Engineered plant extracellular vesicles for natural delivery across physiological barriers.

Extracellular vesicles (EVs) are nanoscale luminal vesicles that participate in the information transfer of proteins, nucleic acids, and lipids between cells, thereby playing a role in the treatment of diseases and the delivery of nutrients. In recent years, plant-derived EVs (PDEVs) containing bioactive compounds have attracted increasing interest due to their better biocompatibility and lower cytotoxicity in healthy tissues. In the biomedical field, PDEVs have been used as cargo carriers to achieve various functions through engineering modification techniques. This review focuses on the biogenesis, isolation, and identification of PDEVs. We discuss the surface functionalization of PDEVs to enhance therapeutic efficacy, thereby improving their efficiency as a next-generation drug delivery vehicle and their feasibility to treat diseases across the physiological barriers, while critically analyzing the current challenges and opportunities.

ß-Ga2O3nanotube arrays for high-performance self-powered ultraviolet photoelectrochemical photodetectors.

Self-powered ultraviolet (UV) photodetectors (PDs) are critical for future energy-efficient optoelectronic systems due to their low energy consumption and high sensitivity. In this paper, the vertically alignedß-Ga2O3nanotube arrays (NTs) have been prepared on GaN/sapphire substrate by the thermal oxidation process combined with the dry etching technology, and applied in the UV photoelectrochemical photodetectors (PEC-PDs) for the first time. Based on the large specific surface area ofß-Ga2O3NTs on GaN/sapphire substrates and the solid/liquid heterojunction, the PEC-PDs exhibit excellent self-powered characteristics under 255 nm (UVA) and 365 nm (UVC) light illumination. Under 255 nm (365 nm) light illumination, the maximum responsivity of 49.9 mA W-1(32.04 mA W-1) and a high detectivity of 1.58 × 1011Jones (1.01 × 1011Jones) were achieved for theß-Ga2O3NTs photodetectors at 0 V bias. In addition, the device shows a fast rise/decay time of 8/4 ms (4/2 ms), which is superior to the level of the previously reported self-powered UV PEC-PDs. This high-performance PEC-PD has potential applications in next-generation low-energy UV detection systems.

Tetramethylpyrazine-loaded liposomes surrounded by hydrogel based on sodium alginate and chitosan as a multifunctional drug delivery System for treatment of atopic dermatitis.

Tetramethylpyrazine (TMP) has low bioavailability due to its fast metabolism and short half-life, which is not conducive to transdermal treatment of atopic dermatitis (AD). Therefore, in this study, TMP was encapsulated into liposomes (Lip) by film dispersion method, and then the surface of Lip was modified by sodium alginate (ALG) and chitosan (CS). The tetramethylpyrazine-loaded liposomes in sodium alginate chitosan hydrogel called T-Lip-AC hydrogel. In vitro experiments, we found that T-Lip-AC hydrogel not only had the antibacterial effect of CS, but also enhanced the anti-inflammatory and antioxidant effects of TMP. In addition, T-Lip-AC hydrogel could also provide a moist healing environment for AD dry skin and produce better skin permeability, and can also achieve sustained drug release, which is conducive to the treatment of AD. The lesions induced by 1-chloro-2,4-dinitrobenzene were used as the AD lesions model to test the therapeutic effect of the T-Lip-AC hydrogel on AD in vivo. The studies have showed that T-Lip-AC hydrogel could effectively promote wound healing. Therefore, we have developed a T-Lip-AC hydrogel as multifunctional hydrogel drug delivery system, which could become an effective, safe and novel alternative treatment method for treating AD.

Sensory neurons promote immune homeostasis in the lung.

Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK1GoF) into mice and observed the development of spontaneous AD-like skin disease but unexpected resistance to lung inflammation when JAK1GoF expression was restricted to the stroma. We identified a previously unrecognized role for JAK1 in vagal sensory neurons in suppressing airway inflammation. Additionally, expression of Calcb/CGRPß was dependent on JAK1 in the vagus nerve, and CGRPß suppressed group 2 innate lymphoid cell function and allergic airway inflammation. Our findings reveal evolutionarily conserved but distinct functions of JAK1 in sensory neurons across tissues. This biology raises the possibility that therapeutic JAK inhibitors may be further optimized for tissue-specific efficacy to enhance precision medicine in the future.

A Simulation of Thermal Management Using a Diamond Substrate with Nanostructures.

In recent years, the rapid progress in the field of GaN-based power devices has led to a smaller chip size and increased power usage. However, this has given rise to increasing heat aggregation, which affects the reliability and stability of these devices. To address this issue, diamond substrates with nanostructures were designed and investigated in this paper. The simulation results confirmed the enhanced performance of the device with diamond nanostructures, and the fabrication of a diamond substrate with nanostructures is demonstrated herein. The diamond substrate with square nanopillars 2000 nm in height exhibited optimal heat dissipation performance. Nanostructures can effectively decrease heat accumulation, resulting in a reduction in temperature from 121 °C to 114 °C. Overall, the simulation and experimental results in this work may provide guidelines and help in the development of the advanced thermal management of GaN devices using diamond micro/nanostructured substrates.

The Study on the Lasing Modes Modulated by the Dislocation Distribution in the GaN-Based Microrod Cavities.

Low-threshold lasing under pulsed optical pumping is demonstrated in GaN-based microrod cavities at room temperature, which are fabricated on the patterned sapphire substrates (PSS). Because the distribution of threading dislocations (TDs) is different at different locations, a confocal micro-photoluminescence spectroscopy (µ-PL) was performed to analyze the lasing properties of the different diameter microrods at the top of the triangle islands and between the triangle islands of the PSS substrates, respectively. The µ-PL results show that the 2 µm-diameter microrod cavity has a minimum threshold of about 0.3 kW/cm2. Whispering gallery modes (WGMs) in the microrod cavities are investigated by finite-difference time-domain simulation. Combined with the dislocation distribution in the GaN on the PSS substrates, it is found that the distribution of the strongest lasing WGMs always moves to the region with fewer TDs. This work reveals the connection between the lasing modes and the dislocation distribution, and can contribute to the development of low-threshold and high-efficiency GaN-based micro-lasers.

Design and Evaluation of Paeonol-Loaded Liposomes in Thermoreversible Gels for Atopic Dermatitis.

Paeonol (PAE) is a hydrophobic drug. In this study, we encapsulated paeonol in a lipid bilayer of liposomes (PAE-L), which delayed drug release and increased drug solubility. When PAE-L was dispersed in gels (PAE-L-G) based on a poloxamer matrix material for local transdermal delivery, we observed amphiphilicity, reversible thermal responsiveness, and micellar self-assembly behavior. These gels can be used for atopic dermatitis (AD), an inflammatory skin disease, to change the surface temperature of the skin. In this study, we prepared PAE-L-G at an appropriate temperature for the treatment of AD. We then assessed the gel's relevant physicochemical properties, in vitro cumulative drug release, and antioxidant properties. We found that PAE-loaded liposomes could be designed to increase the drug effect of thermoreversible gels. At 32 °C, PAE-L-G could change from solution state to gelatinous state at 31.70 ± 0.42 s, while the viscosity was 136.98 ± 0.78 MPa.S and the free radical scavenging rates on DPPH and H2O2 were 92.24 ± 5.57% and 92.12 ± 2.71%, respectively. Drug release across the extracorporeal dialysis membrane reached 41.76 ± 3.78%. In AD-like mice, PAE-L-G could also relieve skin damage by the 12th day. In summary, PAE-L-G could play an antioxidant role and relieve inflammation caused by oxidative stress in AD.

MrgprA3-expressing pruriceptors drive pruritogen-induced alloknesis through mechanosensitive Piezo2 channel.

Although touch and itch are coded by distinct neuronal populations, light touch also provokes itch in the presence of exogenous pruritogens, resulting in a phenomenon called alloknesis. However, the cellular and molecular mechanisms underlying the initiation of pruritogen-induced mechanical itch sensitization are poorly understood. Here, we show that intradermal injections of histamine or chloroquine (CQ) provoke alloknesis through activation of TRPV1- and MrgprA3-expressing prurioceptors, and functional ablation of these neurons reverses pruritogen-induced alloknesis. Moreover, genetic ablation of mechanosensitive Piezo2 channel function from MrgprA3-expressing prurioceptors also dampens pruritogen-induced alloknesis. Mechanistically, histamine and CQ sensitize Piezo2 channel function, at least in part, through activation of the phospholipase C (PLC) and protein kinase C-δ (PKCδ) signaling. Collectively, our data find a TRPV1+/MrgprA3+ prurioceptor-Piezo2 signaling axis in the initiation of pruritogen-induced mechanical itch sensitization in the skin.

A TRPV4-dependent neuroimmune axis in the spinal cord promotes neuropathic pain.

Microglia, resident macrophages of the CNS, are essential to brain development, homeostasis, and disease. Microglial activation and proliferation are hallmarks of many CNS diseases, including neuropathic pain. However, molecular mechanisms that govern the spinal neuroimmune axis in the setting of neuropathic pain remain incompletely understood. Here, we show that genetic ablation or pharmacological blockade of transient receptor potential vanilloid type 4 (TRPV4) markedly attenuated neuropathic pain-like behaviors in a mouse model of spared nerve injury. Mechanistically, microglia-expressed TRPV4 mediated microglial activation and proliferation and promoted functional and structural plasticity of excitatory spinal neurons through release of lipocalin-2. Our results suggest that microglial TRPV4 channels reside at the center of the neuroimmune axis in the spinal cord, which transforms peripheral nerve injury into central sensitization and neuropathic pain, thereby identifying TRPV4 as a potential new target for the treatment of chronic pain.

Ion channel regulation of gut immunity.

Mounting evidence indicates that gastrointestinal (GI) homeostasis hinges on communications among many cellular networks including the intestinal epithelium, the immune system, and both intrinsic and extrinsic nerves innervating the gut. The GI tract, especially the colon, is the home base for gut microbiome which dynamically regulates immune function. The gut's immune system also provides an effective defense against harmful pathogens entering the GI tract while maintaining immune homeostasis to avoid exaggerated immune reaction to innocuous food and commensal antigens which are important causes of inflammatory disorders such as coeliac disease and inflammatory bowel diseases (IBD). Various ion channels have been detected in multiple cell types throughout the GI tract. By regulating membrane properties and intracellular biochemical signaling, ion channels play a critical role in synchronized signaling among diverse cellular components in the gut that orchestrates the GI immune response. This work focuses on the role of ion channels in immune cells, non-immune resident cells, and neuroimmune interactions in the gut at the steady state and pathological conditions. Understanding the cellular and molecular basis of ion channel signaling in these immune-related pathways and initial testing of pharmacological intervention will facilitate the development of ion channel-based therapeutic approaches for the treatment of intestinal inflammation.

Piezo2 channels expressed by colon-innervating TRPV1-lineage neurons mediate visceral mechanical hypersensitivity.

Inflammatory and functional gastrointestinal disorders such as irritable bowel syndrome (IBS) and obstructive bowel disorder (OBD) underlie the most prevalent forms of visceral pain. Although visceral pain can be generally provoked by mechanical distension/stretch, the mechanisms that underlie visceral mechanosensitivity in colon-innervating visceral afferents remain elusive. Here, we show that virally mediated ablation of colon-innervating TRPV1-expressing nociceptors markedly reduces colorectal distention (CRD)-evoked visceromotor response (VMR) in mice. Selective ablation of the stretch-activated Piezo2 channels from TRPV1 lineage neurons substantially reduces mechanically evoked visceral afferent action potential firing and CRD-induced VMR under physiological conditions, as well as in mouse models of zymosan-induced IBS and partial colon obstruction (PCO). Collectively, our results demonstrate that mechanosensitive Piezo2 channels expressed by TRPV1-lineage nociceptors powerfully contribute to visceral mechanosensitivity and nociception under physiological conditions and visceral hypersensitivity under pathological conditions in mice, uncovering potential therapeutic targets for the treatment of visceral pain.

Percutaneous Electroosmosis of Berberine-Loaded Ca2+ Crosslinked Gelatin/Alginate Mixed Hydrogel.

Flexible conductive hydrogel has been driven by scientific breakthroughs and offers a wide variety of applications, including sensors, electronic skins, biomedicine, energy storage, etc. Based on the mixed-ion crosslinking method, gelatin and sodium alginate (Gel-Alg) composite hydrogels were successfully prepared using Ca2+ crosslinking. The migration behavior of berberine hydrochloride (BBH) in the matrix network structure of Gel-Alg hydrogel with a certain pore size under an electric field was studied, and the transdermal effect of berberine hydrochloride under an electric field was also studied. The experimental results show that Gel-Alg has good flexibility and conductivity, and electrical stimulation can enhance the transdermal effect of drugs. Gel-Alg composite hydrogel may be a new material with potential application value in future biomedical directions.

Simulation Study on the Structure Design of p-GaN/AlGaN/GaN HEMT-Based Ultraviolet Phototransistors.

This work investigates the impacts of structural parameters on the performances of p-GaN/AlGaN/GaN HEMT-based ultraviolet (UV) phototransistors (PTs) using Silvaco Atlas. The simulation results show that a larger Al content or greater thickness for the AlGaN barrier layer can induce a higher two-dimensional electron gas (2DEG) density and produce a larger photocurrent. However, they may also lead to a larger dark current due to the incomplete depletion of the GaN channel layer. The depletion conditions with various Al contents and thicknesses of the AlGaN layer are investigated in detail, and a borderline between full depletion and incomplete depletion was drawn. An optimized structure with an Al content of 0.23 and a thickness of 14 nm is achieved for UV-PT, which exhibits a high photocurrent density of 92.11 mA/mm, a low dark current density of 7.68 × 10-10 mA/mm, and a large photo-to-dark-current ratio of over 1011 at a drain voltage of 5 V. In addition, the effects of other structural parameters, such as the thickness and hole concentration of the p-GaN layer as well as the thickness of the GaN channel layer, on the performances of the UV-PTs are also studied in this work.

Ligustrazine as an Extract from Medicinal and Edible Plant Chuanxiong Encapsulated in Liposome-Hydrogel Exerting Antioxidant Effect on Preventing Skin Photoaging.

Long-term sunlight exposure will cause the accumulation of free radicals in the skin and lead to oxidative damage and aging, antioxidant drugs have gradually become the focus of research, but there is little research on antioxidant drugs for percutaneous treatment. The purpose of this study was to prepare ligustrazine hydrochloride (TMPZ)-loaded liposome-hydrogel (TMPZ-LG), evaluate its antioxidant properties, and apply it on the skin of mice to observe whether it had preventive and therapeutic effect on the irradiation under the ultraviolet rays, in an attempt to make it into a new kind of delivery through the skin. TMPZ-LG was prepared by the combination of film dispersion and sodium carboxymethylcellulose (2%, CMC-Na) natural swelling method. The release rates in vitro permeation across the dialysis membrane and ex vivo transdermal had both reached 40%; the scavenging effect of TMPZ-LG on 1,1-diphenyl-2-picrylhydrazyl (DPPH) and H2O2 were 65.57 ± 4.13% and 73.06 ± 5.65%; the inhibition rate of TMPZ-LG on malondialdehyde (MDA) production in liver homogenate and anti-low density lipoprotein (LDL) oxidation experiments ex vivo were 15.03 ± 0.9% and 21.57 ± 1.2%. Compared with untreated mice, the skin pathological symptoms of mice coated with TMPZ-LG were significantly reduced after ultraviolet irradiation, and there was statistical significance. The results showed TMPZ-LG could exert good antioxidant activity in vitro and ex vivo; therefore, it is feasible to prevent and treat skin oxidation.

Gut-innervating nociceptors regulate the intestinal microbiota to promote tissue protection.

Nociceptive pain is a hallmark of many chronic inflammatory conditions including inflammatory bowel diseases (IBDs); however, whether pain-sensing neurons influence intestinal inflammation remains poorly defined. Employing chemogenetic silencing, adenoviral-mediated colon-specific silencing, and pharmacological ablation of TRPV1+ nociceptors, we observed more severe inflammation and defective tissue-protective reparative processes in a murine model of intestinal damage and inflammation. Disrupted nociception led to significant alterations in the intestinal microbiota and a transmissible dysbiosis, while mono-colonization of germ-free mice with Gram+Clostridium spp. promoted intestinal tissue protection through a nociceptor-dependent pathway. Mechanistically, disruption of nociception resulted in decreased levels of substance P, and therapeutic delivery of substance P promoted tissue-protective effects exerted by TRPV1+ nociceptors in a microbiota-dependent manner. Finally, dysregulated nociceptor gene expression was observed in intestinal biopsies from IBD patients. Collectively, these findings indicate an evolutionarily conserved functional link between nociception, the intestinal microbiota, and the restoration of intestinal homeostasis.

The Fabrication of Docetaxel-Containing Emulsion for Drug Release Kinetics and Lipid Peroxidation.

Docetaxel (DTX)-based formulation development is still confronted with significant challenges, due to its refractory solubility and side effects on normal tissues. Inspired by the application of the transdermal drug delivery model to topical treatment, we developed a biocompatible and slow-release DTX-containing emulsion via self-assembly prepared by a high-speed electric stirring method and optimized the formulation. The results of accelerated the emulsion stability experiment showed that the emulsion prepared at 10,000 rpm/min had a stability of 89.15 ± 2.05%. The ADME, skin irritation, skin toxicity and molecular interaction between DTX and excipients were predicted via Discovery Studio 2016 software. In addition, DTX addition in oil or water phases of the emulsion showed different release rates in vitro and ex vivo. The DTX release ex vivo of the DTX/O-containing emulsion and the DTX/W-containing emulsion were 45.07 ± 5.41% and 96.48 ± 4.54%, respectively. In vitro antioxidant assays and anti-lipid peroxidation models revealed the antioxidant potential of DTX. However, DTX-containing emulsions could maintain and even enhance the antioxidant effect, both scavenging free radicals in vitro and inhibiting the process of lipid peroxidation.

Quantification of CGRP-immunoreactive myenteric neurons in mouse colon.

Quantitative data of biological systems provide valuable baseline information for understanding pathology, experimental perturbations, and computational modeling. In mouse colon, calcitonin gene-related peptide (CGRP) is expressed by myenteric neurons with multiaxonal (Dogiel type II) morphology, characteristic of intrinsic primary afferent neurons (IPANs). Analogous neurons in other species and gut regions represent 5-35% of myenteric neurons. We aimed to quantify proportions of CGRP-immunopositive (CGRP+) myenteric neurons. Colchicine-treated wholemount preparations of proximal, mid, and distal colon were labeled for HuC/D, CGRP, nitric oxide synthase (NOS), and peripherin (Per). The pan-neuronal markers (Hu+/Per+) co-labeled 94% of neurons. Hu+/Per- neurons comprised ∼6%, but Hu-/Per+ cells were rare. Thus, quantification was based on Hu+ myenteric neurons (8576 total; 1225 ± 239 per animal, n = 7). CGRP+ cell bodies were significantly larger than the average of all Hu+ neurons (329 ± 13 vs. 261 ± 12 µm2 , p < .0001). CGRP+ neurons comprised 19% ± 3% of myenteric neurons without significant regional variation. NOS+ neurons comprised 42% ± 2% of myenteric neurons overall, representing a lower proportion in proximal colon, compared to mid and distal colon (38% ± 2%, 44% ± 2%, and 44% ± 3%, respectively). Peripherin immunolabeling revealed cell body and axonal morphology in some myenteric neurons. Whether all CGRP+ neurons were multiaxonal could not be addressed using peripherin immunolabeling. However, of 118 putatively multiaxonal neurons first identified based on peripherin immunoreactivity, all were CGRP+ (n = 4). In conclusion, CGRP+ myenteric neurons in mouse colon were comprehensively quantified, occurring within a range expected of a putative IPAN marker. All Per+ multiaxonal neurons, characteristic of Dogiel type II/IPAN morphology, were CGRP+.

AlGaN Quantum Disk Nanorods with Efficient UV-B Emission Grown on Si(111) Using Molecular Beam Epitaxy.

AlGaN nanorods have attracted increasing amounts of attention for use in ultraviolet (UV) optoelectronic devices. Here, self-assembled AlGaN nanorods with embedding quantum disks (Qdisks) were grown on Si(111) using plasma-assisted molecular beam epitaxy (PA-MBE). The morphology and quantum construction of the nanorods were investigated and well-oriented and nearly defect-free nanorods were shown to have a high density of about 2 × 1010 cm-2. By controlling the substrate temperature and Al/Ga ratio, the emission wavelengths of the nanorods could be adjusted from 276 nm to 330 nm. By optimizing the structures and growth parameters of the Qdisks, a high internal quantum efficiency (IQE) of the AlGaN Qdisk nanorods of up to 77% was obtained at 305 nm, which also exhibited a shift in the small emission wavelength peak with respect to the increasing temperatures during the PL measurements.

High Power Figure-of-Merit, 10.6-kV AlGaN/GaN Lateral Schottky Barrier Diode with Single Channel and Sub-100-µm Anode-to-Cathode Spacing.

GaN-based lateral Schottky barrier diodes (SBDs) have attracted great attention for high-power applications due to its combined high electron mobility and large critical breakdown field. However, the breakdown voltage (BV) of the SBDs are far from exploiting the material advantages of GaN at present, limiting the desire to use GaN for ultra-high voltage (UHV) applications. Then, a golden question is whether the excellent properties of GaN-based materials can be practically used in the UHV field? Here, UHV AlGaN/GaN SBDs are demonstrated on sapphire with a BV of 10.6 kV, a specific on-resistance (RON,SP ) of 25.8 mΩ cm2 , yielding a power figure-of-merit (P-FOM = BV2 /RON,SP ) of 4.35 GW cm-2 . These devices are designed with single channel and 85-µm anode-to-cathode spacing, without other additional electric field management, demonstrating its great potential for the UHV application in power electronics.

Miswiring of Merkel cell and pruriceptive C fiber drives the itch-scratch cycle.

Itch sensation provokes the scratch reflex to protect us from harmful stimuli in the skin. Although scratching transiently relieves acute itch through activation of mechanoreceptors, it propagates the vicious itch-scratch cycle in chronic itch by further aggravating itch over time. Although well recognized clinically, the peripheral mechanisms underlying the itch-scratch cycle remain poorly understood. Here, we show that mechanical stimulation of the skin results in activation of the Piezo2 channels on Merkel cells that pathologically promotes spontaneous itch in experimental dry skin. Three-dimensional reconstruction and immunoelectron microscopy revealed structural alteration of MRGPRA3+ pruriceptor nerve endings directed toward Merkel cells in the setting of dry skin. Our results uncover a functional miswiring mechanism under pathologic conditions, resulting in touch receptors triggering the firing of pruriceptors in the skin to drive the itch-scratch cycle.