Rogersonins C-F, 9H-Imidazo[2,1-i]purine-Incorporating Adenine-Polyketide Hybrids from an Ophiocordyceps-Associated Clonostachys rogersoniana.

Rogersonins C-F (1-4), four unprecedented adenine-polyketide hybrids featuring a rare 9H-imidazo[2,1-i]purine (1,N6-ethenoadenine) moiety, were isolated from an Ophiocordyceps-associated fungus, Clonostachys rogersoniana. Their structures were elucidated primarily by NMR experiments. The absolute configurations of 1-4 were assigned by a combination of the modified Mosher method, chemical degradation, electronic circular dichroism (ECD) calculations, and X-ray crystallography using Cu Kα radiation. Compound 3 downregulated the expression of PD-L1 protein in MDA-MB-231 and A549 cells, but did not show detectable effect on mRNA transcription of the PD-L1-encoding gene CD274.

Substituent Effects and Mechanistic Insights on the Catalytic Activities of (Tetraarylcyclopentadienone)iron Carbonyl Compounds in Transfer Hydrogenations and Dehydrogenations.

(Cyclopentadienone)iron carbonyl compounds are catalytically active in carbonyl/imine reductions, alcohol oxidations, and borrowing hydrogen reactions, but the effect of cyclopentadienone electronics on their activity is not well established. A series of (tetraarylcyclopentadienone)iron tricarbonyl compounds with varied electron densities on the cyclopentadienone were prepared, and their activities in transfer hydrogenations and dehydrogenations were explored. Additionally, mechanistic studies, including kinetic isotope effect experiments and modifications to substrate electronics, were undertaken to gain insights into catalyst resting states and turnover-limiting steps of these reactions. As the cyclopentadienone electron density increased, both the transfer hydrogenation and dehydrogenation rates increased. A catalytically relevant, trimethylamine-ligated iron compound was isolated and characterized and was observed in solution under both transfer hydrogenation and dehydrogenation conditions. Importantly, it was catalytically active in both reactions. Kinetic isotope effect data and initial rates in transfer hydrogenation reactions with 4'-substituted acetophenones provided evidence that hydrogen transfer from the catalyst to the carbonyl substrate occurred during the turnover-limiting step, and NMR spectroscopy supports the trimethylamine adduct as an off-cycle resting state and the (hydroxycyclopentadienyl)iron hydride as an on-cycle resting state. In transfer dehydrogenations of alcohols, the use of electronically modified benzylic alcohols provided evidence that the turnover-limiting step involves the transfer of hydrogen from the alcohol substrate to the catalyst. The trimethylamine-ligated compound was proposed as the primary catalyst resting state in dehydrogenations.

Copper-Phosphido Catalysis: Enantioselective Addition of Phosphines to Cyclopropenes.

We describe a copper catalyst that promotes the addition of phosphines to cyclopropenes at ambient temperature. A range of cyclopropylphosphines bearing different steric and electronic properties can now be accessed in high yields and enantioselectivities. Enrichment of phosphorus stereocenters is also demonstrated via a Dynamic Kinetic Asymmetric Transformation (DyKAT) process. A combined experimental and theoretical mechanistic study supports an elementary step featuring insertion of a CuI -phosphido into a carbon-carbon double bond. Density functional theory calculations reveal migratory insertion as the rate- and stereo-determining step, followed by a syn-protodemetalation.

Therapeutic potential of vasoactive intestinal peptide and its receptor VPAC2 in type 2 diabetes.

Owing to the increasing prevalence of type 2 diabetes, the development of novel hypoglycemic drugs has become a research hotspot, with the ultimate goal of developing therapeutic drugs that stimulate glucose-induced insulin secretion without inducing hypoglycemia. Vasoactive intestinal peptide (VIP), a 28-amino-acid peptide, can stimulate glucose-dependent insulin secretion, particularly by binding to VPAC2 receptors. VIP also promotes islet ß-cell proliferation through the forkhead box M1 pathway, but the specific molecular mechanism remains to be studied. The clinical application of VIP is limited because of its short half-life and wide distribution in the human body. Based on the binding properties of VIP and VPAC2 receptors, VPAC2-selective agonists have been developed to serve as novel hypoglycemic drugs. This review summarizes the physiological significance of VIP in glucose homeostasis and the potential therapeutic value of VPAC2-selective agonists in type 2 diabetes.

Effects of the POMC System on Glucose Homeostasis and Potential Therapeutic Targets for Obesity and Diabetes.

The hypothalamus is indispensable in energy regulation and glucose homeostasis. Previous studies have shown that pro-opiomelanocortin neurons receive both central neuronal signals, such as α-melanocyte-stimulating hormone, ß-endorphin, and adrenocorticotropic hormone, as well as sense peripheral signals such as leptin, insulin, adiponectin, glucagon-like peptide-1, and glucagon-like peptide-2, affecting glucose metabolism through their corresponding receptors and related signaling pathways. Abnormalities in these processes can lead to obesity, type 2 diabetes, and other metabolic diseases. However, the mechanisms by which these signal molecules fulfill their role remain unclear. Consequently, in this review, we explored the mechanisms of these hormones and signals on obesity and diabetes to suggest potential therapeutic targets for obesity-related metabolic diseases. Multi-drug combination therapy for obesity and diabetes is becoming a trend and requires further research to help patients to better control their blood glucose and improve their prognosis.

Erythroid lineage Jak2V617F expression promotes atherosclerosis through erythrophagocytosis and macrophage ferroptosis.

Elevated hematocrit is associated with cardiovascular risk; however, the causality and mechanisms are unclear. The JAK2V617F (Jak2VF) mutation increases cardiovascular risk in myeloproliferative disorders and in clonal hematopoiesis. Jak2VF mice with elevated WBCs, platelets, and RBCs display accelerated atherosclerosis and macrophage erythrophagocytosis. To investigate whether selective erythroid Jak2VF expression promotes atherosclerosis, we developed hyperlipidemic erythropoietin receptor Cre mice that express Jak2VF in the erythroid lineage (VFEpoR mice). VFEpoR mice without elevated blood cell counts showed increased atherosclerotic plaque necrosis, erythrophagocytosis, and ferroptosis. Selective induction of erythrocytosis with low-dose erythropoietin further exacerbated atherosclerosis with prominent ferroptosis, lipid peroxidation, and endothelial damage. VFEpoR RBCs had reduced antioxidant defenses and increased lipid hydroperoxides. Phagocytosis of human or murine WT or JAK2VF RBCs by WT macrophages induced ferroptosis, which was prevented by the ferroptosis inhibitor liproxstatin-1. Liproxstatin-1 reversed increased atherosclerosis, lipid peroxidation, ferroptosis, and endothelial damage in VFEpoR mice and in Jak2VF chimeric mice simulating clonal hematopoiesis, but had no impact in controls. Erythroid lineage Jak2VF expression led to qualitative and quantitative defects in RBCs that exacerbated atherosclerosis. Phagocytosis of RBCs by plaque macrophages promoted ferroptosis, suggesting a therapeutic target for reducing RBC-mediated cardiovascular risk.

Innate Immune System Orchestrates Metabolic Homeostasis and Dysfunction in Visceral Adipose Tissue During Obesity.

Arising incidence of metabolic disorders and related diseases caused by obesity is a global health concern. Elucidating the role of the immune system in this process will help to understand the related mechanisms and develop treatment strategies. Here, we have focused on innate immune cells in visceral adipose tissue (VAT) and summarized the roles of these cells in maintaining the homeostasis of VAT. Furthermore, this review reveals the importance of quantitative and functional changes of innate immune cells when the metabolic microenvironment changes due to obesity or excess lipids, and confirms that these changes eventually lead to the occurrence of chronic inflammation and metabolic diseases of VAT. Two perspectives are reviewed, which include sequential changes in various innate immune cells in the steady state of VAT and its imbalance during obesity. Cross-sectional interactions between various innate immune cells at the same time point are also reviewed. Through delineation of a comprehensive perspective of VAT homeostasis in obesity-induced chronic inflammation, and ultimately metabolic dysfunction and disease, we expect to clarify the complex interactive networks among distinct cell populations and propose that these interactions should be taken into account in the development of biotherapeutic strategies.

Reducing Challenges in Organic Synthesis with Stereoselective Hydrogenation and Tandem Catalysis.

Tandem catalysis enables the rapid construction of complex architectures from simple building blocks. This Perspective shares our interest in combining stereoselective hydrogenation with transformations such as isomerization, oxidation, and epimerization to solve diverse challenges. We highlight the use of tandem hydrogenation for preparing complex natural products from simple prochiral building blocks and present tandem catalysis involving transfer hydrogenation and dynamic kinetic resolution. Finally, we underline recent breakthroughs and opportunities for asymmetric hydrogenation.

Waveguide-coupled superconducting nanowire single-photon detectors based on femtosecond laser direct writing.

The implementation of quantum information technologies requires the development of integrated quantum chips. Femtosecond laser direct writing (FLDW) waveguides and superconducting nanowire single-photon detectors (SNSPDs) have been widely applied in integrated quantum photonic circuits. In this work, a novel FLDW waveguide-coupled SNSPD was designed and realized by integrating FLDW waveguides and conventional SNSPDs together. Through a COMSOL simulation, a waveguide end face-nanowire optical coupling structure was designed and verified. The simulation results showed that the FLDW waveguide-coupled SNSPD device, which had a target wavelength of 780 nm, can achieve 87% optical absorption. Then the preparation process of the FLDW waveguide-coupled SNSPD device was developed, and the fabricated device achieved a system detection efficiency of 1.7% at 10 Hz dark count rate. Overall, this method provides a feasible single-photon detector solution for future on-chip integrated quantum photonic experiments and applications.

Enantioselective Addition of α-Nitroesters to Alkynes.

By using Rh-H catalysis, we couple α-nitroesters and alkynes to prepare α-amino-acid precursors. This atom-economical strategy generates two contiguous stereocenters, with high enantio- and diastereocontrol. In this transformation, the alkyne undergoes isomerization to generate a RhIII -π-allyl electrophile, which is trapped by an α-nitroester nucleophile. A subsequent reduction with In powder transforms the allylic α-nitroesters to the corresponding α,α-disubstituted α-amino esters.

Measuring the refractive index of optical adhesives at cryogenic temperatures.

The development of photonic quantum information technologies requires research on the properties of optical adhesives at cryogenic temperatures. In the process of developing microfiber (MF)-coupled superconducting nanowire single-photon detectors (SNSPDs), we invented a cryogenic-temperature refractive index (RI) measurement method based on a kind of MF device. The device was put into the cryostat to observe the variance of MF transmittance with temperature. Then an RI-temperature relationship was established through the correspondence between the confinement conditions of MFs of various diameters in an optical adhesive-${{\rm MgF}_2}$MgF2 environment and transmittance-temperature curves. Using this method, we analyzed the thermal-optical properties of a commercial fluorinated acrylic optical adhesive and obtained the RI values of the adhesive at various temperatures. The results were successfully applied in the development of broadband and high-efficiency MF-coupled SNSPDs.

Sarcosenones A-C, highly oxygenated pimarane diterpenoids from an endolichenic fungus Sarcosomataceae sp.

Three new highly oxygenated pimarane diterpenoids, sarcosenones A-C (1-3), and the known 9α-hydroxy-1,8(14),15-isopimaratrien-3,7,11-trione (4), were isolated from cultures of an endolichenic fungus Sarcosomataceae sp. Their structures were elucidated based on NMR spectroscopic data and electronic circular dichroism (ECD) calculations. Compound 1 showed moderate cytotoxicity against a small panel of four human tumor cell lines, with IC50 values of 7.5-26.4 µM.

Ultra-broadband microfiber-coupled superconducting single-photon detector.

Broadband photon detectors are a key enabling technology for various applications such as spectrometers, light detection and ranging. In this work, we report on an ultra-broadband single-photon detector based on a microfiber (MF)-coupled superconducting nanowires structure operating in the spectral range from visible to near-infrared light. The MF-coupled superconducting nanowire single-photon detector (SNSPD) is formed by placing an MF on top of superconducting niobium nitride (NbN) nanowires, allowing ultra-broadband photon detection due to their nearly lossless transmission/absorption and nearly unity internal efficiency for ultra-broad waveband. The simulation results indicate that with optimal device structure, the optical absorption with efficiency > 90% can be realized over a wavelength range of 350 nm to 2150 nm. The fabricated MF-coupled SNSPD shows unparalleled broadband system detection efficiencies (SDEs) of more than 50% from 630 nm to 1500 nm. The SDEs reach 66% at 785 nm and 45% at 1550 nm. These results pave the way for ultra-broadband weak light detection with quantum-limit sensitivity.

[Knockdown of TRAIL-DR5 gene inhibits autophagy of ER-positive MCF-7 breast cancer cells induced by SAHA].

Objective To clarify the regulation role of tumor necrosis factor-related apoptosis inducing ligand-death receptor 5 (TRAIL-DR5) in cell autophagy induced by suberoylanilidehydroxamic acid (SAHA) in ER-positive breast cancer cell MCF-7. Methods The logarithmic growth phase of MCF-7 cells were divided into control group, SAHA treatment group, TRAIL-DR5 siRNA group and SAHA combined with TRAIL-DR5 siRNA treatment group. Western blotting was used to verify the results of TRAIL-DR5 gene silencing. Real-time quantitative PCR was performed to detect the mRNA levels of autophagy-related gene 9B (ATG9B), microtubule-associated protein 1 light chain 3A (LC3A) and LC3B in the different groups. The expressions of beclin-1, ATG3, ATG5, ATG7, ATG12, ATG16, ATG4A, ATG4B, ATG9B, LC3II, cathepsin B (CTSB) in the breast cancer cells were detected by Western blotting. The level of CTSB in the breast cancer cell culture supernatant was analyzed by ELISA. Immunofluorescence cytochemical staining was used to determine the expression and distribution of LC3II in the breast cancer cells. Results TRAIL-DR5 siRNA transfection significantly decreased the levels of TRAIL-DR5 in MCF-7 cells. After the knock-down of TRAIL-DR5 gene in MCF-7, the mRNA and protein levels of the autophagy-related factors in breast cancer cells markedly decreased, and the protein level of CTSB also decreased. After SAHA treatment of MCF-7 cells, the level of LC3II increased; when knockdown of TRAIL-DR5 receptor, LC3II level was significantly lower than that in the SAHA-alone-treated cells. Conclusion Down-regulating the TRAIL-DR5 gene can inhibit cell autophagy induced by SAHA in ER-positive MCF-7 breast cancer cells.

Microfiber-coupled superconducting nanowire single-photon detector for near-infrared wavelengths.

High-performance superconducting nanowire single-photon detectors (SNSPDs) have facilitated numerous experiments and applications, particularly in the fields of modern quantum optics and quantum communication. Two kinds of optical coupling methods have thus far been developed for SNSPDs: one produces standard fiber-coupled SNSPDs in which the fibers vertically illuminate the meandered nanowires; the other produces waveguide-coupled SNSPDs in which nanowires are fabricated on the surface of a waveguide that guides photons, and the fibers are coupled to the waveguide. In this paper, we report on first experimental demonstration of a new type of SNSPD that is coupled with a microfiber (MF). Photons are guided by the MF and are evanescently absorbed by the nanowires of the SNSPD when the MF is placed on top of superconducting NbN nanowires. Room-temperature optical experiments indicated that this device has a coupling efficiency of up to 90% when a 1.3 µm-diameter MF is used for light with wavelength of 1550 nm. We were also able to demonstrate that our MF-coupled detector achieved system detection efficiencies of 50% and 20% at incident wavelengths of 1064 and 1550 nm, respectively, for a 2 µm-diameter MF at 2.2K. We expect that MF-coupled SNSPDs may show both high efficiency and broadband characteristics upon optimization and will be used for various novel applications, such as micro/nano-fiber optics.

Not only serotonergic system, but also dopaminergic system involved in albiflorin against chronic unpredictable mild stress-induced depression-like behavior in rats.

Albiflorin (AF), separated from the root of Paeonia lactiflora Pall, possesses neuro-protective and anti-inflammatory activities. Based on previous results, our present research aims to investigate the antidepressant-like activity of AF in chronic unpredictable mild stress (CUMS)-induced rat model of depression. Eight weeks of CUMS process successfully established depression-like rat model, as evidenced by the enhanced immobility time in forced swimming test and the reduced sucrose preference, which were reversed to near normal by AF (20 mg/kg and 40 mg/kg) and fluoxetine (3 mg/kg; positive drug) treated. Compared to non-treated depression-like rats, the increased levels of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HTAA) in serum and hypothalamus, and the reduced expressions of 5-HT1A receptor and 5-HT2A receptor in hypothalamus were observed after AF and fluoxetine oral administration indicating that AF-mediated antidepressant-like effect may be related to the normalization of serotonergic system. Additionally, four-week AF treated rats significantly showed improvement in the reduced dopamine and noradrenalin concentration in serum and hypothalamus as observed on depression-like rats. Altered levels of tyrosine hydroxylase, dopamine D2 receptor and dopamine transporter in hypothalamus reverted to the normal level after treatment with both AF and fluoxetine. All these data demonstrate that not only serotonergic system, but also dopaminergic system is involved in AF-mediated antidepressant-like effect in CUMS-induced rat model of depression.