Dual Actions of A2A and A3 Adenosine Receptor Ligand Prevents Obstruction-Induced Kidney Fibrosis in Mice.

Kidney fibrosis is the final outcome of chronic kidney disease (CKD). Adenosine plays a significant role in protection against cellular damage by activating four subtypes of adenosine receptors (ARs), A1AR, A2AAR, A2BAR, and A3AR. A2AAR agonists protect against inflammation, and A3AR antagonists effectively inhibit the formation of fibrosis. Here, we showed for the first time that LJ-4459, a newly synthesized dual-acting ligand that is an A2AAR agonist and an A3AR antagonist, prevents the progression of tubulointerstitial fibrosis. Unilateral ureteral obstruction (UUO) surgery was performed on 6-week-old male C57BL/6 mice. LJ-4459 (1 and 10 mg/kg) was orally administered for 7 days, started at 1 day before UUO surgery. Pretreatment with LJ-4459 improved kidney morphology and prevented the progression of tubular injury as shown by decreases in urinary kidney injury molecular-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) excretion. Obstruction-induced tubulointerstitial fibrosis was attenuated by LJ-4459, as shown by a decrease in fibrotic protein expression in the kidney. LJ-4459 also inhibited inflammation and oxidative stress in the obstructed kidney, with reduced macrophage infiltration, reduced levels of pro-inflammatory cytokines, as well as reduced levels of reactive oxygen species (ROS). These data demonstrate that LJ-4459 has potential as a therapeutic agent against the progression of tubulointerstitial fibrosis.

Widespread Existence of Quorum Sensing Inhibitors in Marine Bacteria: Potential Drugs to Combat Pathogens with Novel Strategies.

Quorum sensing (QS) is a phenomenon of intercellular communication discovered mainly in bacteria. A QS system consisting of QS signal molecules and regulatory protein components could control physiological behaviors and virulence gene expression of bacterial pathogens. Therefore, QS inhibition could be a novel strategy to combat pathogens and related diseases. QS inhibitors (QSIs), mainly categorized into small chemical molecules and quorum quenching enzymes, could be extracted from diverse sources in marine environment and terrestrial environment. With the focus on the exploitation of marine resources in recent years, more and more QSIs from the marine environment have been investigated. In this article, we present a comprehensive review of QSIs from marine bacteria. Firstly, screening work of marine bacteria with potential QSIs was concluded and these marine bacteria were classified. Afterwards, two categories of marine bacteria-derived QSIs were summarized from the aspects of sources, structures, QS inhibition mechanisms, environmental tolerance, effects/applications, etc. Next, structural modification of natural small molecule QSIs for future drug development was discussed. Finally, potential applications of QSIs from marine bacteria in human healthcare, aquaculture, crop cultivation, etc. were elucidated, indicating promising and extensive application perspectives of QS disruption as a novel antimicrobial strategy.

Discovery and Synthesis of Amino Acids Modified Deoxycholic Acid Derivatives and in Vitro Antiproliferative Evaluation.

A series of deoxycholic acid (DCA) derivatives bearing amino acid moiety has been synthesized and investigated for their potential antiproliferative activities. DCA derivative compounds were synthesized by a two or three step synthetic approach. Their bioactivities were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method and Western blotting analysis on three tumor cell lines A549 (human lung cancer cell line), MCF-7 (human breast cancer cell line) and HeLa (human cervical carcinoma cell). The novel derivatives DCA3d, DCA5a, DCA5b, DCA5c, and DCA5d were found to be promising antiproliferative agents. Furthermore, DCA5b showed the greatest cytotoxic activity by induction of apoptosis. These compounds show potentiality for further optimization as antitumor drugs.

Design, synthesis, and anticancer activity of C8-substituted-4'-thionucleosides as potential HSP90 inhibitors.

A series of C8-substituted-4'-thioadenosine analogs 3a-3g, 15, and 17 and their truncated derivatives 4a-4j, 23-25, and 27 have been successfully synthesized from d-ribose and d-mannose, respectively, employing Pummerer type or Vorbrüggen condensation reactions and the functionalization at the C8-position of nucleobase via Stille coupling or nucleophilic aromatic substitution reactions as key steps. All the synthesized compounds were assayed for their HSP90 inhibitory activity, but they were found to be inactive up to 100µM. However, the 8-iodo derivatives 15, 17, and 27 exhibited potent anticancer activity, indicating that different mechanism of action might be involved in their biological activity.

Potential Pharmacological Resources: Natural Bioactive Compounds from Marine-Derived Fungi.

In recent years, a considerable number of structurally unique metabolites with biological and pharmacological activities have been isolated from the marine-derived fungi, such as polyketides, alkaloids, peptides, lactones, terpenoids and steroids. Some of these compounds have anticancer, antibacterial, antifungal, antiviral, anti-inflammatory, antioxidant, antibiotic and cytotoxic properties. This review partially summarizes the new bioactive compounds from marine-derived fungi with classification according to the sources of fungi and their biological activities. Those fungi found from 2014 to the present are discussed.

Design, synthesis, and biofunctional evaluation of novel pentacyclic triterpenes bearing O-[4-(1-piperazinyl)-4-oxo-butyryl moiety as antiproliferative agents.

A series of pentacyclic triterpenoids derivatives bearing O-[4-(1-piperazinyl)-4-oxo-butyryl moiety has been synthesized and investigated for their potential antiproliferative activities. Pentacyclic triterpenoids derivative compounds were synthesized by a four or six step synthetic procedure. The activity studies were evaluated using Cell Counting Kit-8 method, and Western blotting analysis on A549 cells, MCF-7 cells and Hela cells. Compounds methyl 3-O-[4-(1-piperazinyl)-4-oxo-butyryl]olean-12-ene-28-oate (OA-4) and compound 2-O-[4-(1-piperazinyl)-4-oxo-butyryl]-3,23-dihydroxyurs-12-ene-28-oate (AA-5) were found to be promising antiproliferative agents. These compounds show potentiality for further optimization as antitumor drugs.

Structural Modification and Biological Evaluation of 2,8-Disubstituted Adenine and Its Nucleosides as A2A Adenosine Receptor Antagonists: Exploring the Roles of Ribose at Adenosine Receptors.

Building on the preceding structural analysis and a structure-activity relationship (SAR) of 8-aryl-2-hexynyl nucleoside hA2AAR antagonist 2a, we strategically inverted C2/C8 substituents and eliminated the ribose moiety. These modifications aimed to mitigate potential steric interactions between ribose and adenosine receptors. The SAR findings indicated that such inversions significantly modulated hA3AR binding affinities depending on the type of ribose, whereas removal of ribose altered the functional efficacy via hA2AAR. Among the synthesized derivatives, 2-aryl-8-hexynyl adenine 4a demonstrated the highest selectivity for hA2AAR (Ki,hA2A = 5.0 ± 0.5 nM, Ki,hA3/Ki,hA2A = 86) and effectively blocked cAMP production and restored IL-2 secretion in PBMCs. Favorable pharmacokinetic properties and a notable enhancement of anticancer effects in combination with an mAb immune checkpoint blockade were observed upon oral administration of 4a. These findings establish 4a as a viable immune-oncology therapeutic candidate.

Structure-Activity Relationship of Truncated 2,8-Disubstituted-Adenosine Derivatives as Dual A2A/A3 Adenosine Receptor Antagonists and Their Cancer Immunotherapeutic Activity.

Based on hA2AAR structures, a hydrophobic C8-heteroaromatic ring in 5'-truncated adenosine analogues occupies the subpocket tightly, converting hA2AAR agonists into antagonists while maintaining affinity toward hA3AR. The final compounds of 2,8-disubstituted-N6-substituted 4'-thionucleosides, or 4'-oxo, were synthesized from d-mannose and d-erythrono-1,4-lactone, respectively, using a Pd-catalyst-controlled regioselective cross-coupling reaction. All tested compounds completely antagonized hA2AAR, including 5d with the highest affinity (Ki,A2A = 7.7 ± 0.5 nM). The hA2AAR-5d X-ray structure revealed that C8-heteroaromatic rings prevented receptor activation-associated conformational changes. However, the C8-substituted compounds still antagonized hA3AR. Structural SAR features and docking studies supported different binding modes at A2AAR and A3AR, elucidating pharmacophores for receptor activation and selectivity. Favorable pharmacokinetics were demonstrated, in which 5d displayed high oral absorption, moderate half-life, and bioavailability. Also, 5d significantly improved the antitumor effect of anti-PD-L1 in vivo. Overall, this study suggests that the novel dual A2AAR/A3AR nucleoside antagonists would be promising drug candidates for immune-oncology.

Optical flexible biosensors: From detection principles to biomedical applications.

Optical flexible biosensors are novel sensors fabricated on flexible or ductile materials that are used for the detection of analytes. Compared to traditional sensors, these biosensors offer greater flexibility, which allows them to adapt to different working environments, to meet the deformation requirements of humans. Flexible devices can not only detect alterations in analytes in vitro, but can also realize real-time and non-invasive monitoring of the variation of physical conditions or metabolites in vivo. Flexible devices are earning increasing attention from researchers and clinicians. In the present review, we summarize and introduce the detection principles, key analytes, and applications of optical flexible biosensors in the diagnosis/treatment of diseases as well as health detection. Moreover, the remaining challenges of flexible devices and their perspectives have also been addressed. We hope that this review will pave ways for the development of more feasible and multifunctional flexible devices.

Macrolactin Metabolite Production by Bacillus sp. ZJ318 Isolated from Marine Sediment.

A total of 172 microbial strains were screened and isolated from Arctic Ocean marine sediments at a depth of 42 ~ 3,763 m. A microorganism with strong antibacterial activity against Staphylococcus aureus was identified as Bacillus sp. ZJ318 according to the results of 16S rDNA sequencing and phylogenetic tree analyses. Bioactivity-guided isolation of the new/novel metabolite in the ethyl acetate (EA) extract obtained from the fermentation broth of this strain was followed by chromatographic fractionation and subsequent HPLC purification, leading to the isolation of one known macrolactin. The chemical structure of the macrolactin, which indicated macrolactin J isolation from marine microorganisms for the first time, was assigned based on a high-resolution electrospray ionization mass spectrometer system (HR-EMI-MS), nuclear magnetic resonance (NMR) spectral analyses, and a literature review. To improve macrolactin J production, the corresponding effects of nitrogen sources were investigated, and (NH4)2SO4 was determined to produce the best effect. In addition, the optimal culture conditions were determined by an orthogonal experiment. Under these conditions, the yield of macrolactin J was increased to 2.41 mg/L, which was 2.2 times the original yield. This work lays a foundation for follow-up mechanistic and application research on macrolactin J.

GPCR Agonist-to-Antagonist Conversion: Enabling the Design of Nucleoside Functional Switches for the A2A Adenosine Receptor.

Modulators of the G protein-coupled A2A adenosine receptor (A2AAR) have been considered promising agents to treat Parkinson's disease, inflammation, cancer, and central nervous system disorders. Herein, we demonstrate that a thiophene modification at the C8 position in the common adenine scaffold converted an A2AAR agonist into an antagonist. We synthesized and characterized a novel A2AAR antagonist, 2 (LJ-4517), with Ki = 18.3 nM. X-ray crystallographic structures of 2 in complex with two thermostabilized A2AAR constructs were solved at 2.05 and 2.80 Å resolutions. In contrast to A2AAR agonists, which simultaneously interact with both Ser2777.42 and His2787.43, 2 only transiently contacts His2787.43, which can be direct or water-mediated. The n-hexynyl group of 2 extends into an A2AAR exosite. Structural analysis revealed that the introduced thiophene modification restricted receptor conformational rearrangements required for subsequent activation. This approach can expand the repertoire of adenosine receptor antagonists that can be designed based on available agonist scaffolds.

Regio- and stereoselective synthesis of truncated 3'-aminocarbanucleosides and their binding affinity at the A3 adenosine receptor.

The stereoselective synthesis of truncated 3'-aminocarbanucleosides 4a-d via a stereo- and regioselective conversion of a diol 9 to bromoacetate 11a and their binding affinity towards the human A(3) adenosine receptor are described.

Near infrared photothermal conversion materials: mechanism, preparation, and photothermal cancer therapy applications.

Photothermal therapy (PTT) has been widely applied in cancer therapy as a result of its non-invasive, localized treatment and good therapeutic effect. In general, the final therapeutic effect of PTT mainly depends on the photothermal materials, which can be further considered to be determined by the photothermal conversion efficiency, biocompatibility, and photothermal stability of photothermal materials. In this review, photothermal materials including inorganic materials, organic materials, and organic-inorganic composite materials in recent years have been summarized in terms of the mechanism, preparation, and cancer therapy applications. In the end, the perspectives and obstacles in their further development are overviewed.

Subtle Chemical Changes Cross the Boundary between Agonist and Antagonist: New A3 Adenosine Receptor Homology Models and Structural Network Analysis Can Predict This Boundary.

Distinguishing compounds' agonistic or antagonistic behavior would be of great utility for the rational discovery of selective modulators. We synthesized truncated nucleoside derivatives and discovered 6c (Ki = 2.40 nM) as a potent human A3 adenosine receptor (hA3AR) agonist, and subtle chemical modification induced a shift from antagonist to agonist. We elucidated this shift by developing new hA3AR homology models that consider the pharmacological profiles of the ligands. Taken together with molecular dynamics (MD) simulation and three-dimensional (3D) structural network analysis of the receptor-ligand complex, the results indicated that the hydrogen bonding with Thr943.36 and His2727.43 could make a stable interaction between the 3'-amino group with TM3 and TM7, and the corresponding induced-fit effects may play important roles in rendering the agonistic effect. Our results provide a more precise understanding of the compounds' actions at the atomic level and a rationale for the design of new drugs with specific pharmacological profiles.

Urchin-Like Cobalt-Copper (Hydr)oxides as an Efficient Water Oxidation Electrocatalyst.

The development of efficient and low-cost oxygen evolution reaction (OER) catalysts is essential for the generation of clean hydrogen energy from water splitting. Herein, a novel hierarchical urchin-like cobalt-copper (hydr)oxide in situ grown on copper foam (CoCuOx Hy (S)/CF) was synthesized through the electrochemical transformation of cobalt-copper sulfides (Co9 S8 -Cu1.81 S) via anodization process. This CoCuOx Hy (S)/CF anode exhibited a low overpotential (η) of 274 mV at a current density of 100 mA cm-2 with a robust durability over a period of 40 h when operated at 10 mA cm-2 . Further investigations imply that the unique nanowires aggregated urchin-like structure of CoCuOx Hy (S) derived from the in situ anion exchange process could facilitate the exposure of active sites and accelerate electron transfer. More importantly, the incorporation of copper resulted in an electronic delocalization around the cobalt species, which contributed to reach a high-valent catalytically active cobalt species and further improved the OER performance.

Structure-activity relationships of truncated adenosine derivatives as highly potent and selective human A3 adenosine receptor antagonists.

On the basis of potent and selective binding affinity of truncated 4'-thioadenosine derivatives at the human A(3) adenosine receptor (AR), their bioisosteric 4'-oxo derivatives were designed and synthesized from commercially available 2,3-O-isopropylidene-D-erythrono lactone. The derivatives tested in AR binding assays were substituted at the C2 and N(6) positions. All synthesized nucleosides exhibited potent and selective binding affinity at the human A(3) AR. They were less potent than the corresponding 4'-thio analogues, but showed still selective to other subtypes. The 2-Cl series generally were better than the 2-H series in view of binding affinity and selectivity. Among compounds tested, compound 5d (X=Cl, R=3-bromobenzyl) showed the highest binding affinity (K(i)=13.0+/-6.9 nM) at the hA(3) AR with high selectivity (at least 88-fold) in comparison to other AR subtypes. Like the corresponding truncated 4'-thio series, compound 5d antagonized the action of an agonist to inhibit forskolin-stimulated adenylate cyclase in hA(3) AR-expressing CHO cells. Although the 4'-oxo series were less potent than the 4'-thio series, this class of human A(3) AR antagonists is also regarded as another good template for the design of A(3) AR antagonists and for further drug development.

First synthesis of 4'-selenonucleosides showing unusual Southern conformation.

The first synthesis of 4'-selenonucleosides was achieved using a Pummerer-type condensation as a key step. All stereoelectronic effects shown in 4'-oxonucleosides were overwhelmed by the size of selenium and steric interactions, driving the conformation to the C2'-endo/ C3'-exo twist (Southern) conformation.

Relationship between left ventricular diastolic dyssynchrony and systolic dyssynchrony in hypertrophic cardiomyopathy by single-cardiac real-time three-dimensional ultrasonography.

The relationship between left ventricular diastolic and systolic dyssynchrony in hypertrophic cardiomyopathy (HCM) was investigated by single-cardiac real-time three-dimensional ultrasonography. A total of 52 patients with HCM were selected in Jining No. 1 People's Hospital from July 2016 to June 2017. Additionally, a total of 52 healthy people were selected to serve as the control group. All participants received real-time two- and three-dimensional ultrasonography to evaluate left ventricular morphology, function and systolic and diastolic function. The relevant parameters included left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left ventricular ejection fraction (LVEF), end-systolic/diastolic sphericity index (ESSI/EDSI), systolic dyssynchrony index (SDI), diastolic dyssynchrony index (DDI), dispersion end systole (DISPES), diastolic dyssynchrony index-late (DDI-late) and dispersion end diastole (DISPED-late). The LVEF of observation group was significantly lower than that of the control group, while LVEDV, LVESV, E/A and E/Ea were significantly higher than those in control group (P<0.05); EDSI, DDI-late and DISPED-late were significantly higher in observation than in control group (P<0.05); ESSI, SDI and DISPES in observation were significantly higher than those in control group (P<0.05); The 16-segment time-volume curve of observation group was disordered without synchronization, while the curve of control group was regular and smooth with synchronization; Pearson's correlation analysis showed that SDI and DDI were positively correlated (P<0.05). In conclusion, three-dimensional ultrasonography can be used to effectively evaluate left ventricular diastolic and systolic dyssynchrony in HCM. The severity of diastolic is positively correlated with systolic dyssynchrony.

Alternative and improved syntheses of highly potent and selective A3 adenosine receptor agonists, Cl-IB-MECA and thio-Cl-IB-MECA.

Improved syntheses of potent and selective A3 adenosine receptor agonists, Cl-IB-MECA and thio-Cl-IB-MECA were accomplished from cheap stating material, D-ribose. New synthetic methods were found to be superior to old methods from the viewpoint of use of cheap starting material, number of steps, and overall yields.