Downregulation of Ebp1Khib210 promotes keratinocyte proliferation through induction of TIF-IA-mediated rRNA synthesis.

BACKGROUND: Psoriasis is a prevalent chronic inflammatory dermatosis characterized by excessive proliferation of keratinocytes. Protein lysine 2-hydroxyisobutyrylation (Khib) is a newly identified post-translational modification that regulates various biological processes. Abnormal Khib modification has been closely associated with the development of autoimmune diseases. OBJECTIVE: To investigate the abnormal Khib profile and its pathogenic role in psoriasis. METHODS: We utilized liquid chromatography-tandem mass spectrometry to analyze Khib-modified proteins in the epidermis of psoriasis and healthy controls. Mutated cells and mice with downregulated Ebp1Khib210 were generated to investigate its functional effects in psoriasis. RESULTS: The omic analysis revealed dysregulation of Khib modification in psoriatic lesions, exhibiting a distinct profile compared to controls. We observed the downregulation of Ebp1Khib210 in psoriatic lesions and IMQ-induced psoriatic mice. Notably, the expression of Ebp1Khib210 was upregulated in psoriatic patients following effective treatment. Decreased Ebp1Khib210 enhanced keratinocyte viability, proliferation, and survival while inhibiting apoptosis in vitro. Additionally, Pa2g4K210A mice with downregulated Ebp1Khib210 exhibited more severe psoriatic lesions and enhanced keratinocyte proliferation. Moreover, we found that Ebp1K210A mutation increased the interaction between Ebp1 and nuclear Akt, thereby inhibiting MDM2-mediated TIF-IA ubiquitination, and resulting to increased rRNA synthesis and keratinocyte proliferation. The downregulation of Ebp1Khib210 was attributed to inflammation-induced increases in HDAC2 expression. CONCLUSION: Our findings demonstrate that downregulation of Ebp1Khib210 promotes keratinocyte proliferation through modulation of Akt signaling and TIF-IA-mediated rRNA synthesis. These insights into Khib modification provide a better understanding of the pathogenesis of psoriasis and suggest potential therapeutic targets.

Construction methods and biomedical applications of PVA-based hydrogels.

Polyvinyl alcohol (PVA) hydrogel is favored by researchers due to its good biocompatibility, high mechanical strength, low friction coefficient, and suitable water content. The widely distributed hydroxyl side chains on the PVA molecule allow the hydrogels to be branched with various functional groups. By improving the synthesis method and changing the hydrogel structure, PVA-based hydrogels can obtain excellent cytocompatibility, flexibility, electrical conductivity, viscoelasticity, and antimicrobial properties, representing a good candidate for articular cartilage restoration, electronic skin, wound dressing, and other fields. This review introduces various preparation methods of PVA-based hydrogels and their wide applications in the biomedical field.

The occurrence and development mechanisms of esophageal stricture: state of the art review.

BACKGROUND: Esophageal strictures significantly impair patient quality of life and present a therapeutic challenge, particularly due to the high recurrence post-ESD/EMR. Current treatments manage symptoms rather than addressing the disease's etiology. This review concentrates on the mechanisms of esophageal stricture formation and recurrence, seeking to highlight areas for potential therapeutic intervention. METHODS: A literature search was conducted through PUBMED using search terms: esophageal stricture, mucosal resection, submucosal dissection. Relevant articles were identified through manual review with reference lists reviewed for additional articles. RESULTS: Preclinical studies and data from animal studies suggest that the mechanisms that may lead to esophageal stricture include overdifferentiation of fibroblasts, inflammatory response that is not healed in time, impaired epithelial barrier function, and multimethod factors leading to it. Dysfunction of the epithelial barrier may be the initiating mechanism for esophageal stricture. Achieving perfect in-epithelialization by tissue-engineered fabrication of cell patches has been shown to be effective in the treatment and prevention of esophageal strictures. CONCLUSION: The development of esophageal stricture involves three stages: structural damage to the esophageal epithelial barrier (EEB), chronic inflammation, and severe fibrosis, in which dysfunction or damage to the EEB is the initiating mechanism leading to esophageal stricture. Re-epithelialization is essential for the treatment and prevention of esophageal stricture. This information will help clinicians or scientists to develop effective techniques to treat esophageal stricture in the future.

IL-17A is involved in the hyperplasia of blood vessels in local lesions of psoriasis by inhibiting autophagy.

OBJECTIVE: Increased angiogenesis is a pathological feature of psoriasis, but the pathomechanisms of angiogenesis in psoriasis are not clear. Interleukin-17A (IL-17A) is the major effect factor in the pathogenesis of psoriasis. Our results showed that IL-17A can promote angiogenesis and cause endothelial cell inflammation. Autophagy plays an important role not only in regulating inflammation, but also in regulating angiogenesis. Whether angiogenesis in psoriasis is related to autophagy remains unclear. In this study, we treated human umbilical vein endothelial cells (HUVECs) with IL-17A to simulate increased angiogenesis to study whether increased angiogenesis in psoriasis is related to autophagy. METHODS AND RESULTS: Our results showed that treatment of HUVECs with IL-17A significantly increased angiogenesis and expression levels of mRNA for multiple proinflammatory cytokines (CCL20, IL-8, CCL2, IL-6, and IL-1ß) and, while decreasing intracellular levels of nitric oxide (NO) and NO synthase (NOS) activity. Moreover, IL-17A inhibited autophagy as shown that IL-17A significantly increased expression levels of LC3II and p62 proteins. Induction of autophagy ameliorated IL-17A-mediated inflammatory response and inhibited angiogenesis, accompanied by increased p-AMPKα(Thr172) and p-ULK1(Ser555) expression, and decreased p-mTOR(Ser2448) and p-ULK1(Ser757) expression. Furthermore, inhibition of either AMPK or lysosomal acidification completely overrode autophagy-induced changes in angiogenesis and NOS activity. Finally, induction of autophagy decreased apoptosis and caspase-3 activity in IL-17A-treated HUVECs. CONCLUSIONS: These results showed that IL-17A is involved in angiogenesis and inflammatory response by inhibiting autophagy through AMPK signaling pathway, suggesting that autophagy may be a new therapeutic target for psoriasis.

Polymer bilayer-Micro arc oxidation surface coating on pure magnesium for bone implantation.

Background: Pure magnesium-based ortho-implants have a number of advantages. However, vital parameters like degradation rate and biocompatibility still call for significant improvement. Methods: In this study, poly (1,3-trimethylene carbonate) (PTMC) and polydopamine (PDA) bilayer and micro arc oxidation composite coatings were prepared successively on magnesium surface by immersion method and microarc oxidation. Its corrosion resistance and biocompatibility were evaluated by in vitro corrosion tests, cellular compatibility experiments, and in vivo animal experiments. Results: In vitro experiments demonstrated that the composite coating provides excellent corrosion protection and biocompatibility. Animal studies demonstrated that the composite coating slowed the degradation of the implant and was not toxic to animal viscera. Conclusion: In conclusion, the inorganic-organic composite coating proposed in this study provided good corrosion resistance and enhanced biocompatibility for pure magnesium implants. The translational potential of this article: The translational potential of this article is to develop an anti-corrosion composite coating on a pure magnesium surface and to verify the viability of its use in animal models. It is hoped to open up a new approach to the design of new degradable orthopedic magnesium-based implants.

Nanostructured ionic hydrogel with integrated conductivity, stretchability and thermal responsiveness for a high-performance strain and temperature sensor.

Ionic conductive hydrogels are promising candidates for fabricating wearable sensors for human motion detection and disease diagnosis, and electronic skin. However, most of the existing ionic conductive hydrogel-based sensors primarily respond to a single-strain stimulus. Only a few ionic conductive hydrogels can respond to multiple physiological signals. Although some studies have explored multi-stimulus sensors, such as those detecting strain and temperature, the ability to identify the type of stimulus remains a challenge, which limits their applications. Herein, a multi-responsive nanostructured ionic conductive hydrogel was successfully developed by crosslinking the thermally sensitive poly(N-isopropylacrylamide-co-ionic liquid) conductive nanogel (PNI NG) with a poly(sulfobetaine methacrylate-co-ionic liquid) (PSI) network. The resultant hydrogel (PNI NG@PSI) was endowed with good mechanical stretchability (300%), resilience and fatigue resistance, and excellent conductivity (2.4 S m-1). Furthermore, the hydrogel exhibited a sensitive and stable electrical signal response and has a potential application in human motion detection. Moreover, the introduction of a nanostructured thermally responsive PNIPAAm network also endowed it with a sensitive and unique thermal-sensing ability to timely and accurately record temperature changes in the range of 30-45 °C, holding promise for application as a wearable temperature sensor to detect fever or inflammation in the human body. In particular, as a dual strain-temperature sensor, the hydrogel demonstrated an excellent capability of distinguishing the type of stimulus from superposed strain-temperature stimuli via electrical signals. Therefore, the implementation of the proposed hydrogel in wearable multi-signal sensors provides a new strategy for different applications, such as health monitoring and human-machine interactions.

Autophagy Inhibits Inflammation via Down-Regulation of p38 MAPK/mTOR Signaling Cascade in Endothelial Cells.

Objective: Autophagy, an intracellular process of self-digestion, has been shown to modulate inflammatory responses. In the present study, we determined the effects of autophagy on inflammatory response induced by M5 cytokines. Methods: Human umbilical vein endothelial cells (HUVECs) were treated with M5 cytokines to induce inflammation. Expression levels of mRNA for inflammatory cytokines and BIRC2 were compared in HUVECs with vs without induction of autophagy with rapamycin (RAPA) by PCR, while cell apoptosis was assessed by flow cytometry and caspase-3 activity assay kit. Expression levels of LC3, p62, p-p38 MAPK (Thr180/Tyr182), p-mTOR (Ser2445) and p-ULK1 (Ser555) proteins were measured by Western blotting. The nitric oxide (NO) content, NO synthase (NOS) activity and cell angiogenesis were also evaluated. Results: Induction of autophagy with RAPA decreased expression levels of IL6, IL8 and CCL20, in addition to reduction in inflammation-induced apoptosis in HUVECs. Moreover, RAPA increased LC3II, while decreasing p62 expression. Likewise, expression levels of p-p38 MAPK and p-mTOR proteins were markedly decreased by the treatment with RAPA. Finally, RAPA treatment increased the NO content and the NOS activity, and inhibited angiogenesis. Conclusion: Induced autophagy can improve the function of endothelial cells in psoriasis, suggesting approaches to induce autophagy can be used to ameliorate psoriasis.

Nanomaterials-Based Wound Dressing for Advanced Management of Infected Wound.

The effective prevention and treatment of bacterial infections is imperative to wound repair and the improvement of patient outcomes. In recent years, nanomaterials have been extensively applied in infection control and wound healing due to their special physiochemical and biological properties. Incorporating antibacterial nanomaterials into wound dressing has been associated with improved biosafety and enhanced treatment outcomes compared to naked nanomaterials. In this review, we discuss progress in the application of nanomaterial-based wound dressings for advanced management of infected wounds. Focus is given to antibacterial therapy as well as the all-in-one detection and treatment of bacterial infections. Notably, we highlight progress in the use of nanoparticles with intrinsic antibacterial performances, such as metals and metal oxide nanoparticles that are capable of killing bacteria and reducing the drug-resistance of bacteria through multiple antimicrobial mechanisms. In addition, we discuss nanomaterials that have been proven to be ideal drug carriers for the delivery and release of antimicrobials either in passive or in stimuli-responsive manners. Focus is given to nanomaterials with the ability to kill bacteria based on the photo-triggered heat (photothermal therapy) or ROS (photodynamic therapy), due to their unparalleled advantages in infection control. Moreover, we highlight examples of intelligent nanomaterial-based wound dressings that can detect bacterial infections in-situ while providing timely antibacterial therapy for enhanced management of infected wounds. Finally, we highlight challenges associated with the current nanomaterial-based wound dressings and provide further perspectives for future improvement of wound healing.

The osteogenesis and the biologic mechanism of thermo-responsive injectable hydrogel containing carboxymethyl chitosan/sodium alginate nanoparticles towards promoting osteal wound healing.

With the development of minimally invasive orthopedics, injectable materials for bone repair are attracted more attention, especially for those wound with a small external mouth and sizeable internal cavity. In this work, the hydrogel with features of thermo-responsiveness, degradability and injectability was designed and fabricated. The hydrogel, named as FHCS, is composed of Pluronic F-127 (F127) loaded with carboxymethyl chitosan/sodium alginate nanoparticles (nCS) and nanohydroxyapatite (nHA). The hydrogel FHCS was non-toxic and good hemocompatible. It can enhance the ALP activity and extracellular matrix calcification of MC3T3-E1 due to the chitosan-based nanoparticle components (nCS). Moreover, FHCS-5 (containing 5 mg/mL nCS) showed relative high expression of osteogenic genes and protein markers. Osteal regeneration was observed treated by FHCS-5 hydrogel in a critical-size rat calvarial bone defect model. CT scanning showed that the whole defect was basically covered by new bone after FHCS-5 hydrogel. The results of H&E staining and Masson's trichrome staining on histological sections further confirmed that FHCS-5 hydrogel promoted new osteal formation and maturation, which up regulated the osteogenic related genes and proteins of ALP, OCN, OPN through BMP/Smad signaling pathway. Hence, this study suggests that FHCS-5 hydrogels have a promising application for non-loading bone regeneration.

A germline JAK2 exon12 mutation and a late somatic CALR mutation in a patient with essential thrombocythemia.

Background: It has been discovered that Janus kinase 2 (JAK2) exon12 mutations lead to the polycythemia vera (PV) phenotype, while somatic mutations of calreticulin (CALR) are associated with essential thrombocythemia (ET) or primary myelofibrosis. In this article, we report a case of ET with coexistence of JAK2 exon12 and CALR mutations. The objective of this study was to elucidate the pathogenicity mechanism of a JAK2 exon12 mutation (JAK2N533S) and the role of the coexistence of mutations on the hematological phenotype. Methods: We designed a colony analysis of tumor cells obtained from this patient, and attempted to identify mutant genes using DNA from hair follicles. Mutation impairment prediction and conservative analysis were conducted to predict the mutation impairment and structure of JAK2N533S. In addition, we conducted a functional analysis of JAK2N533S by constructing Ba/F3 cell models. Results: Three distinct tumor subclones, namely JAK2N533Shet+/CALRtype1het +, JAK2N533Shet+/CALR wt, and JAK2N533Shet+/CALRtype1hom +, were identified from the 17 selected erythroid and 21 selected granulocyte colonies. The analysis of hair follicles yielded positive results for JAK2N533S. According to the bioinformatics analysis, JAK2N533S may exert only a minor effect on protein function. Functional studies showed that JAK2N533S did not have a significant effect on the proliferation of Ba/F3 cells in the absence of interleukin-3 (IL-3), similar to wild-type JAK2. Notably, there were no increased phosphorylation levels of JAK2-downstream signaling proteins, including signal transducer and activator of transcription 3 (STAT3) and STAT5, in Ba/F3 cells harboring the JAK2N533S. Conclusion: Our study revealed that the JAK2N533Shet+/CALRtype1het+ subclone was linked to a significant expansion advantage in this patient, indicating that it may contribute to the development of the ET phenotype. We further demonstrated that JAK2N533S, as a noncanonical JAK2 exon12 mutation, is a germline mutation that may not exert an effect on cell proliferation and protein function. These results and the present body of available data imply that certain noncanonical JAK2 mutations are not gain-of-function mutations leading to the development of myeloproliferative neoplasms.

The mRNA Expression Profile of Psoriatic Lesion Distinct from Non-Lesion.

Purpose: Psoriasis is a chronic recurring autoimmune skin disease with a complex etiology and chronic progression; however, its molecular mechanisms remain unclear. Patients and Methods: We performed transcriptomic analysis to profile the mRNA expression of psoriatic lesions (PL) and non-lesion (NL) tissues from psoriasis patients along with normal skin from healthy donors. RT-qPCR was used to validate the mRNA expression profiles. Results: A total of 237 differentially expressed genes were screened and identified by RNA sequencing. GO and KEGG analysis indicated that these DEGs were enriched in the PPAR signaling pathway and intermediate filament cytoskeleton. For PPAR signaling pathway, the expression of five genes, including ADIPOQ, AQP7, PLIN1, FABP4 and LPL, were all significantly decreased in psoriatic lesions compared to normal skin by RT-qPCR. There is a clear difference between psoriatic lesions and non-lesion in the expression of ADIPOQ, AQP7 and LPL. For intermediate filament cytoskeleton, including KRT27, KRT25, KRT71, KRT86 and KRT85 were significantly decreased in the psoriasis lesions, showing agreement with the RNA-seq data. Conclusion: This study revealed a significant difference between the mRNA expression profiles of PL, NL tissue and normal skin.

Psoriatic Dermal-Derived Mesenchymal Stem Cells Induced C3 Expression in Keratinocytes.

Purpose: Our recent studies found a splice region mutation in C3 accompanied by a significantly increased C3 in psoriatic peripheral blood. Mesenchymal stem cells (MSCs) are a key immunological suppression cell. We further investigate the regulation of MSCs on C3 in psoriasis. Patients and Methods: We analyzed the C3 and its upstream S100A9, S100A8 and downstream MCP1 in psoriatic and control skin, and in normal human epidermal keratinocytes (NHEKs) co-cultured with psoriatic versus control dermal-derived mesenchymal stem cells (DMSCs) by mRNA, iTRAQ (isobaric tags for relative and absolute quantitative) and simple Western analysis. Results: The mRNA and Simple Western analysis showed that the expression of C3, S100A8 and S100A9 are upregulated in psoriatic lesion (C3: mRNA, 9.23-fold, p = 0.0092; protein, 3.56-fold, p = 0.0244. S100A8: mRNA, 28.35-fold, p = 0.0015; protein, 4.68-fold, p = 0.0215. S100A9: mRNA, 79.45-fold, p = 0.0066; protein, 12.42-fold, p > 0.05). Moreover, the iTRAQ showed that C3 and S100A9 were significantly increased in NHEKs after co-cultured with psoriatic DMSCs compared to that of control DMSCs (C3: 3.40-fold, p = 0, FDR = 0; S100A9: 2.30-fold, p = 9.86E-241, FDR = 6.50E-239), verified by Simple Western. However, the expression of S100A8 and MCP1 was slightly different between the two groups. Conclusion: Our results suggest that psoriatic DMSCs contribute to the increased C3 expression in psoriatic lesion via upregulating S100A9, providing the theoretical basis for the role of C3 and DMSCs in the pathogenesis of psoriasis.

Variants in PRKCE and KLC1, Potential Regulators of Type I Psoriasis.

Purpose: Psoriasis is a multifactorial disease with a complex genetic predisposition. The pathophysiology of psoriasis is associated with genetic variants. To better characterize gene variants in psoriasis and identify the relationship between clinical characteristics and variant genes in its pathogenesis. Patients and Methods: DNA was extracted and purified from eight pairs of monozygotic twins with psoriasis discordance and 282 type I psoriasis patients. Thirteen variable genes were amplified and sequenced using the Sanger method after whole genome sequencing. Results: Thirteen genes were found to be variable in eight pairs of monozygotic twins with psoriasis discordance. Among the 13 genes, the variant frequencies of protein kinase C epsilon (PRKCE) (c.240T>C, 35.9% vs 47.7%, P < 0.05) and kinesin light chain 1 (KLC1) (c.216A>G, 2.9% vs 98.1%, P< 0.01) were significantly lower in psoriasis than in normal Asian individuals. Additionally, we found considerable differences in the relationship between variants in genes CADM2, JPH2, SPTLC3 and clinical characteristics stratified by medical history and family history. Moreover, the variants in MEGF6 (39.52% vs 22.50%, χ 2=3.83, p < 0.05) showed a stronger association with the mild group (PASI ≤10) than the heavy group. Conclusion: Our results provide a comprehensive correlation analysis of regulatory genes that are regulated in psoriasis. This integrated analysis offers novel insight into the pathogenic mechanisms involved in psoriasis.

Normal mesenchymal stem cells can improve the abnormal function of T cells in psoriasis via upregulating transforming growth factor-ß receptor.

Psoriasis, a chronic inflammatory skin disease, is a refractory disorder. Previous studies have shown that the imbalance of the T-helper (Th)17/regulatory T cells (Treg) results in the immune imbalance of T cells in psoriatic patients, and that mesenchymal stem cells display an immunosuppressive role by promoting the differentiation of T cells into Treg, leading to a reduction in the proportion of Th17/Treg. Utility of mesenchymal stem cells is becoming a new approach for the treatment of immune disorders. Following co-culture of dermal mesenchymal stromal cells (DMSC) and CD3+ T cells with or without transforming growth factor (TGF)-ß receptor inhibitor, the biological function and relative signal pathway of CD3+ T cells were assessed by flow cytometry, transwell, real-time polymerase chain reaction and western blotting, respectively. Normal DMSC were more potent than psoriatic DMSC in inhibition of CD3+ T-cell proliferation, and stimulation of CD3+ T-cell apoptosis than psoriasis DMSC. Moreover, normal DMSC decreased the ratio of Th17/Treg, while enhancing the immunosuppressive effect of Tregs on effector T cells. However, TGF-ß receptor (TGF-ßR) inhibitor attenuated the effect of normal DMSC on CD3+ T cells and Th17/Treg ratio. Additionally, the normal DMSC were more potent than the psoriatic DMSC in increasing TGF-ß receptors and activation of TGF-ß/SMAD pathway in psoriatic CD3+ T cells. In conclusion, normal DMSC can partially improve the biological function and immunosuppressive ability of psoriatic CD3+ T cells, possibly via upregulating the TGF-ß receptors.

Psoriatic Serum Induce an Abnormal Inflammatory Phenotype and a Decreased Immunosuppressive Function of Mesenchymal Stem Cells.

Background and Objectives: Mesenchymal stem cells (MSCs) have immunomodulatory function and participate in the pathogenesis of many immunoregulation-related diseases, including psoriasis. Previously, we found that MSCs from psoriatic lesions overexpress the proinflammatory microRNA, miR-155 and exhibit a decreased immunosuppressive capacity. But the origin of these aberrant characteristics is still not clear. To investigate whether inflammatory cytokines in serum and peripheral blood mononuclear cells (PBMCs) from psoriatic patients can regulate the expression patterns of immunoregulation-related cytokines and the immunoregulation function of MSCs. Methods and Results: Normal dermal mesenchymal stem cells (nDMSCs) were treated with serum or PBMCs derived from patients with psoriasis or healthy donors. Expression of miR-155 and immunoregulation-related genes in each MSCs were measured using real-time PCR or western-blot. Meanwhile, the immunosuppressive capacity of DMSCs was evaluated by its inhibitory ability on proliferation of activated PBMCs. Compared to control serum, psoriatic serum significantly increased the expression levels of miR-155 (27.19±2.40 vs. 3.51±1.19, p<0.001), while decreased TAB2 expression (0.28±0.04 vs. 0.72±0.20, p<0.01) in DMSCs. Expression levels of immunoregulation-related genes such as PGE2, IL-10, and TLR4 were also markedly down-regulated following the psoriatic serum treatment. Those DMSCs treated with healthy serum could inhibit PBMC proliferation, while those psoriatic serum-treated DMSCs could not inhibit PBMC proliferation effectively. Conclusions: Psoriatic serum up-regulate the expression of miR-155, down-regulate the expression of immunoregulation- related genes (PGE2, IL-10, and TLR4) in DMSCs, and along with the inhibition of the immunosuppressive function of MSCs.

Development and Prospect of Esophageal Tissue Engineering.

Currently, patients with esophageal cancer, especially advanced patients, usually use autologous tissue for esophageal alternative therapy. However, an alternative therapy is often accompanied by serious complications such as ischemia and leakage, which seriously affect the prognosis of patients. Tissue engineering has been widely studied as one of the ideal methods for the treatment of esophageal cancer. In view of the complex multi-layer structure of the natural esophagus, how to use the tissue engineering method to design the scaffold with structure and function matching with the natural tissue is the principle that the tissue engineering method must follow. This article will analyze and summarize the construction methods, with or without cells, and repair effects of single-layer scaffold and multi-layer scaffold. Especially in the repair of full-thickness and circumferential esophageal defects, the flexible design method and the binding force between the layers of the scaffold are very important. In short, esophageal tissue engineering technology has broad prospects and plays a more and more important role in the treatment of esophageal diseases.