Potential Biological Activity Research Articles

DNA and hemoglobin binding activities: Investigation of coumarin-thiosemicarbazone hybrids

Coumarin and coumarin-thiosemicarbazone hybrids were synthesized and characterized by various techniques such as FT-IR, 1H NMR, 13C NMR, MALDI-TOF-MS spectroscopy, and single crystal X-Ray diffractometer (XRD). The photochemical and photophysical properties of the compounds, such as solvatochromism, solubility, and chemical reactivity, were analyzed using UV–vis spectroscopy in different solvents. Due to the potential biological activities of the synthesized compounds, their binding affinity and mechanisms with calf thymus DNA (ct-DNA) and bovine hemoglobin (BHb) were determined using several useful spectrophotometric and theoretical approaches such as UV–vis absorption and fluorescence spectroscopy, molecular docking, and density functional theory (DFT). The experimental results showed that the compounds exhibited strong binding interactions with DNA and BHb. Additionally, the compounds demonstrated predominantly binding modes, such as intercalation and groove binding with DNA and π–π stacking interactions with BHb.To better understand the thermodynamics of these interactions, quenching constants, binding constants, and Gibbs free energy changes (ΔG°) were calculated. Molecular docking and DFT results supported the experimental data regarding the binding affinity and mechanisms of the compounds to DNA and BHb. Overall, this comprehensive study on coumarin and coumarin-thiosemicarbazone hybrids provides valuable insights into their interaction mechanisms with critical biomolecules, highlighting their potential in therapeutic applications as multifunctional agents.

A Brief Review-an Update on 1,3,4-Oxadiazole

Abstract: The 1,3,4-oxadiazole nucleus is a biologically necessary scaffold that exhibits a wide range of pharmacological activities. The broad and strong activity of 1,3,4-oxadiazole and their derivatives has established them as significant pharmacological scaffolds, particularly in the treatment of cancer disease. A number of di-, tri-, aromatic, and heterocyclic substituted 1,3,4- oxadiazole derivatives have been reported to possess potent biological activities; these substituted 1,3,4-oxadiazoles had different mechanisms of action and contributed to the development of biologically active drugs. This review is intended to supplement previous reviews by reviewing the literature on the different activities of 1,3,4-oxadiazole derivatives from the last fifteen years. 1,3,4-oxadiazole can be produced in a number of ways and has a wide range of possible pharmacological uses. As a result, scientists have created novel procedures for the production of 1,3,4- oxadiazole derivatives and their use in medicine presently. Anticancer, antibacterial, antiinflammatory, anti-HIV, anti-tubercular, anti-diabetic, antifungal, and other properties are among the activities. In this review, we discussed various research works based on 1,3,4-oxadiazole derivatives synthetic procedure and assessment of different biological activities. Many researchers may find the material on this page helpful, which could lead to the discovery of new medicinal species for society.

Design, synthesis, characterization, theoretical calculations, molecular docking studies, and biological evaluation of new Fe(II) and Cu(II) complexes of 2-acetylpyridine derivative sulfonyl hydrazone Schiff base

Sulfonylhydrazones and their metal complexes are known to have potential biological activity. In this study, new Fe(II) (1) and Cu(II) (2) complexes of the 2-acetylpyridine derivative sulfonyl hydrazone (LH) were prepared. The new metal complexes were characterized by elemental analysis, IR spectroscopy, UV spectroscopy, and magnetic moment measurements. The molecular structure of (2) was elucidated by X-ray diffraction analysis, and the crystal package was obtained in three-dimensional space. To support the intermolecular interactions obtained from the X-ray diffraction results, Hirshfeld surface analysis and two-dimensional fingerprint maps of (2) were generated. The optimized molecular structures, total energies, molecular orbital energy values, molecular electrostatic potential maps, percentage distributions of the atomic orbitals to the molecular orbital energy levels, and global reactivity parameters of LH, 1, and 2 are obtained by using DFT/B3LYP/6–311G(d, p) for LH and DFT/B3LYP/LanL2DZ for 1 and 2 is 1:2. Elemental analysis showed that the stoichiometric metal/ligand ratio for 1 and 2. All data indicate that the ligand coordinates with the metal atoms via pyridine imine /nitrogens and sulfonyl oxygen. The well-diffusion approach was also used to test the antibacterial properties of the ligand and complexes against harmful microbes. The compounds were tested for DNA cleavage using agarose gel electrophoresis. Complex 1 was found to be effective on the plasmid DNA of pBR322. Finally, molecular docking studies of LH, 1, and 2 with A-DNA (PDB ID:3V9D), and B-DNA (PDB ID:1BNA) were presented to compare the experimental and theoretical results.

Anti-Schistosomal activity and ADMET properties of 1,2,5-oxadiazinane-containing compound synthesized by visible-light photoredox catalysis.

The incorporation of saturated nitrogen-containing heterocycle 1,2,5-oxadiazinane into small molecules represents a compelling avenue in drug discovery due to its unexplored behavior within biological systems and incomplete protocols for synthesis. In this study, we present 1,2,5-oxadiazinane, an innovative heterocyclic bioisostere of piperizin-2-one and novel chemotype of the anti-schistosomal drug praziquantel (PZQ), which has been the only clinical drug available for three decades. PZQ is associated with significant drawbacks, including poor solubility, a bitter taste, and low metabolic stability. Therefore, the discovery of a new class of anti-schistosomal agents is imperative. To address this challenge, we introduce a pioneering method for the synthesis of 1,2,5-oxadiazinane derivatives through the cycloaddition of nitrones with N,N,N',N'-tetraalkyldiaminomethane in the presence of an IrIII complex photosensitizer. This transformative reaction offers a streamlined route to various kinds of 1,2,5-oxadiazinanes that is characterized by mild reaction conditions and broad substrate scope. Mechanistic investigations suggest that the photoredox pathway underlies the [3 + 3] photocycloaddition process. Thus, based on bioisosteric replacement, we identified a remarkable molecule as a new chemotype of a potent anti-schistosomal compound that not only exhibits superior solubility, but also retains the potent biological activity inherent to PZQ.

Seasonal Study Chemical Profiles and Bioactivities of Hedychium coronarium J. Koenig Essential Oils: Nematicidal, Insecticidal, Phytotoxic, Antifungal Potentials, and Molecular Docking Insights.

Hedychium coronarium plant has attracted considerable attention from researchers due to its diverse phytochemical composition and potential therapeutic applications. The objective of this study was to evaluate the phytochemical profile and biological attributes of H. coronarium essential oils collected during different seasons in the Kumaun region of Uttarakhand. The essential oils were extracted from the rhizomes using hydrodistillation with a Clevenger-type apparatus yielding between 0.07% to 0.38% (w/w). The major compounds identified by GC-MS analysis exhibited seasonal variations and included 1,8-cineole (26.6-38.5%), coronarin E (11.9-18.8%), α-pinene (5.00-14.9%), α-terpineol (4.2-9.3%), (E)-β-caryophyllene (1.2-9.7%), and linalool (0.4-2.9%). To illustrate the variations in oil composition, visualization techniques such as heat map and PCA were employed. The essential oils demonstrated potential biological activity in all tests conducted. The molecular modeling study indicated that the potential mechanism may be associated with acetylcholinesterase. Consequently, this study contributes to the development of novel natural pesticides.

Potential Bioactivities, Chemical Composition, and Conformation Studies of Exopolysaccharide-Derived Aspergillus sp. Strain GAD7.

This research identified a marine fungal isolate, Aspergillus sp. strain GAD7, which produces an acidic and sulfated extracellular polysaccharide (EPS) with notable anticoagulant and antioxidant properties. Six fungal strains from the Egyptian Mediterranean Sea were screened for EPS production, with Aspergillus sp. strain GAD7 (EPS-AG7) being the most potent, yielding ~5.19 ± 0.017 g/L. EPS-AG7 was characterized using UV-Vis and FTIR analyses, revealing high carbohydrate (87.5%) and sulfate (24%) contents. HPLC and GC-MS analyses determined that EPS-AG7 is a heterogeneous acidic polysaccharide with an average molecular weight (Mw¯) of ~7.34 × 103 Da, composed of mannose, glucose, arabinose, galacturonic acid, galactose, and lyxose in a molar ratio of 6.6:3.9:1.8:1.3:1.1:1.0, linked through α- and β-glycosidic linkages as confirmed by NMR analysis. EPS-AG7 adopted a triple helix-like conformation, as evidenced by UV-Vis (Congo Red experiment) and circular dichroism (CD) studies. This helical arrangement demonstrated stability under various experimental conditions, including concentration, ionic strength, temperature, and lipid interactions. EPS-AG7 exhibited significant anticoagulant activity, doubling blood coagulation time at a concentration of 3.0 mg/mL, and showed significant antioxidant activity, with scavenging activities reaching up to 85.90% and 58.64% in DPPH and ABTS+ assays at 5.0 mg/mL, and EC50 values of 1.40 mg/mL and 3.80 mg/mL, respectively. These findings highlight the potential of EPS-AG7 for therapeutic applications due to its potent biological activities.

Recent Advances in the Therapeutic Potential of Fucoidan: A Comprehensive Review

Fucoidan, a polysaccharide primarily comprised of l-fucose and sulfate groups possesses a unique chemical structure that underpins its notable therapeutic potential. Its remarkable biological functions such as antioxidant, anticarcinogenic, antiviral, anticoagulant, antithrombotic, immunoregulatory, and anti-inflammatory properties have gained substantial recognition in the global food and pharmaceutical industries. This review highlights recent advancements in understanding fucoidan’s potential biological activities that could innovate treatments for oral infections and inflammatory diseases. A systematic search for relevant articles published between January 2000 and July 2024 was conducted across multiple databases, including PubMed, Scopus, Web of Science, and Google Scholar. Manual searches of references listed in the identified publications were conducted to ensure thorough coverage of the subject. The inclusion criteria focused on peer-reviewed articles in English-language, encompassing meta-analysis, randomized clinical trials, cohort studies, case-control studies and in vitro studies. Exclusion criteria comprised abstracts, opinion pieces, review articles not providing original analysis, and studies not directly addressing the therapeutic effects of fucoidan. This rigorous selection process aims to encapsulate the most significant and recent scientific evidence regarding the therapeutic applications of fucoidan. Fucoidans, with their diverse pharmacological properties, hold promising therapeutic potential which could emerge as a novel therapeutic option for treating wide range of diseases. Fucoidans have demonstrated anti-inflammatory properties, which may be beneficial in reducing inflammation related to periodontal diseases and other oral conditions. We anticipate that this review will serve as a foundational guide and inspire continued product development centered on fucoidan. Clinical relevance to interdisciplinary dentistry:  Fucoidan, a polysaccharide rich in fucose holds wide pharmacological effects  Enhancement of oral health outcomes through anti- inflammatory properties  Antimicrobial activity against oral pathogens  Wound healing property may aid in periodontal diseases.

Molecular docking analysis of Salvia sclarea flower extracts evaluated for protein target affinity based on different extraction methods

AbstractThis study evaluates the antioxidant activity and total phenolic, flavonoid, flavonol, and tannin contents of extracts obtained from the flower parts of Salvia sclarea using different extraction methods, such as maceration and rotavapor (RE). The results indicate that the maceration method yields extracts with higher antioxidant activity compared to the rotavapor method (DPPH IC50: 260.70 ± 65.41 mg/mL vs. 345.48 ± 27.91 mg/mL). Additionally, the maceration method produces higher values in terms of total phenolic (26.4 ± 7.78 mg GAE/g extract), flavonoid (10.44 ± 0.21 mg QE/g extract), flavonol (9.20 ± 0.84 mg QE/g extract), and tannin contents (8.36 ± 0.39 mg GAE/g extract), whereas the RE method shows lower values (phenolics: 19.8 ± 3.31 mg GAE/g extract, flavonoids: 10.35 ± 0.35 mg QE/g extract, flavanol's: 5.45 ± 0.01 mg QE/g extract, and tannins: 7.72 ± 0.10 mg GAE/g extract). The gas chromatography–mass spectrometry (GC–MS) analysis of the extracts identified various bioactive compounds. Molecular docking studies revealed that Terpinen‐4‐ol obtained through maceration exhibits a strong binding affinity to a specific protein target, indicating potential biological activity. The predicted pharmacokinetic (ADME (absorption, distribution, metabolism, and excretion)) parameters for Terpinen‐4‐ol suggest favorable absorption and central nervous system (CNS) penetration, while Squalene obtained through maceration shows different pharmacokinetic properties. S. sclarea highlights significant antioxidant potential and provides insight into the bioactive compounds obtained through different extraction methods. To further investigate the potential biological interactions arising from these differences, molecular docking studies were conducted.

One-Pot Synthesis of Dihydrobenzo[a]fluorenes via Cascade C-H Annulation of Thiobenzamide with Alkynes.

We herein disclose a highly efficient one-pot synthetic strategy for dihydrobenzo[a]fluorenes via cascade rhodium(III)-catalyzed ortho-C-H activation/annulation of thiobenzamides with aryl ethynyl ketones and subsequently copper(II)-promoted intramolecular C-H/C-H cross-coupling reactions. Mechanistic investigations suggest that Cu(II) plays two crucial roles by serving as a sulfide scavenger to regenerate the Rh(III) catalyst and promoting the intramolecular C-H/C-H cross-coupling reaction. This protocol greatly streamlines accesses to a variety of appealing tetracyclic benzo[a]fluorene skeletons, which may have potential biological activity and medicinal properties.

Synthesis and characterization of a zinc-triazole coordination complex with potent antimicrobial and anticancer properties

The synthesis, characterization, and biological appraisement of a novel coordination compound [Zn(C4N4H5O)2(H2O)2]Cl have been comprehensively studied. The compound was synthesized using N-(1H-1,2,4-triazol-3-yl) acetamide and ZnCl2·6H2O, yielding a product characterized by FT-IR, elemental analysis, thermogravimetric analysis (TGA), and single crystal X-ray diffraction. FT-IR spectra confirmed the successful coordination of the ligand to the zinc ion, with significant shifts in characteristic absorption bands such as CO (1685 cm⁻¹), CN (1624 cm⁻¹), and NH (3394 cm⁻¹). Single crystal X-ray diffraction analyses revealed that the complex crystallized in the monoclinic system with space group P21/c and forms six-membered chelate rings. The unit cell parameters were a = 6.0595(3) Å, b = 14.2956(7) Å, c = 9.4762(4) Å, and β = 93.275(4)°. Thermal analysis showed that the complex undergoes stepwise decomposition with significant mass losses at various temperature intervals, including an overall mass loss of 71.09 % between 200 °C and 885 °C. Molecular docking studies indicated strong interactions between the [Zn(C4N4H5O)2(H2O)2]Cl complex and the 6QF6 cancer-related protein antigen A4, with low binding energy values (-9.32 to -8.44 kcal/mol) suggesting high binding affinity and potential biological activity. In vitro antimicrobial screening against several pathogenic microorganisms, viz. both gram-positive and gram-negative bacteria, demonstrated that the [Zn(C4N4H5O)2(H2O)2]Cl complex exhibited superior antibacterial activity, with inhibition zone diameters of 15.3 ± 0.47 mm for Bacillus subtilis and 24.17±0.56 mm for Agrobacterium tumefaciens, compared to N-(1H-1,2,4-triazol-3-yl) acetamide alone and some standard antibiotics. These findings highlight the [Zn(C4N4H5O)2(H2O)2]Cl complex as a promising candidate for developing new antimicrobial and anticancer agents, providing a foundation for further research and potential therapeutic applications.

Synthesis, spectroscopic characterization, electronic elucidation, chemical reactivity, topological and molecular docking investigations of cefadroxil sulfoxide

The cefadroxil sulfoxide (CDSO) para-hydroxy derivative, derived from cefadroxil, has enormous significance in pharmaceutical applications. The cefadroxil sulfoxide (CDSO) compound was synthesized and characterized by spectroscopic (FT-IR, FT-Raman, and UV–Visible) assessments. Computational investigations have been carried out concurrently with a B3LYP-6-311++G(d,p) basis set and density functional theory (DFT). The molecular vibrational assignments, chemical reactivity, electronic properties, and optical activities are calculated using gas and different solvent phases. The stable ground state configuration of the given molecular compound is investigated using PES analysis. Furthermore, the chemical behavior of the CDSO was thoroughly investigated for different solvent aspects through HOMO-LUMO, MEP, UV–Visible and electron-hole excitation analyses. The molecular occupancy, virtual occupancy, and overlapping bonding energies are investigated by TDOS, PDOS, and COOP spectrum studies. Fukui function and dual descriptor investigations extend to the chemical reactivity of individual atomic sites. The intra-molecular analysis provided a deeper understanding of the molecular interactions performed by natural bond orbitals (NBO) and non-linear optics (NLO), which provided optical activity for the title compound. Additionally, electron localization function (ELF), localized orbital locator (LOL), and reduced density gradient (RDG) analyses were also accomplished to provide insight into the delocalized orbitals in the header composite. The molecular docking was achieved, and the ligand with 4EVM protein is providing the potential antimicrobial biological activity (binding energy −7.12 kcal/mol) of the CDSO compound.

Deep enzymatic hydrolysis of bee pollen with multiple enzymes: Improves nutrient release and potential biological activity of bee pollen

Bee pollen has gained popularity among consumers due to its rich nutritional value. However, the stiff pollen wall severely limits the absorption and biological efficacy of the nutrients in bee pollen. In this study, deep enzymatic hydrolysis (ultrasonication + cellulase, pectinase, and Protamex™) was used to break the wall and improve the utilization of bee pollen nutrients. This treatment resulted in a 64.40% reduction in particle size and a 139.72% increase in specific surface area. Soluble sugar, total phenols, total flavonoids, and soluble protein increased by 20.14%, 92.78%, 103.21%, and 37.80%, respectively. Proteomics and Metabolomic analysis revealed a significant increase in the content of 1447 peptides and 44 compounds in the bee pollen post-multi-enzyme deep enzymatic hydrolysis compared to the untreated control group. These findings indicate that the application of ultrasonication + three enzymes, as a multi-enzyme composite deep enzyme wall breaking method, can significantly improve the release rate of bee pollen nutrients and generate a multitude of small molecule polypeptides, thereby enhancing their potential bioactivity. This study provides technical support and theoretical reference for deeply processing bee pollen and developing high-value products.

Flurbiprofen clubbed schiff's base derivatives as potent anticancer agents: In Vitro and In Silico approach towards breast cancer

In this work, we are reporting nineteen hydrazone-Schiff base derivatives (2a-2l and 3a-3g), containing flurbiprofen drug nucleus. The synthesized products were structurally elucidated through 1H, 13C-NMR and HR-ESI-MS spectroscopic techniques and finally tested for in vitro anti-cancer activity. Among the synthetic series, 2f, 2g, 3g, 3b, and 2e attributed the higher inhibitory potential against the breast cancer cell line (MDA-MB-231) having IC50 values of 21.0 ± 0.4, 21.8 ± 0.2, 27.1 ± 0.3, 28.8 ± 0.3, and 29.6 ± 0.3 µM respectively. However, the remaining derivatives attributed good to less active. DFT was used to calculate frontier molecular orbital of (2a-h, j-l, and 3a-d) including HOMO which concentrated on the substituents aromatic ring, and LUMO focused over flurbiprofen and hydrazide fragments, that indicate the charge transfer from molecule to biological media. The reactivity indices suggested the most active 2f (IC50 = 21.0 ± 0.4 µM) and 2g (IC50 = 21.8 ± 0.2 µM) showed higher indices reactivity namely σ, χ, and ω than lowest active 2g; this relation inversely for Eg, η, and IP. 2a-l had more electrophilic character and higher acceptance ability for biological targets than compounds (3a-g). The MEP map indicated the electron density distribution of 2a-l was more dispersed than that of 3a-g, indicating potential biological activities and are chemically reactive zone suitable for drug action. The docking study contributed to the analysis of cytotoxicity for investigated compounds.

Marine Bacteriocins: An Evolutionary Gold Mine to Payoff Antibiotic Resistance.

The rapid evolution of drug resistance is one of the greatest health issues of the 21st century. There is an alarming situation to find new therapeutic strategies or candidate drugs to tackle ongoing multi-drug resistance development. The marine environment is one of the prime natural ecosystems on Earth, the majority of which is still unexplored, especially when it comes to the microbes. A wide variety of bioactive compounds have been obtained from a varied range of marine organisms; however, marine bacteria-produced bacteriocins are still undermined. Owing to the distinct environmental stresses that marine bacterial communities encounter, their bioactive compounds frequently undergo distinct adaptations that confer on them a variety of shapes and functions, setting them apart from their terrestrial counterparts. Bacterially produced ribosomally synthesized and posttranslationally modified peptides (RiPPs), known as bacteriocins, are one of the special interests to be considered as an alternative to conventional antibiotics because of their variety in structure and diverse potential biological activities. Additionally, the gut microbiome of marine creatures are a largely unexplored source of new bacteriocins with promising activities. There is a huge possibility of novel bacteriocins from marine bacterial communities that might come out as efficient candidates to fight against antibiotic resistance, especially in light of the growing pressure from antibiotic-resistant diseases and industrial desire for innovative treatments. The present review summarizes known and fully characterized marine bacteriocins, their evolutionary aspects, challenges, and the huge possibilities of unexplored novel bacteriocins from marine bacterial communities present in diverse marine ecosystems.

Genes to specialized metabolites: accumulation of scopoletin, umbelliferone and their glycosides in natural populations of Arabidopsis thaliana

BackgroundScopoletin and umbelliferone belong to coumarins, which are plant specialized metabolites with potent and wide biological activities, the accumulation of which is induced by various environmental stresses. Coumarins have been detected in various plant species, including medicinal plants and the model organism Arabidopsis thaliana. In recent years, key role of coumarins in maintaining iron (Fe) homeostasis in plants has been demonstrated, as well as their significant impact on the rhizosphere microbiome through exudates secreted into the soil environment. Several mechanisms underlying these processes require clarification. Previously, we demonstrated that Arabidopsis is an excellent model for studying genetic variation and molecular basis of coumarin accumulation in plants.ResultsHere, through targeted metabolic profiling and gene expression analysis, the gene-metabolite network of scopoletin and umbelliferone accumulation was examined in more detail in selected Arabidopsis accessions (Col-0, Est-1, Tsu-1) undergoing different culture conditions and characterized by variation in coumarin content. The highest accumulation of coumarins was detected in roots grown in vitro liquid culture. The expression of 10 phenylpropanoid genes (4CL1, 4CL2, 4CL3, CCoAOMT1, C3’H, HCT, F6’H1, F6’H2,CCR1 and CCR2) was assessed by qPCR in three genetic backgrounds, cultured in vitro and in soil, and in two types of tissues (leaves and roots). We not only detected the expected variability in gene expression and coumarin accumulation among Arabidopsis accessions, but also found interesting polymorphisms in the coding sequences of the selected genes through in silico analysis and resequencing.ConclusionsTo the best of our knowledge, this is the first study comparing accumulation of simple coumarins and expression of phenylpropanoid-related genes in Arabidopsis accessions grown in soil and in liquid cultures. The large variations we detected in the content of coumarins and gene expression are genetically determined, but also tissue and culture dependent. It is particularly important considering that growing plants in liquid media is a widely used technology that provides a large amount of root tissue suitable for metabolomics. Research on differential accumulation of coumarins and related gene expression will be useful in future studies aimed at better understanding the physiological role of coumarins in roots and the surrounding environments.

Crystal Structure of the Monocarborane Magnesium(II) Acetylide and Its Use in the Synthesis of α,β-Unsaturated Ketones.

We report the first crystal structure of heteroleptic Grignard reagent 2 based on the carborane endo/exo dianion [CB11H11-12-C≡C]2-. Full characterization reveals a rare coordination pattern and affirms the bimetallic nature. Navigating the reactivity landscape, we unlock the potential of 2 in nucleophilic addition with ketones to afford propargylic alcohols 3, renowned for their synthetic versatility and potential biological activities, and unveil the Meyer-Schuster rearrangement, yielding α,β-unsaturated carbonyl compounds 4. This narrative of synthesis, characterization, and reactivity opens new horizons for carborane chemistry, offering avenues for innovation and facile functionalization of carborane scaffolds.

Novel detoxifier of spironolactone against triptolide-induced hepatotoxicity through inhibition of RPB1 degradation

Ethnopharmacological relevanceTriptolide is a major bioactive and toxic ingredient isolated from the traditional Chinese herb Tripterygium wilfordii (T. wilfordii) Hook F. It exhibits potent antitumor, immunosuppressive, and anti-inflammatory biological activities; however, its clinical application is hindered by severe systemic toxicity. Two preparations of T. wilfordii, including T. wilfordii glycoside tablets and T. wilfordii tablets, containing triptolide, are commonly used in clinical practice. However, their adverse side effects, particularly hepatotoxicity, limit their safe use. Therefore, it is crucial to discover potent and specific detoxification medicines for triptolide. Aim of the studyThis study aimed to investigate the detoxification effects and potential mechanism of action of spironolactone on triptolide-induced hepatotoxicity to provide a potential detoxifying strategy for triptolide, thereby promoting the safe applications of T. wilfordii preparations in clinical settings. Materials and methodsCell viability was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and crystal violet staining. Nuclear fragmentation was visualized using 4′,6-diamidino-2-phenylindole (DAPI) staining, and protein expression was analyzed by Western blotting. The inhibitory effect of spironolactone on triptolide-induced hepatotoxicity was evaluated by examining the effects of spironolactone on serum alanine aminotransferase and aspartate aminotransferase levels, as well as liver pathology in a mouse model of triptolide-induced acute hepatotoxicity. Furthermore, a survival assay was performed to investigate the effects of spironolactone on the survival rate of mice exposed to a lethal dose of triptolide. The effect of spironolactone on triptolide-induced global transcriptional repression was assessed through 5-ethynyl uridine staining. ResultsTriptolide treatment decreased the cell viability, increased the nuclear fragmentation and the cleaved caspase-3 levels in both hepatoma cells and hepatocytes. It also increased the alanine aminotransferase and aspartate aminotransferase levels, induced the hepatocyte swelling and necrosis, and led to seven deaths out of 11 mice. The above effects could be mitigated by pretreatment with spironolactone. Additionally, molecular mechanism exploration unveiled that spironolactone inhibited triptolide-induced DNA-directed RNA polymerase II subunit RPB1 degradation, consequently increased the fluorescence intensity of 5-ethynyl uridine staining for nascent RNA. ConclusionsThis study shows that spironolactone exhibits a potent detoxification role against triptolide hepatotoxicity, through inhibition of RPB1 degradation induced by triptolide and, in turn, retardation of global transcriptional inhibition in affected cells. These findings suggest a potential detoxification strategy for triptolide that may contribute to the safe use of T. wilfordii preparations.

A Combined Computational and Experimental Approach to Studying Tropomyosin Kinase Receptor B Binders for Potential Treatment of Neurodegenerative Diseases.

Tropomyosin kinase receptor B (TrkB) has been explored as a therapeutic target for neurological and psychiatric disorders. However, the development of TrkB agonists was hindered by our poor understanding of the TrkB agonist binding location and affinity (both affect the regulation of disorder types). This motivated us to develop a combined computational and experimental approach to study TrkB binders. First, we developed a docking method to simulate the binding affinity of TrkB and binders identified by our magnetic drug screening platform from Gotu kola extracts. The Fred Docking scores from the docking computation showed strong agreement with the experimental results. Subsequently, using this screening platform, we identified a list of compounds from the NIH clinical collection library and applied the same docking studies. From the Fred Docking scores, we selected two compounds for TrkB activation tests. Interestingly, the ability of the compounds to increase dendritic arborization in hippocampal neurons matched well with the computational results. Finally, we performed a detailed binding analysis of the top candidates and compared them with the best-characterized TrkB agonist, 7,8-dyhydroxyflavon. The screening platform directly identifies TrkB binders, and the computational approach allows for the quick selection of top candidates with potential biological activities based on the docking scores.

Dual-functional emulsifier based nano-emulsion adjuvant effectively enhanced immunogenicity of recombinant respiratory syncytial virus vaccine in mice

Oil-in-water nano-emulsion adjuvant (NEA) has been utilized for many years in the development of subunit or/and recombinant vaccines. Nevertheless, worries have been expressed about the safety and potential biological activities of the emulsifier. Herein, tocopheryl polyethylene glycol 1000 succinate (TPGS), which acts not only as an emulsifier but also as an immunostimulant, was used for the preparation of NEA. Benefiting from the hydrophilic-hydrophobic nature of TPGS, NEA possess a homogeneous structure with an extremely narrow size distribution (approximately 160 nm in diameter, polydispersity index <0.15), and exhibits excellent stability over 6 months under test conditions. When such an NEA was used with a recombinant respiratory syncytial virus (RSV) vaccine, the adjuvanted vaccine induced enhanced humoral and cellular immunity in mice compared to the non-adjuvanted vaccine. This is the initial documented finding of TPGS adjuvanticity in an intramuscularly injected vaccine. Furthermore, the TPGS-based NEA showed elevated adjuvant potency compared to the MF59-like emulsion adjuvant assessed. These results imply the potential of NEA as an alternative adjuvant for developing recombinant vaccines with enhanced immunity.

Synthesis of pyrazole and 1,3,4-oxadiazole derivatives of pharmaceutical potential

Heterocyclic compounds are important molecules that serve as scaffolds or linkers for the core structure of numerous drug substances. In particular, pyrazole and 1,3,4-oxadiazole are compounds of great interest due to their comprehensive biological activities and interesting structural features. Here, we described an efficient and economical synthetic route leading to N-phenyl substituted pyrazole and 1,3,4-oxadiazole derivatives. Retrosynthetic disconnective analysis showed that the N-phenyl substituted pyrazole can be obtained from chalcone, accessible from the respective aldehyde, and acetophenone. The disubstituted 1,3,4-oxadiazole can be constructed from the respective aldehyde, which originates from pyrrole-containing compound, and formyl chloride. Based on our retrosynthetic analysis, N-phenyl substituted pyrazole was obtained by cyclization of the respective chalcone with phenylhydrazine to give pyrazoline which was in turn converted into pyrazole by oxidative aromatization. Potassium carbonate and a catalytic amount of molecular iodine were used to oxidatively cyclize semicarbazones into 1,3,4-oxadiazoles in a transition metal-free process. Novel pyrazole and 1,3,4-oxadiazoles with potential biological activity are investigated as antituberculosis, anticonvulsant, antidiabetic, anticancer, and tyrosinase inhibitory agents.