finally, severe vascular oxidative damage and mitochondrial impairments in aorta of transgenic mice expressing human LTB4 (LTB4-Tg) mice were observed compared to wild-type C57BL/6J mice. Overall, the current investigation discovers a novel mechanism through which LTB4 leads to vascular oxidative damage and mitochondrial dysfunction, resulting further understanding of the mechanisms responsible for the effects of LTB4 in the progression of atherosclerosis.
Optimal control of postprandial hyperglycemia is essentially important in the management of diabetes mellitus. The present investigation was undertaken to evaluate the in vitro anti-hyperglycemic, ...antioxidant properties and intestinal glucose uptake inhibition of Endiandra kingiana (E. kingiana) extracts. Previously, our group has identified and characterized the bioactive compounds of E. kingiana extracts, which had discovered several polyketides; endiandric acids and kingianins. Here, the inhibitory potential of bark-ethyl acetate (BEA), bark-methanol (BM), leaf-ethyl acetate (LEA), and leaf-methanol (LM) extracts of E. kingiana against carbohydrate-hydrolyzing enzymes with their mode of inhibitions were evaluated. Further, the antioxidant activities and inhibitory potential on glucose uptake in Caco-2 human intestinal cell monolayers were determined. Our finding showed that BEA extract exhibited the most potent inhibition activities against α-amylase (IC50 = 2.32 μg/mL) and α-glucosidase (IC50 = 1.83 μg/mL) by following inhibition mode of competitive and non-competitive manners, respectively. Meanwhile, BM extract exhibited notable antioxidant capabilities, as evidenced by strongest free radical scavenging (IC50 = 1.18 μg/mL) and reducing power effect (118.53 mM Fe2+ equivalent/g extract) in couple with highest total phenolic contents (10.17 mg GAE/g extract) compared to other extracts. Mechanistically, both BEA and BM extracts of E. kingiana significantly inhibited glucose uptake in Caco-2 cell monolayers under sodium-dependent condition. Collectively, these findings suggest that BM and BEA extracts of E. kingiana exert in vitro anti-hyperglycemic and antioxidant properties, which can be further utilized as a potential candidate for treatment of hyperglycemia–induced oxidative stress conditions.
•The bark extract (ethyl acetate) of Endiandra kingiana (EK) exhibited inhibitory activities on α-amylase and α-glucosidase..•The bark extract (methanol) of EK had high level of total phenolic content and antioxidant compared to other EK extracts.•The bark extracts of EK decreased glucose uptake in Caco-2 cell lines under sodiumdependent condition.•The bark extracts of EK showed promising anti-hyperglycemic and antioxidant properties in vitro.
Accumulating evidence implicates mitochondrial dysfunction-induced insulin resistance in skeletal muscle as the root cause for the greatest hallmarks of type 2 diabetes (T2D). However, the ...identification of specific metabolite-based markers linked to mitochondrial dysfunction in T2D has not been adequately addressed. Therefore, we sought to identify the markers-based metabolomics for mitochondrial dysfunction associated with T2D. First, a cellular disease model was established using human myotubes treated with antimycin A, an oxidative phosphorylation inhibitor. Non-targeted metabolomic profiling of intracellular-defined metabolites on the cultured myotubes with mitochondrial dysfunction was then determined. Further, a targeted MS-based metabolic profiling of fasting blood plasma from normal (n = 32) and T2D (n = 37) subjects in a cross-sectional study was verified. Multinomial logical regression analyses for defining the top 5% of the metabolites within a 95% group were employed to determine the differentiating metabolites. The myotubes with mitochondrial dysfunction exhibited insulin resistance, oxidative stress and inflammation with impaired insulin signalling activities. Four metabolic pathways were found to be strongly associated with mitochondrial dysfunction in the cultured myotubes. Metabolites derived from these pathways were validated in an independent pilot investigation of the fasting blood plasma of healthy and diseased subjects. Targeted metabolic analysis of the fasting blood plasma with specific baseline adjustment revealed 245 significant features based on orthogonal partial least square discriminant analysis (PLS-DA) with a p-value < 0.05. Among these features, 20 significant metabolites comprised primarily of branched chain and aromatic amino acids, glutamine, aminobutyric acid, hydroxyisobutyric acid, pyroglutamic acid, acylcarnitine species (acetylcarnitine, propionylcarnitine, dodecenoylcarnitine, tetradecenoylcarnitine hexadecadienoylcarnitine and oleylcarnitine), free fatty acids (palmitate, arachidonate, stearate and linoleate) and sphingomyelin (d18:2/16:0) were identified as predictive markers for mitochondrial dysfunction in T2D subjects. The current study illustrates how cellular metabolites provide potential signatures associated with the biochemical changes in the dysregulated body metabolism of diseased subjects. Our finding yields additional insights into the identification of robust biomarkers for T2D associated with mitochondrial dysfunction in cultured myotubes.
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