The current work aims to develop a shikonin and tea tree oil loaded nanoemulsion system stabilized by a mixture of GRAS grade surfactants (Tween 20 and monoolein) and a cosurfactant (Transcutol P). ...This system was designed to address the poor aqueous solubility and photostability issues of shikonin. The authenticity of shikonin employed in this study was confirmed using nuclear magnetic resonance (NMR) spectroscopy. The optimized nanoemulsion exhibited highly favorable characteristics in terms of zeta potential (−23.8 mV), polydispersity index (0.216) and particle size (22.97 nm). These findings were corroborated by transmission electron microscopy (TEM) micrographs which confirmed the spherical and uniform nature of the nanoemulsion globules. Moreover, attenuated total reflectance (ATR) and X-ray diffraction analysis (XRD) analysis affirmed improved chemical stability and amorphization, respectively. Photodegradation studies were performed by exposing pure shikonin and the developed nanoemulsion to ultraviolet light for 1 h using a UV lamp, followed by high performance liquid chromatography (HPLC) analysis. The results confirmed that the developed nanoemulsion system imparts photoprotection to pure shikonin in the encapsulated system. Furthermore, the research investigated the effect of the nanoemulsion on biofilms formed by Candida albicans and methicillin resistant Staphylococcus aureus (MRSA). Scanning electron microscopy, florescence microscopy and phase contrast microscopy unveiled a remarkable reduction in biofilm area, accompanied by disruptions in the cell wall and abnormalities on the cell surface of the tested microorganisms. In conclusion, the nanoencapsulation of shikonin with tea tree oil as the lipid phase showcased significantly enhanced antimicrobial and antibiofilm potential compared to pure shikonin against resistant strains of Candida albicans and Staphylococcus aureus.
Abstract
Roylea cinerea
(D.Don) Baillon an indigenous medicinal plant of
Lamiaceae
family used for the treatment of several diseases. In the present study, its aqueous (leaves) extract was tested for ...genoprotective action against atrazine-induced chromosomal aberrations in the root tip cells of
Allium cepa
. Atrazine is a herbicide of triazine class commonly used to inhibit the growth of broad leaf and grassy weeds. In order to find the concentration of atrazine that exhibits maximum toxicity, its different concentrations (1, 5 and 10 µg/mL) were tested. It was observed that 10 µg/mL concentration was more toxic as it reduced the mitotic index and also increased the chromosomal aberrations. Among all the tested concentrations of aqueous (leaves) extracts (0.25. 0.5, 1.0, 1.5 and 3.0 µg/mL), the3.0 µg/mL concentration in both modes of experiments i.e. pre and post showed a significant reduction in chromosomal aberrations induced by atrazine. To understand the mechanism of protection by plant extract on atrazine-induced chromosomal abnormalities the RT-qPCR studies were conducted to observe the expression of marker genes Cyclin-dependent kinases (CDKs) (CDKA:1, CDKB2:1 and CDKD1:1. For this, the RNA was extracted from root tips treated with extract along with atrazine by TRIzol
®
. It was observed that aqueous extract of
Roylea cinerea
(D.Don) Baillon leaves upregulated the CDKs gene expression in both the modes i.e. pre and post treatments. A critical analysis of results indicated that aqueous extract ameliorated the chromosomal aberrations caused by atrazine which may be be due to the increased expression level of CDKs genes.
Purpose
Phellinus fastuosus
(Lév.) S. (
Hymenochaetaceae
,
Hymenochaetales
,
Agaricomycetes
,
Basidiomycota
) is a member of wood-rotting polyporoid fungi that contains numerous metabolites reported ...with many medicinal properties and has been used in traditional medicine for the treatment of various diseases. Inspired by the medicinal properties of this polypore the present study on the antioxidant and antiproliferative potential of methanolic extract of
Phellinus fastuosus
using various in vitro assays was proposed.
Methods
The extraction of the basidiocarp of
Ph. fastuosus
was done sequentially in hot water (
Pfaq
), methanol (
Pfme
) and ethyl acetate (
Pfea
) to obtain the respective extracts. The antioxidant potential of different extracts was examined with 2,2-Diphenyl-1-picrylhydrazyl (DPPH) assay, Ferric ion reducing antioxidant power and Phosphomolybdate assay. The cytotoxicity activity was determined by using MTT assay in human epidermoid carcinoma cells (A431), human cervical cancer (HeLa cells), human osteosarcoma (MG-63) and normal epidermoid cells (L929). For the assessment of changes in cell morphology, and apoptotic induction in A431 cell line was further investigated using phase-contrast microscopy, Hoechst 33342 staining and AO/EtBr dual staining. Flow cytometry was used for the estimation of production of reactive oxygen species (ROS) andmitochondrial membrane potential (MMP).
Results
Among all,
Pfme
extract showed effective free radical scavenging potential in DPPH assay, as compared to the other extracts. Therefore the
Pmfe
extract was further evaluated for the antiproliferative activity in A431, HeLa and MG-63 cell lines. This extract was very effective in A431 with GI
50
(growth inhibitory dose 50%) value of 81.39 compared to its effect in HeLa and MG-63 cells with GI
50
values of 173.47 and 191.53 μg/ml respectively. The
Pfme
extract was further investigated to explore its role in apoptosis induction in A431 cell line. Phase-contrast and fluorescence microscopic studies exhibited all the characteristics indicative of apoptosis, viz., shape change, cell shrinkage, cell rounding-off and nuclear condensation. To understand the cause of effectiveness of
Pfme
extract, HPLC analysis was carried out which showed the presence of different polyphenols.
Conclusions
A critical examination of results highlighted that the
Pmfe
extract induced apoptosis in A431 cells via ROS-mediated apoptotic pathway which may be ascribed to the presence of polyphenols in it.
Graphical Abstract
Bacterial resistance toward available therapeutic agents has become a nightmare for the healthcare system, causing significant mortality as well as prolonged hospitalization, thereby needing the ...urgent attention of research groups working on antimicrobial drug development worldwide. Molecular hybridization is a well-established tool for developing multifunctional compounds to tackle drug resistance. Inspired by the antibacterial profiles of isatin and thymol, along with the efficiency of a triazole linker in molecular hybridization, herein, we report the design, synthesis and antibacterial activity of a novel series of triazole tethered thymol-isatin hybrids. Most of the hybrids exhibited a broad-spectrum antibacterial efficacy against standard human pathogenic as well as clinically isolated multidrug-resistant bacterial strains listed in the WHO's 'priority pathogen' list and also in the ESKAPE group. Among them, hybrid compound AS8 was the most effective against methicillin-resistant
(MIC = 1.9 μM and MBC = 3.9 μM), exhibiting biofilm inhibitory potential. AS8 exhibited dehydrosqualene synthase (CrtM) inhibitory potential in MRSA and decreased the production of virulence factor staphyloxanthin, which is one of the key mechanisms of its anti-MRSA efficacy, which was further supported by molecular docking and simulation studies. Moreover, AS8 was found to be non-toxic and showed a potent
antibacterial efficacy (90% survival at 10 mg kg
) as well as a modulated immune response in the larva-based (
) model of systemic infections. Overall findings confirmed that AS8 can be a promising candidate or take the lead in the treatment and further drug development against drug-resistant infectious diseases, especially against MRSA infections.
Non melanoma skin cancers are common neoplasms worldwide. In India, squamous cell carcinoma (SCC), is the most prevalent skin disorder and its incidence rises quickly with cumulative exposure to sun. ...Numerous techniques are available for SCC but reversion and metastasis are common concern that needs effective and safe strategies for its control. With this in view, the study was planned to investigate the activity of Bakuchiol (Bak), traditionally used in various countries for curing skin ailments but its mechanism of action is unexplored. In our study, we explored anti-proliferative, pro-apoptotic and anti-inflammatory potential of Bak toward human squamous carcinoma (A431) cell line.
The pure compound Bak was isolated from the plant Psoralea corylifolia and characterized using NMR, HRMS and FTIR. To explore their bioefficacy, different in vitro assays were performed against A431 cell line. To have molecular insights, RT-qPCR investigation was done to analyzed the expression level of inflammatory markers (TLR 9, IFN β, IL 23, JAK 3 and STAT 3).
The results showed the growth inhibitory effect on A431 cells after Bak treatment in dose-dependent way. To understand mode of cell death, cells were initially analyzed under phase-contrast, fluorescence and scanning electron microscope that showed characteristics of apoptosis. Furthermore, cell cycle studies with a flow cytometer were carried out which showed increased level of ROS, reduced MMP and cells arrested at G0/G1 phase in Bak treated cells further strengthening the induction of apoptosis. Moreover, RT-qPCR analysis indicated the downregulation of inflammatory markers in Bak-treated A431 cells that further confirmed its therapeutic role. The molecular docking study also confirmed that Bak has perfect scaffold that can complete the pharmacophoric need for JAK3 kinase inhibition.
A critical analysis of results points towards the role of Bak in ameliorating inflammatory markers along with apoptosis induction in A431 cells by regulating the expression level of variable markers.
•Design and synthesis of novel Isatin-benzotriazole hybrids.•Evaluation against five pathogenic Candida strains.•Most potent against fluconazole resistant Candida albicans.•Possess antibiofilm ...efficacy against Candida albicans.•Target sterol 14α-demethylase enzyme (CYP51) and inhibit ergosterol synthesis in Candida albicans.•Molecular modelling studies with 14α-demethylase enzyme (CYP51) of Candida albicans.
A novel series of triazole tethered isatin-benzotriazole hybrids has been designed as potential antifungal agents against Candida strains. Hybrid molecules were synthesised via click chemistry approach and characterized by NMR and Mass spectroscopic techniques. Among the synthesized hybrids, AS14 showed most potent activity against fluconazole resistant Candida albicans with minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) values of 3.9 and 7.8 µM respectively. Structure-activity relationship studies revealed that fluoro (F) substitution on 5th position of isatin nucleus and four carbon distance between isatin and triazole moiety is most tolerable for inhibitory potential of the structure against Candida albicans. AS14 was also capable to inhibit biofilm formation and ergosterol synthesis in Candida albicans. Molecular docking studies revealed the favourable binding pattern of AS14 with sterol 14α-demethylase enzyme (CYP51) of Candida albicans. Furthermore, molecular dynamic studies suggested the stability of enzyme-hybrid complex. Overall study suggested that hybrid AS14 can act as an effective hit lead for further development of potent and safer antifungal agents for tackling Candida infections.
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Keeping in view the inhibitory potential of monoterpenes thymol and carvacrol as well as coumarin nucleus against α-glucosidase, novel series of thymol/carvacrol-coumarin hybrids was designed, ...synthesized and evaluated for α-glucosidase inhibitory potential. Among the series of hybrid molecules, AS14 with IC50 value of 4.32 ± 0.11 μM was selective α-glucosidase inhibitor over α-amylase (IC50 = 37.36 ± 0.84 μM). AS14 was non-toxic toward mouse normal fibroblast cells (L929: IC50 > 100 μM). Molecular docking and dynamic simulation studies confirmed desired interactions of AS14 with α-glucosidase responsible for the inhibition of its catalysis capabilities. Acute oral toxicity study confirmed AS14 as safer molecule for in vivo pharmacological investigations with LD50 value of 300 mg/kg. AS14 also showed acute hypoglycaemic effects reduction in blood glucose levels at 1 h of administration in maltose loading test (at 10 and 20 mg/kg by 62.65 % and 70.12 %) and sucrose loading test (at 10 and 20 mg/kg by 59.65 % and 60.23 %), respectively as well as long term (28 days) fasting blood glucose reduction (At day 28: 10 mg/kg = 54.69 % and 20 mg/kg = 62.23 % reduction in fasting blood glucose levels) capabilities in streptozotocin induced diabetic rats. Overall study represents, AS14 as potential α-glucosidase inhibitor with adequate efficacy and safety profile and act as an effective hit lead for the further development of potent and safer α-glucosidase inhibitors for the management of postprandial hyperglycemia in diabetic patients.
Chronic kidney disease (CKD) affects a huge portion of the world’s population and frequently leads to cardiovascular diseases (CVDs). It might be because of common risk factors between chronic kidney ...disease and cardiovascular diseases. Renal dysfunction caused by chronic kidney disease creates oxidative stress which in turn leads to cardiovascular diseases. Oxidative stress causes endothelial dysfunction and inflammation in heart which results in atherosclerosis. It ends in clogging of veins and arteries that causes cardiac stroke and myocardial infarction. To develop an innovative therapeutic approach and new drugs to treat these diseases, it is important to understand the pathophysiological mechanism behind the CKD and CVDs and their interrelationship. Natural phytoconstituents of plants such as polyphenolic compounds are well known for their medicinal value. Polyphenols are plant secondary metabolites with immense antioxidant properties, which can protect from free radical damage. Nowadays, polyphenols are generating a lot of buzz in the scientific community because of their potential health benefits especially in the case of heart and kidney diseases. This review provides a detailed account of the pathophysiological link between CKD and CVDs and the pharmacological potential of polyphenols and their nanoformulations in promoting cardiovascular and renal health.
Bacterial resistance toward available therapeutic agents has become a nightmare for the healthcare system, causing significant mortality as well as prolonged hospitalization, thereby needing the ...urgent attention of research groups working on antimicrobial drug development worldwide. Molecular hybridization is a well-established tool for developing multifunctional compounds to tackle drug resistance. Inspired by the antibacterial profiles of isatin and thymol, along with the efficiency of a triazole linker in molecular hybridization, herein, we report the design, synthesis and antibacterial activity of a novel series of triazole tethered thymol-isatin hybrids. Most of the hybrids exhibited a broad-spectrum antibacterial efficacy against standard human pathogenic as well as clinically isolated multidrug-resistant bacterial strains listed in the WHO's 'priority pathogen' list and also in the ESKAPE group. Among them, hybrid compound
AS8
was the most effective against methicillin-resistant
Staphylococcus aureus
(MIC = 1.9 μM and MBC = 3.9 μM), exhibiting biofilm inhibitory potential.
AS8
exhibited dehydrosqualene synthase (CrtM) inhibitory potential in MRSA and decreased the production of virulence factor staphyloxanthin, which is one of the key mechanisms of its anti-MRSA efficacy, which was further supported by molecular docking and simulation studies. Moreover,
AS8
was found to be non-toxic and showed a potent
in vivo
antibacterial efficacy (90% survival at 10 mg kg
−1
) as well as a modulated immune response in the larva-based (
Galleria mellonella
) model of systemic infections. Overall findings confirmed that
AS8
can be a promising candidate or take the lead in the treatment and further drug development against drug-resistant infectious diseases, especially against MRSA infections.
Triazole-tethered isatin-thymol hybrids are developed for targeting multidrug-resistant bacterial strains with efficacy against MRSA acting
via
CrtM inhibition. The most active hybrid showed bactericidal and antibiofilm efficacy against MRSA and was capable of rescuing larvae from
in vivo
infection.
