Silver Organometallics that are Highly Potent Thioredoxin and Glutathione Reductase Inhibitors: Exploring the Correlations of Solution Chemistry with the Strong Antibacterial Effects.

The antibacterial activity of silver species is well-established; however, their mechanism of action has not been adequately explored. Furthermore, issues of low-molecular silver compounds with cytotoxicity, stability, and solubility hamper their progress to drug leads. We have investigated silver N-heterocyclic carbene (NHC) halido complexes [(NHC)AgX, X = Cl, Br, and I] as a promising new type of antibacterial silver organometallics. Spectroscopic studies and conductometry established a higher stability for the complexes with iodide ligands, and nephelometry indicated that the complexes could be administered in solutions with physiological chloride levels. The complexes showed a broad spectrum of strong activity against pathogenic Gram-negative bacteria. However, there was no significant activity against Gram-positive strains. Further studies clarified that tryptone and yeast extract, as components of the culture media, were responsible for this lack of activity. The reduction of biofilm formation and a strong inhibition of both glutathione and thioredoxin reductases with IC50 values in the nanomolar range were confirmed for selected compounds. In addition to their improved physicochemical properties, the compounds with iodide ligands did not display cytotoxic effects, unlike the other silver complexes. In summary, silver NHC complexes with iodide secondary ligands represent a useful scaffold for nontoxic silver organometallics with improved physicochemical properties and a distinct mechanism of action that is based on inhibition of thioredoxin and glutathione reductases.

Discovery of novel secondary metabolites from the basidiomycete Lentinus cf. sajor-caju and their inhibitory effects on Staphylococcus aureus biofilms.

Three novel derivatives of microporenic acid, microporenic acids H-J, were identified from submerged cultures of a Lentinus species obtained from a basidiome collected during a field trip in the tropical rainforest in Western Kenya. Their structures were elucidated via HR-ESIMS spectra and 1D/2D NMR spectroscopic analyses, as well as by comparison with known derivatives. Applying biofilm assays based on crystal violet staining and confocal microscopy, two of these compounds, microporenic acids H and I, demonstrated the ability to inhibit biofilm formation of the opportunistic pathogen Staphylococcus aureus. Thereby, they were effective in a concentration range that did not affect planktonic growth. Additionally, microporenic acid I enhanced the anti-biofilm activity of the antibiotics vancomycin and gentamicin when used in combination. This opens up possibilities for the use of these compounds in combination therapy to prevent the formation of S. aureus biofilms.

Recent Advances in Implantable Neural Interfaces for Multimodal Electrical Neuromodulation.

Electrical neuromodulation plays a pivotal role in enhancing patient outcomes among individuals suffering from neurological disorders. Implantable neural interfaces are vital components of the electrical neuromodulation system to ensure desirable performance; However, conventional devices are limited to a single function and are constructed with bulky and rigid materials, which often leads to mechanical incompatibility with soft tissue and an inability to adapt to the dynamic and complex 3D structures of biological systems. In addition, current implantable neural interfaces utilized in clinical settings primarily rely on wire-based techniques, which are associated with complications such as increased risk of infection, limited positioning options, and movement restrictions. Here, the state-of-art applications of electrical neuromodulation are presented. Material schemes and device structures that can be employed to develop robust and multifunctional neural interfaces, including flexibility, stretchability, biodegradability, self-healing, self-rolling, or morphing are discussed. Furthermore, multimodal wireless neuromodulation techniques, including optoelectronics, mechano-electrics, magnetoelectrics, inductive coupling, and electrochemically based self-powered devices are reviewed. In the end, future perspectives are given.

Bioactive Compounds from an Endophytic Pezicula sp. Showing Antagonistic Effects against the Ash Dieback Pathogen.

A fungal endophyte originating from the Canary Islands was identified as a potent antagonist against the fungal phytopathogen Hymenoscyphus fraxineus, which causes the devastating ash dieback disease. This endophyte was tentatively identified as Pezicula cf. ericae, using molecular barcoding. Isolation of secondary metabolites by preparative high-performance liquid chromatography (HPLC) yielded the known compounds CJ-17,572 (1), mycorrhizin A (3) and cryptosporioptides A-C (4-6), besides a new N-acetylated dihydroxyphenylalanin derivative 2, named peziculastatin. Planar structures were elucidated by NMR and HRMS data, while the relative stereochemistry of 2 was assigned by H,H and C,H coupling constants. The assignment of the unknown stereochemistry of CJ-17,572 (1) was hampered by the broadening of NMR signals. Nevertheless, after semisynthetic conversion of 1 into its methyl derivatives 7 and 8, presumably preventing tautomeric effects, the relative configuration could be assigned, whereas comparison of ECD data to those of related compounds determined the absolute configuration. Metabolites 1 and 3 showed significant antifungal effects in vitro against H. fraxineus. Furthermore, 4-6 exhibited significant dispersive effects on preformed biofilms of S. aureus at concentrations up to 2 µg/mL, while the biofilm formation of C. albicans was also inhibited. Thus, cryptosporioptides might constitute a potential source for the development of novel antibiofilm agents.

Sporothioethers: deactivated alkyl citrates from the fungus Hypomontagnella monticulosa.

Submerged cultivation of Hypomontagnella monticulosa MUCL 54604 resulted in formation of a stereoisomeric mixture of new sulfur-containing sporothriolide derivatives named sporothioethers A and B. The presence of the 2-hydroxy-3-mercaptopropanoic acid moiety attenuates the antimicrobial activity in comparison to the precursor sporothriolide suggesting a detoxification mechanism. However, moderate effects on biofilms of Candida albicans and Staphylococcus aureus were observed for sporothriolide and sporothioethers A and B at concentrations below their MICs.

Inhibitory Effects of the Fungal Pigment Rubiginosin C on Hyphal and Biofilm Formation in Candida albicans and Candida auris.

The two fungal human pathogens, Candida auris and Candida albicans, possess a variety of virulence mechanisms. Among them are the formation of biofilms to protect yeast against harsh conditions through the development of (pseudo)hyphae whilst also facilitating the invasion of host tissues. In recent years, increased rates of antifungal resistance have been associated with C. albicans and C. auris, posing a significant challenge for the effective treatment of fungal infections. In the course of our ongoing search for novel anti-infectives, six selected azaphilones were tested for their cytotoxicity and antimicrobial effects as well as for their inhibitory activity against biofilm and hyphal formation. This study revealed that rubiginosin C, derived from stromata of the ascomycete Hypoxylon rubiginosum, effectively inhibited the formation of biofilms, pseudohyphae, and hyphae in both C. auris and C. albicans without lethal effects. Crystal violet staining assays were utilized to assess the inhibition of biofilm formation, while complementary microscopic techniques, such as confocal laser scanning microscopy, scanning electron microscopy, and optical microscopy, were used to investigate the underlying mechanisms. Rubiginosin C is one of the few substances known to effectively target both biofilm formation and the yeast-to-hyphae transition of C. albicans and C. auris within a concentration range not affecting host cells, making it a promising candidate for therapeutic intervention in the future.

Cytochalasans produced by Xylaria karyophthora and their biological activities.

The recent description of the putative fungal pathogen of greenheart trees, Xylaria karyophthora (Xylariaceae, Ascomycota), prompted a study of its secondary metabolism to access its ability to produce cytochalasans in culture. Solid-state fermentation of the ex-type strain on rice medium resulted in the isolation of a series of 19,20-epoxidated cytochalasins by means of preparative high-performance liquid chromatography (HPLC). Nine out of 10 compounds could be assigned to previously described structures, with one compound being new to science after structural assignment via nuclear magnetic resonance (NMR) assisted by high-resolution mass spectrometry (HRMS). We propose the trivial name "karyochalasin" for the unprecedented metabolite. The compounds were used in our ongoing screening campaign to study the structure-activity relationship of this family of compounds. This was done by examining their cytotoxicity against eukaryotic cells and impact on the organization of networks built by their main target, actin-a protein indispensable for processes mediating cellular shape changes and movement. Moreover, the cytochalasins' ability to inhibit the biofilm formation of Candida albicans and Staphylococcus aureus was examined.

Inflammatory mechanisms of Ginkgo Biloba extract in improving memory functions through lncRNA-COX2/NF-κB pathway in mice with status epilepticus.

PURPOSE: This study was to explore whether Ginkgo biloba extract (GBE) improve memory impairment by alleviating neuroinflammation signaling in mice with status epilepticus. METHODS: The status epilepticus (SE) mice model was established by pilocarpine and treated with 100 mg / kg of GBE for 14 days. Spontaneous alternation of Y-maze and new object recognition were used to explore memory impairment. To examine glial cell activation, we performed immunohistochemistry and immunofluorescence staining. The activation of NF-κB signaling and the expression level of lncRNA-COX2 were detected by Western blot and qRT-PCR, respectively. Adeno-associated virus lncRNA-COX2 was injected into mice for overexpression of lncRNA-COX2. RESULTS: After GBE treatment, the spontaneous alternation rate and the recognition coefficient in SE mice were both increased. Moreover, activation of glial cells, NF-κB signaling and lncRNA-COX2 were significantly decreased in SE mice. In the GBE-treated SE mice with lncRNA-COX2 overexpression, NF-κB signaling was up-regulated again; the reduced level of inflammation factors was reversed; the GBE-rescued spontaneous alternation rate of Y-maze was eliminated. CONCLUSION: Our results suggested that GBE reduces the hippocampal inflammation by down-regulating lncRNA-COX2 / NF-κB signaling in the SE mice, leading to the decrease of neuronal damage and the improvement of memory functions.

Syntheses and biological effects of natural Morinda lactone and derivatives.

2-Caffeoyl-3-ketohexulofuranosonic acid γ-lactone (morinda lactone; 1a), a natural constituent of Morinda citrifolia L. (Rubiaceae), and eight derivatives with variance in the aryl residue were synthesised by Tsuji-Trost allylation of vitamin C acetonide with the respective aryl allyl alcohol. They were screened for antibiotic activities and for effects on the growth and persistence of microbial biofilms. Some derivatives were active against biofilms of S. aureus or C. albicans at concentrations not toxic to these microorganisms or mammalian cells.

Effect of High-Frequency Repetitive Peripheral Magnetic Stimulation on Motor Performance in Intracerebral Haemorrhage: A Clinical Trial.

OBJECTIVES: The aim of the randomized, double-blind, sham-controlled trial was to explore the efficacy and safety of HF-rPMS synchronosly applied to the axilla (stimulating the brachial plexus) and the popliteal fossa (stimulating the tibial nerve and common peroneal nerve) in patients with intracerebral hemorrhage on rehabilitation of motor functions. MATERIALS AND METHODS: Patients with intracerebral haemorrhage in the early period were recruited and randomly assigned to the HF-rPMS group or the sham rPMS group. The two synchrous coils of magnetic stimulation in the two groups were respectively applied to the axilla and the popliteal fossa of the affected limb. But the sham group received the ineffective rPMS and only heard the sound as occured in the HF-rPMS group. Clinical outcomes included the change of Fugl-Meyer Assessment (FMA) scale and Medical Research Council (MRC) scale before and after HF-rPMS. RESULTS: Of 76 eligible patients, 30 were included and only 26 patients completed this study. The diferences on the improvement of the upper extremity FMA (P=0.012), the lower extremity FMA (P=0.001), the proximal MRC of upper extremity (p = 0.043), the proximal MRC of lower extremity (p= 0.004) and the distal MRC scores of lower extremity (p= 0.008) between the the HF-rPMS group and sham rPMS group were statistically signifcant. CONCLUSIONS: Synchrous HF-rPMS intervention at the axilla and the popliteal fossa significantly improved motor function and proximal muscle strength of upper and lower limb of patients in acute or early subacute phase of intracerebral hemorrhage.

Synthesis and Bioactivity of Ophiofuranones A and B.

Ophiofuranones A and B, metabolites of the fungus Ophiosphaerella korrae, were synthesized in 16 steps and 12%/22% yield. The stereogenic centers were established by Sharpless dihydroxylations and epoxidation, the 1,3-dienes via Wittig or HWE olefinations. The rings were closed through Knoevenagel-type condensation and lactonization. The ophiofuranones proved nontoxic at relevant concentrations against tumor cells, fibroblasts, and various bacteria and fungi. Ophiofuranone A and the monocyclic precursors 4 were weakly active against microbial biofilms.

Synthesis and Bioactivity of a Macrocidin B Stereoisomer.

A stereoisomer of macrocidin B, a presumed metabolite of the fungus Phoma macrostoma, was synthesized in 18 steps and 2.7% yield from protected l-tyrosine that was N-ß-ketoacylated with a fully functionalized octanoyl Meldrum's acid. Dieckmann condensation gave a 3-acyltetramic acid, which was macrocyclized via Williamson etherification between the phenol and epi-bromohydrin termini. This macrocidin B stereoisomer showed a weaker herbicidal effect than macrocidin A and no similar inhibitory effect on biofilms of Staphylococcus aureus.

Synthesis and Bioactivity of Ancorinoside B, a Marine Diglycosyl Tetramic Acid.

The sponge metabolite ancorinoside B was prepared for the first time in 16 steps and 4% yield. It features a ß-d-galactopyranosyl-(1→4)-ß-d-glucuronic acid tethered to a d-aspartic acid-derived tetramic acid. Key steps were the synthesis of a fully protected d-lactose derived thioglycoside, its attachment to a C20-aldehyde spacer, functionalization of the latter with a terminal N-(ß-ketoacyl)-d-aspartate, and a basic Dieckmann cyclization to close the pyrrolidin-2,4-dione ring with concomitant global deprotection. Ancorinoside B exhibited multiple biological effects of medicinal interest. It inhibited the secretion of the cancer metastasis-relevant matrix metalloproteinases MMP-2 and MMP-9, and also the growth of Staphylococcus aureus biofilms by ca 87% when applied at concentrations as low as 0.5 µg/mL. This concentration is far below its MIC of ca 67 µg/mL and thus unlikely to induce bacterial resistance. It also led to a 67% dispersion of preformed S. aureus biofilms when applied at a concentration of ca 2 µg/mL. Ancorinoside B might thus be an interesting candidate for the control of the general hospital, catheter, or joint protheses infections.

Total Synthesis via Biomimetic Late-Stage Heterocyclization: Assignment of the Relative Configuration and Biological Evaluation of the Nitraria Alkaloid (±)-Nitrabirine.

The racemic total synthesis of nitrabirine (5) together with its previously undescribed epimer 2-epi nitrabirine (5') is accomplished via a six-step route based on a biomimetic late-stage heterocyclization. This allowed the assignment of the relative configuration of nitrabirine by the lanthanide-induced shifts (LIS) experiment, which was later on confirmed by X-ray diffraction of obtained single crystals. Furthermore, oxidation studies demonstrated that the direct N-oxidation of nitrabirine does not yield nitrabirine N-oxide as reported earlier. In contrast, the reaction of hydrogen peroxide with nitrabirine (5) yields the salt 24', whereas 2-epi nitrabirine (5') surprisingly leads to a previously uncharacterized product 22 under the same conditions. Finally, a Fischer indole reaction gave access to novel tetracyclic nitrabirine derivatives 26a-d. A comprehensive biological evaluation of nitrabirine (5), 2-epi nitrabirine (5'), and all derivatives synthesized in this study revealed general biofilm dispersal effects against Candida albicans. Moreover, specific compounds showed moderate antibacterial activities as well as potent cytotoxic activities.

Dual Agents: Fungal Macrocidins and Synthetic Analogues with Herbicidal and Antibiofilm Activities.

Eight analogues of the bioherbicides macrocidin A (1) and Z (2) with structural variance in the size of the macrocycle, its para- or meta-cyclophane character, and its functional groups were synthesized on two modular routes and tested for herbicidal, antibiotic, and antibiofilm activities. Apart from the lead compounds 1 and 2, the structurally simplified dihydromacrocidin Z (3) and normacrocidin Z (4) showed high herbicidal activity in either thistles, dandelions or in both. The derivatives 2, 3, and dibromide 9 also inhibited the growth of Staphylococcus aureus biofilms by ca 70% when applied at subtoxic concentrations as low as ca 20 µM, which are unlikely to induce bacterial resistance. They also led to the dispersion of preformed biofilms of S. aureus, exceeding a similar effect by microporenic acid A, a known biofilm inhibitor. Compounds 3 and 9 showed no noticeable cytotoxicity against human cancer and endothelial cells at concentrations below 50 µM, making them conceivable candidates for application as anti-biofilm agents in a medicinal context.

Synthesis of the fungal macrolide berkeleylactone A and its inhibition of microbial biofilm formation.

The fungal macrolide berkeleylactone A was synthesised in 13 steps and 24% yield using (R)-propylene oxide and an asymmetric Noyori hydrogenation of a ß-ketoester to install the stereogenic centres. A domino addition-Wittig olefination of a 13-hydroxytetradecanal intermediate with the cumulated ylide Ph3PCCO closed the macrocyle by establishing the α,ß-unsaturated ester group, necessary for the attachment of the sidechain thiol via a thia-Michael reaction. The synthetic berkeleylactone A inhibited the formation of Staphylococcus aureus biofilms and showed significant dispersive effects on preformed biofilms of Candida albicans by at least 45% relative to untreated controls at concentrations as low as 1.3 µg mL-1.

Macrooxazoles A-D, New 2,5-Disubstituted Oxazole-4-Carboxylic Acid Derivatives from the Plant Pathogenic Fungus Phoma macrostoma.

In our ongoing search for new bioactive fungal metabolites, four previously undescribed oxazole carboxylic acid derivatives (1-4) for which we proposed the trivial names macrooxazoles A-D together with two known tetramic acids (5-6) were isolated from the plant pathogenic fungus Phoma macrostoma. Their structures were elucidated based on high-resolution mass spectrometry (HR-MS) and nuclear magnetic resonance (NMR) spectroscopy. The hitherto unclear structure of macrocidin Z (6) was also confirmed by its first total synthesis. The isolated compounds were evaluated for their antimicrobial activities against a panel of bacteria and fungi. Cytotoxic and anti-biofilm activities of the isolates are also reported herein. The new compound 3 exhibited weak-to-moderate antimicrobial activity as well as the known macrocidins 5 and 6. Only the mixture of compounds 2 and 4 (ratio 1:2) showed weak cytotoxic activity against the tested cancer cell lines with an IC50 of 23 µg/mL. Moreover, the new compounds 2 and 3, as well as the known compounds 5 and 6, interfered with the biofilm formation of Staphylococcus aureus, inhibiting 65%, 75%, 79%, and 76% of biofilm at 250 µg/mL, respectively. Compounds 5 and 6 also exhibited moderate activity against S. aureus preformed biofilm with the highest inhibition percentage of 75% and 73% at 250 µg/mL, respectively.

Stretchable MoS2 Electromechanical Sensors with Ultrahigh Sensitivity and Large Detection Range for Skin-on Monitoring.

Although two-dimensional (2D) layered molybdenum disulfide (MoS2) has widespread electrical applications in catalysis, energy storage, display, and photodetection, very few reports are available to achieve MoS2 for electromechanical sensing. Here, we report a novel solution-processed MoS2 strain sensor by constructing nanojunctions between layered MoS2 nanosheets and high-conductivity silver nanofibers (AgNFs) inside an elastic film. Benefiting from the outstanding lubrication property of layered MoS2 nanosheets, these nanojunctions can be easily separated by strains, giving rise to excellent electromechanical response. The resulting MoS2 strain sensor for the first time exhibits ultrahigh sensitivity with a gauge factor of 3,300 in a large detection range over 10%. The pronounced strain-sensing ability, combined with fast response speed and good operational stability, enables the MoS2 sensor for real-time and skin-on monitorings of various physiological signals such as finger movements, pulse, and breath. Our results may pave the way to extend 2D materials in novel applications such as soft robotics and human-machine interfaces.

An ultra-stretchable, highly sensitive and biocompatible capacitive strain sensor from an ionic nanocomposite for on-skin monitoring.

Flexible strain sensors that can be comfortably attached onto the skin for real-time and accurate detection of physiological signals are particularly important for the realization of healthcare, soft robotics and human-machine interfacing. It is still challenging to develop strain sensors that satisfy both high stretchability and high sensitivity. Here, we demonstrate an ultra-stretchable, highly sensitive and biocompatible capacitive-type strain sensor based on a nanocomposite containing ionic hydrogels and silver nanofibers (AgNFs). The sensor exhibits an ultra-high stretchability of 1000% and high sensitivity with a maximum gauge factor (GF) of up to 165. We find that the incorporation of AgNFs greatly increases the electrical-double layer (EDL) area at the hydrogel/metal interface and hence enhances by 3 orders of magnitude the strain sensitivity. With a short response time and good operation stability, the sensor and its matrix were successfully applied to monitor various physiological signals such as arm and finger motions, pulse, electrocardiographs (ECG), breath, speaking and emotion changes.

Flexible and Broad-Spectral Hybrid Optical Modulation Transistor Based on a Polymer-Silver Nanoparticle Blend.

The light-matter interplay on a soft substrate is critically important for novel optoelectronic applications such as soft robotics, human-machine interfaces, and wearable devices. Here, we for the first time report a flexible and efficiency-enhanced hybrid optical modulation transistor (h-OMT) in the ultraviolet-infrared spectral range by blending a polymer with silver nanoparticles (AgNPs). The h-OMT device exhibits a unipolar transport and an ultrahigh on-off ratio of ∼4.8 × 106 in a small voltage range of ∼2 V. Using charge modulation reflection spectroscopy, we demonstrate that the h-OMT device shows a broad-spectral response from 400 to 2000 nm and maximum optical modulation of ∼15% at λ = 785 nm, 6-fold higher magnitude than that of the device without AgNPs. Furthermore, the incorporation of AgNPs enhances the extinction ratio by 4-fold magnitude without any complex geometry designs. We find that the performance improvement relies on the AgNP-induced electron trap states and electrochemical dopings in the polymer. Importantly, the device exhibits pronounced mechanical flexibility, and the optical modulation is kept down to a bending radius of 0.5 mm. Our data provide the possibility of organic materials for constructing novel optoelectronic systems in the future.