Stimuli-responsive release of active anionophore from RGD-peptide-linked proanionophore.

Integrin-mediated cellular delivery was attempted to optimize practical applications of hydrophobic ionophores. The potent ionophore preferentially transports H+/Cl- across the lipid bilayers following a symport mechanism. The RGD-peptide-appended tag was stimulated by glutathione to generate the active ionophore, prompting the transport of Cl- under the cellular environment.

Quinoline Thiourea-Based Zinc Ionophores with Antibacterial Activity.

The increasing resistance of bacteria to commercially available antibiotics threatens patient safety in healthcare settings. Perturbation of ion homeostasis has emerged as a potential therapeutic strategy to fight against antibacterial resistance and other channelopathies. This study reports the development of 8-aminoquinoline (QN) derivatives and their transmembrane Zn2+ transport activities. Our findings showed that a potent QN-based Zn2+ transporter exhibits promising antibacterial properties against Gram-positive bacteria with reduced hemolytic activity and cytotoxicity to mammalian cells. Furthermore, this combination showed excellent in vivo efficacy against Staphylococcus aureus. Interestingly, this combination prevented bacterial resistance and restored susceptibility of gentamicin and methicillin-resistant S. aureus to commercially available ß-lactam and other antibiotics that had lost their activity against the drug-resistant bacterial strain. Our findings suggest that the transmembrane transport of Zn2+ by QN derivatives could be a promising strategy to combat bacterial infections and restore the activity of other antibiotics.

Performance of Density Functionals and Semiempirical 3c Methods for Small Gold-Thiolate Clusters.

In light of the recent surge in computational studies of gold thiolate clusters, we present a comparison of popular density functionals (DFAs) and three-part corrected methods (3c-methods) on their performance by taking a data set named as AuSR18 consisting of 18 isomers of Aun(SCH3)m (m ≤ n = 1-3). We have compared the efficiency and accuracy of the DFAs and 3c-methods in geometry optimization with RI-SCS-MP2 as the reference method. Similarly, the performance for accurate and efficient energy evaluation was compared with DLPNO-CCSD(T) as the reference method. The lowest energy structure among the isomers of the largest stoichiometry from our data set, AuSR18, i.e., Au3(SCH3)3, is considered to evaluate the computational time for SCF and gradient evaluations. Alongside this, the numbers of optimization steps to locate the most stable minima of Au3(SCH3)3 are compared to assess the efficiency of the methods. A comparison of relevant bond lengths with the reference geometries was made to estimate the accuracy in geometry optimization. Some methods, such as LC-BLYP, ωB97M-D3BJ, M06-2X, and PBEh-3c, could not locate many of the minima found by most of the other methods; thus, the versatility in locating various minima is also an important criterion in choosing a method for the given project. To determine the accuracy of the methods, we compared the relative energies of the isomers in each stoichiometry and the interaction energy of the gold core with the ligands. The dependence of basis set size and relativistic effects on energies are also compared. The following are some of the highlights. TPSS has shown accuracy, while mPWPW shows comparable speed and accuracy. For the relative energies of the clusters, the hybrid range-separated DFAs are the best option. CAM-B3LYP excels, whereas B3LYP performs poorly. Overall, LC-BLYP is a balanced performer considering both the geometry and relative stability of the structures, but it lacks diversity. The 3c-methods, although fast, are less impressive in relative stability.

A photo-responsive fluorescent amphiphile for target-specific and image-guided drug delivery applications.

Multifunctional drug delivery systems are the centerpiece of effective chemotherapeutic strategies. Herein, we report the synthesis of an acetazolamide-linked cyanine-3-based NIR-responsive fluorescent macrocyclic amphiphile that self-assembled into spherical nanostructures in the aqueous medium via a J-aggregation pattern. The amphiphile shows various favorable properties of lipids. The photocleavage of the strained dioxacycloundecine ring induces spherical to nanotubular self-assembly with concomitant release of an encapsulated anticancer drug, doxorubicin (Dox), in a controlled manner. The CA-IX targeted amphiphile also showed lower cytotoxicity, effective cellular uptake, and Dox delivery to the model carcinoma cells.

Oxygenolysis of a series of copper(II)-flavonolate adducts varying the electronic factors on supporting ligands as a mimic of quercetin 2,4-dioxygenase-like activity.

Four copper(II)-flavonolate compounds of type [Cu(LR)(fla)] {where LR = 2-(p-R-benzyl(dipyridin-2-ylmethyl)amino)acetate; R = -OMe (1), -H (2), -Cl (3) and -NO2 (4)} have been developed as a structural and functional enzyme-substrate (ES) model of the Cu2+-containing quercetin 2,4-dioxygenase enzyme. The ES model complexes 1-4 are synthesized by reacting 3-hydroxyflavone in the presence of a base with the respective acetate-bound copper(II) complexes, [Cu(LR)(OAc)]. In the presence of dioxygen the ES model complexes undergo enzyme-type oxygenolysis of flavonolate (dioxygenase type bond cleavage reaction) at 80 °C in DMF. The reactivity shows a substituent group dependent order as -OMe (1) > -H (2) > -Cl (3) > -NO2 (4). Experimental and theoretical studies suggest a single-electron transfer (SET) from flavonolate to dioxygen, rather than valence tautomerism {[CuII(fla-)] ↔ [CuI(fla˙)]}, to generate the reactive flavonoxy radical (fla˙) that reacts further with the superoxide radical to bring about the oxygenative ring opening reaction. The SET pathway has been further verified by studying the dioxygenation reaction with a redox-inactive Zn2+ complex, [Zn(LOMe)(fla)] (5).

Sulfonium-based liposome-encapsulated antibiotics deliver a synergistic antibacterial activity.

The devastating antibacterial infections, coupled with their antibiotic resistance abilities, emphasize the need for effective antibacterial therapeutics. In this prospect, liposomal delivery systems have been employed in improving the efficacy of the antibacterial agents. The liposome-based antibiotics enhance the therapeutic potential of the new or existing antibiotics and reduce their adverse effects. The current study describes the development of sulfonium-based antibacterial lipids that demonstrate the delivery of existing antibiotics. The presence of cationic sulfonium moieties and inherent membrane targeting abilities of the lipids could help reduce the antibiotic resistance abilities of the bacteria and deliver the antibiotics to remove the infectious pathogens electively. The transmission electron microscopic images and dynamic light scattering analyses revealed the liposome formation abilities of the sulfonium-based amphiphilic compounds in the aqueous medium. The effectiveness of the compounds was tested against the Gram-negative and Gram-positive bacterial strains. The viability of the bacterial cells was remarkably reduced in the presence of the compounds. The sulfonium-based compounds with pyridinium moiety and long hydrocarbon chains showed the most potent antibacterial activities among the tested compounds. Mechanistic studies revealed the membrane-targeted bactericidal activities of the compounds. The potent compound also showed tetracycline and amoxicillin encapsulation and sustained release profiles in the physiologically relevant medium. The tetracycline and amoxicillin-encapsulated lipid showed much higher antibacterial activities than the free antibiotics at similar concentrations, emphasizing the usefulness of the synergistic effect of sulfonium-based lipid and the antibiotics, signifying that the sulfonium lipid penetrated the bacterial membrane and increased the cellular uptake of the antibiotics. The potent lipid also showed therapeutic potential, as it is less toxic to mammalian cells (like HeLa and HaCaT cells) at concentrations higher than their minimum inhibitory concentration values against S. aureus, E. coli, and MRSA. Hence, the sulfonium-based lipid exemplifies a promising framework for assimilating various warheads, and provides a potent antibacterial material.

Photoresponsive transformation from spherical to nanotubular assemblies: anticancer drug delivery using macrocyclic cationic gemini amphiphiles.

We developed NIR-light-responsive macrocyclic cationic gemini amphiphiles, one of which displayed various favorable properties of lipids. The NIR-light-mediated cleavage of the strained dioxacycloundecine ring led to the conversion of the spherical to a nanotubular self-assembly in the aqueous medium. This photo-mediated transformation from the spherical to nanotubular self-assembly resulted in the release of encapsulated hydrophobic anticancer drug molecule doxorubicin (Dox) in a controlled manner. The potent cationic gemini amphiphile also displayed lower cytotoxicity and efficient NIR-light-mediated Dox release efficacy to cancerous cells.

Transforming growth factor beta orchestrates PD-L1 enrichment in tumor-derived exosomes and mediates CD8 T-cell dysfunction regulating early phosphorylation of TCR signalome in breast cancer.

Tumor cells promote immune evasion through upregulation of programmed death-ligand 1 (PD-L1) that binds with programmed cell death protein 1 (PD1) on cytotoxic T cells and promote dysfunction. Though therapeutic efficacy of anti-PD1 antibody has remarkable effects on different type of cancers it is less effective in breast cancer (BC). Hence, more details understanding of PD-L1-mediated immune evasion is necessary. Here, we report BC cells secrete extracellular vesicles in form of exosomes carry PD-L1 and are highly immunosuppressive. Transforming growth factor beta (TGF-ß) present in tumor microenvironment orchestrates BC cell secreted exosomal PD-L1 load. Circulating exosomal PD-L1 content is highly correlated with tumor TGF-ß level. The later also found to be significantly associated with CD8+CD39+, CD8+PD1+ T-cell phenotype. Recombinant TGF-ß1 dose dependently induces PD-L1 expression in Texos in vitro and blocking of TGF-ß dimmed exosomal PD-L1 level. PD-L1 knocked down exosomes failed to suppress effector activity of activated CD8 T cells like tumor exosomes. While understanding its effect on T-cell receptor signaling, we found siPD-L1 exosomes failed to block phosphorylation of src family proteins, linker for activation of T cells and phosphoinositide phospholipase Cγ of CD8 T cells more than PD-L1 exosomes. In vivo inhibition of exosome release and TGF-ß synergistically attenuates tumor burden by promoting Granzyme and interferon gamma release in tumor tissue depicting rejuvenation of exhausted T cells. Thus, we establish TGF-ß as a promoter of exosomal PD-L1 and unveil a mechanism that tumor cells follow to promote CD8 T-cell dysfunction.

Sunlight-Mediated Thiol-Ene/Yne Click Reaction: Synthesis and DNA Transfection Efficiency of New Cationic Lipids.

The design of green synthetic reaction conditions is very challenging, especially for biomaterials, but worthwhile if the compounds can be easily synthesized in the aqueous medium. Herein, we report the development of sunlight-mediated thiol-ene/yne click reaction in the presence of a catalytic amount of tert-butyl hydroperoxide (TBHP) in an aqueous medium. The optimized reaction conditions were successfully applied to synthesize a series of small molecules and lipids in a single step in the aqueous medium. The synthetic cationic lipid/co-lipid formed positively charged stable nanosized liposomes that effectually bind with the genetic materials. The in vitro DNA transfection and cellular uptake assays showed that the synthesized cationic lipids have comparable efficiency to commercially available Lipofectamine 2000. This mild synthetic strategy can also be used for smart design of novel or improvement of prevailing lipid-based nonviral gene delivery systems. Such chemical transformations in the aqueous medium are more environment-friendly than other reported thiol-ene/yne click reactions performed in an organic solvent medium.

A stimuli-responsive anticancer drug delivery system with inherent antibacterial activities.

We describe a novel class of stimuli-sensitive sulfonium-based synthetic lipids, which exhibit several favorable biophysical properties of phospholipids. The potent sulfonium-based lipid was successfully disassembled by glutathione to release the encapsulated drug molecules in a controlled manner. The cationic lipid also showed lower cytotoxicity against mammalian cells and displayed moderate antibacterial activities.

Mononuclear Ruthenium-Based Water Oxidation Catalyst Supported by Anionic, Redox-Non-Innocent Ligand: Heterometallic O-O Bond Formation via Radical Coupling Pathway.

Cerium(IV)-driven water oxidation catalysis mediated by a mononuclear ruthenium(III) complex, [Ru(L)(pic)3] (H3L = 2,2'-iminodibenzoic acid, pic = 4-methylpyridine), has been demonstrated in this work. The mechanistic details of water oxidation have been investigated by the combined use of spectroscopy, electrochemistry, kinetic analysis, and computational studies. It was found that water oxidation proceeds via formal high-valent RuVII species. The capability of accessing such a high-valent state is derived from the non-innocent behavior of the anionic tridentate ligand frame which helps in accumulation of oxidative equivalents in cooperation with metal center. This metal-ligand cooperation facilitates the multi-electron-transfer reaction such as water oxidation. Kinetic analysis suggests water oxidation at a single site of Ru where O-O bond formation occurs via radical-radical coupling pathway between the oxygen atom of ruthenium-oxo species and the oxygen atom of the hydroxocerium(IV) ion.

Tuning the solubility of ionophores: glutathione-mediated transport of chloride ions across hydrophobic membranes.

A stimuli-responsive anion transport strategy was successfully employed to regulate the water solubility of ionophores and promote controlled transport of Cl- ions across lipid bilayers. A sulfonium-based proanionophore was efficiently activated by glutathione to regenerate the active anionophore, which allowed controlled transport of Cl- ions in a cellular environment with lower cytotoxicity.

Myeloma-associated systemic amyloidosis masquerading as NASH-associated cirrhosis and diabetic microvascular complications.

Authors describe the case of a 60-year-old diabetic man who presented with jaundice, ascites and significant weight loss over a period of 2 months. Physical examination revealed firm hepatomegaly with ascites. On evaluation, nephropathy, axonal neuropathy, carpal tunnel syndrome and decompensated cryptogenic liver disease with portal hypertension were found fitting with the diagnosis of diabetic nephropathy and neuropathy and nonalcoholic steato-hepatitis-associated cirrhosis, respectively. It was only after tissue diagnosis and serum protein electrophoresis that a definitive diagnosis of myeloma-related amyloidosis was made. This case emphasizes the fact that due to nonspecific initial presentation and multisystem involvement, a high index of suspicion and prompt use of appropriate tests including tissue diagnosis may be required to diagnose amyloid light-chain amyloidosis, which may be a rare presenting feature of myeloma. It should be differentiated from a commoner multisystem disease like diabetes and its complications.

Liver abscess caused by Burkholderia pseudomallei in a young man: A case report and review of literature.

Pyogenic liver abscess is a common entity in Indian subcontinent and is mostly caused by gram negative bacteria. Melioidosis is not commonly seen in India and only a few cases are reported. It can give rise to multiple abscesses at different sites including liver. We report a case of isolated liver abscess caused by Burkholderia pseudomallei (B. pseudomallei) in a 29-year-old recently diagnosed diabetic, immunocompetent male. Diagnosis was made by imaging and culture of pus aspirated from the abscess and he was treated with percutaneous pigtail catheter drainage followed by antibiotics (meropenem and trimethoprim-sulphmethoxazole). Melioidosis is an emerging infection in India and has high mortality rate, so early diagnosis and prompt management is warranted which requires clinical vigilance and an intensive microbiological workup. Clinicians should be aware of isolated liver abscess caused by B. pseudomallei in appropriate clinical settings.