Highly potent Platinum(IV) complexes with multiple-bond ligands targeting mitochondria to overcome cisplatin resistance.

The efficacy and resistance of cisplatin-based compounds are very intractable problems at present. This study reports a series of platinum(IV) compounds containing multiple-bond ligands, which exhibited better tumor cell inhibitory activity and antiproliferative and anti-metastasis activities than cisplatin. The meta-substituted compounds 2 and 5 were particularly excellent. Further research showed that compounds 2 and 5 possessed appropriate reduction potential and performed significantly better than cisplatin in cellular uptake, reactive oxygen species response, the up-regulation of apoptosis and DNA lesion-related genes, and drug-resistant cell activity. The title compounds exhibited better antitumor potential and fewer side effects than cisplatin in vivo. Multiple-bond ligands were introduced into cisplatin to form the title compounds in this study, which not only enhanced their absorption and overcame drug resistance but also demonstrated the potential to target mitochondria and inhibit the detoxification of tumor cells.

Synthesis and Biological Evaluation of Piperazine Hybridized Coumarin Indolylcyanoenones with Antibacterial Potential.

A class of piperazine hybridized coumarin indolylcyanoenones was exploited as new structural antibacterial frameworks to combat intractable bacterial resistance. Bioactive assessment discovered that 4-chlorobenzyl derivative 11f showed a prominent inhibition on Pseudomonas aeruginosa ATCC 27853 with a low MIC of 1 µg/mL, which was four-fold more effective than norfloxacin. Importantly, the highly active 11f with inconspicuous hemolysis towards human red blood cells displayed quite low proneness to trigger bacterial resistance. Preliminary explorations on its antibacterial behavior disclosed that 11f possessed the ability to destroy bacterial cell membrane, leading to increased permeability of inner and outer membranes, the depolarization and fracture of membrane, and the effusion of intracellular components. Furthermore, bacterial oxidative stress and metabolic turbulence aroused by 11f also accelerated bacterial apoptosis. In particular, 11f could not only effectively inset into DNA, but also bind with DNA gyrase through forming supramolecular complex, thereby affecting the biological function of DNA. The above findings of new piperazine hybridized coumarin indolylcyanoenones provided an inspired possibility for the treatment of resistant bacterial infections.

Reduction of SLC7A11 and GPX4 Contributing to Ferroptosis in Sperm from Asthenozoospermia Individuals.

Ferroptosis is a newly defined form of regulated cell death, which is involved in various pathophysiological conditions. However, the role of ferroptosis in male infertility remains unclear. In this study, 42 asthenozoospermic and 45 normozoospermic individuals participated. To investigate the ferroptosis level in the two groups, the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and iron were measured, and mitochondrial membrane potential (MMP) was detected as an indicator of mitochondrial injuries. Compared with the normozoospermic group, ROS (p < 0.05), MDA (p < 0.001), and iron (p < 0.001) of the asthenozoospermic group were significantly increased. However, the asthenozoospermia group had a decreased MMP level (p < 0.05). In addition, the expression levels of GSH-dependent peroxidase 4 (GPX4) (p < 0.001) and solute carrier family 7 member 11 (SLC7A11) (p < 0.05) were also reduced in asthenozoospermic individuals. In asthenozoospermic samples, a significantly high positive correlation was observed between GPX4 mRNA levels and progressive motility (r = 0.397, p = 0.009) and total motility (r = 0.389, p = 0.011), while a negative correlation was observed between GPX4 and iron concentration (r = - 0.276, p = 0.077). The function of ferroptosis in asthenozoospermic males has never been studied before. In our study, we concluded that GPX4 and SLC7A11 expression levels in asthenozoospermia patients were related to increased ferroptosis and impaired sperm function, revealing novel molecular insights into the complex systems involved in male infertility.

miR-381 Inhibits Proliferation and Invasion of Non-Small-Cell Cancer Cells by Targeting USP39.

It is known that miR-381 plays a therapeutic role in a variety of cancers, but the regulatory mechanism of miR-381 in the treatment of lung cancer remains unclear. This study is aimed at exploring the expression level and mechanism of miR-381 in lung cancer. In this experiment, quantitative real-time PCR (qRT-PCR), western blot, and other methods were used to detect the expression of miR-381 and ubiquitin-specific protease 39 (USP39) in lung cancer tissues. The target genes of miR-381 were predicted by bioinformatics techniques, and the targeting relationship between miR-381 and USP39 was verified by the dual-luciferase reporting method. The expression levels of miR-381 and USP39 were adjusted to verify the effect of miR-381 on the expression of USP39 gene. The effect of miR-381 expression on proliferation of lung cancer cells was verified by cell proliferation and invasion experiments. miR-381 was downregulated in non-small-cell lung cancer tissues and cell lines, while USP39 was upregulated. The dual-luciferase reporter gene assay showed that miR-381 and USP39 had targeted binding sites. After transfection with miR-381 mimics, USP39 expression was significantly decreased, cell proliferation decreased, and apoptosis increased. After transfection with miR-381 inhibitor, USP39 expression was significantly increased, cell proliferation increased, and cell apoptosis decreased. Overexpression of USP39 significantly increased the invasion ability and cell survival curve (p < 0.05). In conclusion, overexpression of miR-381 can regulate the expression of USP39, inhibit the proliferation and invasion of cancer cells, and induce apoptosis of cancer cells. This may provide a new perspective and strategy for targeted therapy of non-small-cell lung cancer.

Discovery of novel phenylhydrazone-based oxindole-thiolazoles as potent antibacterial agents toward Pseudomonas aeruginosa.

With the soaring of bacterial infection and drug resistance, it is imperative to exploit new efficient antibacterial agents. This work constructed a series of unique phenylhydrazone-based oxindole-thiolazoles to combat monstrous bacterial resistance. Some target molecules showed potent antibacterial activity, among which oxindole-thiolimidazole derived carboxyphenylhydrazone 4e exhibited an 8-fold stronger inhibitory ability than norfloxacin on the growth of P. aeruginosa, with MIC value of 1 µg/mL. Compound 4e with imperceptible hemolysis could hamper bacterial biofilm formation and significantly impede the development of bacterial resistance. Subsequent mechanism studies demonstrated that 4e could destruct bacterial cytoplasmic membrane, causing the leakage of cellular contents (protein and nucleic acid). Moreover, metabolic stagnation and intracellular oxidative stress caused by 4e expedited the death of bacteria. Furthermore, molecule 4e existed supramolecular interactions with DNA to block DNA proliferation. These research results provided a promising light for phenylhydrazone-based oxindole-thiolazoles as novel potential antibacterial agents.

Unique Carbazole-Oxadiazole Derivatives as New Potential Antibiotics for Combating Gram-Positive and -Negative Bacteria.

Novel carbazole-oxadiazoles were developed as new potential antibacterial agents to combat dreadful resistance. Some target compounds displayed predominant inhibitory effects on the tested Gram-positive and -negative bacteria, and carbazole-oxadiazoles 5g, 5i-k, 16a-c, and tetrazole analogues 23b-c were found to be efficient in impeding the growth of MRSA and Pseudomonas aeruginosa ATCC 27853 (MICs = 0.25-4 µg/mL). Furthermore, compounds 5g and 23b-c not only possessed rapid bactericidal ability and low tendency to develop resistance but also exhibited low cytotoxic effects toward Hek 293T, HeLa, and red blood cells (RBCs), especially molecule 5g also showed low toxicity in vivo, which showed the therapeutic potential of these compounds. Further exploration indicated that compounds 5g, 5i, and 23b-c could disintegrate the integrity of bacterial cell membranes to leak the cytoplasmic contents, thus exerting excellent antibacterial effects. These facts mean that carbazole-based antibacterial agents might have bright prospects in confronting bacterial infections.

Dieckmann Condensation of Ugi N-Acylamino Amide Product: Facile Access to Functionalized 2,2-Disubstituted Indolin-3-ones.

Structurally unique 2,2-disubstituted indolin-3-ones with a quaternary carbon center have been constructed through a novel C-C bond formation at the C3 position of Ugi N-acylamino amide adducts employing an organic base-mediated Dieckmann condensation. This facile, flexible protocol can be fine-tuned to construct drug-like pyrazino[1,2-a]indole fragments with the same quaternary carbon center only through the variation of the acid part in Ugi input. This novel and expeditious methodology has a broad scope and can rapidly generate the drug-like indolin-3-one core.

A Novel Diagnostic Method for Invasive Fungal Disease Using the Factor G Alpha Subunit From Limulus polyphemus.

Deaths due to invasive fungal disease (IFD) have been increasing every year. Early and rapid detection is important to reduce the mortality rate associated with IFD. In this study, we explored a novel diagnostic method for detecting IFD, which involves the G Factor α subunit (GFαSub) from Limulus polyphemus. The GFαSub double-sandwich method was developed to detect (1,3)-ß-D-glucans in human serum using purified GFαSub and horseradish peroxidase-labeled GFαSub. The GFαSub double-sandwich method and the G test were performed and compared. Using GFαSub sequence analysis, the expression plasmid pET30a-GFαSub252-668 was synthesized, and GFαSub252-668 was expressed and purified via isopropyl-ß-d-thiogalactoside induction and nickel-nitrilotriacetic acid affinity. The optimization method was established via the orthogonal method. Using this method, the sera of 36 patients with IFD and 92 volunteers without IFD underwent detection, and the receiver operating characteristic curve of the GFαSub252-668 double-sandwich method was described. The sensitivity and specificity of the GFαSub252-668 double-sandwich method were 91.67 and 82.61%, respectively, and there was good correlation with the G test for the serum specimens of 36 patients with pulmonary IFD (R 2 = 0.7592). In conclusion, our study suggests that the GFαSub252-668 double-sandwich method was satisfactory at detecting IFD cases. This method can be promoted and further developed as a novel method for diagnosing IFD.

Biomineralization improves the stability of a Streptococcus pneumoniae protein vaccine at high temperatures.

Aim: Protein vaccines have been the focus of research for vaccine development due to their safety record and facile production. Improving the stability of proteins is of great significance to the application of protein vaccines. Materials & methods: Based on the proteins pneumolysin and DnaJ of Streptococcus pneumoniae, biomineralization was carried out to prepare protein nanoparticles, and their thermal stability was tested both in vivo and in vitro. Results: Mineralized nanoparticles were formed successfully and these calcium phosphate-encapsulated proteins were resistant to proteinase K degradation and were thermally stable at high temperatures. The mineralized proteins retained the immunoreactivity of the original proteins. Conclusion: Mineralization technology is an effective means to stabilize protein vaccines, presenting a safe and economical method for vaccine administration.

A facile reaction to access novel structural sulfonyl-hybridized imidazolyl ethanols as potential DNA-targeting antibacterial agents.

A novel type of sulfonyl-hybridized imidazolyl ethanols as potential DNA-targeting antibacterial agents was constructed via the unique ring-opened reaction of oxiranes by imidazoles for the first time. Some developed target hybrids showed potential antimicrobial potency against the tested microbes. Especially, imidazole derivative 5f could strongly suppressed the growth of MRSA (MIC = 4 µg/mL), which was 2-fold and 16-fold more potent than the positive control sulfathiazole and norfloxacin. This compound exhibited quite low propensity to induce bacterial resistance. Antibacterial mechanism exploration indicated that compound 5f could embed in MRSA DNA to form steady 5f-DNA complex, which possibly hinder DNA replication to exert antimicrobial behavior. Molecular docking showed that molecule 5f could bind with dihydrofolate synthetase through hydrogen bonds. These results implied that imidazole derivative 5f could be served as a promising molecule for the exploration of novel antibacterial candidates.

Silencing of Long Non-Coding RNA FGD5-AS1 Inhibits the Progression of Non-Small Cell Lung Cancer by Regulating the miR-493-5p/DDX5 Axis.

BACKGROUND: Long non-coding RNA FGD5 antisense RNA 1 (FGD5-AS1), identified to be a carcinogenic lncRNA, exhibits a regulatory role in some malignancies including non-small cell lung cancer (NSCLC). The aim of the present research is to decipher the function and underlying mechanism of FGD5-AS1 in progression of NSCLC. METHODS: Expression of FGD5-AS1, miR-493-5p and DEAD-box protein 5 (DDX5) in NSCLC tissues and cells was quantified utilizing qRT-PCR. Cell proliferation was assessed by CCK-8 method. Scratch healing test and Transwell assay were used for assaying cell migration and invasion. Expressions of DDX5 and epithelial-mesenchymal transition (EMT)-related proteins were examined by Western blot. Additionally, targeting relationships between FGD5-AS1 and miR-493-5p, miR-493-5p and DDX5 were verified by dual-luciferase reporter gene assay. RESULTS: Expression of FGD5-AS1 in NSCLC tissues and cell lines was up-regulated. Expression of FGD5-AS1 was in association with enlarged tumor size and lymph node metastasis of the patients. Knockdown of FGD5-AS1 led to the inhibition of proliferation, migration, invasion and EMT of NSCLC cells. FGD5-AS1 directly targeted miR-493-5p, while DDX5 was the target of miR-493-5p in NSCLC cells. Additionally, FGD5-AS1 could positively regulate the expression of DDX5 via suppressing miR-493-5p. CONCLUSION: FGD5-AS1 facilitates the proliferation, migration, invasion and EMT of NSCLC cells by sponging miR-493-5p and up-regulating DDX5.

Facile synthesis and biological evaluation of tryptamine-piperazine-2,5-dione conjugates as anticancer agents.

A facile and efficient route to synthesize N-heterocyclic fused tryptamine-piperazine-2,5-dione conjugates was developed via a post-Ugi cascade reaction. The targeted compounds were prepared by means of a mild reaction and simple operation procedure, which could be applied to a broad scope of starting materials. Compound 6h was demonstrated to induce significant growth inhibition of AsPC-1 and SW1990 human pancreatic cancer cell lines (IC50 = 6 ± 0.85 µM). Our protocol allows for the construction of a structurally diverse compound library and paves a new avenue for the discovery of pancreatic cancer drug candidates.

Strategy Used to Control the Mechanism of Homogeneous Alkyne/Olefin Hydrogenation: AIMD Simulations and DFT Calculations.

Understanding the mechanism of the catalytic reaction is an effective way to design new high-performance catalysts. The mechanisms of alkyne/olefin hydrogenations catalyzed by a nonclassical Co-N2 catalyst are explored by ab initio molecular dynamics simulations and density functional theory calculations. From the calculated results, the hydrogenation mechanisms, i.e., molecular or atomic mechanisms, can be effectively controlled via employing the different interaction between the catalyst and substrates. The origination of excellent selectivity toward E-olefins for the Co-N2 catalyst is also taken into account with the help of investigating the olefin hydrogenation process. The mechanism indicates that the negligible energy barrier of rotation is the main reason for highly selective semihydrogenation of a Co-N2 catalyst, which leads to the trans-olefin formation. These investigations may provide some useful information and guidelines on the current understanding of the hydrogenation reaction and designing the high-performance catalysts.

Synthesis of Pyridodiindoles with Anticancer Activity by a Three-Component Cascade Condensation.

A novel three-component cascade reaction was discovered and developed to synthesize pyridodiindoles with the assistance of microwave irradiation. A collection of pyridodiindoles was prepared by means of the mild reaction and simple operation procedure, which could be applicable to a broad scope of functional aldehydes. Screening demonstrated that compound 5g exhibited a good potency in HCT116 cell lines, and this work validated the feasibility of this novel reaction for generating promising bioactive compounds.

Functionalized Spiroindolines with Anticancer Activity through a Metal-Free Post-Ugi Diastereoselective One-Pot Cascade Reaction.

A post-Ugi diastereoselective one-pot cascade reaction requiring no metal catalyst was developed. The reaction scope was wide with mild conditions and good yields. A collection of spiroindolines was prepared by the protocol and screening tests in several difficult-to-inhibit cancer cell lines were conducted. The relationship of structure and anticancer activities was promising and in the Huh7 cell lines compound 16 j is more potent than Vinbalstine. The cyclization design strategy could be applicable to other multicomponent reactions (MCRs) for synthesizing bioactive and drug-like heterocycles.

Recent advances in the development of polycyclic skeletons via Ugi reaction cascades.

Isocyanide-based multicomponent reactions are among the most powerful synthetic tools available. Particularly, the isocyanide-based Ugi reaction can allow rapid preparation of [Formula: see text]-aminoacyl amide derivatives and polyazaheterocycles with extensive pharmaceutical applications. Moreover, bridged polyazaheterocycles, including one or more quaternary carbon centers, can be constructed via the Ugi cascade reaction in a few steps. This review will emphasize synthesis and bioactivities of bridged compounds with quaternary centers constructed through Ugi cascade reactions.

Efficient Synthesis of Fused Oxazepino-isoquinoline Scaffolds via an Ugi, Followed by an Intramolecular Cyclization.

A mild and efficient protocol was developed for the synthesis of oxazepino-isoquinolines via a one-pot Ugi four-component reaction, followed by the intramolecular addition of the resulting alcohol to an alkyne moiety under microwave irradiation conditions. Notably, this process only required one purification step, providing facile access to two series of complex and potentially interesting biologically active scaffolds.

Metal-organic frameworks based on rigid ligands as separator membranes in supercapacitor.

Two thermally stable MOFs formulated as CoL(1,4-bdc)·2DMF (L = 3,5-bis(5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)pyridine), 1,4-H2bdc = 1,4-benzenedicarboxylic acid) (1) and CdL(4,4'-bpc)·3DMF (4,4'-H2bpc = 4,4'-biphenyldicarboxylic acid) (2) have been solvothermally synthesized and exhibit a similar uninodal 6-connected 3D architecture with {4(12)·6(3)}-pcu topology. MOF1 shows a non-interpenetrated network with larger channel, whereas MOF 2 exhibits a 3-fold interpenetrating framework with smaller pore size. When the two MOFs are used as separator membranes in a supercapacitor, the equivalent series resistance (Res) is larger than the Res in the blank supercapacitor, and the smaller the current density, the more the Res. After being charged and discharged at the low current density, the supercapacitor with MOF 1 as separator membrane (denoted as 1a) possesses a much larger specific capacitance (SC) than the blank supercapacitor, and the amorphous separator membrane 1a shows a more porous morphology than the original MOF membrane 1.

Serotype-independent protection against pneumococcal infections elicited by intranasal immunization with ethanol-killed pneumococcal strain, SPY1.

The 23-valent polysaccharide vaccine and the 7-valent pneumococcal conjugate vaccine are licensed vaccines that protect against pneumococcal infections worldwide. However, the incidence of pneumococcal diseases remains high in low-income countries. Whole-cell vaccines with high safety and strong immunogenicity may be a favorable choice. We previously obtained a capsule-deficient Streptococcus pneumoniae mutant named SPY1 derived from strain D39. As an attenuated live pneumococcal vaccine, intranasal immunization with SPY1 elicits broad serotype-independent protection against pneumococcal infection. In this study, for safety consideration, we inactivated SPY1 with 70% ethanol and intranasally immunized BALB/c mice with killed SPY1 plus cholera toxin adjuvant for four times. Results showed that intranasal immunization with inactivated SPY1 induced strong humoral and cellular immune responses. Intranasal immunization with inactivated SPY1 plus cholera toxin adjuvant elicited effective serotype-independent protection against the colonization of pneumococcal strains 19F and 4 as well as lethal infection of pneumococcal serotypes 2, 3, 14, and 6B. The protection rates provided by inactivated SPY1 against lethal pneumococcal infection were comparable to those of currently used polysaccharide vaccines. In addition, vaccine-specific B-cell and T-cell immune responses mediated the protection elicited by SPY1. In conclusion, the 70% ethanol-inactivated pneumococcal whole-cell vaccine SPY1 is a potentially safe and less complex vaccine strategy that offers broad protection against S. pneumoniae.