Search

Objective To assess effect of licochalcone A (LicA) on amyloid-β (Aβ) peptide fragment 25–35–induced nerve injury and reveal the potential molecular mechanisms involved. Methods Viability of SH-SY5Y cells was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay after treatment with Aβ25–35 and/or LicA, following which apoptosis was detected by flow cytometry and Hoechst staining. Then, reactive oxygen species, glutathione, and superoxide dismutase were measured with flow cytometry and spectrophotometry. The ultrastructure of mitochondria was examined by transmission electron microscopy, and the biomarker proteins of autophagy, apoptosis, and phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway were measured with Western blotting. Results LicA improved cell viability and decreased lactate dehydrogenase leakage remarkably in Aβ25–35–induced injury in SH-SY5Y cells. After treatment with LicA, reactive oxygen species, glutathione, and superoxide dismutase levels in cells all were significantly decreased, which indicated that LicA has an antioxidative effect on Aβ25–35-induced oxidative injury. LicA could also significantly reduce Aβ25–35–induced autophagy in SH-SY5Y cells. In the cells injured by Aβ25–35, LicA prevented the transformation from light chain protein 3-I to light chain protein 3-II and reduced the levels of proteins GRP78, GRP94, CHOP, and Bax, but increased the levels of antiapoptotic protein and phosphorylation of PI3K, Akt, and mTOR. These effects of LicA were restored or suppressed by mTOR inhibitor rapamycin or PI3K inhibitor LY294002. Conclusions LicA protects SH-SY5Y cells against Aβ25–35–induced injury, wherein suppressed autophagy and activated PI3K/Akt/mTOR signaling pathway are involved, and mTOR-dependent autophagy at least plays some role.

Pyrazolines are five-membered heterocyclic compounds containing two nitrogen atoms that represent a privileged scaffold for various bioactive compounds with diverse pharmacological activities. Chalcones and hydrazine derivatives are excellent precursors for pyrazolines, which provide easy access for fabricating the pyrazoline ring at N1, C3 and C5 positions that give rise to a wide range of pyrazoline designs. In addition, this method institutes a new asymmetric center at C5 position and extent of the conjugation between phenyl group at C3 position to N1 that could greatly enhance the physicochemical and pharmacological properties towards the target enzymes and hence they are reported to have a wide spectrum of biological activities such as anti-cancer, antiinflammatory, etc. Most importantly, they have remarkable effects on the central nervous system (CNS). Several reports show that the pyrazoline derivatives have a significant inhibitory effect towards the monoamine oxidase enzymes (MAOs), which are known to be responsible for neurodegenerative disorders. These enzymes have two isoforms, namely MAO-A and MAO-B which are, in particular, responsible for psychiatric and neurological disorders, respectively. Chalcones are generally potential and more selective inhibitors towards MAO-B isoform whereas pyrazolines derived from chalcones mostly turned into selective inhibitors of MAO-A isoform may be due to the presence of two nitrogen heteroatoms. Therefore, these two derivatives have received much attention from medicinal chemists as they could solve entire CNS-related issues; however pyrazolines have not been studied as much as chalcones. Our group already documented the importance of pyrazolines towards MAO-A inhibition in 2013. With their growing importance, several studies on pyrazolines have constantly been reported for their MAO inhibitions. Therefore, in this review, we report up-to-date developments (after 2014) on pyrazolines as potential MAO inhibitors.

Licochalcone A (LA) is a chalcone flavonoid of Glycyrrhiza inflata, which has anti-cancer, antioxidant, anti-inflammatory, and neuroprotective effects. However, no anti-aging benefits of LA have been demonstrated in vitro or in vivo. In this study, we explored whether LA has an anti-aging effect in adipose-derived stem cells (ADSCs). We performed β-galactosidase staining and measured reactive oxygen species, relative telomere lengths, and P16ink4a mRNA expression. Osteogenesis was assessed by Alizarin Red staining and adipogenesis by was assessed Oil Red O staining. Protein levels of related markers runt-related transcription factor 2 and lipoprotein lipase were also examined. RNA sequencing and measurement of glycolysis activities showed that LA significantly activated glycolysis in ADSCs. Together, our data strongly suggest that the LA have an anti-aging effect through activate the glycolysis pathway.

Reactive oxygen/nitrogen species (ROS/RNS) are produced physiologically by several mechanisms, especially during the inflammatory response. However, their overproduction can lead to the evolution of conditions known as oxidative/nitrosative stress, resulting in the establishment of chronic inflammatory diseases. Chalcones are considered as a class of flavonoids having the molecular pattern 1,3-diaryl-2-propen-1-one. In the last few years, the antioxidant property of chalcones has been extensively studied, mainly due to their ability to inhibit the production or scavenging ROS/RNS. The antioxidant activity of chalcones, focusing on the production of ROS/RNS during the inflammatory response, is demonstrated and discussed in the present review. This literature revision was based on the modulatory effects of chalcones against different enzymes, such as superoxide dismutase (SOD), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, catalase (CAT), myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS), and, in the scavenging of ROS/RNS. Whenever possible, the structure-activity relationship (SAR) was established. Through the analysis accomplished in this review, it can be observed that the presence of substituents, e.g. hydroxyl, methoxyl, prenyl, and halogen atoms in the chalcones scaffold, often occurs and can improve their modulatory activities, namely, in the production of ROS/RNS during the inflammatory response.

Paclitaxel is widely used in the first-line treatment of ovarian cancer. Nevertheless, the development of acquired resistance to paclitaxel is a major obstacle for the therapy in clinic. Cardamonin is a novel anticancer chalcone which exhibits a wide range of pharmacological activities. However, the effect of cardamonin on paclitaxel-resistant ovarian cancer cells and its underlying molecular mechanisms are unknown. Here, we revealed whether cardamonin had a resensitivity for paclitaxel and furtherly explored the underlying mechanisms on SKOV3-Taxol cells. Our results showed that cardamonin combined with paclitaxel had a synergistic effect of anti-proliferation in SKOV3-Taxol cells, and CI was less than one. Cells apoptosis and G2/M phase arrest were enhanced by cardamonin with paclitaxel in a concentration-dependent way on SKOV3-Taxol cells (P < 0.05). Cardamonin significantly increased drug accumulation in SKOV3-Taxol cells (P < 0.05). Similar to verapamil, cardamonin decreased MDR1 mRNA and P-gp expression (P < 0.05). Cardamonin restrained NF-κB activation in SKOV3-Taxol cells (P < 0.05). Inhibitory effect of P-gp and NF-κB p65 (nuclear protein) expression was enhanced by cardamonin combined with PDTC, a NF-κB inhibitor. Cardamonin significantly inhibited the upregulation of NF-κB p65 (nuclear protein) and P-gp expression induced by TNF-α (P < 0.05). Taken together, cardamonin enhanced the effect of paclitaxel on inhibiting cell proliferation, inducing apoptosis and G2/M phase arrest, and then strengthened the cytotoxic effect of paclitaxel in SKOV3-Taxol cells. The mechanism might be involved in inhibition of P-gp efflux pump, reducing MDR1 mRNA and P-gp expression by cardamonin via suppression of NF-κB activation in SKOV3-Taxol cells.

Chalcones are an interesting class of compounds endowed with a plethora of biological activities beneficial to human health. These chemotypes have continued to attract increased research attention over the years; hence, numerous natural and synthetic chalcones have found with interesting anticancer activities through the inhibition of various molecular targets including ABCG2, BCRP, P-glycoprotein, 5α-reductase, Androgen Receptor (AR), Histone Deacetylases (HDAC), Sirtuin 1, proteasome, Vascular Endothelial Growth Factor (VEGF), Cathepsin-K, tubulin, CDC25B phosphatase, Topoisomerase, EBV, NF-κB, mTOR, BRAF, and Wnt/β-catenin. Moreover, the study of intrinsic mechanisms of action, particularly relating to specific cellular pathways and modes of engagement with molecular targets, may help medicinal chemists to develop more effective, selective, and cost-effective chalcone-based anticancer drugs. This review, therefore, sheds light on the effect of structural variations on the anticancer potency of chalcone hybrids reported in 2018-2019 alongside their mechanism of action, molecular targets, and potential impacts on effective cancer chemotherapy.

Loss of neuronal tissue is a hallmark of age-related neurodegenerative diseases. Since adult neurogenesis has been confirmed in the human brain, great interest has arisen in substances stimulating the endogenous neuronal regeneration mechanism based on adult neural stem cells. Medicinal plants are a valuable source of neuroactive small molecules. In the structure-activity study presented here, the activities of prenyl- and pyranochalcones were compared to each other, using a differentiation assay based on the doublecortin promoter sequences. The latter revealed that the pyrano ring is a crucial structural element for the induction of neuronal differentiation of adult neural stem cells, while compounds with a prenyl group show significantly lower activities. Furthermore, a decrease of pro-differentiation activity was observed following structural modifications, such as substitutions on the pyrano ring and on the B-ring of the chalcone. We also initiated the elucidation of the structural characteristics of the newly discovered lead substance xanthohumol C, which correlated with the activation of the doublecortin promoter during neuronal differentiation.

Background: The inhibition of α-amylase enzyme is one of the best therapeutic approach for the management of type II diabetes mellitus. Chalcone possesses a wide range of biological activities. Objective: In the current study chalcone derivatives (1-16) were synthesized and evaluated their inhibitory potential against α-amylase enzyme. Methods: For that purpose, a library of substituted (E)-1-(naphthalene-2-yl)-3-phenylprop-2-en-1-ones was synthesized by Claisen-Schmidt condensation reaction of 2-acetonaphthanone and substituted aryl benzaldehyde in the presence of base and characterized via different spectroscopic techniques such as EI-MS, HRESI-MS, 1H-, and 13C-NMR. Results: Sixteen synthetic chalcones were evaluated for in vitro porcine pancreatic α-amylase inhibition. All the chalcones demonstrated good inhibitory activities in the range of IC50 = 1.25 ± 1.05 to 2.40 ± 0.09 μM as compared to the standard commercial drug acarbose (IC50 = 1.34 ± 0.3 μM). Conclusion: Chalcone derivatives (1-16) were synthesized, characterized, and evaluated for their α- amylase inhibition. SAR revealed that electron donating groups in the phenyl ring have more influence on enzyme inhibition. However, to insight the participation of different substituents in the chalcones on the binding interactions with the α-amylase enzyme, in silico (computer simulation) molecular modeling analyses were carried out.

The incidence of ulcerative colitis (UC), one of the two types of inflammatory bowel disease, is increasing in many countries. Various natural products have been demonstrated with therapeutic potentials for UC. Herein, the therapeutic effects and mechanisms of isobavachalcone (IBC), a natural chalcone, were evaluated in dextran sulfate sodium (DSS)-induced colitis mice and lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The results demonstrated that IBC treatment significantly improved the clinical symptoms, assessed by the disease activity index (DAI) scores and the histological changes of the colon. The levels of myeloperoxidase (MPO), TNF-α, IL-6, IL-1β, and prostaglandin E2 (PGE2) in colon tissues were suppressed by IBC. The upregulation of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and NF-κB p65 in colon tissues were reversed by IBC as well. Furthermore, IBC significantly inhibited LPS-triggered secretion of TNF-α, IL-6, and nitrite, and nuclear translocation of NF-κB p65, in RAW264.7 cells. The luciferase reporter assay indicated that IBC significantly inhibited LPS-triggered transcription of toll-like receptor 4 (TLR4). Molecular docking results showed that the binding pocket of IBC was adjacent to Ser276 of p65-p50 heterodimer and IBC could form H-bond with Thr191. Collectively, these results demonstrated that IBC ameliorated colitis in mice possibly through inhibition of NF-κB p65.

Background and Objectives: Despite various technological advances for the treatment of cancer, the identification of new chemical entities with potent anticancer effects remain an indispensable requirement of the time due to multi-drug resistance exhibited by previously developed anticancer drugs. Particularly, the hybrid drugs incorporating two individual bioactive pharmacophores present medicinally important structural leads, thus improving the pharmacodynamic profile of the drug molecules. The antiproliferative and pro-apoptotic activity of the carbazole-chalcone hybrids on human breast and cervical cancer cells will be examined. Materials and Methods: To overcome such complications, in the current study, we evaluated the cytotoxic effects of carbazole-chalcone hybrids on human breast adenocarcinoma (MCF-7), cervical adenocarcinoma (HeLa) cells and normal cells i.e., baby hamster kidney cells (BHK-21) using MTT (dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide) assay. The mechanistic studies were performed on potent compound 4g by fluorescent microscopic studies, release of lactate dehydrogenase (LDH) and mitochondrial membrane potential, activation of caspase-9 and -3 and flow cytometric analysis. Results: As revealed by MTT assay, compound 4g was identified as the most potent derivative among the tested series with IC50 values of 5.64 and 29.15μM against HeLa and MCF-7 cells, respectively. The results were compared with cisplatin. Fluorescent microscopic studies using 4′,6-diamidino-2-phenylindole (DAPI) and Propidium Iodide (PI) staining confirmed the occurrence of apoptosis in HeLa cells treated with the most active compound 4g. Moreover, compound 4g also triggered the release of Lactate Dehydrogenase (LDH) in treated HeLa and MCF-7 cells while a fluorescence assay displayed a remarkable increase in the activity of caspase-9 and -3. Moreover, flow cytometric results revealed that compound 4g caused G0/G1 arrest in the treated HeLa cells. Conclusion: Our results demonstrated that the compound 4g possesses chemotherapeutic properties against breast cancer and cervical adenocarcinoma cells, thus warranting further research to test the anticancer potential of this compound at preclinical and clinical level.

Background and purpose: Tyrosinase enzyme has a key role in melanin biosynthesis by converting tyrosine into dopaquinone. It also participates in the enzymatic browning of vegetables by polyphenol oxidation. Therefore, tyrosinase inhibitors are useful in the fields of medicine, cosmetics, and agriculture. Many tyrosinase inhibitors having drawbacks have been reported to date; so, finding new inhibitors is a great need. Experimental approach: A variety of 6-hydroxy-3,4-dihydronaphthalenone chalcone-like analogs ( C1 - C10 ) have been synthesized by aldol condensation of 6-hydroxy tetralone and differently substituted benzaldehydes. The compounds were evaluated for their inhibitory effect on mushroom tyrosinase by a spectrophotometric method. Moreover, the inhibition manner of the most active compound was determined by Lineweaver-Burk plots. Docking study was done using AutoDock 4.2. The drug-likeness scores and ADME features of the active derivatives were also predicted. Results/Findings: Most of the compounds showed remarkable inhibitory activity against the tyrosinase enzyme. 6-Hydroxy-2-(3,4,5-trimethoxybenzylidene)-3,4-dihydronaphthalen-1(2H)-one ( C2 ) was the most potent derivative amongst the series with an IC 50 value of 8.8 μM which was slightly more favorable to that of the reference kojic acid (IC 50 = 9.7 μM). Inhibitory kinetic studies revealed that C2 behaves as a competitive inhibitor. According to the docking results, compound C2 formed the most stable enzyme-inhibitor complex, mainly via establishing interactions with the two copper ions in the active site. I n silico drug-likeness and pharmacokinetics predictions for the proposed tyrosinase inhibitors revealed that most of the compounds including C2 have proper drug-likeness scores and pharmacokinetic properties. Conclusion and implications: Therefore, C2 could be suggested as a promising tyrosinase inhibitor that might be a good lead compound in medicine, cosmetics, and the food industry, and further drug development of this compound might be of great interest.

Background: Chalcones, originated from natural product, have been broadly studied their biological activity against various proteins which at the molecular level, are responsible for the progress of the diseases in cancer (e.g. kinases), inflammation (oxidoreductases), atherosclerosis (cathepsins receptor), and diabetes (e.g. α-glucosidase). Objective: Here we synthesize 10 chalcone derivatives to be evaluated their in vitro enzymatic inhibition activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Methods: The synthesis was carried out using Claissen-Schimdt condensation and the in vitro assay was conducted using Ellman Method. Results: Compounds 2b and 4b demonstrated as the best IC50 of 9.3 μM and 68.7 μM respectively, towards AChE and BChE inhibition. Molecular docking studies predicted that this activity might be due to the interaction of the chalcones with important amino acid residues in the binding site of AChE such as SER200 and in that of BChE, such as TRP82, SER198, TRP430, TYR440, LEU286 and VAL288. Conclusion: Chalcone can be used as the scaffold for cholinesterase inhibitor, in particularly either fluorine or nitro group to be augmented at the para-position of Ring B, whereas the hydrophobic chain is necessary at the meta-position of Ring B.

The chalcone derivatives of 20-oxo-lupanes have been synthesised and screened for some types of biological activity. Ozonolysis of lupanes afforded 20-oxo-derivatives with the following condensation using different aromatic aldehydes by Claisen‒Schmidt reaction to the target compounds. The

Flavonols, anthocyanins, and chalcones were determined during the flowering phase in two genotypes of Cosmos sulphureus (regular species and its cultivar ‘Cosmic Orang’) grown in the М.М.Gryshko National Botanical Garden in Kyiv. Inflorescences, leaves, stems, roots, and separated ray and disc florets were dried and crushed to prepare extracts following three different techniques. In particular, with 80 % (v/v) ethanol following Andreeva & Kalinkina (2000), 3.5 % HCl following Kriventsov (1982), and 0.1 NHCl following Udovenko (1988). The absorbance of flavonoids was measured at 390nm wavelength for flavonols, 530 nm – for anthocyanins, and 364 nm – for chalcones. The highest content of flavonols was found in inflorescences of both genotypes (87.79 ± 1.64 and 87.99 ± 1.75 mg / 100 g of dry weight (DW), respectively). The content of anthocyanins was found to be ranked by overground organs: inflorescences > leaves > stems. In particular, the content of anthocyanins in the inflorescences of these two genotypes was 188.95 ± 5.20 and 177.14 ± 6.81 mg / 100 g DW, respectively. In the leaves, the content of anthocyanins was 61.32 ± 1.97 and 41.33 ± 2.27 mg / 100 g DW, respectively. In the stems, the content of anthocyanins was 31.63 ± 1.16 and 25.31 ± 0.95 mg / 100 g DW, respectively. In the roots, the anthocyanins were not detected. Among the flavonoids, the highest content, in general, was found for anthocyanins. Similarly, chalcones were also localized in overground organs only and mostly in the inflorescences (39.65 ± 1.25 and 37.93 ± 0.88 mg / 100 g DW, respectively). The content of chalcones in the leaves and stems was much lower than the content of the anthocyanins and flavonols; it significantly varied for two investigated genotypes. During the detailed investigation of the flavonoids content in different parts of the inflorescence, it was found that disc florets in both genotypes had fewer flavonoids than the ray florets.

Isoliquiritigenin (ISO) is a flavonoid extracted from the root of licorice, which serves various biological and pharmacological functions including antiinflammatory, antioxidation, liver protection, and heart protection. However, the mechanism of its action remains elusive and the direct target proteins of ISO have not been identified so far. Through cell-based screening, we identified ISO as a potent lipid-lowering compound. ISO treatment successfully ameliorated fatty acid-induced cellular lipid accumulation and improved nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) by increasing PPARα-dependent lipid oxidation and decreasing SREBPs-dependent lipid synthesis. Both these signaling required the activation of SIRT1. Knockdown of SIRT1 resulted in the reversal of ISO beneficiary effects suggesting that the lipid-lowering activity of ISO was regulated by SIRT1 expression. To identify the direct target of ISO, limited proteolysis combined with mass spectrometry (LiP-SMap) strategy was applied and IQGAP2 was identified as the direct target for ISO in regulating lipid homeostasis. In the presence of ISO, both mRNA and protein levels of SIRT1 were increased; however, this effect was abolished by blocking IQGAP2 expression using siRNA. To explore how IQGAP2 regulated the expression level of SIRT1, proteome profiler human phospho-kinase array kit was used to reveal possible phosphorylated kinases and signaling nodes that ISO affected. We found that through phosphorylation of CREB, ISO transduced signals from IQGAP2 to upregulate SIRT1 expression. Thus, we not only demonstrated the molecular basis of ISO in regulating lipid metabolism but also exhibited for the first time a novel IQGAP2-CREB-SIRT1 axis in treating NAFLD/NASH.

Eleven piperazine-containing 1,3-diphenylprop-2-en-1-one derivatives (PC1-PC11) were evaluated for their inhibitory activities against monoamine oxidases (MAOs), cholinesterases (ChEs), and β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) with a view toward developing new treatments for neurological disorders. Compounds PC10 and PC11 remarkably inhibited MAO-B with IC50 values of 0.65 and 0.71 μM, respectively. Ten of the eleven compounds weakly inhibited AChE and BChE with > 50% of residual activities at 10 μM, although PC4 inhibited AChE by 56.6% (IC50 = 8.77 μM). Compound PC3 effectively inhibited BACE-1 (IC50 = 6.72 μM), and PC10 and PC11 moderately inhibited BACE-1 (IC50 =14.9 and 15.3 μM, respectively). Reversibility and kinetic studies showed that PC10 and PC11 were reversible and competitive inhibitors of MAO-B with Ki values of 0.63 ± 0.13 and 0.53 ± 0.068 μM, respectively. ADME predictions for lead compounds revealed that PC10 and PC11 have central nervous system (CNS) drug-likeness. Molecular docking simulations showed that fluorine atom and trifluoromethyl group on PC10 and PC11, respectively, interacted with the substrate cavity of the MAO-B active site. Our results suggested that PC10 and PC11 can be considered potential candidates for the treatment of neurological disorders such as Alzheimer’s disease and Parkinson’s disease.

This study was to assess the possibility of using competitive and slow binding experiments with affinity-based ultrafiltration UPLC-QTof-MS analysis to identify potent bacterial neuraminidase (bNA) inhibitors from the Broussonetia papyrifera roots extract. To isolate unbound compounds from the enzyme-binding complex, the root bark extracts were either incubated in the absence of bNA, in the presence of bNA, or with the time-dependent bNA before the ultrafiltration was performed. Thirteen flavonoids were separated from the target extract, and their inhibitory activities were tested against bNA. The isolated flavonoids exhibited potent inhibition against NA (IC50 = 0.7–54.0 μM). Our kinetic analysis of representative active flavonoids (1, 2, and 6) showed slow and time-dependent reversible inhibition. Additionally, chalcones exhibited noncompetitive inhibition characteristics, whereas flavonols and flavans showed mixed-type behavior. The computational results supported the experimental behaviors of flavonoids 2, 6, 10, and 12, indicating that bounded to the active site, but flavonoids 6 and 10 binds near but not accurately at the active site. Although this is mixed-type inhibition, their binding can be considered competitive.

Isobavachalcone (IBC) has been shown to induce apoptosis and differentiation of acute myeloid leukemia (AML) cells. However, the underlying molecular mechanisms are not fully understood. Herein, IBC exhibited significant inhibition on the cell viability, proliferation, and the colony formation ability of AML cells. Moreover, IBC induced mitochondrial apoptosis evidenced by reduced mitochondrial membrane potential, increased Bax level, decreased Bcl-2, Bcl-xL, and Mcl-1 levels, elevated cytochrome c level in the cytosol and increased cleavage of caspase-9, caspase-3, and PARP. Furthermore, IBC obviously promoted the differentiation of AML cells, accompanied by the increase of the phosphorylation of MEK and ERK and the C/EBPα expression as well as the C/EBPβ LAP/LIP isoform ratio, which was significantly reversed by U0126, a specific inhibitor of MEK. Notably, IBC enhanced the intracellular ROS level. More importantly, IBC-induced apoptosis and differentiation of HL-60 cells were significantly mitigated by NAC. In addition, IBC also exhibited an obvious anti-AML effect in NOD/SCID mice with the engraftment of HL-60 cells. Together, our study suggests that the ROS-medicated signaling pathway is highly involved in IBC-induced apoptosis and differentiation of AML cells.

A large body of research has demonstrated a synergistic anticancer effect between docosahexaenoic acid (DHA) and standard chemotherapy regimens against colorectal cancer (CRC). In this study, we investigated the chemotherapeutic potential of cotreatment with DHA and isoliquiritigenin (ISL) against CRC HCT-116 cells. Apoptosis was confirmed by Annexin V/PI staining and expression of apoptosis-associated proteins. The synergistic effect of DHA and ISL combination on apoptosis was detected using combination index approaches. Flow cytometry was carried out using fluorescent probes to measure the production of reactive oxygen species (ROS). DHA and ISL in combination synergistically enhanced the decrease in cell viability versus the compounds used alone. Moreover, we demonstrated that the synergistic anti-CRC activity of cotreatment with these two compounds was achieved by inducing the apoptosis caspase-dependently mediated through augmented ROS generation followed by increased Fas ligand mRNA expression and cytochrome c release. Our data also demonstrated that cotreating with DHA and ISL strongly upregulated the phosphorylation of ERK and JNK, which are functionally associated with ROS induced by the two compounds in combination. Interestingly, further study revealed that inhibiting ERK phosphorylation strongly enhanced Fas ligand mRNA expression and the combination of the two compounds induced stronger cytotoxicity, whereas inhibiting JNK phosphorylation significantly reduced the apoptotic signals mediated by cotreatment with these two compounds. Excessive ROS-induced JNK activation and cytochrome c release from mitochondria played a key role in the synergistic anticancer activity of CRC cells by cotreating with DHA and ISL.

New piperazine–chalcone hybrids and related pyrazoline derivatives have been designed and synthesised as potential vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors. The National Cancer Institute (NCI) has selected six compounds to evaluate their antiproliferative activity in vitro against 60 human cancer cells lines. Preliminary screening of the examined compounds indicated promising anticancer activity against number of cell lines. The enzyme inhibitory activity against VEGFR-2 was evaluated and IC50 of the tested compounds ranged from 0.57 µM to 1.48 µM. The most potent derivatives Vd and Ve were subjected to further investigations. A cell cycle analysis showed that both compounds mainly arrest HCT-116 cell cycle in the G2/M phase. Annexin V-FITC apoptosis assay showed that Vd and Ve induced an approximately 18.7-fold and 21.2-fold total increase in apoptosis compared to the control. Additionally, molecular docking study was performed against VEGFR (PDB ID: 4ASD) using MOE 2015.10 software and Sorafenib as a reference ligand., Graphical Abstract

Defined differently from apoptosis, necrosis, and autophagy, ferroptosis has been implicated in acute kidney injury (AKI) such as ischemia-reperfusion injury induced AKI, folic acid caused AKI and cisplatin induced AKI. However, whether ferroptosis is involved in LPS induced AKI could be remaining unclear and there is still a lack of therapies associated with ferroptosis in LPS induced AKI without side effects. This study aimed to elucidate the role of isoliquiritigenin (ISL) in ferroptosis of LPS-induced AKI. We used LPS to induce renal tubular injury, followed by treatment with ISL both in vitro and in vivo. Human renal tubular HK2 cells were pretreated with 50 μM or 100 μM ISL for 5 h before stimulation with 2 μg/mL LPS. Mice were administered a single dose of either 50 mg/kg ISL orally or 5 mg/kg ferroptosis inhibitor ferrostatin-1 intraperitoneally before 10 mg/kg LPS injection. We found that LPS could induce mitochondria injury of renal tubular presented as the shape of mitochondria appeared smaller than normal with increased membrane density and are faction or destruction of mitochondrial crista through scanning electron microscope. Ferrostatin-1 significantly protected mice against renal dysfunction and renal tubular damage in LPS-induced AKI. ISL inhibited Fe2+ and lipid peroxidation accumulation in LPS-stimulated HK2 cells. It also increased the expression of GPX4 and xCT, reduced the expression of HMGB1 and NCOA4 then attenuated mitochondria injury in renal tubular following LPS stimulation. These results indicated the potential role of ISL against ferritinophagy-mediated ferroptosis in renal tubular following LPS stimulation.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases without any effective medicine treatments. The neurofibrillary tangles containing hyperphosphorylated tau protein are one important pathological characteristic. Thus, one practicable strategy for AD drug design is to discover compounds that could inhibit tau protein aggregation and/or phosphorylation. In this study, isobavachalcone, a natural plant-derived compound, has been shown to inhibit tau protein aggregation and disaggregate tau fibrils in vitro by directly interacting with tau protein at amino acids I278, V309, etc. It is able to reduce tau phosphorylation at four disease-related sites in vivo by regulating the critical kinase and protein phosphatase, GSK3β and PP2A. The compound also exhibits protection against tau oligomers-induced apoptosis through the mitochondria and ER mediated apoptotic pathways. In summary, isobavachalcone is a promising candidate for further evaluation as a potential preventive and therapeutic medicine for AD.

The in vitro antimicrobial properties of some chalcones (1a–1c ) and chalcone tethred 1,4-disubstituted 1,2,3-triazoles (2a–2u) towards different microbial strains viz. Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Aspergillus niger and Candida albicans are reported. Compounds 2g and 2u exhibited better potency than the standard Fluconazole with MIC values of 0.0063 µmol/mL and 0.0068 µmol/mL, respectively. Furthermore, molecular docking was performed to investigate the binding modes of two potent compounds 2q and 2g with E. coli topoisomerase II DNA gyrase B and C. albicans lanosterol 14α-demethylase, respectively. Based on these results, a statistically significant quantitative structure activity relationship (QSAR) model was successfully summarized for antibacterial activity against B. subtilis.

Hydroxylated chalcones are phytochemicals which are biosynthetic precursors of flavonoids and their 1,3-diaryl-prop-2-en-1-one structure is used as a scaffold for drug development. In this study, the structure-dependent activation of aryl hydrocarbon receptor (AhR)-responsive CYP1A1, CYP1B1, and UGT1A1 genes was investigated in Caco2 colon cancer cells and in non-transformed young adult mouse colonocytes (YAMC) cells. The effects of a series of di- and trihydroxychalcones as AhR agonists was structure dependent with maximal induction of CYP1A1, CYP1B1, and UGT1A1 in Caco2 cells observed for compounds containing 2,2′-dihydroxy substituents and this included 2,2′-dihydroxy-, 2,2′,4′-trihydroxy-, and 2,2′,5′-trihydroxychalcones. In contrast, 2′,4,5′-, 2′3′,4′-, 2′,4,4′-trihydroxy, and 2′,3-, 2′,4-, 2′,4′-, and 2′,5-dihydroxychalcones exhibited low to non-detectable AhR activity in Caco2 cells. In addition, all of the hydroxychalcones exhibited minimal to non-detectable activity in YAMC cells, whereas 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced CYP1A1, CYP1B1, and UGT1A1 in Caco2 and YAMC cells. The activity of AhR-active chalcones was confirmed by determining their effects in AhR-deficient Caco2 cells. In addition, 2,2′-dihydroxychalcone induced CYP1A1 protein and formation of an AhR-DNA complex in an in vitro assay. Simulation and modeling studies of hydroxylated chalcones confirmed their interactions with the AhR ligand-binding domain and were consistent with their structure-dependent activity as AhR ligands. Thus, this study identifies hydroxylated chalcones as AhR agonists with potential for these phytochemicals to impact AhR-mediated colonic pathways.

Diabetic nephropathy (DN) as a global health concern is closely related to inflammation and oxidation. Isoliquiritigenin (ISL), a natural flavonoid compound, has been demonstrated to inhibit inflammation in macrophages. Herein, we investigated the effect of ISL in protecting against the injury in STZ-induced type 1 DN and in high glucose-induced NRK-52E cells. In this study, it was revealed that the administration of ISL not only ameliorated renal fibrosis and apoptosis, but also induced the deterioration of renal function in diabetic mice. Mediated by MAPKs and Nrf-2 signaling pathways, respectively, upstream inflammatory response and oxidative stress were neutralized by ISL in vitro and in vivo. Moreover, as further revealed by the results of molecular docking, sirtuin 1 (SIRT1) binds to ISL directly, and the involvement of SIRT1 in ISL-mediated renoprotective effects was confirmed by studies using in vitro models of SIRT1 overexpression and knockdown. In summary, by reducing inflammation and oxidative stress, ISL has a significant pharmacological effect on the deterioration of DN. The benefits of ISL are associated with the direct binding to SIRT1, the inhibition of MAPK activation, and the induction of Nrf-2 signaling, suggesting the potential of ISL for DN treatment.

Dysfunction of epidermal growth factor receptor (EGFR) signalling plays a critical role in the oncogenesis of non–small‐cell lung cancer (NSCLC). Here, we reported the natural product, licochalcone A, exhibited a profound anti‐tumour efficacy through directly targeting EGFR signalling. Licochalcone A inhibited in vitro cell growth, colony formation and in vivo tumour growth of either wild‐type (WT) or activating mutation EGFR‐expressed NSCLC cells. Licochalcone A bound with L858R single‐site mutation, exon 19 deletion, L858R/T790M mutation and WT EGFR ex vivo, and impaired EGFR kinase activity both in vitro and in NSCLC cells. The in silico docking study further indicated that licochalcone A interacted with both WT and mutant EGFRs. Moreover, licochalcone A induced apoptosis and decreased survivin protein robustly in NSCLC cells. Mechanistically, we found that treatment with licochalcone A translationally suppressed survivin through inhibiting EGFR downstream kinases ERK1/2 and Akt. Depletion of the translation initiation complex by eIF4E knockdown effectively inhibited survivin expression. In contrast, knockdown of 4E‐BP1 showed the opposite effect and dramatically enhanced survivin protein level. Overall, our data indicate that targeting survivin might be an alternative strategy to sensitize EGFR‐targeted therapy.

A series of ferrocenyl chalcones using acetylferrocene, with ferrocenyl group at the keto carbonyl group, and different aldehydes were synthesized and their bioefficacy evaluation was done against ...

Chalcones are biologically active class of compounds, known for their anticancer activities. Here we show for the first time that out of the six synthetic derivatives of chalcone tested, 2'-hydroxy-retrochalcone (HRC) was the most effective in inducing extensive cytoplasmic vacuolation mediated death called paraptosis in malignant breast and cervical cancer cells. The cell death by HRC is found to be nonapoptotic in nature due to the absence of DNA fragmentation, PARP cleavage, and phosphatidylserine externalization. It was also found to be nonautophagic as there was an increase in the levels of autophagic markers LC3I, LC3II and p62. Immunofluorescence with the endoplasmic reticulum (ER) marker protein calreticulin showed that the cytoplasmic vacuoles formed were derived from the ER. This ER dilation was due to ER stress as evidenced from the increase in polyubiquitinated proteins, Bip and CHOP. Docking studies revealed that HRC could bind to the Thr1 residue on the active site of the chymotrypsin-like subunit of the proteasome. The inhibition of proteasomal activity was further confirmed by the fluorescence based assay of the chymotrypsin-like subunit of the 26S proteasome. The cell death by HRC was also triggered by the collapse of mitochondrial membrane potential and depletion of ATP. Pretreatment with thiol antioxidants and cycloheximide were able to inhibit this programmed cell death. Thus our data suggest that HRC can effectively kill cancer cells via paraptosis, an alternative death pathway and can be a potential lead molecule for anticancer therapy.

Chalcones are considered effective templates for the development of monoamine oxidase (MAO) and cholinesterase (ChE) inhibitors. The present work describes the syntheses of selected 1,3-benzodioxine-containing chalcones (CD3, CD8 and CD10), and their inhibitory activities against MAO-A, MAO-B, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). Compound CD8 most potently inhibited MAO-B with an IC50 value of 0.026 μM, followed by CD10 and CD3 (1.54 and 1.68 μM, respectively). CD8 potently and non-selectively inhibited MAO-A (IC50 value of 0.023 μM). On the other hand, CD10 and CD8 inhibited AChE with IC50 values of 5.40 and 9.57 μM, respectively. Kinetics and reversibility experiments showed that all synthesized molecules were competitive and reversible inhibitors, and the Ki values of CD8 for MAO-A and MAO-B were 0.018 and 0.0019 μM, respectively. By in vitro and in silico analyses, all compounds were found to have high passive human gastrointestinal absorptions, blood-brain barrier permeabilities, and non-toxicities. Molecular docking simulations revealed that docking affinity of each compound for MAO-B was higher than that for MAO-A. The results indicate that CD8 is a potent non-selective MAO inhibitor, and CD10 is an effective selective MAO-B inhibitor, and both possess AChE inhibitory activity. Therefore, we suggest that CD8 and CD10 be considered potential dual-targeting inhibitors of MAO and AChE for the treatment of various neurodegenerative disorders.

DNA damage is one of major culprits in many complex diseases; thus, there is great interest in the discovery of novel lead compounds regulating DNA damage. However, there remain plenty of challenges to evaluate DNA damage through counting the amount of intranuclear foci. Herein, a deep-learning-based open-source pipeline, FociNet, was developed to automatically segment full-field fluorescent images and dissect DNA damage of each cell. We annotated 6000 single-nucleus images to train the classification ability of the proposed computational pipeline. Results showed that FociNet achieved satisfying performance in classifying a single cell into a normal, damaged, or nonsignaling (no fusion-protein expression) state and exhibited excellent compatibility in the assessment of DNA damage based on fluorescent foci images from various imaging platforms. Furthermore, FociNet was employed to analyze a data set of over 5000 foci images from a high-content screening of 315 natural compounds from traditional Chinese medicine. It was successfully applied to identify several novel active compounds including evodiamine, isoliquiritigenin, and herbacetin, which were found to reduce 53BP1 foci for the first time. Among them, isoliquiritigenin from Glycyrrhiza uralensis Fisch. exerts a significant effect on attenuating double strand breaks as indicated by the comet assay. In conclusion, this work provides an artificial intelligence tool to evaluate DNA damage on the basis of microscopy images as well as a potential strategy for high-content screening of active compounds.

Activating mutations in FLT3 receptor tyrosine kinase are found in a third of acute myeloid leukemia (AML) patients and are associated with disease relapse and a poor prognosis. The majority of these mutations are internal tandem duplications (ITDs) in the juxtamembrane domain of FLT3, which have been validated as a therapeutic target. The clinical success of selective inhibitors targeting oncogenic FLT3, however, has been limited due to the acquisition of drug resistance. Herein the identification of a dual FLT3/microtubule polymerization inhibitor, chalcone 4 (2'-allyloxy-4,4'-dimethoxychalcone), is reported through screening of 15 related chalcones for differential antiproliferative activity in leukemia cell lines dependent on FLT3-ITD (MV-4-11) or BCR-ABL (K562) oncogenes and by subsequent screening for mitotic inducers in the HCT116 cell line. Three natural chalcones (1-3) were found to be differentially more potent toward the MV-4-11 (FLT3-ITD) cell line compared to the K562 (BCR-ABL) cell line. Notably, the new semisynthetic chalcone 4, which is a 2'-O-allyl analogue of the natural chalcone 3, was found to be more potent toward the FLT3-ITD+ cell line and inhibited FLT3 signaling in FLT3-dependent cells. An in vitro kinase assay confirmed that chalcone 4 directly inhibited FLT3. Moreover, chalcone 4 induced mitotic arrest in these cells and inhibited tubulin polymerization in both cellular and biochemical assays. Treatment of MV-4-11 cells with this inhibitor for 24 and 48 h resulted in apoptotic cell death. Finally, chalcone 4 was able to overcome TKD mutation-mediated acquired resistance to FLT3 inhibitors in a MOLM-13 cell line expressing FLT3-ITD with the D835Y mutation. Chalcone 4 is, therefore, a promising lead for the discovery of dual-target FLT3 inhibitors.

Trypanosoma cruzi is the agent of Chagas disease, an infection that affects around 8 million people worldwide. The search for new anti-T. cruzi drugs are relevant, mainly because the treatment of this disease is limited to two drugs. The objective of this study was to investigate the trypanocidal and cytotoxic activity and elucidate the chemical profile of extracts from the roots of the Lonchocarpus cultratus. Roots from L. cultratus were submitted to successive extractions with hexane, dichloromethane, and methanol, resulting in LCH, LCD, and LCM extracts, respectively. Characterization of extracts was done using 1H-RMN, 13C-RMN, CC and TLC. Treatment of T. cruzi forms (epimastigotes, trypomastigotes, and amastigotes) with crescent concentrations of LCH, LCD, and LCM was done for 72, 48, and 48 h, respectively. After this, the percentage of inhibition and IC50/LC50 were calculated. Benznidazole was used as a positive control. Murine macrophages were treated with different concentrations of both extracts for 48 h, and after, the cellular viability was determined by the MTT method and CC50 was calculated. The chalcones derricin and lonchocarpine were identified in the hexane extract, and for the first time in the genus Lonchocarpus, the presence of a dihydrolonchocarpine derivative was observed. Other chalcones such as isocordoin and erioschalcone B were detected in the dichloromethane extract. The dichloromethane extract showed higher activity against all tested forms of T. cruzi than the other two extracts, with IC50 values of 10.98, 2.42, and 0.83 µg/mL, respectively; these values are very close to those of benznidazole. Although the dichloromethane extract presented a cytotoxic effect against mammalian cells, it showed selectivity against amastigotes. The methanolic extract showed the lowest anti-T. cruzi activity but was non-toxic to peritoneal murine macrophages. Thus, the genus Lonchocarpus had demonstrated in the past action against epimastigotes forms of T. cruzi but is the first time that the activity against infective forms is showed, which leading to further studies with in vivo tests.

Five new series of hydroxybenzofuranyl-pyrazolyl chalcones 3a,b, hydroxyphenyl-pyrazolyl chalcones 6a-c and their corresponding pyrazolylpyrazolines 4a, d, 7a-c and 8a-f have been synthesized and evaluated for their in vitro cyclooxygenase (COX)-1 and COX-2 inhibitory activity. All the synthesized compounds exhibited dual COX-1 and COX-2 inhibitory activity with obvious selectivity against COX-2. The pyrazolylpyrazolines 4a-d and 8a-f bearing two vicinal aryl moieties in the pyrazoline nucleus showed more selectivity towards COX-2. Within these two series, derivatives 4c, d and 8d-f bearing the benzenesulfonamide group were the most selective. Compounds 4a-d and 8a-f were further subjected to in vivo anti-inflammatory screening, ulcerogenic liability and showed good anti-inflammatory activity with no ulcerogenic effect. In addition compounds 4c and 8d as examples showed prostaglandin (PG)E2 inhibition % 44.23 and 51.4 respectively, tumor necrosis factor α (TNFα) inhibition % 33.48 and 41.41 respectively and gastroprotective effect in ethanol induced rodent gastric ulcer model. In addition, to explore the binding mode and selectivity of our compounds, 8d and celecoxib were docked into the active site of COX-1 and COX-2. It was found that compound 8d exhibited a binding pattern and interactions similar to that of celecoxib with COX-2 active site, while bitter manner of interaction than celecoxib to COX-1 active site.

Introduction In order to develop novel anticancer HDAC/tubulin dual inhibitors, a novel series of α-phthalimido-substituted chalcones-based hybrids was synthesized and characterized by IR, 1H NMR, 13C NMR, mass spectroscopy and X-ray analysis. Methods All the synthesized compounds were evaluated for their in vitro anticancer activity against MCF-7 and HepG2 human cancer cell lines using MTT assay. To explore the mechanism of action of the synthesized compounds, in vitro β-tubulin polymerization and HDAC 1 and 2 inhibitory activity were measured for the most potent anticancer hybrids. Further, cell cycle analysis was also evaluated. Results The trimethoxy derivative 7j showed the most potent anticancer activity, possessed the most potent β-tubulin polymerase and HDAC 1 and 2 inhibitory activity and efficiently induced cell cycle arrest at both G2/M and preG1phases in the MCF-7 cell line.

Hepatocellular carcinoma (HCC) ranks as the fifth most common and the second deadliest cancer worldwide. HCC is extremely resistant to the conventional chemotherapeutics. Hence, it is vital to develop new treatment options. Chalcones were previously shown to have anticancer activities in other cancer types. In this study, 11 chalcones along with quercetin, papaverin, catechin, Sorafenib and 5FU were analyzed for their bioactivities on 6 HCC cell lines and on dental pulp stem cells (DPSC) which differentiates into hepatocytes, and is used as a model for untransformed control cells. 3 of the chalcones (1, 9 and 11) were selected for further investigation due to their high cytotoxicity against liver cancer cells and compared to the other clinically established compounds. Chalcones did not show significant bioactivity (IC 50> 20 μ M) on dental pulp stem cells. Cell cycle analysis revealed that these 3 chalcone-molecules induced SubG1/G1 arrest. Akt protein phosphorylation was inhibited by these molecules in PTEN deficient, drug resistant, mesenchymal like Mahlavu cells leading to the activation of p21 and the inhibition of NFκB-p65 transcription factor. Hence the chalcones induced apoptotic cell death pathway through NFκB-p65 inhibition. On the other hand, these molecules triggered p21 dependent activation of Rb protein and thereby inhibition of cell cycle and cell growth in liver cancer cells. Involvement of PI3K/Akt pathway hyperactivation was previously described in survival of liver cancer cells as carcinogenic event. Therefore, our results indicated that these chalcones can be considered as candidates for liver cancer therapeutics particularly when PI3K/Akt pathway involved in tumor development., Scientific and Technological Research Council of Turkey (TÜBİTAK); COST Action; European Union (European Union); Horizon 2020

The readily synthesized 3-(4-Hydroxy-1-methyl-1,2-dihydro-2-oxoquinolin-3-yl)-1-phenyl-1H-pyrazole-4-carbaldehyd (5) and 3-(2-Oxo-2H-chromen-3-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde (6) were utilized as a convenient starting precursor materials for synthesis of novel enone system 4-hydroxy-1-methyl-3-(4-(2H-2-oxo-chromen-3-yl)prop-2-enoyl)-1-phenyl-1H-pyrazol-4-yl)quinolin-2(1H)-one (7) and4-hydroxy-1-methyl-3-(2E)-3-(3-(2-oxo-2H-chromen-3-yl)-1-phenyl-1H-pyrazol-4-yl)acryloyl)quinolin-2(1H)-one (8). Simple homonuclear NOE experiment (NOESY 1D) method was performed for structure elucidation of the novel quinolinyl chalcones. The synthesized compounds have been estimated for their effect of growth on some selective crop of plants (Hibiscus, Mint and Basil).

Rooibos (Aspalathus linearis) has various health benefits. Two case studies have associated chronic Rooibos consumption with conventional prescription medications, including atorvastatin (ATV), with hepatotoxicity. Statins act by inhibiting hydroxymethylglutaryl‐coenzyme A reductase, a rate‐limiting enzyme in cholesterol synthesis. Although rare, statins are potentially hepatotoxic. The aim was to investigate interactions between aspalathin‐rich Rooibos extract GRT™ and ATV‐induced hepatotoxicity in C3A liver cells cultured with and without palmitate. Effects of co‐treatment of GRT + ATV on cell viability, oxidative stress, apoptosis, mitochondrial integrity, and cellular reactive oxygen species (ROS) production were assessed. Significantly increased ROS production was observed in cells exposed to ATV and palmitate. Combination therapy of GRT + ATV also showed significant increases in ROS production. Under palmitate‐treated conditions, ATV‐induced significant apoptosis which was not ameliorated by GRT + ATV co‐treatment. Despite studies purporting hepatoprotection from Rooibos, our study showed that GRT was unable to modulate ATV‐induced hepatotoxic effects in this model., Effects of rooibos extract (GRT) and atorvastatin (ATV) treatments on reactive oxygen species (ROS) production in C3A cells without palmitate and cells treated with 500 µM palmitate for 24 hrs. The addition of GRT failed to ameliorate ROS production induced by ATV treatment.

Glycyrrhizae radix has been widely accepted as a functional food in Asia. Isoliquiritigenin is a characteristic bioactive chemical in this medicinal plant. In this work, the neuroprotective effect of isoliquiritigenin and the possible mechanisms were investigated. The results revealed that isoliquiritigenin exhibited better neuroprotective and antioxidant activities than quercetin, a commercial natural antioxidant. Isoliquiritigenin significantly inhibited the release of lactate dehydrogenase, and the generation of reactive oxygen species in H2O2-treated cells. The activities of superoxide dismutase, glutathione peroxidase and catalase were improved. The mRNA expression levels related to oxidative defense and cell apoptosis were reversed by isoliquiritigenin. Moreover, isoliquiritigenin might inhibit the cell apoptosis via ameliorating the loss of mitochondrial membrane potential and the change of nucleus morphology.

Background: Since the beginning of the HIV/AIDS epidemic, 75 million people have been infected with the HIV and about 32 million people have died of AIDS. Investigation of the molecular mechanisms critical to the HIV replication cycle led to the identification of potential drug targets for AIDS therapy. One of the most important discoveries is HIV-1 protease, an enzyme that plays an essential role in the replication cycle of HIV. Objective: The aim of the present study is to synthesize and investigate anti-HIV-1 protease activity of some chalcone derivatives with the hope of discovering new lead structure devoid drug resistance. Methods: 20 structurally similar chalcone derivatives were synthesized and their physico-chemical characterization was performed. Binding of chalcones to HIV-1 protease was investigated by fluorimetric assay. Molecular docking studies were conducted to understand the interactions. Results: The obtained results revealed that all compounds showed anti-HIV-1 protease activity. Compound C1 showed the highest inhibitory activity with an IC50 value of 0.001 μM, which is comparable with commercial product Darunavir. Conclusion: It is difficult to provide general principles of inhibitor design. Structural properties of the compounds are not the only consideration; ease of chemical synthesis, low molecular weight, bioavailability, and stability are also of crucial importance. Compared to commercial products the main advantage of compound C1 is the ease of chemical synthesis and low molecular weight. Furthermore, compound C1 has a structure that is different to peptidomimetics, which could contribute to its stability and bioavailability.

In the present study, the degradation of C-glucosidic dihydrochalcone aspalathin as the major phenolic compound in rooibos (Aspalathus linearis) was investigated. Analyses by gas chromatography-mass spectrometry of aqueous aspalathin-lysine incubations after silylation showed the formation of dihydrocaffeic acid [3-(3,4-dihydroxyphenyl)-propionic acid] under oxidative conditions as a novel degradation product up to 10 mol %. High-performance liquid chromatography analyses revealed the concurrent formation of the dihydrocaffeic acid lysine amide at about 30-fold lower concentrations, which was unequivocally verified by synthesis of an authentic reference standard. The amide was also verified in aspalathin-protein incubations after enzymatic hydrolysis by high-performance liquid chromatography-tandem mass spectrometry analyses. Thus, the covalent interaction of phenolic plant compounds with proteins under mild conditions (ambient temperatures and neutral pH) was confirmed for the first time. Acid and free amide were also quantitated in rooibos teas with significantly higher values in fermented varieties. The mechanism of formation was clarified to be initiated by singlet oxygen and to include a rearrangement-fragmentation mechanism with 1,2,3,5-tetrahydroxybenzene as the counterpart.

Isoliquiritigenin (2’,4’,4-trihydroxychalcone, ISL) is one of the most important chalcone compounds which is mainly derived from licorice root and many other plants. It exhibits a remarkable range of potent biological and pharmacological activities such as antioxidative, antitumor, antiaging, anti-inflammatory, anti-diabetic activities, etc. Numerous research teams have demonstrated that ISL posseses the ability to carry out antigrowth and proliferation in various cancer cells in vitro and in vivo. Meanwhile, the underlying mechanisms of ISL that inhibit cancer cell proliferation have not been well explored. However, the poor bioavailability and low water-soluble limit its clinical application. This review aims at providing a comprehensive overview of the pharmacology antitumor activity of ISL and its mechanisms in different malignancy especially in breast cancer cell line and summarize developments of formulation utilized to overcome the barrier between its delivery characteristics and application in clinics over the past 20 years.

Cardamonin, a monomeric alkaloid, is isolated from Alpinia conchigera Griff and other natural plants. Recently, it has been focused on its anticancer activities, and no information showing its immune effects on leukemia mice was reported. In this study, we investigated the immune effects of cardamonin on WEHI-3 cell-generated leukemia mice. Forty BALB/c mice were randomly divided into four groups: Group I mice were normal animals and groups II-IV were leukemia. Group II mice, as a positive control, were administered with normal diet, and group III and IV mice were treated with 1 and 5 mg/kg of cardamonin, respectively, by intraperitoneal injection every 2 days for 14 days. The population of white blood cells, macrophage phagocytosis, and the proliferations of T and B cells were analyzed by flow cytometry. Another forty mice were also separated randomly into four groups for the determination of survival rate. Results showed that cardamonin did not affect body weight. Cardamonin decreased CD3, CD11b, and Mac-3 cell populations but increased CD19 number. Cardamonin enhanced phagocytic abilities of macrophages from the peripheral blood mononuclear cells of leukemia mice. Furthermore, cardamonin at 1 mg/kg treatment improved the survival rate of leukemia mice in vivo. Therefore, cardamonin could be applied for a leukemia therapeutic reagent at a defined dose.

Licochalcone A (LCA) was found to possess anticancer effects. This study aimed to investigate the anticancer effects and mechanisms of LCA in melanoma. A375 and B16 melanoma cells were stimulated with LCA, MTT assay was used to assess cell proliferation. Expression of miR-142-3p, microphthalmia-associated transcription factor (MITF, which regulates melanin production) and autophagy-related genes was determined by Real-time PCR or western blot. The apoptosis was analyzed by flow cytometry and caspase-3 activity. The roles of miR-142-3p and Ras homolog enriched in brain (Rheb) in LCA-affected cells were investigated by gain- and loss-of functions. LCA inhibited proliferation and MITF expression, but increased apoptosis and autophagy of melanoma cells. Moreover, LCA elevated miR-142-3p expression, but decreased its target gene Rheb expression. The effects of LCA on melanoma cells were abrogated by miR-142-3p inhibitor or Rheb overexpression. LCA suppressed mTOR signaling activation via Rheb. Additionally, rapamycin (a mTOR antagonist) notably attenuated the effects of Rheb on the autophagy, proliferation, apoptosis, and MITF expression in LCA-treated melanoma cells. In conclusion, LCA restrained MITF expression and growth by activating autophagy in melanoma cells via miR-142-3p/Rheb/mTOR pathway. This study suggested that LCA might be a potential therapeutic candidate for prevention and treatment of melanoma.

Background/aim Development of new potential drugs to overcome multidrug resistance to chemotherapy is a big challenge for cancer treatment. Attention is also given to the natural compounds and their derivatives. The study aimed at evaluating the impact of a new chalcone derivative (1C) on multidrug resistant cell lines, focusing on P-glycoprotein (P-gp, ABCB1) inhibition, as well as 1C-doxorubicin interaction in vitro. Materials and methods Cytotoxic and antiproliferative effects of the 1C compound were assessed by thiazolyl blue tetrazolium bromide (MTT) method in mouse T-cell lymphoma and human colon adenocarcinoma cells expressing ABCB1. Alterations in ABCB1 activity were evaluated by rhodamine 123 accumulation assay using flow cytometry. Drug-drug interaction was studied using combination assay. Results Our results confirmed antiproliferative, cytotoxic, as well as ABCB1 inhibitory potential of 1C in both tested ABCB1-expressing cancer cell lines. Furthermore, 1C displayed synergistic interaction with doxorubicin. Conclusion Our results suggest the 1C chalcone derivative as a promising compound against resistant lymphoma and colon cancer, which could be used in monotherapy or in combination with other chemotherapeutics.

Background: The diazenyl compounds (-N=N- linkage) have been reported to have antimicrobial activity. In modern drug discovery, the drug-receptor interactions are generally explored by the molecular docking studies. Materials and Methods: Three categories of diazenyl scaffolds were screened for the docking studies to explore the binding mechanism of interaction with various microbial targets. The diazenyl Schiff bases (SBN-20, SBN-21, SBN-25, SBN-33, SBN-39, SBN-40 and SBN-42), naphthol pharmacophore based diazenyl Schiff bases (NS-2, NS-8, NS-12, NS-15, NS-21, and NS-23), morpholine based diazenyl chalcones (MD-6, MD-9, MD-14, MD-16, MD-20, and MD-21) were docked against various bacterial and fungal proteins in comparison with different standard drugs. Further, the drug likeliness and ADME properties of these molecules were predicted by QikProp module of the Schrodinger software. Results: Most of the derivatives had shown less docking scores and binding energies towards bacterial proteins, such as dihydropteroate synthase (PDB:2VEG), glucosamine-6-phosphate synthase (PDB:2VF5), dihydrofolate reductase (PDB:3SRW) in comparison with the standard drugs. The naphthol based diazenyl Schiff bases NS-21 and NS-23 were predicted to act on the cytochrome P450 sterol 14-alpha-demethylase (CYP51) (PDB:5FSA) involved in sterol biosynthesis, an essential target for antifungal drugs. The derivative MD-6, NS-2, NS-21, and NS-23 had shown high docking scores against bacterial DNA topoisomerase (PDB:3TTZ) in comparison with the standard drug ciprofloxacin. Further, most of the synthesized derivatives had shown drug like characters. Conclusion: Hence, these compounds can be developed as novel antibacterial agents as potent DNA topoisomerase inhibitors and antifungal agents as CYP51 inhibitors.

Plants produce interesting secondary metabolites that are a valuable source of both medicines for human use, along with significant advantages for the manufacturer species. The active compounds which lead to these instrumental effects are generally secondary metabolites produced during various plant growth phases, which provide the host survival advantages while affecting human health inadvertently. Different chemical classes of secondary metabolites are biosynthesized by the plant type III polyketide synthases (PKSs). They are simple homodimeric proteins with the unique mechanistic potential to produce a broad array of secondary metabolites by utilizing simpler starter and extender units. These PKS derived products are majorly the precursors of some important secondary metabolite pathways leading to products such as flavonoids, stilbenes, benzalacetones, chromones, acridones, xanthones, cannabinoids, aliphatic waxes, alkaloids, anthrones, and pyrones. These secondary metabolites have various pharmaceutical, medicinal and industrial applications which make biosynthesizing type III PKSs an important tool for bioengineering purposes. Because of their structural simplicity and ease of manipulation, these enzymes have garnered interest in recent years due to their application in the generation of unnatural natural polyketides and modified products in the search for newer drugs for a variety of health problems. The following review covers the biosynthesis of a variety of type III PKS-derived secondary metabolites, their biological relevance, the associated enzymes, and recent research.

Glycyrrhiza glabra (Licorice) belongs to the Fabaceae family and its extracts have exhibited significant fungicidal activity against phytopathogenic fungi, which has mainly been attributed to the presence of phenolic compounds such as flavonoids, isoflavonoids and chalcones. In this study, a series of licorice flavonoids, isoflavonoids and chalcones were evaluated for their fungicidal activity against phytopathogenic fungi. Among them, glabridin exhibited significant fungicidal activity against ten kinds of phytopathogenic fungi. Notably, glabridin displayed the most active against Sclerotinia sclerotiorum with an EC50 value of 6.78 µg/mL and was 8-fold more potent than azoxystrobin (EC50, 57.39 µg/mL). Moreover, the in vivo bioassay also demonstrated that glabridin could effectively control S. sclerotiorum. The mechanism studies revealed that glabridin could induce reactive oxygen species accumulation, the loss of mitochondrial membrane potential and cell membrane destruction through effecting the expression levels of phosphatidylserine decarboxylase that exerted its fungicidal activity. These findings indicated that glabridin exhibited pronounced fungicidal activities against S. sclerotiorum and could be served as a potential fungicidal candidate.

Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived immunostimulatory factor, which activates several immune cells such as dendritic cells, T cells, and mast cells. Recently, epithelial cell-derived TSLP has gained immense attention as a cytokine that induces allergic immune responses. Therefore, understanding the regulation of TSLP production is an important step in uncovering the pathophysiology of allergic diseases. Moreover, the compounds that regulate TSLP production can be used as therapeutic drugs for the treatment of allergic diseases. We aim to elucidate the detailed regulation of TSLP production from epithelial cells, and in doing so discovered new regulating factors and an inhibitor of TSLP production. This review article explains the role of TSLP in allergic diseases, its regulation, and our research results.

Our group has progressively reported on the impact of bioactive compounds found in rooibos (Aspalathus linearis) and their capacity to modulate glucose homeostasis to improve metabolic function in experimental models of type 2 diabetes. In the current study, we investigated how the dietary flavone, orientin, modulates the essential genes involved in energy regulation to enhance substrate metabolism. We used a well-established hepatic insulin resistance model of exposing C3A liver cells to a high concentration of palmitate (0.75 mM) for 16 hrs. These insulin-resistant liver cells were treated with orientin (10 µM) for 3 h to assess the therapeutic effect of orientin. In addition to assessing the rate of metabolic activity, end point measurements assessed include the uptake or utilization of glucose and palmitate, as well as the expression of genes involved in insulin signaling and regulating cellular energy homeostasis. Our results showed that orientin effectively improved metabolic activity, mainly by maintaining substrate utilization which was marked by enhanced glucose and palmitate uptake by liver cells subjected to insulin resistance. Interestingly, these effects can be explained by the improvement in the expression of genes involved in glucose transport (Glut2), insulin signaling (Irs1 and Pi3k), and energy regulation (Ampk and Cpt1). These preliminary findings lay an important foundation for future research to determine the bioactive properties of orientin against dyslipidemia or insulin resistance in reliable and well-established models of type 2 diabetes.

Calcium signaling plays a vital role in the regulation of various cellular processes, including activation, proliferation, and differentiation of T-lymphocytes, which is mediated by ORAI1 and potassium (K+) channels. These channels have also been identified as highly attractive therapeutic targets for immune-related diseases. Licochalcone A is a licorice-derived chalconoid known for its multifaceted beneficial effects in pharmacological treatments, including its anti-inflammatory, anti-asthmatic, antioxidant, antimicrobial, and antitumorigenic properties. However, its anti-inflammatory effects involving ion channels in lymphocytes remain unclear. Thus, the present study aimed to investigate whether licochalcone A inhibits ORAI1 and K+ channels in T-lymphocytes. Our results indicated that licochalcone A suppressed all three channels (ORAI1, Kv1.3, and KCa3.1) in a concentration-dependent matter, with IC50 values of 2.97 ± 1.217 µM, 0.83 ± 1.222 µM, and 11.21 ± 1.07 µM, respectively. Of note, licochalcone A exerted its suppressive effects on the IL-2 secretion and proliferation in CD3 and CD28 antibody-induced T-cells. These results indicate that the use of licochalcone A may provide an effective treatment strategy for inflammation-related immune diseases.