Discovery and biosynthesis of bacterial drimane-type sesquiterpenoids from Streptomyces clavuligerus.

Drimane-type sesquiterpenoids (DMTs) are characterized by a distinctive 6/6 bicyclic skeleton comprising the A and B rings. While DMTs are commonly found in fungi and plants, their presence in bacteria has not been reported. Moreover, the biosynthetic pathways for DMTs have been primarily elucidated in fungi, with identified P450s only acting on the B ring. In this study, we isolated and characterized three bacterial DMTs, namely 3ß-hydroxydrimenol (2), 2α-hydroxydrimenol (3), and 3-ketodrimenol (4), from Streptomyces clavuligerus. Through genome mining and heterologous expression, we identified a cav biosynthetic gene cluster responsible for the biosynthesis of DMTs 2-4, along with a P450, CavA, responsible for introducing the C-2 and C-3 hydroxy groups. Furthermore, the substrate scope of CavA revealed its ability to hydroxylate drimenol analogs. This discovery not only broadens the known chemical diversity of DMTs from bacteria, but also provides new insights into DMT biosynthesis in bacteria.

Voltage, thermal and magnetic field fiber sensors based on magnetic nanoparticles-doped photonic liquid crystal fibers.

In this article, highly sensitive voltage, thermal and magnetic field fiber sensors were obtained in magnetic nanoparticles-doped E7 liquid crystals filled into photonic crystal fibers (PLCF). The voltage and temperature sensitivity reached at 12.598 nm/V and -3.874 nm/°C, respectively. The minimum voltage response time is 48.2 ms. The phase transition temperature Tc of liquid crystal with magnetic dopant was reduced from 60 °C to 46 °C. The magnetic field sensor based on magnetic nanoparticles-doped PLCF were obtained with sensitivity of 118.2 pm/mT from 400 to 460 mT.

Discovery, Structure, and Mechanism of a Class II Sesquiterpene Cyclase.

Terpene cyclases (TCs), extraordinary enzymes that create the structural diversity seen in terpene natural products, are traditionally divided into two classes, class I and class II. Although the structural and mechanistic features of class I TCs are well-known, the corresponding details in class II counterparts have not been fully characterized. Here, we report the genome mining discovery and structural characterization of two class II sesquiterpene cyclases (STCs) from Streptomyces. These drimenyl diphosphate synthases (DMSs) are the first STCs shown to possess ß,γ-didomain architecture. High-resolution X-ray crystal structures of DMS from Streptomyces showdoensis (SsDMS) in complex with both a farnesyl diphosphate and Mg2+ unveiled an induced-fit mechanism, with an unprecedented Mg2+ binding mode, finally solving one of the lingering questions in class II TC enzymology. This study supports continued genome mining for novel bacterial TCs and provides new mechanistic insights into canonical class II TCs that will lead to advances in TC engineering and synthetic biology.

Sesquiterpenes from the endophytic fungus Periconia sp. F-31.

One new eremophilane sesquiterpene periconianone L (1), together with four known guaiane-type sesquiterpenes 4,10,11-trihydroxyguaiane (2), (-)-guai-1(10)-ene-4α,11-diolhydroxymecuration (3), guaidiol A (4), and epi-guaidiol A (5) were isolated from the endophytic fungus Periconia sp. F-31. The structure of the new compound was established by spectroscopic methods, including UV, IR, HRESIMS, and extensive NMR techniques. Compound 3 was isolated as natural product for the first time.

NIR-II Excitation Phototheranostic Nanomedicine for Fluorescence/Photoacoustic Tumor Imaging and Targeted Photothermal-Photonic Thermodynamic Therapy.

The success of phototheranostics is hampered by some intrinsic defects, such as limited light penetration depth, heat resistance of tumor cells to photothermal therapy (PTT) induced by heat shock protein (HSP) and stress resistance against photodynamic therapy (PDT) caused by hypoxia microenvironment of tumor. Herein, a second near infrared (NIR-II) light excitation phototheranostic nanomedicine has been fabricated by integrating the semiconducting polymer, azo compound, and HSP inhibitor into a thermosensitive liposome, followed by modification with targeting aptamer, forming Lip(PTQ/GA/AIPH) for multimodal phototheranostics of triple-negative breast cancer (TNBC). The phototheranostic nanomedicine provides tumor targeting NIR-II fluorescence and photoacoustic dual-modal imaging, as well as NIR-II PTT. The released HSP inhibitor can effectively inhibit the activity of HSP for enhanced NIR-II PTT. Moreover, azo compound can be decomposed by the NIR-II photothermal activation, generating cytotoxic free radicals and realizing oxygen-irrelevant photonic thermodynamic therapy (PTDT) effects. Under the NIR-II laser irradiation, NIR-II fluorescence/photoacoustic dual-modal imaging guided enhanced NIR-II PTT and PTDT by Lip(PTQ/GA/AIPH), can achieve precise diagnosis and effective suppression of deep-seated TNBC with negligible side effects. This work develops a promising NIR-II excitation phototheranostic nanomedicine for spatiotemporally specific diagnosis and combination therapy of TNBC.

Method for controlling temperature sensitivity of the fiber intermodal sensor and its application in the torsion sensor.

Temperature crosstalk has always been a critical problem for fiber intermodal sensors. In this work, we have proposed a novel method based on the special temperature response of photosensitive fiber to control the temperature sensitivity of the fiber intermodal sensor. The control of temperature sensitivity has been realized via adjusting the proportion of photosensitive fiber to single-mode fiber in the sensing part. The temperature sensitivity as high as -192 pm/°C, and as low as -2.6 pm/°C can be obtained, satisfying the demand in both research and application. The torsion sensor is taken as an example to illustrate feasibility of this method, showing no evident interference in the measurement of torsion parameters. The proposed method outstrips the conventional one by simple structure, facile manufacture, multiple use and low cost, which brings great promise for further employment in laboratory and industry.

Comparison of Fracture Load and Surface Wear of Microhybrid Composite and Ceramic Occlusal Veneers.

PURPOSE: To compare in vitro fracture load, surface wear, and roughness after thermal cycling and cyclic mechanical fatigue loading among cemented microhybrid resin-based composite and ceramic occlusal veneers fabricated at two thicknesses (1.5 and 2.5 mm). MATERIALS AND METHODS: Sixty-four extracted premolars without root canal treatment were prepared and restored with occlusal veneers of two thicknesses (1.5 and 2.5 mm), using four different materials: microhybrid composite (MC), fiber-reinforced microhybrid composite (FMC), heat-pressed lithium disilicate ceramic (HPC), and computer-aided design/computer-aided manufactured lithium disilicate ceramic (CCC). The specimens underwent thermal cycling and cyclic mechanical fatigue loading, and were then subjected to fracture testing, with loads at failure recorded as fracture load. Wear and surface roughness were recorded before and after fatigue loading. Results were analyzed using one-way ANOVA, two-way ANOVA (α = 0.05). RESULTS: All specimens survived thermal cycling and cyclic mechanical fatigue loading. At 1.5-mm thickness, the mean fracture load of FMC was highest (3926.48 ± 556.54 N), while that of CCC was highest (3066.45 ± 559.94 N) at 2.5 mm. Regardless of thickness, the fracture load of CCC was higher than that of HPC (p = 0.004 and p = 0.023). The wear of MC and FMC was significantly higher than those of HPC and CCC (p ≤ 0.001), but was similar in terms of the wear rate of tooth enamel. HPC exhibited the lowest surface roughness after fatigue loading (p ≤ 0.001). CONCLUSION: All tested occlusal veneers exhibited a fracture load considerably exceeding the maximum occlusal force in the posterior dentition. When the attainable space for restoration varies, different occlusal veneer materials should be considered. The surface wear and roughness also need to be considered when selecting materials.

Ep7GT, a glycosyltransferase with sugar donor flexibility from Epimedium pseudowushanense, catalyzes the 7-O-glycosylation of baohuoside.

Icariin (1a), a 7-O-glycosylated flavonoid glycoside, is recognized as the major pharmacologically active ingredient of Epimedium plants, which have been used in traditional Chinese medicine for thousands of years. However, no glycosyltransferase (GT) responsible for the 7-O-glycosylation of flavonoids has been identified from Epimedium plants to date. Herein, a GT, Ep7GT, was identified from E. pseudowushanense B. L. Guo, which can regiospecifically transfer a glucose moiety to baohuoside (1) at 7-OH to form icariin (1a). Ep7GT showed a rare broad donor substrate spectrum, including UDP-glucose, UDP-xylose, UDP-N-acetylglucosamine, UDP-rhamnose, UDP-galactose, UDP-glucuronic acid and TDP-glucose. Moreover, two new derivatives of icariin (1a), 7-O-ß-d-[2-(acetylamino)-2-deoxy-glucopyranosyl]-baohuoside (1b) and 7-O-ß-d-xylosyl-baohuoside (1c), were biosynthesized by using Ep7GT in vitro. Engineered Escherichia coli harbouring Ep7GT was constructed, and 10.1 µg mL-1 icariin (1a) was yielded by whole-cell biotransformation with baohuoside (1) as the substrate. The present work not only characterizes the GT responsible for the 7-O-glycosylation in the biosynthesis of icariin in Epimedium plants, but also indicates the significant potential of an enzymatic approach for the production of glycosylated baohuoside derivatives with different sugar moieties. What's more, these findings also provide a promising alternative for producing natural/unnatural bioactive flavonoid glycosides by metabolic engineering.

Four new monoterpenoids from an endophytic fungus Periconia sp. F-31.

Five monoterpenoids were isolated from the endophytic fungus Periconia sp. F-31, including three new carene-type monoterpenoids, 2-carene-5,8-diol (1), 2-carene-8,10-diol (2), 2-carene-8-acetamide (3), one new menthene-type monoterpenoid 8-hydroxy-1,7-expoxy-2-menthene (4), and one known monoterpenoid anethofuran (5). The structures of all compounds were elucidated based on a comprehensive spectroscopic data analysis, electronic circular dichroism (ECD), and calculated ECD.

Observation of the photonic Hall effect and photonic magnetoresistance in random lasers.

Modulation of scattering in random lasers (RLs) by magnetic fields has attracted much attention due to its rich physical insights. We fabricate magnetic gain polymer optical fiber to generate RLs. From macroscopic experimental phenomena, with the increase of the magnetic field strength, the magnetic transverse photocurrent exists in disordered multiple scattering of RLs and the emission intensity of RLs decreases, which is the experimental observation of photonic Hall effect (PHE) and photonic magnetoresistance (PMR) in RLs. At the microscopic level, based on the field dependence theory of magnetic disorder in scattered nanoparticles and the replica symmetry breaking theory, the magnetic-induced transverse diffusion of photons reduces the scattering disorder, and then decreases the intensity fluctuation disorder of RLs. Our work establishes a connection between the above two effects and RLs, visualizes the influence of magnetic field on RL scattering at the microscopic level, which is crucial for the design of RLs.

Electrocatalytic nitrite-to-ammonia reduction on isolated Cu sites.

We report that isolated Cu atoms anchored on MnO2 nanowires (Cu1/MnO2) can be an effective catalyst towards the electrocatalytic NO2--to-NH3 reduction (NO2RR). A combination of experiments and theoretical calculations reveals that isolated Cu sites can effectively activate NO2-, lower the energy barrier of *NO→*NOH rate-determining step and suppress the competitive hydrogen evolution, thus facilitating both activity and selectivity towards the NO2RR. As a result, Cu1/MnO2 shows the maximum NH3-Faradaic efficiency of 93.3% with a corresponding NH3 yield rate of 439.8 µmol h-1 cm-2 at -0.7 V vs. RHE, together with an excellent electrocatalytic durability.

Functional characterization of a cycloartenol synthase and four glycosyltransferases in the biosynthesis of cycloastragenol-type astragalosides from Astragalus membranaceus.

Astragalosides are the main active constituents of traditional Chinese medicine Huang-Qi, of which cycloastragenol-type glycosides are the most typical and major bioactive compounds. This kind of compounds exhibit various biological functions including cardiovascular protective, neuroprotective, etc. Owing to the limitations of natural sources and the difficulties encountered in chemical synthesis, re-engineering of biosynthetic machinery will offer an alternative and promising approach to producing astragalosides. However, the biosynthetic pathway for astragalosides remains elusive due to their complex structures and numerous reaction types and steps. Herein, guided by transcriptome and phylogenetic analyses, a cycloartenol synthase and four glycosyltransferases catalyzing the committed steps in the biosynthesis of such bioactive astragalosides were functionally characterized from Astragalus membranaceus. AmCAS1, the first reported cycloartenol synthase from Astragalus genus, is capable of catalyzing the formation of cycloartenol; AmUGT15, AmUGT14, AmUGT13, and AmUGT7 are four glycosyltransferases biochemically characterized to catalyze 3-O-xylosylation, 3-O-glucosylation, 25-O-glucosylation/O-xylosylation and 2'-O-glucosylation of cycloastragenol glycosides, respectively. These findings not only clarified the crucial enzymes for the biosynthesis and the molecular basis for the structural diversity of astragalosides in Astragalus plants, also paved the way for further completely deciphering the biosynthetic pathway and constructing an artificial pathway for their efficient production.

Profiling the Major Aroma-Active Compounds of Microwave-Dried Jujube Slices through Molecular Sensory Science Approaches.

To discriminate the aroma-active compounds in dried jujube slices through microwave-dried treatments and understand their sensory attributes, odor activity value (OAV) and detection frequency analysis (DFA) combined with sensory analysis and analyzed through partial least squares regression analysis (PLSR) were used collaboratively. A total of 21 major aromatic active compounds were identified, among which 4-hexanolide, 4-cyclopentene-1,3-dione, 5-methyl-2(5H)-furanone, 4-hydroxy-2,5-dimethyl-3(2H)furanone, 3,5-dihydroxy-2-methyl-4-pyrone were first confirmed as aromatic compounds of jujube. Sensory evaluation revealed that the major characteristic aromas of dried jujube slices were caramel flavor, roasted sweet flavor, and bitter and burnt flavors. The PLSR results showed that certain compounds were related to specific taste attributes. 2,3-butanedione and acetoin had a significant positive correlation with the roasted sweet attribute. On the other hand, γ-butyrolactone, 4-cyclopentene-1,3-dione, and 4-hydroxy-2,5-dimethyl-3(2H)furanone had a significant positive impact on the caramel attributes. For the bitter attribute, 2-acetylfuran and 5-methyl-2(5H)-furanone were positively correlated. Regarding the burnt flavor, 5-methyl-2-furancarboxaldehyde and 3,5-dihydroxy-2-methyl-4-pyrone were the most influential odor-active compounds. Finally, 2-furanmethanol and 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4-one were identified as the primary sources of the burnt and bitter flavors. Importantly, this work could provide a theoretical basis for aroma control during dried jujube slices processing.

Drimane-type sesquiterpenoids from fungi.

Sesquiterpenoids are comprised of three C5 units and derived from farnesyl diphosphate. In these C15 family of terpenoids, drimane-type sesquiterpenoids are unique as their chemical structure of decahydronaphthalene along with the methyl group decorations resemble the A/B rings of labdane derived diterpenoids and the eastern part of many meroterpenoids. In the past decades, based on their chemical structural features and diverse bioactivities, great efforts have been made to perform chemical and biological research on this family of natural products, leading to the characterization of a large of new compounds and a few biosynthetic pathways. In this review, we collected 164 new drimane-type sesquiterpenoids from fungi between January 2004 and October 2021 and classified them into three major subfamilies, so as to highlight their diverse chemical structures, biological activities, and biosynthetic pathways,.

Near-infrared-II light excitation thermosensitive liposomes for photoacoustic imaging-guided enhanced photothermal-chemo synergistic tumor therapy.

Despite the great success of photothermal therapy (PTT), it still suffers from many obstacles, such as the limited penetration depth of light, thermoresistance of tumors, and limitations of mono-therapeutic modalities. Herein, second near-infrared (NIR-II, 1064 nm) light excitation thermosensitive liposomes (DG@TLs) were fabricated for photoacoustic imaging (PAI) guided enhanced PTT-chemotherapy. DG@TLs were constructed by encapsulating NIR-II light excitation semiconducting polymers into liposomes composed of phase change materials (PCMs), along with gambogic acid (GA) with chemotherapeutic and heat shock protein inhibition effects. Under 1064 nm laser irradiation, DG@TLs exhibited superior NIR-II PAI and PTT performances with deep tissue penetration while triggering the thermoresponsive release of GA based on the phase transition of PCMs from solid to liquid. The released GA could enhance the NIR-II PTT efficacy by inhibiting the activity of HSP90, reducing the thermoresistance of tumors, exhibiting significant chemotherapeutic effects, and achieving synergistic anti-tumor efficiency. This work provides a new strategy for achieving on-demand drug release and effective theranostics in deep-seated tumor regions.

Injectable and Thermosensitive Liposomal Hydrogels for NIR-II Light-Triggered Photothermal-Chemo Therapy of Pancreatic Cancer.

An injectable hydrogel sustained drug release system could be a promising technique for in situ treatment. Herein, an injectable hydrogel was prepared for photothermal-chemo therapy of cancer based on the thermosensitive liposomal hydrogel (Lip-Gel). The Lip-Gel system was fabricated by encapsulation of the NIR-II photothermal agent (DPP-BTz) and chemotherapy drugs (GEM) in thermosensitive liposomes and then combined with hydrogel precursor solution. The hydrogel precursor was used as an injectable flowing solution at room temperature and transferred into a cross-linked gel structure at physiological temperature. After being injected into the tumor, DPP-BTz in the Lip-Gel system can generate heat under irradiation of 1064 nm laser, breaking the thermosensitive liposomes and releasing GEM to kill tumor cells. From the treatment results, the Lip-Gel system showed a significant antitumor effect through chemo-/photothermal therapy combination therapy triggered by the NIR-II laser. This work provides a useful scheme for the development of drug delivery and drug treatment directions for local cancer therapy.

Tumor Microenvironment-Responsive Fe(III)-Porphyrin Nanotheranostics for Tumor Imaging and Targeted Chemodynamic-Photodynamic Therapy.

The development of effective and safe tumor nanotheranostics remains a research imperative. Herein, tumor microenvironment (TME)-responsive Fe(III)-porphyrin (TCPP) coordination nanoparticles (FT@HA NPs) were prepared using a simple one-pot method followed by modification with hyaluronic acid (HA). FT@HA NPs specifically accumulated in CD44 receptor-overexpressed tumor tissues through the targeting property of HA and upon endocytosis by tumor cells. After cell internalization, intracellular acidic microenvironments and high levels of glutathione (GSH) triggered the rapid decomposition of FT@HA NPs to release free TCPP molecules and Fe(III) ions. The released Fe(III) ions could trigger GSH depletion and Fenton reaction, activating chemodynamic therapy (CDT). Meanwhile, the fluorescence and photodynamic effects of the TCPP could be also activated, achieving controlled reactive oxygen species (ROS) generation and avoiding side effects on normal tissues. Moreover, the rapid consumption of GSH further enhanced the efficacy of CDT and photodynamic therapy (PDT). The in vivo experiments further demonstrated that the antitumor effect of these nanotheranostics was significantly enhanced and that their toxicity and side effects against normal tissues were effectively suppressed. The FT@HA NPs can be applied for activated tumor combination therapy under the guidance of dual-mode imaging including fluorescence imaging and magnetic resonance imaging, providing an effective strategy for the design and preparation of TME-responsive multifunctional nanotheranostics for precise tumor imaging and combination therapy.