New insight into prurigo nodularis: Proadrenomedullin N-terminal 20 peptide mediates mouse mast cell activation via Mrgprb2.

BACKGROUND: Prurigo nodularis (PN) is a chronic inflammatory skin disorder that is characterized by extremely itchy nodules. Proadrenomedullin N-terminal 20 (PAMP) activates mast cell degranulation via Mas-related G protein-coupled receptor X2 (MRGPRX2), which is associated with pruritus in allergic contact dermatitis. However, the mechanisms underlying the action of PAMP and MRGPRX2 in PN remain unclear. OBJECTIVE: To determine the role of PAMP-induced mast cell activation via MRGPRX2 (mouse homologous Mrgprb2) in PN. METHODS: The expression of PAMP and the number of MRGPRX2-expressing mast cells in the skin biopsies of patients with PN, atopic dermatitis (AD), and healthy participants were analyzed using immunohistochemistry and immunofluorescence, respectively. The biphasic response of PAMP9-20 mediated by Mrgprb2 in mouse peritoneal mast cells (PMC) was validated in vitro using qRT-PCR, ELISA, flow cytometry, and siRNA techniques. RESULTS: PAMP expression and the number of MRGPRX2+ mast cells in lesional PN skin, but not in AD, were elevated compared to healthy skin. PAMP9-20 mediates the immediate and delayed phase responses of PMC, such as degranulation, histamine and ß-hexosaminidase release, and secretion of inflammatory factors such as CCL2, TNF-α, and GM-CSF. These effects were inhibited when Mrgprb2 expression was silenced. Silencing Mrgprb2 did not affect the biphasic response of PMC that was induced by IgE-FcεRI activation. CONCLUSIONS: The results show that PAMP mediates mouse mast cell activation via Mrgprb2, which may be involved in the pathogenesis of PN. The PAMP/ Mrgprb2 pathway, independent of classical IgE signaling, could be developed as a candidate drug target for treating PN.

Molecular mechanisms of pruritus in prurigo nodularis.

Pruritus is the most common symptom of dermatological disorders, and prurigo nodularis (PN) is notorious for intractable and severe itching. Conventional treatments often yield disappointing outcomes, significantly affecting patients' quality of life and psychological well-being. The pathogenesis of PN is associated with a self-sustained "itch-scratch" vicious cycle. Recent investigations of PN-related itch have partially revealed the intricate interactions within the cutaneous neuroimmune network; however, the underlying mechanism remains undetermined. Itch mediators play a key role in pruritus amplification in PN and understanding their action mechanism will undoubtedly lead to the development of novel targeted antipruritic agents. In this review, we describe a series of pruritogens and receptors involved in mediating itching in PN, including cytokines, neuropeptides, extracellular matrix proteins, vasculogenic substances, ion channels, and intracellular signaling pathways. Moreover, we provide a prospective outlook on potential therapies based on existing findings.

Highly-stable flexible pressure sensor using piezoelectric polymer film on metal oxide TFT.

In this study, a flexible pressure sensor with highly stable performance is presented. The pressure sensor was fabricated to work under low voltage conditions by using a high mobility amorphous indium-gallium-zinc oxide (a-IGZO) thin-film transistor (TFT) and a stretched polyvinylidene fluoride (PVDF) film. To prepare a stable sensor suitable for practical use, we designed a device structure that shields ambient noise by grounding the control gate. The shielding structure significantly improves the stability of the device. Moreover, the sensor was fabricated on a flexible substrate and delaminated via a laser lift-off (LLO) technique to meet the urgent needs for flexibility. The pressure sensor showed good sensitivity and reliability over a pressure ranging from 0 to 75 kPa which covers the human touch pressure range. Especially, good linearity over a wide pressure range and high stability over 1000 repeated loadings were realized. Due to the simple structure, the pressure sensor demonstrates the advantage of being inexpensive to be manufactured and holds the potential to be integrated into the display backplane. Therefore, the proposed sensor has great potential in the production of flexible touch screens, human-machine interacting applications, and even electronic skins in the future.

Self-assembly supramolecular drug delivery system for combination of photodynamic therapy and chemotherapy.

AIMS: To construct a self-assembly supramolecular drug delivery system (DDS) to co-deliver chlorin e6 (Ce6) and tripeptide tyroseroleutide (YSL) and evaluate the anti-tumour effects. METHODS: A supramolecular DDS was constructed via self-assembly of Ce6 and YSL based on π-π stacking and hydrogen-bond interaction. The size, morphology, stability, in vitro drug release, cellular uptake, cytotoxicity, pharmacokinetics analysis and pharmacodynamics analysis were respectively studied. RESULTS: Ce6-YSL nanoparticles with a uniform size of 75 ± 3.5 nm (PDI = 0.128) and monodispersed spherical morphology were constructed. The nanoparticles exhibited good stability with zeta potential -21.2 ± 1.73 mV. Under the weak acidic conditions, the accumulative drug release was 82.8% (w/w) (pH = 6.0) and 91.5% (w/w) (pH = 5.0), respectively, indicating that nanoparticles performed smart responsive properties and achieved controlled release characteristics in acidic tumour microenvironment. In addition, nanoparticles could easily enter the tumour cells and induce ROS production and inhibit cell proliferation in SMMCC-7721 cells with IC50 value 3.4 ± 0.023 µg/mL under laser irradiation. Furthermore, the nanoparticles could retain a much higher blood concentration in vivo and displayed excellent antitumor effect in tumour-bearing mice, showing no influence on body weight. CONCLUSIONS: This self-assembly supramolecular DDS can be used for combination of photodynamic therapy and chemotherapy in future research.

Ultrathin Nanofibrous Membranes Containing Insulating Microbeads for Highly Sensitive Flexible Pressure Sensors.

Highly sensitive and flexible pressure sensors were developed based on dielectric membranes composed of insulating microbeads contained within polyvinylidene fluoride (PVDF) nanofibers. The membrane is fabricated using a simple electrospinning process. The presence of the microbeads enhances porosity, which in turn enhances the sensitivity (1.12 kPa-1 for the range of 0-1 kPa) of the membrane when used as a pressure sensor. The microbeads are fixed in position and uniformly distributed throughout the nanofibers, resulting in a wide dynamic range (up to 40 kPa) without any sensitivity loss. The fluffy and nonsticky PVDF nanofiber features low hysteresis and ultrafast response times (∼10 ms). The sensor has also demonstrated reliable pressure detection over 10 000 loading cycles and 250 bending cycles at a 13 mm bending radius. These pressure sensors were successfully applied to detect heart rate and respiratory signals, and an array of sensors was fabricated and used to recognize spatial pressure distribution. The sensors described herein are ultrathin and ultralight, with a total thickness of less than 100 µm, including the electrodes. All of the materials comprising the sensors are flexible, making them suitable for on-body applications such as tactile sensors, electronic skins, and wearable healthcare devices.