Mycoplasma pneumoniae-induced Kawasaki disease via PINK1/Parkin-mediated mitophagy.

Kawasaki disease (KD) is a systemic vasculitis with an unknown cause that primarily affects children. The objective of this study was to explore the function and underlying mechanism of mitophagy in Mycoplasma pneumoniae (MP)-induced KD. To create MP-induced KD models, Human coronary endothelial cells (HCAECs) and DBA/2 mice were employed and treated with Mp-Lipid-associated membrane proteins （LAMPs）. Lactate dehydrogenase (LDH) levels were tested to determine cellular damage or death. The inflammatory cytokines tumor necrosis factor (TNF)--α and interleukin (IL)-6 were measured using the Enzyme-Linked Immunosorbent Assay (ELISA) method. RT-qPCR and Western blotting were used to determine the expression of Intercellular Adhesion Molecule(ICAM)-1, vascular cell adhesion molecule (VCAM)-1, inducible nitric oxide synthase(iNOS), LC3, p62, PINK1(a mitochondrial serine/threonine-protein kinase), and PARKIN(a cytosolic E3-ubiquitin ligase). The adenosine triphosphate （ATP）, reactive oxygen species （ROS）, and mitochondrial membrane potential（MMP） levels were measured to determine mitochondrial function. Mitophagy was investigated using immunofluorescence and a mitophagy detection test. Autophagosome and mitochondrial morphology were examined using transmission electron microscopy. To identify inflammatory cell infiltration, hematoxylin and eosin staining was utilized. Mp-LAMPs increased the levels of TNF-α, IL-6, ICAM-1, VCAM-1, and iNOS in an HCAEC cell model, along with LDH release. After Mp-LAMPs exposure, there was a rise in LC3 and a reduction in p62. Meanwhile, the expression of PINK1 and Parkin was increased. Cyclosporin A dramatically increased ATP synthesis and MMP in HCAEC cells treated with Mp-LAMPs, while suppressing ROS generation, demonstrating excessive mitophagy-related mitochondrial dysfunction. Additionally, neither body weight nor artery tissue were affected due to PINK1 and Parkin suppression Cyclosporin A in Mp-LAMPs-treated mice. These findings indicated that PINK1/Parkin-mediated mitophagy inhibition may be a therapeutic target for MP-induced KD.

BFGF attenuates aortic valvular interstitial cell calcification by inhibiting endoplasmic reticulum stress-mediated apoptosis.

The potential protective effect of basic fibroblast growth factor (BFGF) on the cardiovascular system has been proposed previously, however, its effect on calcific aortic valve disease (CAVD) and underlying mechanisms have not been elucidated. The valvular interstitial cell (VIC) were isolated from porcine aortic valve leaflets. To investigate the effect of BFGF on osteogenic differentiation of VIC, the osteogenic induced medium (OIM) and BFGF were added. The protein expression level was detected by Western blot, and apoptosis was determined by flow cytometry. The effect of BFGF on CAVD process in vivo was assessed by a rat CAVD model, which was identified by echocardiography and Alizarin red staining. The expression level of BFGF in the aortic valve and serum were significantly upregulated in CAVD patients compared to control group. In addition, exogenous BFGF injection attenuates CAVD process in vivo. The protein markers of osteogenic differentiation, endoplasmic reticulum stress (ERS), and apoptosis were significantly upregulated by culture with OIM. On the contrary, the aforementioned proteins were suppressed after adding 100 ng/mL of BFGF. Inhibition of PI3K/Akt and ERK1/2 pathways by specific inhibitors abolished the protective effect of BFGF. In conclusion, BFGF could alleviate the VIC calcification by inhibiting ERS-mediated apoptosis, which is partly regulated by activation of the PI3K/Akt and ERK1/2 signaling pathways. BFGF may provide a potential avenue for CAVD therapy.

Quantifying the hydrodynamic contribution to electrical transport in non-Brownian suspensions.

Electrical transport in semiconducting and metallic particle suspensions is an enabling feature of emerging grid-scale battery technologies. Although the physics of the transport process plays a key role in these technologies, no universal framework has yet emerged. Here, we examine the important contribution of shear flow to the electrical transport of non-Brownian suspensions. We find that these suspensions exhibit a strong dependence of the transport rate on the particle volume fraction and applied shear rate, which enables the conductivity to be dynamically changed by over 107 decades based on the applied shear rate. We combine experiments and simulations to conclude that the transport process relies on a combination of charge and particle diffusion with a rate that can be predicted using a quantitative physical model that incorporates the self-diffusion of the particles.

A distinct dimer configuration of a diatom Get3 forming a tetrameric complex with its tail-anchored membrane cargo.

BACKGROUND: Most tail-anchored (TA) membrane proteins are delivered to the endoplasmic reticulum through a conserved posttranslational pathway. Although core mechanisms underlying the targeting and insertion of TA proteins are well established in eukaryotes, their role in mediating TA protein biogenesis in plants remains unclear. We reported the crystal structures of algal arsenite transporter 1 (ArsA1), which possesses an approximately 80-kDa monomeric architecture and carries chloroplast-localized TA proteins. However, the mechanistic basis of ArsA2, a Get3 (guided entry of TA proteins 3) homolog in plants, for TA recognition remains unknown. RESULTS: Here, for the first time, we present the crystal structures of the diatom Pt-Get3a that forms a distinct ellipsoid-shaped tetramer in the open (nucleotide-bound) state through crystal packing. Pulldown assay results revealed that only tetrameric Pt-Get3a can bind to TA proteins. The lack of the conserved zinc-coordination CXXC motif in Pt-Get3a potentially leads to the spontaneous formation of a distinct parallelogram-shaped dimeric conformation in solution, suggesting a new dimer state for subsequent tetramerization upon TA targeting. Pt-Get3a nonspecifically binds to different subsets of TA substrates due to the lower hydrophobicity of its α-helical subdomain, which is implicated in TA recognition. CONCLUSIONS: Our study provides new insights into the mechanisms underlying TA protein shielding by tetrameric Get3 during targeting to the diatom's cell membrane.

Phonon Directionality Impacts Electron-Phonon Coupling and Polarization of the Band-Edge Emission in Two-Dimensional Metal Halide Perovskites.

Two-dimensional metal halide perovskites are highly versatile for light-driven applications due to their exceptional variety in material composition, which can be exploited for the tunability of mechanical and optoelectronic properties. The band-edge emission is defined by the structure and composition of both organic and inorganic layers, and electron-phonon coupling plays a crucial role in the recombination dynamics. However, the nature of the electron-phonon coupling and what kind of phonons are involved are still under debate. Here we investigate the emission, reflectance, and phonon response from single two-dimensional lead iodide microcrystals with angle-resolved polarized spectroscopy. We find an intricate dependence of the emission polarization with the vibrational directionality in the materials, which reveals that several bands of low-frequency phonons with nonorthogonal directionality contribute to the band-edge emission. Such complex electron-phonon coupling requires adequate models to predict the thermal broadening of the emission and provides opportunities to design polarization properties.

Dual Roles of the Photooxidation of Organic Amines for Enhanced Triplet-Triplet Annihilation Upconversion in Nanoparticles.

Oxygen-mediated triplet-triplet annihilation upconversion (TTA-UC) quenching limits the application of such organic upconversion materials. Here, we report that the photooxidation of organic amines is an effective and versatile strategy to suppress oxygen-mediated upconversion quenching in both organic solvents and aqueous solutions. The strategy is based on the dual role of organic amines in photooxidation, i.e., as singlet oxygen scavengers and electron donors. Under photoexcitation, the photosensitizer sensitizes oxygen to produce singlet oxygen for the oxidation of alkylamine, reducing the oxygen concentration. However, photoinduced electron transfer among photosensitizers, organic amines, and oxygen leads to the production of superoxide anions that suppress TTA-UC. To observe oxygen-tolerating TTA-UC, we find that alkyl secondary amines can balance the production of singlet oxygen and superoxide anions. We then utilize polyethyleneimine (PEI) to synthesize amphiphilic polymers to encapsulate TTA-UC pairs for the formation of water-dispersible, ultrasmall, and multicolor-emitting TTA-UC nanoparticles.

Near Infrared-II Excited Triplet Fusion Upconversion with Anti-Stokes Shift Approaching the Theoretical Limit.

The anti-Stokes shift represents the capacity of photon upconversion to convert low-energy photons to high-energy photons. Although triplet exciton-mediated photon upconversion presents outstanding performance in solar energy harvesting, photoredox catalysis, stereoscopic 3D printing, and disease therapeutics, the interfacial multistep triplet exciton transfer leads to exciton energy loss to suppress the anti-Stokes shift. Here, we report near infrared-II (NIR-II) excitable triplet exciton-mediated photon upconversion using a hybrid photosensitizer consisting of lead sulfide quantum dots (PbS QDs) and new surface ligands of thiophene-substituted diketopyrrolopyrrole (Th-DPP). Under 1064 nm excitation, this photon upconversion revealed a record-corrected upconversion efficiency of 0.37% (normalized to 100%), with the anti-Stokes shift (1.07 eV) approaching the theoretical limit (1.17 eV). The observation of this unexpected result is due to our discovery of the presence of a weak interaction between the sulfur atom on Th-DPP and Pb2+ on the PbS QDs surface, facilitating electronic coupling between PbS QDs and Th-DPP, such that the realization of triplet exciton transfer efficiency is close to 100% even when the energy gap is as small as 0.04 eV. With this premise, this photon upconversion as a photocatalyst enables the production of standing organic gel via photopolymerization under 1064 nm illumination, displaying NIR-II photon-driven photoredox catalysis. This research not only establishes the foundation for enhancing the performance of NIR-II excitable photonic upconversion but also promotes its development in photonics and photoredox catalysis.

Natural Protein Photon Upconversion Supramolecular Assemblies for Background-Free Biosensing.

The diagnosis of disease biomarkers is crucial for the identification, monitoring, and prognostic assessment of malignant disease. However, biological samples with autofluorescence, complex components, and heterogeneity pose major challenges to reliable biosensing. Here, we report the self-assembly of natural proteins and the triplet-triplet annihilation upconversion (TTA-UC) pair to form upconverted protein clusters (∼8.2 ± 1.1 nm), which were further assembled into photon upconversion supramolecular assemblies (PUSA). This PUSA exhibited unique features, including a small size (∼44.1 ± 4.1 nm), oxygen tolerance, superior biocompatibility, and easy storage via lyophilization, all of which are long sought after for photon upconversion materials. Further, we have revealed that the steric hindrance of the annihilator suppresses the stacking of the annihilator in PUSA, which is vital for maintaining the water dispersibility and enhancing the upconversion performance of PUSA. In conjunction with sarcosine oxidase, this near infrared (NIR)-excitable PUSA nanoprobe could perform background-free biosensing of urinary sarcosine, which is a common biomarker for prostatic carcinoma (PCa). More importantly, this nanoprobe not only allows for qualitative identification of urinary samples from PCa patients by the unaided eye under NIR-light-emitting diode (LED) illumination but also quantifies the concentration of urinary sarcosine. These remarkable findings have propelled photon upconversion materials to a new evolutionary stage and expedited the progress of upconversion biosensing in clinical diagnostics.

EIF4A3-negatively driven circular RNA ß-catenin (circß-catenin) promotes colorectal cancer progression via miR-197-3p/CTNND1 regulatory axis.

BACKGROUND: Circß-catenin, our first reported circRNA, has been reported to mediate tumorigenesis in various cancers. However, its biological functions and underlying mechanisms in colorectal cancer (CRC) remain unknown. METHODS: The qRT-PCR examination was used to detect the expression of circß-catenin, miR-197-3p, and CTNND1 in cells and human tissues. Western blot was conducted to detect the protein expression levels. The biological function of circß-catenin was verified by MTT, colony formation, wound healing, and transwell assays. The in vivo effects of circß-catenin were verified by nude mice xenograft and metastasis models. The regulatory network of circß-catenin/miR-197-3p/CTNND1 was confirmed via dual-luciferase reporter and RIP assays. RESULTS: In the present study, circß-catenin was found to promote CRC cell proliferation and metastasis in vitro and in vivo. Mechanistically, circß-catenin served as miRNA decoy to directly bind to miR-197-3p, then antagonized the repression of the target gene CTNND1, and eventually promoted the malignant phenotype of CRC. More interestingly, the inverted repeated Alu pairs termed AluJb1/2 and AluY facilitated the biogenesis of circß-catenin, which could be partially reversed by EIF4A3 binding to Alu element AluJb2. CONCLUSIONS: Our findings illustrated a novel mechanism of circß-catenin in modulating CRC tumorigenesis and metastasis, which provides a potential therapeutic target for CRC patients.

Philadelphia chromosome-positive or Philadelphia chromosome-like B-cell precursor acute lymphoblastic leukemia with multilineage involvement in pediatric patients: a report of two cases and literature review.

Based on driver mutations and gene expression profiles, the International Consensus Classification currently divided the entity 'Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (ALL)' into two subtypes: lymphoid-only and multilineage involvement (Ph+ ALL-L and -M, respectively). The similar biological characteristics of Ph-like ALL and Ph+ ALL drove us to assume that Ph-like ALL-M subtypes exist. This report presents two pediatric ALL cases (one Ph+ and one Ph-like) with minimal residual disease negativity established by multicolor flow cytometry but persistent transcript detection by quantitative PCR (qPCR) even after second-line treatment with tyrosine kinase inhibitors combined with blinatumomab immunotherapy. Using droplet digital PCR, BCR::ABL1 or TPM3::PDGFRB transcripts were identified in CD19+ cells as well as in non-CD19+ cells, suggesting the presence of a Ph+ or Ph-like ALL-M subtype originating from hematopoietic stem cells. This report provides information for better characterization, diagnosis, and treatment of these ALL subtypes.

Critical roles of tubular mitochondrial ATP synthase dysfunction in maleic acid-induced acute kidney injury.

Maleic acid (MA) induces renal tubular cell dysfunction directed to acute kidney injury (AKI). AKI is an increasing global health burden due to its association with mortality and morbidity. However, targeted therapy for AKI is lacking. Previously, we determined mitochondrial-associated proteins are MA-induced AKI affinity proteins. We hypothesized that mitochondrial dysfunction in tubular epithelial cells plays a critical role in AKI. In vivo and in vitro systems have been used to test this hypothesis. For the in vivo model, C57BL/6 mice were intraperitoneally injected with 400 mg/kg body weight MA. For the in vitro model, HK-2 human proximal tubular epithelial cells were treated with 2 mM or 5 mM MA for 24 h. AKI can be induced by administration of MA. In the mice injected with MA, the levels of blood urea nitrogen (BUN) and creatinine in the sera were significantly increased (p < 0.005). From the pathological analysis, MA-induced AKI aggravated renal tubular injuries, increased kidney injury molecule-1 (KIM-1) expression and caused renal tubular cell apoptosis. At the cellular level, mitochondrial dysfunction was found with increasing mitochondrial reactive oxygen species (ROS) (p < 0.001), uncoupled mitochondrial respiration with decreasing electron transfer system activity (p < 0.001), and decreasing ATP production (p < 0.05). Under transmission electron microscope (TEM) examination, the cristae formation of mitochondria was defective in MA-induced AKI. To unveil the potential target in mitochondria, gene expression analysis revealed a significantly lower level of ATPase6 (p < 0.001). Renal mitochondrial protein levels of ATP subunits 5A1 and 5C1 (p < 0.05) were significantly decreased, as confirmed by protein analysis. Our study demonstrated that dysfunction of mitochondria resulting from altered expression of ATP synthase in renal tubular cells is associated with MA-induced AKI. This finding provides a potential novel target to develop new strategies for better prevention and treatment of MA-induced AKI.

Inhibition of visceral adipose tissue-derived pathogenic signals by activation of adenosine A2AR improves hepatic and cardiac dysfunction of NASH mice.

A2AR-disrupted mice is characterized by severe systemic and visceral adipose tissue (VAT) inflammation. Increasing adenosine cyclase (AC), cAMP, and protein kinase A (PKA) formation through A2AR activation suppress systemic/VAT inflammation in obese mice. This study explores the effects of 4 wk A2AR agonist PSB0777 treatment on the VAT-driven pathogenic signals in hepatic and cardiac dysfunction of nonalcoholic steatohepatitis (NASH) obese mice. Among NASH mice with cardiac dysfunction, simultaneous decrease in the A2AR, AC, cAMP, and PKA levels were observed in VAT, liver, and heart. PSB0777 treatment significantly restores AC, cAMP, PKA, and hormone-sensitive lipase (HSL) levels, decreased SREBP-1/FASN, MCP-1, and CD68 levels, reduces infiltrated CD11b+ F4/80+ cells and adipogenesis in VAT of NASH + PSB0777 mice. The changes in VAT were accompanied by the suppression of hepatic and cardiac lipogenic/inflammatory/injury/apoptotic/fibrotic markers, the normalization of cardiac contractile [sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2)] marker, and cardiac dysfunction. The in vitro approach revealed that conditioned media (CM) of VAT of NASH mice (CMnash) trigger palmitic acid (PA)-like lipotoxic (lipogenic/inflammatory/apoptotic/fibrotic) effects in AML-12 and H9c2 cell systems. Significantly, A2AR agonist pretreatment-related normalization of A2AR-AC-cAMP-PKA levels was associated with the attenuation of CMnash-related upregulation of lipotoxic markers and the normalization of lipolytic (AML-12 cells) or contractile (H9C2 cells) marker/contraction. The in vivo and in vitro experiments revealed that A2AR agonists are potential agent to inhibit the effects of VAT inflammation-driven pathogenic signals on the hepatic and cardiac lipogenesis, inflammation, injury, apoptosis, fibrosis, hypocontractility, and subsequently improve hepatic and cardiac dysfunction in NASH mice.NEW & NOTEWORTHY Protective role of adenosine A2AR receptor (A2AR) and AC-cAMP-PKA signaling against nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) possibly via its actions on adipocytes is well known in the past decade. Thus, this study evaluates pharmacological activities of A2AR agonist PSB0777, which has already demonstrated to treat NASH. In this study, the inhibition of visceral adipose tissue-derived pathogenic signals by activation of adenosine A2AR with A2AR agonist PSB0777 improves the hepatic and cardiac dysfunction of high-fat diet (HFD)-induced NASH mice.

Leaping Supercapacitor Performance via a Flash-Enabled Graphene Photothermal Coating.

Elevating the working temperature delivers a simple and universal approach to enhance the energy storage performances of supercapacitors owing to the fundamental improvements in ion transportation kinetics. Among all heating methods, introducing green and sustainable photothermal heating on supercapacitors (SCs) is highly desired yet remains an open challenge, especially for developing an efficient and universal photothermal heating strategy that can be generally applied to arbitrary SC devices. Flash-enabled graphene (FG) absorbers are produced through a simple and facile flash reduction process, which can be coated on the surface of any SC devices to lift their working temperature via a photothermal effect, thus, improving their overall performance, including both power and energy densities. With the systematic temperature-dependent investigation and the in-depth numerical simulation of SC performances, an evident enhancement in capacitance up to 65% can be achieved in photothermally enhanced SC coin cell devices with FG photo-absorbers. This simple, practical, and universal enhancement strategy provides a novel insight into boosting SC performances without bringing complexity in electrode fabrication/optimization. Also, it sheds light on the highly efficient utilization of green and renewable photothermal energies for broad application scenarios, especially for energy storage devices.

Trace Cu-Induced Low C─N Coupling Barrier on Amorphous Co Metallene Boride for Boosting Electrochemical Urea Production.

The electrochemical C─N coupling of carbon dioxide (CO2) and nitrate(NO3 -) is an alternative strategy to the traditional high-energy industrial pathway for urea synthesis, which urgently requires the design of efficient catalysts to achieve high yield and Faraday efficiency (FE). Here, amorphous low-content copper-doped cobalt metallene boride (a-Cu0.1CoBx metallene) is designed for urea synthesis via electrochemical C─N coupling. The a-Cu0.1CoBx metallene can drive electrocatalytic C─N coupling of CO2 and NO3 - for urea synthesis in CO2-saturated 0.1 m KNO3 electrolyte, with 27.7% of FE and 312 µg h-1 mg-1 cat. of yield at -0.5 V, as well as superior cycling stability. The in situ Fourier transform infrared and theoretical calculations reveal that electronic effect between Cu, Co, and B causes Cu and Co as dual active sites to promote the adsorption of reactants. Furthermore, the introduced trace Cu reduces the reaction energy barrier of the C─N coupling to facilitate urea synthesis. This work provides a promising route for the optimization of Co-based metallene for the electrosynthesis of urea through C─N coupling.

Ultrafast Unidirectional On-Chip Heat Transfer.

Effective and rapid heat transfer is critical to improving electronic components' performance and operational stability, particularly for highly integrated and miniaturized devices in complex scenarios. However, current thermal manipulation approaches, including the recent advancement in thermal metamaterials, cannot realize fast and unidirectional heat flow control. In addition, any defects in thermal conductive materials cause a significant decrease in thermal conductivity, severely degrading heat transfer performance. Here, the utilization of silicon-based valley photonic crystals (VPCs) is proposed and numerically demonstrated to facilitate ultrafast, unidirectional heat transfer through thermal radiation on a microscale. Utilizing the infrared wavelength region, the approach achieves a significant thermal rectification effect, ensuring continuous heat flow along designed paths with high transmission efficiency. Remarkably, the process is unaffected by temperature gradients due to the unidirectional property, maintaining transmission directionality. Furthermore, the VPCs' inherent robustness affords defect-immune heat transfer, overcoming the limitations of traditional conduction methods that inevitably cause device heating, performance degradation, and energy waste. The design is fully CMOS compatible, thus will find broad applications, particularly for integrated optoelectronic devices.

Augmenting Neutrophil Extracellular Traps with Carbonized Polymer Dots: A Potential Treatment for Bacterial Sepsis.

Sepsis is a life-threatening condition that can progress to septic shock as the body's extreme response to pathogenesis damages its own vital organs. Staphylococcus aureus (S. aureus) accounts for 50% of nosocomial infections, which are clinically treated with antibiotics. However, methicillin-resistant strains (MRSA) have emerged and can withstand harsh antibiotic treatment. To address this problem, curcumin (CCM) is employed to prepare carbonized polymer dots (CPDs) through mild pyrolysis. Contrary to curcumin, the as-formed CCM-CPDs are highly biocompatible and soluble in aqueous solution. Most importantly, the CCM-CPDs induce the release of neutrophil extracellular traps (NETs) from the neutrophils, which entrap and eliminate microbes. In an MRSA-induced septic mouse model, it is observed that CCM-CPDs efficiently suppress bacterial colonization. Moreover, the intrinsic antioxidative, anti-inflammatory, and anticoagulation activities resulting from the preserved functional groups of the precursor molecule on the CCM-CPDs prevent progression to severe sepsis. As a result, infected mice treated with CCM-CPDs show a significant decrease in mortality even through oral administration. Histological staining indicates negligible organ damage in the MRSA-infected mice treated with CCM-CPDs. It is believed that the in vivo studies presented herein demonstrate that multifunctional therapeutic CPDs hold great potential against life-threatening infectious diseases.

Glycosylation of 6-gingerol and unusual spontaneous deglucosylation of two novel intermediates to form 6-shogaol-4'-O-ß-glucoside by bacterial glycosyltransferase.

6-Gingerol is a major phenolic compound within ginger (Zingiber officinale), often used in healthcare; however, its lower bioavailability is partly due to its poor solubility. Four bacterial glycosyltransferases (GTs) were tested to glycosylate 6-gingerol into soluble gingerol glucosides. BsUGT489 was a suitable GT to biotransform 6-gingerol into five significant products, which could be identified via nucleic magnetic resonance and mass spectrometry as 6-gingerol-4',5-O-ß-diglucoside (1), 6-gingerol-4'-O-ß-glucoside (2), 6-gingerol-5-O-ß-glucoside (3), 6-shogaol-4'-O-ß-glucoside (4), and 6-shogaol (5). The enzyme kinetics of BsUGT489 showed substrate inhibition toward 6-gingerol for producing two glucosides. The kinetic parameters were determined as KM (110 µM), kcat (862 min-1), and KI (571 µM) for the production of 6-gingerol-4'-O-ß-glucoside (2) and KM (104 µM), kcat (889 min-1), and KI (545 µM) for the production of 6-gingerol-5-O-ß-glucoside (3). The aqueous solubility of the three 6-gingerol glucosides, compound (1) to (3), was greatly improved. However, 6-shogaol-4'-O-ß-glucoside (4) was found to be a product biotransformed from 6-shogaol (5). This study first confirmed that the glucose moiety at the C-5 position of both 6-gingerol-4',5-O-ß-diglucoside (1) and 6-gingerol-5-O-ß-glucoside (3) caused spontaneous deglucosylation through ß-elimination to form 6-shogaol-4'-O-ß-glucoside (4) and 6-shogaol (5), respectively. Moreover, the GTs could glycosylate 6-shogaol to form 6-shogaol-4'-O-ß-glucoside (4). The assays showed 6-shogaol-4'-O-ß-glucoside (4) had higher anti-inflammatory activity (IC50 value of 10.3 ± 0.2 µM) than 6-gingerol. The 6-gingerol-5-O-ß-glucoside (3) possessed 346-fold higher solubility than 6-shogaol, in which the highly soluble glucoside is a potential prodrug of 6-shogaol via spontaneous deglucosylation. This unusual deglucosylation plays a vital role in influencing the anti-inflammatory activity. IMPORTANCE: Both 6-gingerols and 6-shogaol possess multiple bioactivities. However, their poor solubility limits their application. The present study used bacterial GTs to catalyze the glycosylation of 6-gingerol, and the resulting gingerol glycosides were found to be new compounds with improved solubility and anti-inflammatory activity. In addition, two of the 6-gingerol glucosides were found to undergo spontaneous deglucosylation to form 6-shogaol or 6-shogaol glucosides. The unique spontaneous deglucosylation property of the new 6-gingerol glucosides makes them a good candidate for the prodrug of 6-shogaol.

Ultra-compact electro-optic phase modulator based on a lithium niobate topological slow light waveguide.

Electro-optic modulators (EOMs) are essential devices of optical communications and quantum computing systems. In particular, ultra-compact EOMs are necessary for highly integrated photonic chips. Thin film lithium niobate materials are a promising platform for designing highly efficient EOMs. However, EOMs based on conventional waveguide structures are at a millimeter scale and challenging to scale down further, greatly hindering the capability of on-chip integration. Here, we design an EOM based on lithium niobate valley photonic crystal (VPC) structures for the first time. Due to the high effective refractive index introduced by the strong slow light effect, the EOM can achieve an ultra-compact size of 4 µm×14 µm with a half-wave voltage of 1.4 V. The EOM has a high transmittance of 0.87 in the 1068 nm because of the unique spin-valley locking effect in VPC structures. The design is fully compatible with current nanofabrication technology and immune to fabrication defects. Therefore, it opens a new possibility in designing lithium niobate electro-optic modulators and will find broad applications in optical communication and quantum photonic devices.

Structural determinants of parabens in inhibiting human and rat gonadal 3ß-hydroxysteroid dehydrogenase.

This study delved into the impacts of 10 parabens on the activity of human and rat gonadal 3ß-hydroxysteroid dehydrogenase (3ß-HSD) within human KGN cell and rat testicular microsomes, as well as on the secretion of progesterone in KGN cells and the inhibitory potency was compared between human and rats. Intriguingly, the outcomes revealed that ethyl, propyl, butyl, hexyl, heptyl, nonyl, phenyl, and benzyl parabens displayed varying IC50 values for human 3ß-HSD2, from 4.15 to 139.96 µM, demonstrating characteristics of mixed inhibitors. Notably, within KGN cells, all examined parabens, excluding nonyl and phenyl parabens, significantly inhibited progesterone secretion at 5-50 µM. In the case of rats, the IC50 values for these parabens on gonadal 3ß-HSD1 fluctuated between 7.15 and 110.76 µM, likewise functioning as mixed inhibitors. Through docking analysis, it was proposed that most parabens effectively bind to NAD+ and/or steroid binding site. Moreover, bivariate correlation analysis unveiled an inverse correlation between IC50 values and structural characteristics such as LogP, molecular weight, heavy atom number, and carbon number within the alcohol moiety of parabens. 3D-QSAR elucidated pivotal regions, comprising hydrogen bond donor, hydrogen bond acceptor, and hydrophobic region, with the most potent inhibitor nonyl paraben engaging with all regions, while the weakest inhibitor ethyl paraben interacted with the regions except for the hydrophobic region. In conclusion, this investigation underscored the inhibitory effects imparted by several parabens on both human and rat gonadal 3ß-HSD activity, with their inhibitory potency being modulated by aspects of hydrophobicity and carbon chain length.

In Situ Self-Assembly of Antibody-Rhamnose Complex as a Pre-Targeting Strategy for Enhanced Cancer Immunotherapy.

Enhancing the Fc effector functions of monoclonal antibodies (mAbs) is a proven strategy for improving cancer immunotherapy. In this study, we present a novel pre-targeting approach that integrates host-guest chemistry with an antibody-recruiting concept to create mAbs with superior effector functions. Using rituximab (RTX), a clinically approved anti-CD20 mAb, as our model, we modified RTX by conjugating it with adamantane (Ada) derivatives and various polyethylene glycol (PEG) linkers to produce RTX-Ada conjugates. These conjugates effectively formed RTX-rhamnose (Rha) complexes in situ through self-assembly, driven by host-guest interactions with Rha-modified ß-cyclodextrin. This mechanism successfully redirected endogenous anti-Rha antibodies to target cells, enhancing the availability of Fc domains for improved effector functions, including complement-dependent cytotoxicity (CDC). A structure-activity relationship study indicated that the potency of these in situ complexes was significantly influenced by the length of the PEG linker used; shorter PEG linkers correlated with higher CDC activity. Given the variability in endogenous antibody levels among individuals, this strategy presents a flexible and promising platform for enhancing the efficacy of mAb-based cancer immunotherapy.