The analgesic effects of dezocine in rats with chronic constriction injuries.

Neuropathic pain (NP) is caused by diseases or dysfunction of nervous system and has a considerable negative impact on patients' quality of life. Opioid analgesics can be used for NP treatment. However, the effect of dezocine on NC remains unknown. In this study, we aimed to investigate the analgesic and intestinal effects of various doses of dezocine in rats with chronic constriction injuries (CCI). 100 rats were equally divided into 5 groups: the low (D1 group), medium (D2 group), and high (D3 group) doses of dezocine, and sham operation and model groups. The effects of dezocine on pain, analgesic effect, pain response, and tension and contraction frequencies of intestinal smooth muscles were assessed. With an increase in the dezocine dosage, the cumulative pain scores of rats decreased and analgesic effect significantly increased; mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) improved in varying degrees. The expression of the NP-related proteins glial fibrillary acidic protein (GFAP) and connexin 43 (Cx43) was also improved by dezocine treatment. The results of western blot and ELISA showed that IL-6, and monocyte chemotactic protein-1 (MCP-1) levels also decreased significantly with an increase in the dezocine dose, indicated that dezocine alleviated the inflammatory microenvironment. The dezocine exhibited no significant effect on the tension or contraction frequencies of intestinal smooth muscles of rats. In conclusion, the analgesic effect of dezocine on rats with CCI is dose-dependent and has little effect on the tension or contraction frequencies of intestinal smooth muscles. Our research proved the analgesic effect of dezocine in rats with CCI, and provided further insights into new therapies for NP treatment.

Reduced VOC Deficit of Mixed Lead-Tin Perovskite Solar Cells via Strain-Releasing and Synergistic Passivation Additives.

The power conversion efficiency (PCE) of tin-lead perovskite solar cells (PSCs) is normally lower than that of Pb cells, mainly due to greater open circuit voltage (VOC ) losses. Herein, the additive 2,6-diaminopyridine (TNPD) is designed to anchor on the surface of the perovskite precursor colloid as nucleating agent to modulate the growth of Pb-Sn perovskites. It is observed that the TNPD not only effectively induces crystal growth during the nucleation stage, remaining on the crystal surface and ultimately passivating the resulting perovskite films, but also releases the micro-strain generated during the film growth. Furthermore, TNPD could lower the defect density (Sn4+ amount) by screening the perovskite against oxygen and by synergistically bonding with undercoordinated Sn/Pb on the surface. Finally, a high VOC of 0.85 V is obtained, corresponding to a voltage deficit of 0.41 V using a perovskite absorber with a bandgap of 1.26 eV, and a high PCE (20.35%) reported so far for Pb-Sn PSCs. Moreover, the stability of the TNPD-incorporated device is significantly improved, and the PCE maintains 50% of the initial value after about 1000 h storage in glovebox without encapsulated, in comparison to that of the control device (about 700 h, maintaining 30% of the initial value).

Clinical applications of smart wearable sensors.

Smart wearable sensors are electronic devices worn on the body that collect, process, and transmit various physiological data. Compared to traditional devices, their advantages in terms of portability and comfort have made them increasingly important in the medical field. This review takes a unique clinical physician's standpoint, diverging from conventional sensor-type-based classifications, and provides a comprehensive overview of the diverse clinical applications of wearable sensors in recent years. In this review, we categorize these applications according to different diseases, encompassing skin diseases and injuries, cardiovascular diseases, abnormal human motion, as well as endocrine and metabolic disorders. Additionally, we discuss the challenges and perspectives hindering the development of sensors for clinical use, emphasizing the critical need for interdisciplinary collaboration between medical and engineering professionals. Overall, this review would serve as an important reference for the future direction of sensor devices in clinical use.

Role of Type I Cannabinoid Receptor in Sensory Neurons in Psoriasiform Skin Inflammation and Pruritus.

Type I cannabinoid receptor (CB1R) has been reported to exhibit favorable anti-inflammation and antipruritus effects against inflammation-based skin diseases, but the specific mechanism remains to be explored. In this study, we found that the activation of CB1R significantly relieved the scratching behavior and skin inflammation in a psoriatic mouse model, whereas CB1R antagonist aggravated these symptoms. Because the expression of CB1R was abundant in dorsal root ganglia, we constructed mice with conditional CB1R knockout in primary sensory neurons and found that imiquimod-induced psoriasiform inflammation and itch were both worsened in CB1R-conditional knockout mice. Next, we observed that the CB1R was mostly located in peptidergic neurons, and deletion of CB1R in primary sensory neurons promoted the production and release of substance P to the skin tissue. Furthermore, the elevated substance P in the skin affected the activation of extracellular signal‒regulated kinase in keratinocytes and induced the accumulation of mast cells in the dermis. Finally, we showed that blocking the substance P signal significantly alleviated the exacerbation of psoriasiform inflammation and itch caused by imiquimod in CB1R-conditional knockout mice. Together, our work reveals that CB1R in sensory neurons plays a key role in psoriasiform skin inflammation and pruritus by regulating substance P expression.

ANGPTL4 Regulates Psoriasis via Modulating Hyperproliferation and Inflammation of Keratinocytes.

Background: Psoriasis is characterized by keratinocyte proliferation and massive inflammatory leukocytes infiltration, affecting 0.14%-1.99% of the world's population. Our aim was to identify novel potential therapeutic strategies for psoriasis. Methods: Weighted gene co-expression network analysis (WGCNA) was performed to identify gene modules that were closely related to psoriasis based on the GSE30999 dataset, which contained expression data from 85 patients with moderate-to-severe psoriasis. Then, angiopoietin-like 4 (ANGPTL4), one of the most related hub genes, was selected for in vitro and in vivo functional assays. In our experiments, imiquimod (IMQ)-induced psoriasiform dermatitis in mice and human keratinocytes (HaCaT) cells were used to study the potential roles and mechanisms of ANGPTL4 in psoriasis. Results: WGCNA analysis revealed the turquoise module was most correlated with psoriasis, and ANGPTL4 is one of the most related hub genes that significantly upregulated in psoriasis lesions compared with non-lesional skin. Consistent with the bioinformatic analysis, the expression of ANGPTL4 was significantly upregulated in IMQ-induced psoriasiform skin of mice. Exogenous recombinant ANGPLT4 protein treatment could promote the proliferation and induce the expression of inflammatory cytokines in HaCaTs, whereas silencing of ANGPTL4 effectively inhibited these effects. Then we demonstrated that recombinant ANGPTL4 protein exacerbated psoriasiform inflammation and epidermal hyperproliferation in vivo. Mechanismly, extracellular signal-regulated kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) pathways were involved in ANGPTL4-mediated regulation of proliferation and inflammation. Conclusion: We found ANGPTL4 was significantly increased in IMQ-induced psoriasiform skin of mice. ANGPTL4 could promote keratinocyte proliferation and inflammatory response via ERK1/2 and STAT3 dependent signaling pathways in psoriasis.

CB2R Deficiency Exacerbates Imiquimod-Induced Psoriasiform Dermatitis and Itch Through the Neuro-Immune Pathway.

Background: Cannabinoid receptor 2 (CB2R) is a potential target for anti-inflammatory and pain therapeutics given its significant immunomodulatory and analgesic effects. However, the role of CB2R in imiquimod (IMQ)-induced psoriasiform dermatitis (PsD) and itch is poorly understood. Objective: To investigate the function and mechanism of CB2R in PsD and itch in mice. Methods: Following daily treatment with topical IMQ cream for 5-7 consecutive days in C56BL/6 wild-type (WT) and CB2R gene knockout (KO) mice, we assessed the Psoriasis Area and Severity Index (PASI) scores and the scratch bouts every day, and hematoxylin and eosin (H&E) staining, toluidine blue staining were used to observe the histological changes. mRNA levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Protein levels were detected by western blotting (WB), immunohistochemistry (IHC), immunofluorescence (IF) and cytometric bead array (CBA). Flow cytometry (FCM) was used to examine the proportion of Th17/Treg cells. Results: We found that CB2R expression levels were increased in mice with psoriasis. Compared with WT mice, CB2R deficiency exacerbated IMQ-induced PsD and scratching bouts and upregulated the expression of proinflammatory cytokines by increasing the infiltration of CD4+ T cells and the Th17/Treg ratio. Obvious proliferation and prolongation of nerve fibers and high expression of nerve growth factor (NGF) were observed in PsD and CB2R KO mice. Pretreatment with the CB2R agonist, JWH-133 significantly reversed inflammation and scratching bouts. CB2R didn't participate in the induction of itch in psoriasis by regulating the expression of IL-31, thymic stromal lymphopoietin (TSLP) and mast cells in mouse skins. Conclusion: Our results demonstrate that CB2R plays a pivotal role in the pathophysiology of psoriasis, providing a new potential target for anti-inflammatory and antipruritic drugs.

Endoplasmic reticulum stress in melanoma pathogenesis and resistance.

Melanoma is the most lethal skin cancer with rising incidence worldwide. Despite significant advances in target therapy and immunotherapy, low response rates and the development of drug resistance remain key clinical barriers affecting patient prognosis. The complex interplay between multiple signaling molecules and pathways has brought little understanding of melanoma pathogenesis and resistance. The genetic mutation and hypermetabolic environment of melanoma cells lead to increasing demands for protein synthesis and perturb proteostasis resulting in endoplasmic reticulum (ER) stress. Subsequently, three unfolded protein response (UPR) signaling branches, represented by IRE1α, PERK and ATF6, are activated to direct cell fate towards pro-survival or pro-apoptosis depending on the intensity and duration of ER stress. In this review, we summarize ER stress and UPR in melanoma cells and tumor-infiltrating immune cells along with the crosstalk among these pathways. We provide the latest advances in understanding melanoma pathogenesis and resistance and discuss the potential of targeting the ER stress or UPR process for melanoma therapy.

Narciclasine inhibits phospholipase A2 and regulates phospholipid metabolism to ameliorate psoriasis-like dermatitis.

Introduction: Psoriasis is a common inflammatory skin disease recognized by the World Health Organization as "an incurable chronic, noninfectious, painful, disfiguring and disabling disease." The fact that metabolic syndrome (MetS) is the most common and important comorbidities of psoriasis suggests an important role of lipid metabolism in the pathogenesis of psoriasis. Narciclasine (Ncs) is an alkaloid isolated from the Amaryllidaceae plants. Its biological activities include antitumor, antibacterial, antiinflammatory, anti-angiogenic and promoting energy expenditure to improve dietinduced obesity. Here, we report that Ncs may be a potential candidate for psoriasis, acting at both the organismal and cellular levels. Methods: The therapeutic effect of Ncs was assessed in IMQ-induced psoriasis-like mouse model. Then, through in vitro experiments, we explored the inhibitory effect of Ncs on HaCaT cell proliferation and Th17 cell polarization; Transcriptomics and lipidomics were used to analyze the major targets of Ncs; Single-cell sequencing data was used to identify the target cells of Ncs action. Results: Ncs can inhibit keratinocyte proliferation and reduce the recruitment of immune cells in the skin by inhibiting psoriasis-associated inflammatory mediators. In addition, it showed a direct repression effect on Th17 cell polarization. Transcriptomic and lipidomic data further revealed that Ncs extensively regulated lipid metabolismrelated genes, especially the Phospholipase A2 (PLA2) family, and increased antiinflammatory lipid molecules. Combined with single-cell data analysis, we confirmed that keratinocytes are the main cells in which Ncs functions. Discussion: Taken together, our findings indicate that Ncs alleviates psoriasiform skin inflammation in mice, which is associated with inhibition of PLA2 in keratinocytes and improved phospholipid metabolism. Ncs has the potential for further development as a novel anti-psoriasis drug.

A Porphyrin-Involved Benzene-1,3,5-Tricarboxamide Dendrimer (Por-BTA) as a Multifunctional Interface Material for Efficient and Stable Perovskite Solar Cells.

Surface defects of perovskite films are the major sources of nonradiative recombination which limit the efficiency and stability of perovskite solar cells. Surface passivation represents one of the most efficient strategies to solve this problem. Herein, for the first time we designed a porphyrin-involved benzene-1,3,5-tricarboxamide dendrimer (Por-BTA) as a multifunctional interface material between the interface of the perovskite and the hole-transporting layer (spiro-OMeTAD) for the surface passivation of perovskite films. The results suggested that Por-BTA not only efficiently passivated the perovskite surface defects via the coordination of the exposed Pb2+ with the carbonyl unit and basic sites of pyrrole units in Por-BTA but also improved the interface contact and the charge transfer between the perovskite and spiro-OMeTAD ascribed to the strong intermolecular π-π stacking of Por-BTA. It was shown that the PSC devices with the Por-BTA treatment exhibited improved power conversion efficiency with the champion of 22.30% achieved (21.30% for the control devices), which is mainly attributed to the increased short-circuit current density and fill factor. Interestingly, the stability of moisture for the Por-BTA-treated device was also enhanced compared to those without the Por-BTA treatment. This work presents a promising direction toward the design of multifunctional organic molecules as the interface materials to improve the cell performance of PSCs.

Identification of an Immune-Related Prognostic Signature Associated With Immune Infiltration in Melanoma.

Melanoma is the leading cause of cancer-related death among skin tumors, with an increasing incidence worldwide. Few studies have effectively investigated the significance of an immune-related gene (IRG) signature for melanoma prognosis. Here, we constructed an IRGs prognostic signature using bioinformatics methods and evaluated and validated its predictive capability. Then, immune cell infiltration and tumor mutation burden (TMB) landscapes associated with this signature in melanoma were analyzed comprehensively. With the 10-IRG prognostic signature, melanoma patients in the low-risk group showed better survival with distinct features of high immune cell infiltration and TMB. Importantly, melanoma patients in this subgroup were significantly responsive to MAGE-A3 in the validation cohort. This immune-related prognostic signature is thus a reliable tool to predict melanoma prognosis; as the underlying mechanism of this signature is associated with immune infiltration and mutation burden, it might reflect the benefit of immunotherapy to patients.

Inhibition of keratinocyte necroptosis mediated by RIPK1/RIPK3/MLKL provides a protective effect against psoriatic inflammation.

Psoriasis is a common autoimmune and chronic inflammatory skin disorder globally affecting 0.51-11.43% of adults. Inflammation-associated cell death in keratinocytes plays a key role in the process of integrate inflammatory cascade in psoriasis. Necroptosis is a regulated necrotic cell death mediated by receptor interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like pseudokinase (MLKL), which participates in many human inflammatory diseases. However, the mechanism and function of programmed necrosis in psoriasis is not well-illustrated. In the current study, we provide evidence for the involvement of necroptosis in psoriasis. RIPK1 and MLKL were significantly upregulated and localized in all layers of the epidermis in human psoriatic lesions, while RIPK3 and phosphorylated MLKL were mainly expressed in keratinocytes, which located in the upper layers. Increased tendency of necroptosis was also found in IMQ-induced psoriasiform skin of mice. Further, we discovered that both the inhibitor of RIPK1 R-7-Cl-O-Necrostatin-1 (Nec-1s) and MLKL-inhibitor necrosulfonamide (NSA) suppressed necroptosis in HaCaT cells and IMQ mouse models, powerfully blocked IMQ-induced inflammatory responses in vivo, and significantly downregulated the production of inflammatory factors like IL-1ß, IL-6, IL-17A, IL-23a, CXCL1, and CCL20. These findings promote the development of new therapies for the treatment of necroptosis-activated pathologies for psoriasis.

TET2 is involved in DNA hydroxymethylation, cell proliferation and inflammatory response in keratinocytes.

DNA methylation and hydroxymethylation are the most common epigenetic modifications associated with the cell cycle and the inflammatory response. The present study aimed to investigate the role of 5­hydroxymethyl­cytosine (5­hmC) and ten­eleven translocation­2 (TET2) in keratinocytes. Following TET2 knockdown, dot blot analysis was performed to assess the levels of 5­hmC in keratinocytes, using HaCaT cells. Subsequently, the viability and cell cycle of HaCaT cells were assessed by MTT, Cell Counting Kit­8 assay and flow cytometric assays. Cyclin­dependent kinase inhibitor 2A and proinflammatory cytokine protein and mRNA expression levels were also detected. The present results suggested that TET2 may play an important role in regulating cellular proliferation by mediating DNA hydroxymethylation in HaCaT cells. In addition, TET2 knockdown decreased the production of proinflammatory cytokines, including lipocalin 2, S100 calcium binding protein A7, matrix metallopeptidase 9, C­X­C motif chemokine ligand 1, interferon regulatory factor 7 and interleukin­7 receptor. The present study suggested that TET2 regulated cell viability, apoptosis and the expression of inflammatory mediators in keratinocytes. Collectively, the results indicated that TET2 knockdown may relieve inflammatory responses in the skin.

Au Nanocage-Strengthened Dissolving Microneedles for Chemo-Photothermal Combined Therapy of Superficial Skin Tumors.

For superficial skin tumors (SST) with high incidence, surgery and systemic therapy are relatively invasive and possible to cause severe side effect, respectively. Yet, topical therapy is confronted with the limited transdermal capacity because of the stratum corneum barrier layer of skin. Therefore, it is crucial to develop a highly effective and minimally invasive alternative transdermal approach for treating SST. Here, we developed gold nanocage (AuNC)- and chemotherapeutic drug doxorubicin (DOX)-loaded hyaluronic acid dissolving microneedle (MN) arrays. The loaded AuNCs are not only reinforcers to enhance the mechanical strength of the MNs, but also effective agents for photothermal therapy to obtain effective transdermal therapy for SST. The resultant MNs can effectively penetrate the skin, dissolve in the skin and release cargoes within the tumor site. Photothermal effect of AuNCs initiated by near-infrared laser irradiation combined with the chemotherapy effect of DOX destroyed tumors synergistically. Moreover, we verified the potent antitumor effects of the DOX/AuNC-loaded MNs after four administrations to SST-bearing mice without obvious side effects. Therefore, the drug/AuNC-loaded dissolving MN system provides a promising platform for effective, safe, minimally invasive combined treatment of SST.