Synthesis of a tetralone derivative of ampicillin to control ampicillin-resistant Staphylococcusaureus.

Due to the rapid emergence of antibiotic resistant new bacterial strains and new infections, there is an urgent need for novel or newly modified and efficient alternatives of treatment. However, conventional antibiotics are still used in therapeutic settings but their efficacy is uncertain due to the rapid evolution of drug resistance. In the present study, we have synthesized a new derivative of conventional antibiotic ampicillin using SN2-type substitution reaction. NMR and mass analysis of the newly synthesized derivative of ampicillin confirmed it as ampicillin-bromo-methoxy-tetralone (ABMT). Importantly, ABMT is revealed to have efficient activity against Staphylococcus aureus (S. aureus) with a MIC value of 32 µg ml-1 while ampicillin was not effective, even at 64 µg ml-1 of concentration. Electron microscopy results confirmed the membrane-specific killing of S. aureus at 1 h of treatment. Additionally, molecular docking analysis revealed a strong binding affinity of ABMT with ß-lactamase via the formation of a closed compact bridge. Our findings, avail a new derivative of ampicillin that could be a potential alternative to fight ampicillin-resistant bacteria possibly by neutralizing the ß-lactamase action.

Drug-Resistant Epithelial Ovarian Cancer: Current and Future Perspectives.

Epithelial ovarian cancer (EOC) is a complex disease with diverse histological subtypes, which, based on the aggressiveness and course of disease progression, have recently been broadly grouped into type I (low-grade serous, endometrioid, clear cell, and mucinous) and type II (high-grade serous, high-grade endometrioid, and undifferentiated carcinomas) categories. Despite substantial differences in pathogenesis, genetics, prognosis, and treatment response, clinical diagnosis and management of EOC remain similar across the subtypes. Debulking surgery combined with platinum-taxol-based chemotherapy serves as the initial treatment for High Grade Serous Ovarian Carcinoma (HGSOC), the most prevalent one, and for other subtypes, but most patients exhibit intrinsic or acquired resistance and recur in short duration. Targeted therapies, such as anti-angiogenics (e.g., bevacizumab) and PARP inhibitors (for BRCA-mutated cancers), offer some success, but therapy resistance, through various mechanisms, poses a significant challenge. This comprehensive chapter delves into emerging strategies to address these challenges, highlighting factors like aberrant miRNAs, metabolism, apoptosis evasion, cancer stem cells, and autophagy, which play pivotal roles in mediating resistance and disease relapse in EOC. Beyond standard treatments, the focus of this study extends to alternate targeted agents, including immunotherapies like checkpoint inhibitors, CAR T cells, and vaccines, as well as inhibitors targeting key oncogenic pathways in EOC. Additionally, this chapter covers disease classification, diagnosis, resistance pathways, standard treatments, and clinical data on various emerging approaches, and advocates for a nuanced and personalized approach tailored to individual subtypes and resistance mechanisms, aiming to enhance therapeutic outcomes across the spectrum of EOC subtypes.

The PCOS-NAFLD Multidisease Phenotype Occurred in Medaka Fish Four Generations after the Removal of Bisphenol A Exposure.

As a heterogeneous reproductive disorder, polycystic ovary syndrome (PCOS) can be caused by genetic, diet, and environmental factors. Bisphenol A (BPA) can induce PCOS and nonalcoholic fatty liver disease (NAFLD) due to direct exposure; however, whether these phenotypes persist in future unexposed generations is not currently understood. In a previous study, we observed that transgenerational NAFLD persisted in female medaka for five generations (F4) after exposure to an environmentally relevant concentration (10 µg/L) of BPA. Here, we demonstrate PCOS in the same F4 generation female medaka that developed NAFLD. The ovaries contained immature follicles, restricted follicular progression, and degenerated follicles, which are characteristics of PCOS. Untargeted metabolomic analysis revealed 17 biomarkers in the ovary of BPA lineage fish, whereas transcriptomic analysis revealed 292 genes abnormally expressed, which were similar to human patients with PCOS. Metabolomic-transcriptomic joint pathway analysis revealed activation of the cancerous pathway, arginine-proline metabolism, insulin signaling, AMPK, and HOTAIR regulatory pathways, as well as upstream regulators esr1 and tgf signaling in the ovary. The present results suggest that ancestral BPA exposure can lead to PCOS phenotypes in the subsequent unexposed generations and warrant further investigations into potential health risks in future generations caused by initial exposure to EDCs.

The Power of Kinetic Inertness in Improving Platinum Anticancer Therapy by Circumventing Resistance and Ameliorating Nephrotoxicity.

Even in the modern era of precision medicine and immunotherapy, chemotherapy with platinum (Pt) drugs remains among the most commonly prescribed medications against a variety of cancers. Unfortunately, the broad applicability of these blockbuster Pt drugs is severely limited by intrinsic and/or acquired resistance, and high systemic toxicity. Considering the strong interconnection between kinetic lability and undesired shortcomings of clinical Pt drugs, we rationally designed kinetically inert organometallic Pt based anticancer agents with a novel mechanism of action. Using a combination of in vitro and in vivo assays, we demonstrated that the development of a remarkably efficacious but kinetically inert Pt anticancer agent is feasible. Along with exerting promising antitumor efficacy in Pt-sensitive as well as Pt-resistant tumors in vivo, our best candidate has the ability to mitigate the nephrotoxicity issue associated with cisplatin. In addition to demonstrating, for the first time, the power of kinetic inertness in improving the therapeutic benefits of Pt based anticancer therapy, we describe the detailed mechanism of action of our best kinetically inert antitumor agent. This study will certainly pave the way for designing the next generation of anticancer drugs for effective treatment of various cancers.

Sensory evaluation of microwave-ultrasound treated bottle gourd juice using hybrid features of fuzzy logic and proportional odd modelling approach.

In the present investigation, sensory evaluation of bottle gourd juice (BGJ) samples, obtained from microwave-ultrasound based combined treatment was performed. The raw (sample-1) and conventionally treated (sample-2) alongside microwave-ultrasound treated (sample-3) were considered for the assessment of sensory evaluation. An innovative approach of hybrid fuzzy logic and proportional odd modelling (FL-POM) was implemented for the analysis of the sensory scores. The similarity values for the juice samples and their quality attributes were resolved from the results obtained by fuzzy logic. These values were considered as input for hybridization with the POM approach. The assessed coefficients obtained from the results of POM were considered for the ranking of the samples and quality traits. The ranking of the BGJ samples was observed in the order of sample-1 > sample-3 > sample-2, and their related quality attributes ranked in the order color > taste > aroma > mouth feel. The microwave-ultrasound treated BGJ evinced as the best sample in comparison to the raw one.

Multinuclear PtII Complexes: Why Three is Better Than Two to Enhance Photophysical Properties.

The self-assembly of platinum complexes is a well-documented process that leads to interesting changes of the photophysical and electrochemical behavior as well as to a change in reactivity of the complexes. However, it is still not clear how many metal units must interact in order to achieve the desired properties of a large assembly. This work aimed to clarify the role of the number of interacting PtII units leading to an enhancement of the spectroscopic properties and how to address inter- versus intramolecular processes. Therefore, a series of neutral multinuclear PtII complexes were synthesized and characterized, and their photophysical properties at different concentration were studied. Going from the monomer to dimers, the growth of a new emission band and the enhancement of the emission properties were observed. Upon increasing the platinum units up to three, the monomeric blue emission could not be detected anymore and a concentration independent bright-yellow/orange emission, due to the establishment of intramolecular metallophilic interactions, was observed.

Optimized microwave-assisted extraction of bioflavonoids from Albizia myriophylla bark using response surface methodology.

Bioflavonoids are of great interest due to their health-benefitting properties and possible protection against certain types of diseases. A microwave-assisted extraction (MAE) method was investigated for maximum retention of total bioflavonoids from Albizia myriophylla bark (AMB). Response surface methodology (RSM) using central composite design were employed for obtaining the best possible combination of MAE process parameters including microwave power (400-900 W), liquid/solid ratio (20-40 ml/g), extraction time (20-40 min) and ethanol concentration (60-100%). Optimum conditions of extraction under which predicted maximum bioflavonoids yield of 152.74 mg QE/g DW and antioxidant activity of 75.33% in close proximity with the experimental values were: microwave power 728 W, liquid/solid ratio 24.70 ml/g, extraction time 39.86 min and ethanol concentration 70.36%. Satisfactory statistical parameters (R2), ANOVA for the model and lack-of-fit testing provided an adequate mathematical description of the MAE of bioflavonoids with high antioxidant activity. Therefore, MAE of AMB using RSM could be termed as a time-saving and an efficient method resulting to high yield with increased antioxidant activity. Also, HPLC analysis of AMB revealed the presence of bioflavonoids viz., naringin, quercetin and apigenin; which may be further extensively studied for use as therapeutics against various health issues.

Ligand-Regulated Uptake of Dipolar-Aromatic Guests by Hydrophobically Assembled Suprasphere Hosts.

The selective uptake of guests by capsules, cages, and containers, and porous solid-state materials such as zeolites and metal-organic frameworks (MOFs), is generally controlled by pore size and by the dimensions and chemical properties of interior host domains. For soluble and solid-state structures, however, few options are available for modifying their outer pores to impart chemoselectivity to the uptake of similarly sized guests. We now show that by using alkane-coated gold cores as structural building units (SBUs) for the hydrophobic self-assembly of water-soluble suprasphere hosts, ligand exchange can be used to tailor the chemical properties at the pores that provide access to their interiors. For polar polyethylene glycol functionalized ligands, occupancies after equal times increase linearly with the dipole moments of chloro-, nitro- dichloro-, and dinitro- (o-, m-, and p-) benzene guests. Selectivity is reversed, however, upon incorporation of hydrophobic ligands. The findings demonstrate how self-assembled gold-core SBUs, with replaceable ligands, inherently provide for rationally introducing finely tuned and quantitatively predictable chemoselectivity to host-guest chemistry in water.

Alcohols as Latent Hydrophobes: Entropically Driven Uptake of 1,2-Diol Functionalized Ligands by a Porous Capsule in Water.

Alcohols, with hydroxyl groups compositionally identical to water itself, are consummate hydrophiles, whose high solubilities preclude spontaneous self-assembly in water. Nevertheless, the solute-solvent interactions associated with their highly favorable solvation enthalpies impose substantial entropic costs, similar in magnitude to those that drive the hydrophobic assembly of alkanes. We now show that under nanoconfined conditions this normally dormant "hydrophobicity" can emerge as the driving force for alcohol encapsulation. Using a porous molecular capsule, the displacement of endohedrally coordinated formate ligands (HCO2-) by 1,2-hydroxyl-functionalized l-glycerate (l-gly, l-HOCH2(HO)CHCO2-) was investigated by van't Hoff analysis of variable-temperature 1H NMR in D2O. At pD 5.8, l-gly uptake is enthalpically inhibited. Upon attenuation of this unfavorable change in enthalpy by cosequestration of protons within the alcoholic environment provided by encapsulated diol-functionalized ligands, - TΔ S° dominates over Δ H°, spontaneously filling the capsule to its host capacity of 24 l-gly ligands via an entropically driven hydrophobic response.

Monitoring Metallo-Macromolecular Assembly Equilibria by Ion Mobility-Mass Spectrometry.

Ion mobility-mass spectrometry (IM-MS) allows the separation of isomeric and isobaric species on the basis of their size, shape, and charge. The fast separation timescale (ms) and high sensitivity of these measurements make IM-MS an ideally suitable method for monitoring changes in macromolecular structure, such as those occurring in interconverting terpyridine-based metallosupramolecular self-assemblies. IM-MS is used to verify the elemental composition (size) and architecture (shape) of the self-assembled products. Additionally, this article demonstrates its applicability to the elucidation of concentration-driven association-dissociation (fusion-fission) equilibria between isobaric structures. IM-MS enables both quantitative separation and identification of the interconverting complexes as well as derivation of the corresponding equilibrium constants (i.e., thermodynamic information) from extracted IM-MS abundance data.

Terpyridine-based metallosupramolecular constructs: tailored monomers to precise 2D-motifs and 3D-metallocages.

This overview represents a comprehensive summary of the recent developments in the growing field of terpyridine-based, discrete metallosupramolecular architectures. The N-heteroaromatic ligand [2,2':6',2'']terpyridine (tpy) presents a convergent N,N',N''-chelating donor set and has the ability to bind diverse metal ions to form stable pseudo-octahedral tpy-M2+-tpy bonds. Use of tpy-M2+-tpy connectivity for the edges and directed organic vertices has opened the door to diverse, dynamic, utilitarian macromolecular materials. New strategies have been employed to synthesize a range of 2D- and 3D-fractals as well as novel macrocyclic constructs by employing new designer strategies, such as: triangle-based frameworks, hexagonal fractal designs, flexible polyterpyridine linkers, and noncovalent interactions for spontaneous quantitative self-assembly. Numerous examples of heteroleptic self-assembly have been described along with the synthesis of heterometallic conjugates using step-wise protocols. Utilizing multiplanar, directed spacer units in the polyterpyridine vertices, new 3D-polyhedra were obtained facilitating the assembly of hybrid fractal-dendritic materials. These constructs are shown to undergo tunable conformational transformations by responding to specific stimuli such as concentration, temperature, and counter ions. The increasing ability to exploit hierarchical self-assembly of complex, higher order supramolecular nanomaterials is discussed.

Biofilm development of Bacillus thuringiensis on MWCNT buckypaper: Adsorption-synergic biodegradation of phenanthrene.

Adsorption-synergic biodegradation of a model PAH (phenanthrene, Phe) on MWCNT buckypaper surface with a potential PAH biodegrading bacterial strain Bacillus thuringiensis AT.ISM.11 has been studied in aqueous medium. Adsorption of Phe on buckypaper follows Dubinin-Ashtakhov model (R2 = 0.9895). MWCNT generally exerts toxicity to microbes but adsorbed layer of Phe prevents the direct contact between MWCNT and bacterial cell wall. FESEM study suggests that formation of biofilms occurred on buckypaper. Lower layer cells are disrupted and flattened as they are in direct contact with MWCNT but the upper layer cells of the developed biofilm are fully intact and functional. Force-distance curves of Bacillus thuringiensis AT.ISM.11 with buckypaper indicates adhesion forces varied from -10.3 to -15.6 nN with increasing contact time, which supports the phenomenon of biofilm formation. AFM surface statistical data of buckypaper suggests increase in bacterial cell count increases the Rms roughness (95.7242-632.565) while adhering to the buckypaper surface to form biofilm. We observed an enhanced Phe biodegradation of 93.81% from that of the 65.71% in 15 days' study period, using buckypaper as a bio-carrier or a matrix for the microbial growth. GC-MS study identified phthalic acid ester as metabolite, which is the evidence of protocatechuate pathway degradation of Phe. Current study enlightens the interaction between hydrocarbons and microbes in presence of MWCNT buckypaper matrix in aqueous system for the first time. An enhancement in biodegradation of Phe by 28.10% has also been reported which can be a basis for CNT aided enhanced biodegradation studies in future.

Terpyridine-Based, Flexible Tripods: From a Highly Symmetric Nanosphere to Temperature-Dependent, Irreversible, 3D Isomeric Macromolecular Nanocages.

A three-dimensional, highly symmetric sphere-like nanocage was synthesized using a terpyridine (tpy)-based, flexible tris-dentate ligand and characterized by single crystal X-ray analysis. To introduce more rigidity, one of the tpy units of the tris-dentate ligand was preblocked by stable connectivity to form the corresponding Ru2+-dimer. The complexation between Ru2+-dimer and Fe2+ demonstrates an unexpected temperature-dependent assembly between two irreversible isomeric 3D nanocages. Investigation of the coordination process and structural configurations of the metal-ligand framework, affected by the introduction of rigidity and in the presence of external stimuli (temperature), is reported.

Polyamide-Polyamine Cryptand as Dicarboxylate Receptor: Dianion Binding Studies in the Solid State, in Solution, and in the Gas Phase.

Polyamide-polyamine hybrid macrobicycle L is explored with respect to its ability to bind α,ω-dicarboxylate anions. Potentiometric studies of protonated L with the series of dianions from succinate (suc2-) through glutarate (glu2-), α-ketoglutarate (kglu2-), adipate (adi2-), pimelate (pim2-), suberate (sub2-), to azelate (aze2-) have shown adipate preference with association constant value of K = 4900 M-1 in a H2O/DMSO (50:50 v/v) binary solvent mixture. The binding constant increases from glu2- to adi2- and then continuously decreases with the length of the anion chain. Further, potentiometric studies suggest that hydrogen bonding between the guest anions and the amide/ammonium protons of the receptor also contributes to the stability of the associations along with electrostatic interactions. Negative-mode electrospray ionization of aqueous solutions of host-guest complexes shows clear evidence for the selective formation of 1:1 complexes. Single-crystal X-ray structures of complexes of the receptor with glutaric acid, α-ketoglutaric acid, adipic acid, pimelic acid, suberic acid, and azelaic acid assist to understand the observed binding preferences. The solid-state structures reveal a size/shape complementarity between the host and the dicarboxylate anions, which is nicely reflected in the solution state binding studies.

Bis-Heteroleptic Ruthenium(II) Complex of Pendant Urea Functionalized Pyridyl Triazole and Phenathroline for Recognition, Sensing, and Extraction of Oxyanions.

A new bis-heteroleptic RuII complex based ditopic receptor, 1[PF6]2, having an anion binding triazole -CH unit and appended 4-fluorophenyl urea arm has been developed. 1H NMR and isothermal titration calorimetry (ITC) experiments showed binding of 1[PF6]2 toward oxyanions such as phosphates (e.g., H2PO4- and HP2O73-) and carboxylates (e.g., CH3CO2- and C6H5CO2-) anions selectively. 1H NMR studies showed that highly basic phosphate anions such as HP2O73-/H2PO4- are bound by both -CH and -NH units of complex 1[PF6]2. However, comparatively less basic CH3CO2-, C6H5CO2- anions interacted with the urea -NH protons only. Thermodynamic parameters obtained from ITC experiments suggested that binding of all the interacting anions with complex 1[PF6]2 are highly enthalpy and entropy driven processes. Importantly, complex 1[PF6]2 showed extraction of H2PO4-, CH3CO2-, and C6H5CO2- anions from aqueous solution via liquid-liquid extraction with efficiencies of 28%, 74%, and 80%, respectively. The influential role of the urea moiety in the course of extraction is demonstrated by comparison with a model complex, 2[PF6]2. Additionally, complex 1[PF6]2 is capable of selective sensing of phosphate anions among all investigated anions.

Quantification of hydrogen peroxide in plant tissues using Amplex Red.

Reactive oxygen species (ROS) are by-products of photosynthesis and respiration in plant tissues. Abiotic and biotic stressors also induce the production and temporary accumulation of ROS in plants, including hydrogen peroxide (H2O2), whereby they can act as secondary messengers/chemical mediators in plant defense signaling and lead to programmed cell death. H2O2 acts as a hub for critical information flow in plants. Despite such key roles in fundamental cellular processes, reliable determination of H2O2 levels in plant tissues is hard to achieve. We optimized an Amplex Red-based quantitation method for H2O2 estimation from plant tissue lysate. The standard limit of detection and quantitation was determined as 6 and 18picomol respectively. In this study we also quantified constitutive and/or induced levels of H2O2 in three model plants, Pinus nigra (Austrian pine), Oryza sativa (rice), and Arabidopsis thaliana. Overall, assay sensitivity was in the nmolg-1 FW range. Commonly used additives for H2O2 extraction such as activated charcoal, ammonium sulfate, perchloric acid, polyvinylpolypyrrolidone, and trichloroacetic acid either degraded H2O2 directly or interfered with the Amplex Red assay. Finally, We measured stability of Amplex Red working solution over one month of storage at -80°C and found it to be significantly stable over time. With appropriate modifications, this optimized method should be applicable to any plant tissue.

Comprehensive profiling of functional attributes, virulence potential and evolutionary dynamics in mycobacterial secretomes.

Mycobacterium is an interesting genus which not only includes intimidating pathogens, associated with severe devastations globally, but also comprises of non-pathogenic eco-friendly members that detoxify environmental pollutants. Secretory proteins of the mycobacterial communities are essential components which are firmly believed to facilitate proper cross-talk and apt communication with host cellular surroundings and environmental niche. Secretory elements also play vital roles in mycobacterial pathogenesis. In the present endeavor, an extensive profiling of mycobacterial secretomes, considering both pathogenic and non-pathogenic members, has been executed. Thorough analysis on amino acid composition and functional behavior of the mycobacterial secretory proteins has also been performed. In-depth scrutiny of biosynthetic cost of the secretory proteins with respect to the non-secretory ones indicated that the genus Mycobacterium strictly follows the policy of cost-minimization among the sets of imperative secretory proteins. Comprehensive assessment of potential virulence among the key secretory components signified that the pathogenic mycobacterial members possess a larger share of potentially virulent secretory elements in comparison to their non-pathogenic counterparts. Present analysis also revealed contrasted evolutionary features of the secretomes wherein secretory proteins were found to evolve faster than non-secretory proteins in mycobacterial pathogens but not in the concerned non-pathogens. Outcomes of present investigation promise to provide novel insights into the enigma of mycobacterial pathogenesis, bioremediation and adaptation in diverse niche and aid further scientific investigations associated with concerned research area.

Polyoxometalate-Engineered Building Blocks with Gold Cores for the Self-Assembly of Responsive Water-Soluble Nanostructures.

The controlled assembly of gold nanoparticles (AuNPs) with the size of quantum dots into predictable structures is extremely challenging as it requires the quantitatively and topologically precise placement of anisotropic domains on their small, approximately spherical surfaces. We herein address this problem by using polyoxometalate leaving groups to transform 2 nm diameter gold cores into reactive building blocks with hydrophilic and hydrophobic surface domains whose relative sizes can be precisely tuned to give dimers, clusters, and larger micelle-like organizations. Using cryo-TEM imaging and 1 H DOSY NMR spectroscopy, we then provide an unprecedented "solution-state" picture of how the micelle-like structures respond to hydrophobic guests by encapsulating them within 250 nm diameter vesicles whose walls are comprised of amphiphilic AuNP membranes. These findings provide a versatile new option for transforming very small AuNPs into precisely tailored building blocks for the rational design of functional water-soluble assemblies.

Pyrazine motif containing hexagonal macrocycles: synthesis, characterization, and host-guest chemistry with nitro aromatics.

The synthesis and characterization of cationic two-dimensional metallamacrocycles having a hexagonal shape and cavity are described. Both macrocycles utilize a pyrazine motif containing an organometallic acceptor tecton with platinum(II) centers along with different donor ligands. While one macrocycle is a relatively larger [6 + 6], the other is a relatively smaller [2 + 2] polygon. A unique feature of the smaller ensemble is that it is an irregular polygon in which all six edges are not of equal length. Molecular modeling of these macrocycles confirmed the presence of hexagonal cavities. The ability of these π-electron rich macrocycles to act as potential hosts for relatively electron deficient nitroaromatics (DNT = 2,4-dinitrotoluene and PA = picric acid) has been studied using isothermal titration calorimetry (ITC) as a tool. Molecular dynamics simulation studies were subsequently performed to gain critical insight into the binding interactions between the nitroaromatic guest molecules (PA/DNT) and the ionic macrocycles reported herein.