ABSTRACT
Background: Restoring and maintaining sinus rhythm in patients with atrial fibrillation (AF) and acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI) has been studied in clinical trials to reduce symptoms and improve quality of life. Limited data exist on the effectiveness of rate or rhythm control therapy in these patients. Methods: Consecutive patients with AF and ACS or referred for PCI were prospectively recruited in Fuwai Hospital during 2017-2020. The primary endpoints were all-cause death and major adverse cardiovascular and cerebrovascular events (MACCEs), including cardiovascular mortality, myocardial infarction, ischemic stroke, non-central nervous system embolism and ischemia-driven revascularization. Kaplan-Meier curves and Cox regressions were performed to evaluate the association between rhythm/rate control and subsequent outcomes. For the primary endpoints, we used the Benjamini-Hochberg correction for multiple comparisons. Results: A total of 1499 patients with AF and ACS or undergoing PCI were included, with a median follow-up of 34.7 months. Compared to non-rate control, rate control strategy reduced the risk of subsequent MACCEs (adjusted HR, 0.320; 95 % CI 0.220-0.466; p <0.001; *p <0.002) and all-cause death (adjusted HR, 0.148; 95 % CI 0.093-0.236; p <0.001; *p <0.002). Similar trends were observed across all predefined subgroups (p <0.001). In the final multivariate model, rhythm control was not associated with a lower subsequent MACCEs but significantly improved all-cause mortality compared to non-rhythm control (adjusted HR, 0.546; 95 % CI 0.313-0.951; p =0.033; *p =0.044). Conclusions: In this real-world study, rate control strategy was associated with lower risk of MACCEs and all-cause death in AF and ACS or undergoing PCI. Besides, management with rhythm control strategy may improve all-cause mortality.
ABSTRACT
Acne inversa (AI) is an inflammatory skin disease associated with nicastrin (NCSTN) mutations. Despite the dysregulated bacterial-host immune interactions being an essential event in AI, the interaction between bacteria and keratinocytes in AI pathophysiology remains unclear. In this study, the NCSTN gene was suppressed using short hairpin RNA in HaCaT cells. Using RNA sequencing, real-time polymerase chain reaction, and western blotting, the expression of IL-36 cytokines was analyzed. The impact of Staphylococcus aureus on AI keratinocyte inflammation and underlying regulatory molecules was investigated by exposing the HaCaT cells to S. aureus. By stimulating NCSTN knockdown HaCaT cells with IFN-γ, the expression and regulatory mechanism of Cathepsin S (Cat S), an IL-36γ cleavage and activating protease, were investigated. After NCSTN knockdown, the IL-36α expression increased, and the IL-36Ra expression was downregulated. NCSTN/MEK/ERK impairment-induced Krüppel-like factor 4 (KLF4) up-regulation in concert with S. aureus-induced nuclear factor kappa B elevation acts synergistically to promote IL-36γ production with the subsequent IL-8 activation in HaCaT cells. NCSTN/MEK/ERK impairment was also observed in familial AI lesions. IFN-γ-induced Cat S in keratinocytes was enhanced after NCSTN knockdown. The expression of IFN-II pathway molecules was significantly upregulated in both NCSTN knockdown HaCaT cells and familial AI lesions. The Cat S expression was significantly elevated in the patient's AI lesions. Our findings suggested a synergistic relationship between S. aureus and NCSTN/MAPK/KLF4 axis in IL-36γ-induced familial AI keratinocytes.
ABSTRACT
The longevity of grafts remains a major challenge in allogeneic transplantation due to immune rejection. Systemic immunosuppression can impair graft function and can also cause severe adverse effects. Here, we report a local immuno-protective strategy to enhance post-transplant persistence of allografts using a mesenchymal stem cell membrane-derived vesicle (MMV)-crosslinked hydrogel (MMV-Gel). MMVs are engineered to upregulate expression of Fas ligand (FasL) and programmed death ligand 1 (PD-L1). The MMVs are retained within the hydrogel by crosslinking. The immuno-protective microenvironment of the hydrogel protects allografts by presenting FasL and PD-L1. The binding of these ligands to T effector cells, the dominant contributors to graft destruction and rejection, results in apoptosis of T effector cells and generation of regulatory T cells. We demonstrate that implantation with MMV-Gel prolongs the survival and function of grafts in mouse models of allogeneic pancreatic islet cells and skin transplantation.
Subject(s)
Fas Ligand Protein , Hydrogels , Islets of Langerhans Transplantation , Mice, Inbred C57BL , Skin Transplantation , T-Lymphocytes, Regulatory , Transplantation, Homologous , Animals , Hydrogels/chemistry , Mice , Fas Ligand Protein/metabolism , Fas Ligand Protein/immunology , T-Lymphocytes, Regulatory/immunology , Islets of Langerhans Transplantation/methods , Skin Transplantation/methods , B7-H1 Antigen/metabolism , B7-H1 Antigen/immunology , Mesenchymal Stem Cells/immunology , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/drug effects , Mice, Inbred BALB C , Graft Survival/drug effects , Graft Survival/immunology , Graft Rejection/prevention & control , Graft Rejection/immunology , Humans , Male , Apoptosis/drug effectsABSTRACT
TRPV3 is a temperature-sensitive calcium-permeable channel. In previous studies, we noticed prominent TUNEL-positive keratinocytes in patients with Olmsted syndrome and Trpv3+/G568V mice, both of which carry gain-of-function variants in the TRPV3 gene. However, it remains unclear how the keratinocytes die and whether this process contributes to more skin disorders. In this study, we showed that gain-of-function variant or pharmacological activation of TRPV3 resulted in poly(ADP-ribose) polymerase 1 (PARP1)/AIFM1/macrophage migration inhibitory factor axis-mediated parthanatos, which is an underestimated form of cell death in skin diseases. Chelating calcium, scavenging ROS, or inhibiting nitric oxide synthase effectively rescued the parthanatos, indicating that TRPV3 regulates parthanatos through calcium-mediated oxidative stress. Furthermore, inhibiting PARP1 downregulated TSLP and IL33 induced by TRPV3 activation in HaCaT cells, reduced immune cell infiltration, and ameliorated epidermal thickening in Trpv3+/G568V mice. Marked parthanatos was also detected in the skin of MC903-treated mice and patients with atopic dermatitis, whereas inhibiting PARP1 largely alleviated the MC903-induced dermatitis. In addition, stimulating parthanatos in mouse skin with methylnitronitrosoguanidine recapitulated many features of atopic dermatitis. These data demonstrate that the TRPV3-regulated parthanatos-associated PARP1/AIFM1/macrophage migration inhibitory factor axis is a critical contributor to the pathogenesis of Olmsted syndrome and atopic dermatitis, suggesting that modulating the PARP1/AIFM1/macrophage migration inhibitory factor axis is a promising therapy for these conditions.
ABSTRACT
Nagashima-type palmoplantar keratoderma is an autosomal recessive genodermatosis caused by loss-of-function variants in SERPINB7 and is the most prevalent form of inherited palmoplantar keratodermas among Asians. However, there is currently no effective therapy for Nagashima-type palmoplantar keratoderma because its pathogenesis remains unclear. In this study, Serpinb7-/- mice were generated and spontaneously developed a disrupted skin barrier, which was further exacerbated by acetone-ether-water treatment. The skin of these Serpinb7-/- mice showed weakened cytoskeletal proteins. In addition, SERPINB7 deficiency consistently led to decreased epidermal differentiation in a 3-dimensional human epidermal model. We also demonstrated that SERPINB7 was an inhibitory serpin that mainly inhibited the protease legumain. SERPINB7 bound directly with legumain and inhibited legumain activity both in vitro and in vivo. Furthermore, we found that SERPINB7 inhibited legumain in a protease-substrate manner and identified the cleavage sites of SERPINB7 as Asn71 and Asn343. Overall, we found that SERPINB7 showed the nature of a cysteine protease inhibitor and identified legumain as a key target protease of SERPINB7. Loss of SERPINB7 function led to overactivation of legumain, which might disrupt cytoskeletal proteins, contributing to the impaired skin barrier in Nagashima-type palmoplantar keratoderma. These findings may lead to the development of therapeutic strategies for Nagashima-type palmoplantar keratoderma.
ABSTRACT
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief and the authors. The authors requested post acceptance two new names to be added to the authorship of the article. However, the authors were not able to provide a satisfactory explanation for the requested authorship change and demanded the retraction of the article. Consequently, the Editor no longer has confidence in this article and decided to retract it.
Subject(s)
Authorship , Humans , Female , Male , Reproducibility of Results , China , Adult , Middle Aged , Surveys and QuestionnairesABSTRACT
Acne is a common chronic inflammatory disease of the pilosebaceous unit. Transient receptor potential vanilloid 3 (TRPV3) is an ion channel that is involved in inflammatory dermatosis development. However, the involvement of TRPV3 in acne-related inflammation remains unclear. Here, we used acne-like mice and human sebocytes to examine the role of TRPV3 in the development of acne. We found that TRPV3 expression increased in the skin lesions of Propionibacterium acnes (P. acnes)-injected acne-like mice and the facial sebaceous glands (SGs) of acne patients. TRPV3 promoted inflammatory cytokines and chemokines secretion in human sebocytes and led to neutrophil infiltration surrounding the SGs in acne lesions, further exacerbating sebaceous inflammation and participating in acne development. Mechanistically, TRPV3 enhanced TLR2 level by promoting transcriptional factor phosphorylated-FOS-like antigen-1 (p-FOSL1) expression and its binding to the TLR2 promoter, leading to TLR2 upregulation and downstream NF-κB signaling activation. Genetic or pharmacological inhibition of TRPV3 both alleviated acne-like skin inflammation in mice via the TLR2-NF-κB axis. Thus, our study revealed the critical role of TRPV3 in sebaceous inflammation and indicated its potential as an acne therapeutic target.
Subject(s)
Acne Vulgaris , Sebaceous Glands , TRPV Cation Channels , Toll-Like Receptor 2 , Toll-Like Receptor 2/metabolism , Toll-Like Receptor 2/genetics , Animals , Acne Vulgaris/metabolism , Acne Vulgaris/pathology , Acne Vulgaris/genetics , Acne Vulgaris/immunology , TRPV Cation Channels/metabolism , TRPV Cation Channels/genetics , Humans , Mice , Sebaceous Glands/metabolism , Sebaceous Glands/pathology , Sebaceous Glands/immunology , Inflammation/metabolism , Inflammation/pathology , Inflammation/genetics , Propionibacterium acnes , Male , NF-kappa B/metabolism , Signal Transduction , Mice, Inbred C57BL , FemaleABSTRACT
PURPOSE: To investigate the application and effectiveness of tension-reducing suture in the repair of hypertrophic scars. METHODS: A retrospective analysis of clinical data was conducted on 82 patients with hypertrophic scars treated at the Department of Burns and Plastic Surgery of Nanjing Drum Tower Hospital from September 2021 to December 2022. Patients were operated with combination of heart-shaped tension-reducing suturing technique and looped, broad, and deep buried (LBD) suturing technique or conventional suture method. Outcomes of surgical treatment were assessed before and 6 months after surgery using the Patient and Observer Scar Assessment Scale (POSAS) and the Vancouver Scar Scale (VSS). RESULTS: Improvements were achieved on scar quality compared to that preoperatively, with a reduction in scar width (1.7 ± 0.6 cm vs. 0.7 ± 0.2 cm, P < 0.001). Assessment using the POSAS and VSS scales showed significant improvements in each single parameter and total score compared to preoperative values (P < 0.05). The Combination method group achieved better score in total score of VSS scale, in color, stiffness, thickness and overall opinion of PSAS scale, and in vascularity, thickness, pliability and overall opinion of OSAS scale. CONCLUSION: The amalgamation of the heart-shaped tension-reducing suturing technique and the LBD suturing technique has shown promising outcomes, garnering notably high levels of patient satisfaction in the context of hypertrophic scar repair. Patients have exhibited favorable postoperative recoveries, underscoring the clinical merit and the prospective broader applicability of this approach in the realm of hypertrophic scar management.
Subject(s)
Cicatrix, Hypertrophic , Suture Techniques , Humans , Cicatrix, Hypertrophic/etiology , Cicatrix, Hypertrophic/prevention & control , Retrospective Studies , Male , Female , Adult , Middle Aged , Treatment Outcome , Young Adult , Sutures , AdolescentABSTRACT
Cancer vaccines show huge potential for cancer prevention and treatment. However, their efficacy remains limited due to weak immunogenicity regarding inefficient stimulation of cytotoxic T lymphocyte (CTL) responses. Inspired by the unique characteristic and biological function of high-density lipoprotein (HDL), we here develop an HDL-mimicking nanovaccine with the commendable lymph-targeted capacity to potently elicit antitumor immunity using lipid nanoparticle that is co-loaded with specific cancer cytomembrane harboring a collection of tumor-associated antigens and an immune adjuvant. The nanoparticulate impact is explored on the efficiency of lymphatic targeting and dendritic cell uptake. The optimized nanovaccine promotes the co-delivery of antigens and adjuvants to lymph nodes and maintains antigen presentation of dendritic cells, resulting in long-term immune surveillance as the elevated frequency of CTLs within lymphoid organs and tumor tissue. Immunization of nanovaccine suppresses tumor formation and growth and augments the therapeutic efficacy of checkpoint inhibitors notably on the high-stemness melanoma in the mouse models.
Subject(s)
Melanoma , Nanoparticles , Neoplasms , Animals , Mice , Nanovaccines , T-Lymphocytes, Cytotoxic , Melanoma/pathology , Antigens, Neoplasm , Adjuvants, Immunologic/pharmacology , Immunotherapy/methods , Mice, Inbred C57BLSubject(s)
Asian People , Keratoderma, Palmoplantar , Serpins , Humans , Serpins/genetics , Keratoderma, Palmoplantar/genetics , Keratoderma, Palmoplantar/diagnosis , Male , Female , Asian People/genetics , Pedigree , China , Mutation , Adult , East Asian PeopleABSTRACT
The regeneration and upgrading of spent LiFePO4 cathodes (S-LFP) were achieved via a one-step hydrothermal treatment. The reducing effect of phytic acid could restore the degraded structure associated with an aqueous Li source. Meanwhile, Li ions are easily chelated by phytic acid groups, and a Li3PO4 coating layer could be formed to reconstruct the surface of the LFP. The regenerated LFP exhibits faster reaction kinetics, larger high-rate charge/discharge capacity, and better cycling performance than commercial LFPs, suggesting that our proposed strategy is a promising technology for the recovery of spent cathode materials.
ABSTRACT
Keratosis follicularis spinulosa decalvans (KFSD) is a rare X-linked hereditary disorder characterized by the triad of follicular hyperkeratosis-photophobia-alopecia. The clinical heterogeneity makes the diagnosis difficult. To investigate the clinicopathologic and trichoscopic features of KFSD and to further clarify the essential requisites for the diagnosis, we conducted a retrospective study of patients with KFSD. The clinical information, histologic features, and trichoscopic findings were evaluated. Eight patients were from seven separate families. Two females were mother and daughter from the same family and the other six patients were male and represented sporadic cases. The average age of onset of alopecia was 21.25 years. Involvement of the scalp hairs leading to progressive scarring alopecia on the midline of the scalp with variable degrees of inflammation was the pathognomonic feature. It typically began after puberty. Vellus hair-associated follicular hyperkeratosis affected all of the patients. However, photophobia was not a constant feature. Histopathologic examination revealed disorders of the hair follicle with an acute-chronic inflammatory response. Follicular changes including fused infundibulum, the protrusion of the outer root sheath into the follicular canal, and a dilatation of the follicles at the isthmus level caused by the occlusion of keratin were observed. The trichoscopic features included perifollicular scaling, tufted hairs, and loss of follicular openings. In conclusion, terminal hair involvement, either scalp hairs, eyebrows, or eyelashes, and the hyperkeratosis of the follicle of vellus hairs is the diagnostic basis of KFSD. We hypothesize that follicular changes in histopathology are the primary event that trigger variable inflammation and further follicular destruction.
Subject(s)
Abnormalities, Multiple , Darier Disease , Eyebrows , Genetic Diseases, X-Linked , Ichthyosis , Skin Diseases, Genetic , Female , Humans , Male , Young Adult , Adult , Eyebrows/pathology , Retrospective Studies , Darier Disease/diagnosis , Darier Disease/pathology , Alopecia/pathology , Photophobia/pathology , Inflammation/pathologyABSTRACT
During the process of wound healing, fibroblasts migrate to the wound site and perform essential functions in promoting cell proliferation, as well as synthesizing and secreting the extracellular matrix (ECM). However, in diabetic wounds, senescent fibroblasts exhibit impaired proliferative capacity and fail to synthesize essential ECM components. Pyruvate dehydrogenase kinase 4 (PDK4), a key enzyme regulating energy metabolism, has been implicated in modulating cellular senescence and fibroblast function. However, its specific role in diabetic wounds remains poorly understood. In this study, we conducted a series of in vivo and in vitro experiments using STZ-induced diabetic mice and human dermal fibroblasts. We evaluated cellular senescence markers, including SA-ß-gal, P53, P16, P21, and PAI-1, as well as senescence-associated secretory phenotype (SASP) factors. Finally, we observed that PDK4 increased in normal wound healing, but its expression was insufficient in diabetic wounds. Significantly, the overexpression of PDK4 demonstrated the potential to accelerate diabetic wound healing and improve the senescence phenotype both in vivo and in vitro. Furthermore, our study elucidated the underlying mechanism by which PDK4 improved the senescent phenotype through the enhancement of glycolysis and regulation of YAP and JNK pathway. The effect was dependent on metabolic reprogramming and subsequent reduction of reactive oxygen species (ROS), which was mediated by PDK4. Overall, our findings highlight the potential of PDK4 as a promising therapeutic target for addressing diabetic wounds.
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IMPORTANCE: Compared to multiplex PCR assays that are available in the Chinese market, the Acaruiter Respiratory Panel (fluorescent PCR) covers a wider range of pathogens including eight viruses, five bacteria, Mycoplasma pneumoniae and Chlamydia pneumoniae, and has high accuracy and effectiveness in the detection of pathogens. This is the first study to evaluate the performance of the Acaruiter Respiratory Panel. This regent may be a promising assay for comprehensive testing for respiratory pathogens from nasopharyngeal swab specimens in Chinese children.
Subject(s)
Respiratory Tract Infections , Viruses , Child , Humans , Respiratory Tract Infections/microbiology , Bacteria , Viruses/genetics , Mycoplasma pneumoniae/genetics , Multiplex Polymerase Chain ReactionABSTRACT
Cancer stem-like cells (CSCs) identified by self-renewal ability and tumor-initiating potential are responsible for tumor recurrence and metastasis in many cancers. Conventional chemotherapy fails to eradicate CSCs that hold a state of dormancy and possess multi-drug resistance. Spurred by the progress of nanotechnology for drug delivery and biomedical applications, nanomedicine has been increasingly developed to tackle stemness-associated chemotherapeutic resistance for cancer therapy. This review focuses on advances in nanomedicine-mediated therapeutic strategies to overcome chemoresistance by specifically targeting CSCs, the combination of chemotherapeutics with chemopotentiators, and programmable controlled drug release. Perspectives from materials and formulations at the nano-scales are specifically surveyed. Future opportunities and challenges are also discussed.