Autografts of skin of 3 rabbits were embedded in the subcutis of their backs.Samplingswere separately taken 2,4,6,8,10 and 12 d after grafting,A dynamic observation of the effectsof the anti-keratin autoantibodies(AK ...Autografts of skin of 3 rabbits were embedded in the subcutis of their backs.Samplingswere separately taken 2,4,6,8,10 and 12 d after grafting,A dynamic observation of the effectsof the anti-keratin autoantibodies(AK auto Ab)on the autoepidermis was made by HE,directimmunofluorescence(DIF)and peroxidase-antiperoxidase(PAP)stainings on frozen sections.It wasshown that the embedded autoepidermis could rapidly proliferate,extend and surround the keratinto form cysts.The specific IgG deposition was seen near the stratum corneum before the epidermiswas proliferated,and also there were obvious increases of IgG deposited in the granular layer ofproliferated epidermis,keratin and exfoliative keratinocytoplasm.But,after the keratin wascompletely blocked,it was found that the IgG decreased in the above areas.It is suggested that theconjugation of AK auto Ab with keratin may provide the earliest“biological information”of theabove-described reaction of epidermis.Dyskeratotic cells and hyaline corpuscles may be the resultsof interaction of the AK auto Ab of the exfoliative keratinocytes.展开更多
Background:Limited information exists regarding the impact of severe acute respiratory syndrome-coronavirus-2(SARS-CoV-2)infection on psoriasis patients.The objective of this study was to identify clinical factors ass...Background:Limited information exists regarding the impact of severe acute respiratory syndrome-coronavirus-2(SARS-CoV-2)infection on psoriasis patients.The objective of this study was to identify clinical factors associated with the prognosis of psoriasis following SARS-CoV-2 infection.Methods:A retrospective,multicenter study was conducted between March and May 2023.Univariable and multivariable logistic regression analyses were employed to identify factors associated with coronavirus disease 2019(COVID-19)-related psoriasis outcomes.The study included 2371 psoriasis patients from 12 clinical centers,with 2049 of them having been infected with SARS-CoV-2.Results:Among the infected groups,lower exacerbation rates were observed in individuals treated with biologics compared to those receiving traditional systemic or nonsystemic treatments(22.3%[236/1058]vs.39.8%[92/231]vs.37.5%[140/373],P<0.001).Psoriasis progression with lesions(adjusted odds ratio[OR]=8.197,95%confidence interval[95%CI]=5.685-11.820,compared to no lesions),hypertension(adjusted OR=1.582,95%CI=1.068-2.343),traditional systemic(adjusted OR=1.887,95%CI=1.263-2.818),and nonsystemic treatment(adjusted OR=1.602,95%CI=1.117-2.297)were found to be associated with exacerbation of psoriasis after SARS-CoV-2 infection,but not biologics(adjusted OR=0.931,95%CI=0.680-1.274,compared to no treatment),according to multivariable logistic regression analysis.Conclusions:A reduced risk of psoriasis exacerbation after SARS-CoV-2 infection was observed with biologics compared to traditional systemic and nonsystemic treatments.Significant risk factors for exacerbation after infection were identified as existing psoriatic lesions and hypertension.展开更多
Dermatomyositis,an idiopathic inflammatory myopathy,is characterized by distinctive skin manifestations,proximal muscle weakness,and multiple organ involvement and can be accompanied by malignancies.To provide a refer...Dermatomyositis,an idiopathic inflammatory myopathy,is characterized by distinctive skin manifestations,proximal muscle weakness,and multiple organ involvement and can be accompanied by malignancies.To provide a reference for dermatologists and clinicians in other relevant fields of clinical practice,experts from the Dermatology Branch of the China International Exchange and Promotion Association for Medical and Health Care and the National Clinical Research Center for Dermatologic and Immunologic Diseases developed this consensus on the diagnosis and treatment of adult dermatomyositis using Chinese and international literature and expert advice.展开更多
Balanoposthitis(BP),a common male genitalia inflammation,is managed by clinicians from different specialties,including urology,pediatrics,dermatology,and venereology.Due to this diverse array of clinicians involved,th...Balanoposthitis(BP),a common male genitalia inflammation,is managed by clinicians from different specialties,including urology,pediatrics,dermatology,and venereology.Due to this diverse array of clinicians involved,there exists a lack of consistent,evidence-based recommendations for BP.The development of the consensus engaged 19 representative hospitals and it adhered to rigorous protocols,encompassing international registration(IPGRP-2021CN003)and the application of evidence grading criteria and recommendation standards[Appendix S1,Supplementary File,http://links.lww.com/CM9/C42].Over the period from December 2020 to October 2022,consensus on 12 clinical issues was reached through comprehensive evidence searches and two iterations of Delphi surveys[Supplementary File,http://links.lww.com/CM9/C42].展开更多
The link of hedgehog (Hh) signaling activation to human cancer and synthesis of a variety of Hh signaling inhibitors raise great expectation that inhibiting Hh signaling may be effective in human cancer treatment. Cyc...The link of hedgehog (Hh) signaling activation to human cancer and synthesis of a variety of Hh signaling inhibitors raise great expectation that inhibiting Hh signaling may be effective in human cancer treatment. Cyclopamine (Cyc), an alkaloid from the Veratrum plant, is a specific natural product inhibitor of the Hh pathway that acts by targeting smoothened (SMO) protein. However, its poor solubility, acid sensitivity, and weak potency relative to other Hh antagonists prevent the clinical development of Cyc as a therapeutic agent. Here, we report properties of cyclopamine tartrate salt (CycT) and its activities in Hh signaling-mediated cancer in vitro and in vivo. Unlike Cyc, CycT is water soluble (5-10 mg/mL). The median lethal dose (LD50) of CycT was 62.5 mg/kg body weight compared to 43.5 mg/kg for Cyc, and the plasma half-life (T1/2) of CycT was not significantly different from that of Cyc. We showed that CycT had a higher inhibitory activity for Hh signaling-dependent motor neuron differentiation than did Cyc (IC50 = 50 nmol/L for CycT vs. 300 nmol/L for Cyc). We also tested the antitumor effectiveness of these Hh inhibitors using two mouse models of basal cell carcinomas (K14cre:Ptch1neo/neo and K14cre:SmoM2YFP). After topical application of CycT or Cyc daily for 21 days, we found that all CycT-treated mice had tumor shrinkage and decreased expression of Hh target genes. Taken together, we found that CycT is an effective inhibitor of Hh signaling-mediated carcinogenesis.展开更多
Mutations of PTEN-induced kinase I(PINK1)cause early-onset Parkinson’s disease(PD)with selective neurodegeneration in humans.However,current PINK1 knockout mouse and pig models are unable to recapitulate the typical ...Mutations of PTEN-induced kinase I(PINK1)cause early-onset Parkinson’s disease(PD)with selective neurodegeneration in humans.However,current PINK1 knockout mouse and pig models are unable to recapitulate the typical neurodegenerative phenotypes observed in PD patients.This suggests that generating PINK1 disease models in non-human primates(NHPs)that are close to humans is essential to investigate the unique function of PINK1 in primate brains.Paired single guide RNA(sgRNA)/Cas9-D10A nickases and truncated sgRNA/Cas9,both of which can reduce off-target effects without compromising on-target editing,are two optimized strategies in the CRISPR/Cas9 system for establishing disease animal models.Here,we combined the two strategies and injected Cas9-D10A mRNA and two truncated sgRNAs into one-cell-stage cynomolgus zygotes to target the PINK1 gene.We achieved precise and efficient gene editing of the target site in three newborn cynomolgus monkeys.The frame shift mutations of PINK1 in mutant fibroblasts led to a reduction in mRNA.However,western blotting and immunofluorescence staining confirmed the PINK1 protein levels were comparable to that in wild-type fibroblasts.We further reprogramed mutant fibroblasts into induced pluripotent stem cells(iPSCs),which showed similar ability to differentiate into dopamine(DA)neurons.Taken together,our results showed that co-injection of Cas9-D10A nickase mRNA and sgRNA into one-cell-stage cynomolgus embryos enabled the generation of human disease models in NHPs and target editing by pair truncated sgRNA/Cas9-D10A in PINK1 gene exon 2 did not impact protein expression.展开更多
AIM: To understand the pathogen characteristics and its sensitivity against antimicrobial agents in fatal bacterial granuloma after eyelid trauma (FBGT) in vitro, and to provide laboratory evidence for diagnosis. METH...AIM: To understand the pathogen characteristics and its sensitivity against antimicrobial agents in fatal bacterial granuloma after eyelid trauma (FBGT) in vitro, and to provide laboratory evidence for diagnosis. METHODS: The FBGT pathogens were isolaated and cultured with reformed rabbit-brain anaerobic enriched broth (RRAB), and identified by ATB/API 20A system. The minimum inhibiting concentration (MIC) was determined by anaerobic broth dilution method. RESULTS: A total of 22 strains of pathogen were separated from 21 patients with FBGT and identified as Propionibacterium acnes (PA) by ATB/API 20A system. The MIC of ciprofloxacin for 22 PA strains was 0.0625-0.5mg/L, the MIC of penicillin, ampicillin, ampicillin/sulbactam, cefoperazone, lincomycin, and imipenem/cilastatin were 0.125-0.5mg/L, the MIC of ticarcillin/clavulanic acid was 0.250-1.000mg/L, and the MIC of metronidazole was 64-256mg/L. The pathogen of FBGT was strictly anaerobic PA, which growed slowly and better in nutritious RRAB broth. All PA were resistant to metronidazole, but susceptive to other routine antimicrobial agents, such as penicillin, ampicillin and lincomycin. CONCLUSION: FBGT should not be treated with metronidazole. Clinicians should choose combined use of drugs or operation to treat FBGT according to patients' individual condition and the results of drug sensitivity test.展开更多
Toll-like receptors(TLRs)play important roles in immune responses against pathogens and tumors.Recently,TLR8 has gained attention because of its association with multiple inflammatory diseases,infections and antitumor...Toll-like receptors(TLRs)play important roles in immune responses against pathogens and tumors.Recently,TLR8 has gained attention because of its association with multiple inflammatory diseases,infections and antitumor responses.TLR8 senses the degradation products of single-stranded RNA from microbes and self-released RNA to induce type I interferons,inflammatory gene expression and nucleotide-binding and oligomerization domain–,leucine-rich repeat–and pyrin domain–containing protein 3(NLRP3)inflammasome activation.So far,the understanding of TLR8 function in vivo is still limited,partially because of lacking a reliable rodent animal model.Murine Tlr8 cannot sense the ligands of human TLR8.In mammals,TLR8 distinguishes live bacteria from dead bacteria to regulate the magnitude of immune responses.Recently,TLR8 has been reported to recognize severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)RNA to induce inflammatory responses,suggesting that TLR8 participates in coronavirus disease 2019(COVID-19).In this review,we discuss the mechanism of ligand recognition by TLR8,TLR8-mediated signaling pathways and signaling crosstalk between TLR8 and other molecules,and untangle the contribution of TLR8 to inflammatory diseases,infectious diseases,antitumor immunity and vaccination.展开更多
On the basis of the detection of IgG anti-keratin autoantibody (AK auto Ab)in human body fluids,it was shown that IgG AK auto Ab could hardly pass the blood-brain barrier,but it could easily penetrate the capillary wa...On the basis of the detection of IgG anti-keratin autoantibody (AK auto Ab)in human body fluids,it was shown that IgG AK auto Ab could hardly pass the blood-brain barrier,but it could easily penetrate the capillary walls into epithelial tissues.Un-der electron microscope,the interaction between AK auto Ab and keratinocyte is largelylocated in tonofilaments and desmosomes and is irrelevant to other organellae.Dynamicobservations of AK auto Ab suggest that the accumulation of AK auto Ab in keratinocy-te cytoplasm and transitory decrease of IgG AK auto Ab in serum of rabbits with sodiumsulfide dermatitis are related predominantly to keratinocytic injury.展开更多
To the Editor:Vitiligo is a chronic disease that impacts many aspects of a patient’s life.The prevalence of vitiligo has been increasing,and currently involves up to 0.5%to 2%of all races worldwide.[1]Although this c...To the Editor:Vitiligo is a chronic disease that impacts many aspects of a patient’s life.The prevalence of vitiligo has been increasing,and currently involves up to 0.5%to 2%of all races worldwide.[1]Although this condition very rarely produces any direct physical discomfort,the cosmetic problems and disfiguring appearance resulting from the depigmented lesions severely affect the quality of life(QoL)in these individuals.展开更多
Background: Identification of critical autoantigenic T-cell epitopes is key to developing antigen-based therapies for autoimmune diseases, including psoriasis. Our previous work demonstrated that 3 peptides on keratin...Background: Identification of critical autoantigenic T-cell epitopes is key to developing antigen-based therapies for autoimmune diseases, including psoriasis. Our previous work demonstrated that 3 peptides on keratin 17 are able to stimulate peripheral blood lymphocytes of HLA-DRB1 07-positive patients with psoriasis and to serve as immunodominant T cell epitopes. Objective: We sought to determine antagonistic altered peptide ligands to psoriatic T cells with a down-modulatory effect in inhibiting keratinocyte proliferation. Methods: Psoriatic altered peptide ligands were generated by single alanine residue substitutions at a critical T-cell receptor contact residue position. Antagonistic altered peptide ligands were identified by suppression screening of psoriatic T-cell activation and keratinocyte proliferation. Results: Altered peptide ligands 119R and 355L can inhibit psoriatic T-cell activation more effectively than other altered peptide ligands, especially 355L, with inhibition of T-cell proliferation and the secretion of interferon gamma and interleukin 2 in parallel with the upregulation of interleukins 4 and 10 as well as transforming growth factor-β . In coincubation assay, altered peptide ligands 119R and 355L can down-regulate the function of psoriatic T cells more effectively than wild-type epitopes solely, but less effectively than altered peptide ligands solely. In prepulse assay altered peptide ligand 119R can down-regulate the activation of psoriatic T cells more effectively than in coincubation but less effectively as compared with altered peptide ligand 119R only. Altered peptide ligand 355L was also shown to have a similar presentation. T-cell culture supernatants (1:100) from the concentrations (10 μ g · mL-1 and 100 μ g · mL-1 with 119R, 100 μ g · mL-1 with 355L) were more effective than the other ratios in inhibiting keratinocyte proliferation. Limitations: This study had a relatively small sample size (52 patients and 48 healthy controls). Conclusion: Our findings show that the altered peptide ligands 119R (VAALEEANTELEVKI) and 355L (ENRYCVQASQIQGLI) are capable of inhibiting proliferative responses of psoriatic T cells and keratinocyte proliferation in vitro, at least, with enhanced helper T cell type 2 polarization. Thus, to our knowledge, this article is the first report of the demonstration of therapeutic activity of altered peptide ligands derived from keratin 17.展开更多
Background:There is a need for effective and safe therapies for psoriasis that provide sustained benefits.The aim of this study was to assess the efficacy and safety of tildrakizumab,an anti-interleukin-23p19 monoclon...Background:There is a need for effective and safe therapies for psoriasis that provide sustained benefits.The aim of this study was to assess the efficacy and safety of tildrakizumab,an anti-interleukin-23p19 monoclonal antibody,for treating moderate-to-severe plaque psoriasis in Chinese patients.Methods:In this multi-center,double-blind,phase III trial,patients with moderate-to-severe plaque psoriasis were enrolled and randomly assigned(1:1)to receive subcutaneous tildrakizumab 100 mg or placebo at weeks 0 and 4.Patients initially assigned to placebo were switched to receive tildrakizumab at weeks 12,16,and every 12 weeks thereafter.Patients in the tildrakizumab group continued with tildrakizumab at week 16,and every 12 weeks until week 52.The primary endpoint was the Psoriasis Area and Severity Index(PASI 75)response rate at week 12.Results:At week 12,tildrakizumab demonstrated significantly higher PASI 75 response rates(66.4%[73/110]vs.12.7%[14/110];difference,51.4%[95%confidence interval(CI),40.72,62.13];P<0.001)and Physician’s Global Assessment(60.9%[67/110]vs.10.0%[11/110];difference,49.1%[95%CI,38.64,59.62];P<0.001)compared to placebo.PASI 75 response continued to improve over time in both tildrakizumab and placebo-switching to tildrakizumab groups,reaching maximal efficacy after 28 weeks(86.8%[92/106]vs.82.4%[89/108])and maintained up to 52 weeks(91.3%[95/104]vs.87.4%[90/103]).Most treatment-emergent adverse events were mild and not related to tildrakizumab.Conclusion:Tildrakizumab demonstrated durable efficacy through week 52 and was well tolerated in Chinese patients with moderate-to-severe plaque psoriasis.Trial registration:ClinicalTrials.gov,NCT05108766.展开更多
With over a million cases detected each year,skin disease is a global public health problem that diminishes the quality of life due to its difficulty to eradicate,propensity for recurrence,and potential for post-treat...With over a million cases detected each year,skin disease is a global public health problem that diminishes the quality of life due to its difficulty to eradicate,propensity for recurrence,and potential for post-treatment scarring.Photodynamic therapy(PDT)is a treatment with minimal invasiveness or scarring and few side effects,making it well tolerated by patients.However,this treatment requires further research and development to improve its effective clinical use.Here,a piezoelectric-driven microneedle(PDMN)platform that achieves high efficiency,safety,and non-invasiveness for enhanced PDT is proposed.This platform induces deep tissue cavitation,increasing the level of protoporphyrin IX and significantly enhancing drug penetration.A clinical trial involving 25 patients with skin disease was conducted to investigate the timeliness and efficacy of PDMN-assisted PDT(PDMN-PDT).Our findings suggested that PDMN-PDT boosted treatment effectiveness and reduced the required incubation time and drug concentration by 25%and 50%,respectively,without any anesthesia compared to traditional PDT.These findings suggest that PDMN-PDT is a safe and minimally invasive approach for skin disease treatment,which may improve the therapeutic efficacy of topical medications and enable translation for future clinical applications.展开更多
Melanoma is the most lethal skin cancer that originates from the malignant transformation of melanocytes.Although melanoma has long bee n regarded as a cancerous malig nancy with few therapeutic opti ons,in creased bi...Melanoma is the most lethal skin cancer that originates from the malignant transformation of melanocytes.Although melanoma has long bee n regarded as a cancerous malig nancy with few therapeutic opti ons,in creased biological understandi ng and unprecedented innovations in therapies targeting mutated driver genes and immune checkpoints have substantially improved the prog nosis of patients.However,the low response rate and inevitable occurre nee of resistance to curre ntly available targeted therapies have posed the obstacle in the path of melanoma management to obtain further amelioration.Therefore,it is necessary to understand the mechanisms underlying melanoma pathogenesis more comprehensively,which might lead to more substantial progress in therapeutic approaches and expand clinical options for melanoma therapy.In this review,we firstly make a brief introduction to melanoma epidemiology,clinical subtypes,risk factors,and current therapies.Then,the signal pathways orchestrati ng mela noma pathogenesis,in eluding gen etic mutatio ns,key tran scripti onal regulators,epige netic dysregulati ons,metabolic reprogramming,crucial metastasis-related signals,tumor-promoting inflammatory pathways,and pro-angiogenic factors,have been systemically reviewed and discussed.Subsequently,we outline current progresses in therapies targeting mutated driver genes and immune checkpoi nts,as well as the mecha nisms underlying the treatment resista nee.Finally,the prospects and challe nges in the developme nt of mela noma therapy,especially immu no therapy and related ongoing din ical trials,are summarized and discussed.展开更多
Antimicrobial peptides(AMPs)are small molecules produced by a myriad of cells and play important roles not only in protecting against infections and sustaining skin barrier homeostasis but also in contributing to immu...Antimicrobial peptides(AMPs)are small molecules produced by a myriad of cells and play important roles not only in protecting against infections and sustaining skin barrier homeostasis but also in contributing to immune dysregulation under pathological conditions.Recently,increasing evidence has indicated that AMPs,including cathelicidin(LL-37),humanβ-defensins,S100 proteins,lipocalin 2,and RNase 7,are highly expressed in psoriatic skin lesions.These peptides broadly regulate immunity by interacting with various immune cells and linking innate and adaptive immune responses during the progression of psoriasis.In this review,we summarize the recent findings regarding AMPs in the pathogenesis of psoriasis with a main focus on their immunomodulatory abilities.展开更多
Secreted frizzled-related protein 5(SFRP5)plays a pivotal role in regulating the development of many tissues and organs,however,as an inhibitor of Wnt signaling,the role of SFRP5 in vitiligo remains unknown.Hence,we s...Secreted frizzled-related protein 5(SFRP5)plays a pivotal role in regulating the development of many tissues and organs,however,as an inhibitor of Wnt signaling,the role of SFRP5 in vitiligo remains unknown.Hence,we speculated that SFRP5 might be associated with melanogenesis in melanocytes by regulating Wnt signaling in vitiligo.In this study,we found that SFRP5 was overexpressed in the skin lesions of patients with vitiligo.Compared with that in normal epidermal melanocytes(PIG1),the expression of SFRP5 was increased in vitiligo melanocytes(PIG3V).To investigate the effect of SFRP5 on melanin synthesis,PIG1 cells were infected with recombinant SFRP5 adenovirus(AdSFRP5),and PIG3V cells were infected with recombinant siSFRP5 adenovirus(AdsiSFRP5).The results showed that SFRP5 overexpression inhibited melanin synthesis in PIG1 cells through downregulation of microphthalmia-associated transcription factor(MITF)and its target proteins via suppression of the Wnt/b-catenin signaling pathway.Accordingly,SFRP5 silencing increased melanin synthesis and activated the Wnt signaling pathway in PIG3V cells.Moreover,SFRP5 overexpression also downregulated the transcriptional activity of T cell factor/lymphoid enhancer factor(TCF/LEF)in PIG1 cells.Furthermore,this inhibitory effect of SFRP5 on melanin synthesis was reversed by treatment with the b-catenin agonist,SKL2001.The inhibitory action of SFRP5 in pigmentation was further confirmed in vivo using a nude mouse model.Hence,our results indicate that SFRP5 can inhibit melanogenesis in melanocytes.Additionally,our findings showed that SFRP5 plays a vital role in the development of vitiligo,and thus may serve as a potential therapeutic target for vitiligo.展开更多
Objective: To observe the effects of Xuebijing Injection (血必净注射液) on dendritic cells (DCs) and T lymphocytes, and the potential mechanisms of its therapeutic effect on systemic lupus erythematosus (SLE). ...Objective: To observe the effects of Xuebijing Injection (血必净注射液) on dendritic cells (DCs) and T lymphocytes, and the potential mechanisms of its therapeutic effect on systemic lupus erythematosus (SLE). Methods: A widely used mouse model, SLE-prone BLLF1 mice aged 8-10 weeks, was employed. Mice were randomly divided into 4 groups: a normal group, a model group and two treatment groups treated with Xuebijing Injection with a dose of 6.4 mL/kg via intraperitoneal administration for SLE-prone BLLF1 mice aged 8 weeks (treatment A group) and 10 weeks (treatment B group). Renal tissue sections were stained with Masson's trichrome and periodic acid-silver methenamine. Histopathological changes in the kidney were evaluated by a light microscopy. The capacity of the DCs isolated from the spleen to stimulate the T cell proliferation in response to concanavalin A (Con A) was determined. Results: Compared with the model group, levels of anti-dsDNA antibodies in the two treatment groups decreased remarkablely (P〈0.01, P〈0.05), and levels of serum creatinine and blood urea nitrogen increased (P〈0.01, P〈0.05). Pathological changes were found in the kidney in the model group. Histopathological abnormalities were alleviated in the two treatment groups. Treatment with Xuebijing injection also significantly upregulated the expression of CD80, CD86 and major histocompatibility class Ⅱ by DCs compared with the model group (P〈0.05). When splenic T lymphocytes from BLLF1 mice were co-cultured with DCs at ratios of 1:100, 1:150 and 1:200 for 3 and 5 days, the proliferation of T lymphocytes was suppressed compared with the normal group (P〈0.05), but this was restored by Xuebijing Injection under the same conditions. In the model group, levels of tumor necrosis factor (TNF)-α in supernatants were significantly elevated compared with the normal group (P〈0.01), interleukin-2 levels decreased (P〈0.05), while these changes were significantly alleviated in the Xuebijing treatment groups. Conclusions: Xuebijing Injection alleviated renal injury in SLE-prone BLLF-1 mice. The mechanism might be through influencing T cell polarization mediated by DCs, and Xuebijing Injection might be a potential drug that suppresses immune dysfunction in patients with SLE.展开更多
Background:Psoriasis is a common chronic inflammatory skin disease with 2%to 3%prevalence worldwide and a heavy social-psychological burden for patients and their families.As the exact pathogenesis of psoriasis is sti...Background:Psoriasis is a common chronic inflammatory skin disease with 2%to 3%prevalence worldwide and a heavy social-psychological burden for patients and their families.As the exact pathogenesis of psoriasis is still unknown,the current treatment is far from satisfactory.Thus,there is an urgent need to find a more effective therapy for this disease.Keratin 17(K17),a type I intermediate filament,is overexpressed in the psoriatic epidermis and plays a critical pathogenic role by stimulating T cells in psoriasis.Therefore,we hypothesized that inhibiting K17 may be a potential therapeutic approach for psoriasis.This study aimed to investigate the therapeutic effect of K17-specific small interfering RNA(siRNA)on mice with imiquimod(IMQ)-induced psoriasis-like dermatitis.Methods:Eight-week-old female BALB/c mice were administered a 5%IMQ cream on both ears to produce psoriatic dermatitis.On day 3,K17 siRNA was mixed with an emulsion matrix and applied topically to the left ears of the mice after IMQ application every day for 7 days.The right ears of the mice were treated in parallel with negative control(NC)siRNA.Inflammation was evaluated by gross ear thickness,histopathology,the infiltration of inflammatory cells(CD3+T cells and neutrophils)using immunofluorescence,and the expression of cytokine production using real-time quantitative polymerase chain reaction.The obtained data were statistically evaluated by unpaired t-tests and a one-way analysis of variance.Results:The severity of IMQ-induced dermatitis on K17 siRNA-treated mice ears was significantly lower than that on NC siRNA-treated mice ears,as evidenced by the alleviated ear inflammation phenotype,including decreased ear thickness,infiltration of inflammatory cells(CD3+T cells and neutrophils),and inflammatory cytokine/chemokine expression levels(interleukin 17[IL-17],IL-22,IL-23,C-X-C motif chemokine ligand 1,and C-C motif chemokine ligand 20)(P<0.05 vs.the Blank or NC siRNA groups).Compared to the NC siRNA treatment,the K17 siRNA treatment resulted in increased K1 and K10 expression,which are characteristic of keratinocyte differentiation(vs.NC siRNA,K17 siRNA1 group:K1,t=4.782,P=0.0050;K10,t=3.365,P=0.0120;K17 siRNA2 group:K1,t=4.104,P=0.0093;K10,t=4.168,P=0.0042;siRNA Mix group:K1,t=3.065,P=0.0221;K10,t=10.83,P<0.0001),and decreased K16 expression,which is characteristic of keratinocyte proliferation(vs.NC siRNA,K17 siRNA1 group:t=4.156,P=0.0043;K17 siRNA2 group:t=2.834,P=0.0253;siRNA Mix group:t=2.734,P=0.0250).Conclusions:Inhibition of K17 expression by its specific siRNA significantly alleviated inflammation in mice with IMQ-induced psoriasis-like dermatitis.Thus,gene therapy targeting K17 may be a potential treatment approach for psoriasis.展开更多
Background Heat shock protein 70 (HSP70) is expressed highly in epithelial tumours associated closely with human papillomavirus 16 (HPV16) infections. However, evidence about the direct relationship between HSP70 ...Background Heat shock protein 70 (HSP70) is expressed highly in epithelial tumours associated closely with human papillomavirus 16 (HPV16) infections. However, evidence about the direct relationship between HSP70 expression and HPVs infections are still lacking. In the present study, we examined the expression of HSP70 in keratinocytes introduced with HPV16 E6/E7 oncogenes. Methods Stable transfected cells were established by transfection of the plasmids pLXSN16E6/E7 into cultured primary keratinocytes and subsequently selected by plasmid specific selection antibiotic (G418) at the required concentration. The expression of HSP70 in pLXSN16E6/E7 transfected keratinocytes was determined by Western blot. The correlation of HSP70 expression and E6/E7 transfeetion was further confirmed by doubly labelled immunofluorescent staining. Results Compared to non-transfected keratinocytes, there was a significant trend for higher levels of HSP70 in pLXSN16E6/E7 transfected keratinocytes. Doubly labelled immunofluorescent staining experiment showed that the co-localization of HPV16 E6/E7 and HSP70 in transfeeted keratinoeytes was observed and increased expression of HSP70 was strongly associated with the transfection of HPV16 E6/E7. Conclusions Our studies demonstrated increased levels of HSP70 proteins in keratinocytes stably transfected by HPV16 E6/E7 oncogenes. It suggests that the expression of HSP70 is modulated by HPV16 E6/E7 proteins, which may be involved in HPV16 E6/E7 induced immortalization.展开更多
To the Editor:Bullous pemphigoid(BP)is an autoimmune blistering disease that is caused by autoantibodies and is associated with complement activation.[1]Autoantibody-mediated complement activation is involved in BP pa...To the Editor:Bullous pemphigoid(BP)is an autoimmune blistering disease that is caused by autoantibodies and is associated with complement activation.[1]Autoantibody-mediated complement activation is involved in BP pathogenesis.Complement-regulatory proteins(CRPs)including CD35,CD46,CD55,and CD59 comprise an important class of regulatory proteins in the complement system that control the enzyme cascades,assembly of the membrane-attack complex,and complement system homeostasis.[2]Classically,both CD55 and CD46 negatively regulate complement system activation by inhibiting the production of new C3 and C5 convertases and accelerating the degradation of those already formed,thereby protecting cells from complement activation-induced damage.展开更多
基金Supported by the National Natural Science Foundation of China No.38970687
文摘Autografts of skin of 3 rabbits were embedded in the subcutis of their backs.Samplingswere separately taken 2,4,6,8,10 and 12 d after grafting,A dynamic observation of the effectsof the anti-keratin autoantibodies(AK auto Ab)on the autoepidermis was made by HE,directimmunofluorescence(DIF)and peroxidase-antiperoxidase(PAP)stainings on frozen sections.It wasshown that the embedded autoepidermis could rapidly proliferate,extend and surround the keratinto form cysts.The specific IgG deposition was seen near the stratum corneum before the epidermiswas proliferated,and also there were obvious increases of IgG deposited in the granular layer ofproliferated epidermis,keratin and exfoliative keratinocytoplasm.But,after the keratin wascompletely blocked,it was found that the IgG decreased in the above areas.It is suggested that theconjugation of AK auto Ab with keratin may provide the earliest“biological information”of theabove-described reaction of epidermis.Dyskeratotic cells and hyaline corpuscles may be the resultsof interaction of the AK auto Ab of the exfoliative keratinocytes.
基金supported by a grant from the Clinical Research Project on COVID-19 infection at the Xijing Hospital(No.XJZT23XG29).
文摘Background:Limited information exists regarding the impact of severe acute respiratory syndrome-coronavirus-2(SARS-CoV-2)infection on psoriasis patients.The objective of this study was to identify clinical factors associated with the prognosis of psoriasis following SARS-CoV-2 infection.Methods:A retrospective,multicenter study was conducted between March and May 2023.Univariable and multivariable logistic regression analyses were employed to identify factors associated with coronavirus disease 2019(COVID-19)-related psoriasis outcomes.The study included 2371 psoriasis patients from 12 clinical centers,with 2049 of them having been infected with SARS-CoV-2.Results:Among the infected groups,lower exacerbation rates were observed in individuals treated with biologics compared to those receiving traditional systemic or nonsystemic treatments(22.3%[236/1058]vs.39.8%[92/231]vs.37.5%[140/373],P<0.001).Psoriasis progression with lesions(adjusted odds ratio[OR]=8.197,95%confidence interval[95%CI]=5.685-11.820,compared to no lesions),hypertension(adjusted OR=1.582,95%CI=1.068-2.343),traditional systemic(adjusted OR=1.887,95%CI=1.263-2.818),and nonsystemic treatment(adjusted OR=1.602,95%CI=1.117-2.297)were found to be associated with exacerbation of psoriasis after SARS-CoV-2 infection,but not biologics(adjusted OR=0.931,95%CI=0.680-1.274,compared to no treatment),according to multivariable logistic regression analysis.Conclusions:A reduced risk of psoriasis exacerbation after SARS-CoV-2 infection was observed with biologics compared to traditional systemic and nonsystemic treatments.Significant risk factors for exacerbation after infection were identified as existing psoriatic lesions and hypertension.
基金supported by National High-level Hospital Clinical Research Funding(2022-PUMCH-B-092).
文摘Dermatomyositis,an idiopathic inflammatory myopathy,is characterized by distinctive skin manifestations,proximal muscle weakness,and multiple organ involvement and can be accompanied by malignancies.To provide a reference for dermatologists and clinicians in other relevant fields of clinical practice,experts from the Dermatology Branch of the China International Exchange and Promotion Association for Medical and Health Care and the National Clinical Research Center for Dermatologic and Immunologic Diseases developed this consensus on the diagnosis and treatment of adult dermatomyositis using Chinese and international literature and expert advice.
基金National Natural Science Foundation of China(No.82273538)Public Health Research and Development Program of the Shenyang Science and Technology Bureau(No.22-321-33-12)National Key R&D Program of China(No.2023YFC2508200)
文摘Balanoposthitis(BP),a common male genitalia inflammation,is managed by clinicians from different specialties,including urology,pediatrics,dermatology,and venereology.Due to this diverse array of clinicians involved,there exists a lack of consistent,evidence-based recommendations for BP.The development of the consensus engaged 19 representative hospitals and it adhered to rigorous protocols,encompassing international registration(IPGRP-2021CN003)and the application of evidence grading criteria and recommendation standards[Appendix S1,Supplementary File,http://links.lww.com/CM9/C42].Over the period from December 2020 to October 2022,consensus on 12 clinical issues was reached through comprehensive evidence searches and two iterations of Delphi surveys[Supplementary File,http://links.lww.com/CM9/C42].
基金supported by a grant from the National Institute of Health, USA (No. R01-CA94160)
文摘The link of hedgehog (Hh) signaling activation to human cancer and synthesis of a variety of Hh signaling inhibitors raise great expectation that inhibiting Hh signaling may be effective in human cancer treatment. Cyclopamine (Cyc), an alkaloid from the Veratrum plant, is a specific natural product inhibitor of the Hh pathway that acts by targeting smoothened (SMO) protein. However, its poor solubility, acid sensitivity, and weak potency relative to other Hh antagonists prevent the clinical development of Cyc as a therapeutic agent. Here, we report properties of cyclopamine tartrate salt (CycT) and its activities in Hh signaling-mediated cancer in vitro and in vivo. Unlike Cyc, CycT is water soluble (5-10 mg/mL). The median lethal dose (LD50) of CycT was 62.5 mg/kg body weight compared to 43.5 mg/kg for Cyc, and the plasma half-life (T1/2) of CycT was not significantly different from that of Cyc. We showed that CycT had a higher inhibitory activity for Hh signaling-dependent motor neuron differentiation than did Cyc (IC50 = 50 nmol/L for CycT vs. 300 nmol/L for Cyc). We also tested the antitumor effectiveness of these Hh inhibitors using two mouse models of basal cell carcinomas (K14cre:Ptch1neo/neo and K14cre:SmoM2YFP). After topical application of CycT or Cyc daily for 21 days, we found that all CycT-treated mice had tumor shrinkage and decreased expression of Hh target genes. Taken together, we found that CycT is an effective inhibitor of Hh signaling-mediated carcinogenesis.
基金supported by the National Key Research and Development Program(2016YFA0101401 and 2018YFA0801400)Major Basic Research Project of Science and Technology of Yunnan(2019FY002 and 202001BC070001)。
文摘Mutations of PTEN-induced kinase I(PINK1)cause early-onset Parkinson’s disease(PD)with selective neurodegeneration in humans.However,current PINK1 knockout mouse and pig models are unable to recapitulate the typical neurodegenerative phenotypes observed in PD patients.This suggests that generating PINK1 disease models in non-human primates(NHPs)that are close to humans is essential to investigate the unique function of PINK1 in primate brains.Paired single guide RNA(sgRNA)/Cas9-D10A nickases and truncated sgRNA/Cas9,both of which can reduce off-target effects without compromising on-target editing,are two optimized strategies in the CRISPR/Cas9 system for establishing disease animal models.Here,we combined the two strategies and injected Cas9-D10A mRNA and two truncated sgRNAs into one-cell-stage cynomolgus zygotes to target the PINK1 gene.We achieved precise and efficient gene editing of the target site in three newborn cynomolgus monkeys.The frame shift mutations of PINK1 in mutant fibroblasts led to a reduction in mRNA.However,western blotting and immunofluorescence staining confirmed the PINK1 protein levels were comparable to that in wild-type fibroblasts.We further reprogramed mutant fibroblasts into induced pluripotent stem cells(iPSCs),which showed similar ability to differentiate into dopamine(DA)neurons.Taken together,our results showed that co-injection of Cas9-D10A nickase mRNA and sgRNA into one-cell-stage cynomolgus embryos enabled the generation of human disease models in NHPs and target editing by pair truncated sgRNA/Cas9-D10A in PINK1 gene exon 2 did not impact protein expression.
文摘AIM: To understand the pathogen characteristics and its sensitivity against antimicrobial agents in fatal bacterial granuloma after eyelid trauma (FBGT) in vitro, and to provide laboratory evidence for diagnosis. METHODS: The FBGT pathogens were isolaated and cultured with reformed rabbit-brain anaerobic enriched broth (RRAB), and identified by ATB/API 20A system. The minimum inhibiting concentration (MIC) was determined by anaerobic broth dilution method. RESULTS: A total of 22 strains of pathogen were separated from 21 patients with FBGT and identified as Propionibacterium acnes (PA) by ATB/API 20A system. The MIC of ciprofloxacin for 22 PA strains was 0.0625-0.5mg/L, the MIC of penicillin, ampicillin, ampicillin/sulbactam, cefoperazone, lincomycin, and imipenem/cilastatin were 0.125-0.5mg/L, the MIC of ticarcillin/clavulanic acid was 0.250-1.000mg/L, and the MIC of metronidazole was 64-256mg/L. The pathogen of FBGT was strictly anaerobic PA, which growed slowly and better in nutritious RRAB broth. All PA were resistant to metronidazole, but susceptive to other routine antimicrobial agents, such as penicillin, ampicillin and lincomycin. CONCLUSION: FBGT should not be treated with metronidazole. Clinicians should choose combined use of drugs or operation to treat FBGT according to patients' individual condition and the results of drug sensitivity test.
文摘Toll-like receptors(TLRs)play important roles in immune responses against pathogens and tumors.Recently,TLR8 has gained attention because of its association with multiple inflammatory diseases,infections and antitumor responses.TLR8 senses the degradation products of single-stranded RNA from microbes and self-released RNA to induce type I interferons,inflammatory gene expression and nucleotide-binding and oligomerization domain–,leucine-rich repeat–and pyrin domain–containing protein 3(NLRP3)inflammasome activation.So far,the understanding of TLR8 function in vivo is still limited,partially because of lacking a reliable rodent animal model.Murine Tlr8 cannot sense the ligands of human TLR8.In mammals,TLR8 distinguishes live bacteria from dead bacteria to regulate the magnitude of immune responses.Recently,TLR8 has been reported to recognize severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)RNA to induce inflammatory responses,suggesting that TLR8 participates in coronavirus disease 2019(COVID-19).In this review,we discuss the mechanism of ligand recognition by TLR8,TLR8-mediated signaling pathways and signaling crosstalk between TLR8 and other molecules,and untangle the contribution of TLR8 to inflammatory diseases,infectious diseases,antitumor immunity and vaccination.
基金The project was supported by National Natural Science Foundation of China
文摘On the basis of the detection of IgG anti-keratin autoantibody (AK auto Ab)in human body fluids,it was shown that IgG AK auto Ab could hardly pass the blood-brain barrier,but it could easily penetrate the capillary walls into epithelial tissues.Un-der electron microscope,the interaction between AK auto Ab and keratinocyte is largelylocated in tonofilaments and desmosomes and is irrelevant to other organellae.Dynamicobservations of AK auto Ab suggest that the accumulation of AK auto Ab in keratinocy-te cytoplasm and transitory decrease of IgG AK auto Ab in serum of rabbits with sodiumsulfide dermatitis are related predominantly to keratinocytic injury.
基金supported by Capulin(Beijing Sanheli Cosmetics Technology Co.,Ltd.).
文摘To the Editor:Vitiligo is a chronic disease that impacts many aspects of a patient’s life.The prevalence of vitiligo has been increasing,and currently involves up to 0.5%to 2%of all races worldwide.[1]Although this condition very rarely produces any direct physical discomfort,the cosmetic problems and disfiguring appearance resulting from the depigmented lesions severely affect the quality of life(QoL)in these individuals.
文摘Background: Identification of critical autoantigenic T-cell epitopes is key to developing antigen-based therapies for autoimmune diseases, including psoriasis. Our previous work demonstrated that 3 peptides on keratin 17 are able to stimulate peripheral blood lymphocytes of HLA-DRB1 07-positive patients with psoriasis and to serve as immunodominant T cell epitopes. Objective: We sought to determine antagonistic altered peptide ligands to psoriatic T cells with a down-modulatory effect in inhibiting keratinocyte proliferation. Methods: Psoriatic altered peptide ligands were generated by single alanine residue substitutions at a critical T-cell receptor contact residue position. Antagonistic altered peptide ligands were identified by suppression screening of psoriatic T-cell activation and keratinocyte proliferation. Results: Altered peptide ligands 119R and 355L can inhibit psoriatic T-cell activation more effectively than other altered peptide ligands, especially 355L, with inhibition of T-cell proliferation and the secretion of interferon gamma and interleukin 2 in parallel with the upregulation of interleukins 4 and 10 as well as transforming growth factor-β . In coincubation assay, altered peptide ligands 119R and 355L can down-regulate the function of psoriatic T cells more effectively than wild-type epitopes solely, but less effectively than altered peptide ligands solely. In prepulse assay altered peptide ligand 119R can down-regulate the activation of psoriatic T cells more effectively than in coincubation but less effectively as compared with altered peptide ligand 119R only. Altered peptide ligand 355L was also shown to have a similar presentation. T-cell culture supernatants (1:100) from the concentrations (10 μ g · mL-1 and 100 μ g · mL-1 with 119R, 100 μ g · mL-1 with 355L) were more effective than the other ratios in inhibiting keratinocyte proliferation. Limitations: This study had a relatively small sample size (52 patients and 48 healthy controls). Conclusion: Our findings show that the altered peptide ligands 119R (VAALEEANTELEVKI) and 355L (ENRYCVQASQIQGLI) are capable of inhibiting proliferative responses of psoriatic T cells and keratinocyte proliferation in vitro, at least, with enhanced helper T cell type 2 polarization. Thus, to our knowledge, this article is the first report of the demonstration of therapeutic activity of altered peptide ligands derived from keratin 17.
文摘Background:There is a need for effective and safe therapies for psoriasis that provide sustained benefits.The aim of this study was to assess the efficacy and safety of tildrakizumab,an anti-interleukin-23p19 monoclonal antibody,for treating moderate-to-severe plaque psoriasis in Chinese patients.Methods:In this multi-center,double-blind,phase III trial,patients with moderate-to-severe plaque psoriasis were enrolled and randomly assigned(1:1)to receive subcutaneous tildrakizumab 100 mg or placebo at weeks 0 and 4.Patients initially assigned to placebo were switched to receive tildrakizumab at weeks 12,16,and every 12 weeks thereafter.Patients in the tildrakizumab group continued with tildrakizumab at week 16,and every 12 weeks until week 52.The primary endpoint was the Psoriasis Area and Severity Index(PASI 75)response rate at week 12.Results:At week 12,tildrakizumab demonstrated significantly higher PASI 75 response rates(66.4%[73/110]vs.12.7%[14/110];difference,51.4%[95%confidence interval(CI),40.72,62.13];P<0.001)and Physician’s Global Assessment(60.9%[67/110]vs.10.0%[11/110];difference,49.1%[95%CI,38.64,59.62];P<0.001)compared to placebo.PASI 75 response continued to improve over time in both tildrakizumab and placebo-switching to tildrakizumab groups,reaching maximal efficacy after 28 weeks(86.8%[92/106]vs.82.4%[89/108])and maintained up to 52 weeks(91.3%[95/104]vs.87.4%[90/103]).Most treatment-emergent adverse events were mild and not related to tildrakizumab.Conclusion:Tildrakizumab demonstrated durable efficacy through week 52 and was well tolerated in Chinese patients with moderate-to-severe plaque psoriasis.Trial registration:ClinicalTrials.gov,NCT05108766.
基金Department of Science and Technology of Hunan Province,High-tech Industry Science and Technology Innovation Leading Program(grant 2020SK2003 to Z.C.)Science Fund for Distinguished Young Scholars of Hunan Province(grant 2021JJ10069 to Z.C.)+1 种基金Mobile Healthcare:Ministry of Education,China Mobile Joint Laboratory(grant CMCMII-202200349 to S.Z.)National Natural Science Foundation of China(grant 2022YFC2504700 to X.C.).
文摘With over a million cases detected each year,skin disease is a global public health problem that diminishes the quality of life due to its difficulty to eradicate,propensity for recurrence,and potential for post-treatment scarring.Photodynamic therapy(PDT)is a treatment with minimal invasiveness or scarring and few side effects,making it well tolerated by patients.However,this treatment requires further research and development to improve its effective clinical use.Here,a piezoelectric-driven microneedle(PDMN)platform that achieves high efficiency,safety,and non-invasiveness for enhanced PDT is proposed.This platform induces deep tissue cavitation,increasing the level of protoporphyrin IX and significantly enhancing drug penetration.A clinical trial involving 25 patients with skin disease was conducted to investigate the timeliness and efficacy of PDMN-assisted PDT(PDMN-PDT).Our findings suggested that PDMN-PDT boosted treatment effectiveness and reduced the required incubation time and drug concentration by 25%and 50%,respectively,without any anesthesia compared to traditional PDT.These findings suggest that PDMN-PDT is a safe and minimally invasive approach for skin disease treatment,which may improve the therapeutic efficacy of topical medications and enable translation for future clinical applications.
基金This work has received funding from the National Natural Science Foundation of China(Nos.81625020,81902791)Support Program of Young Talents in Shaanxi Province(No.20200303)Young Eagle Project of Fourth Military Medical University(No.2019cyjhgwn).
文摘Melanoma is the most lethal skin cancer that originates from the malignant transformation of melanocytes.Although melanoma has long bee n regarded as a cancerous malig nancy with few therapeutic opti ons,in creased biological understandi ng and unprecedented innovations in therapies targeting mutated driver genes and immune checkpoints have substantially improved the prog nosis of patients.However,the low response rate and inevitable occurre nee of resistance to curre ntly available targeted therapies have posed the obstacle in the path of melanoma management to obtain further amelioration.Therefore,it is necessary to understand the mechanisms underlying melanoma pathogenesis more comprehensively,which might lead to more substantial progress in therapeutic approaches and expand clinical options for melanoma therapy.In this review,we firstly make a brief introduction to melanoma epidemiology,clinical subtypes,risk factors,and current therapies.Then,the signal pathways orchestrati ng mela noma pathogenesis,in eluding gen etic mutatio ns,key tran scripti onal regulators,epige netic dysregulati ons,metabolic reprogramming,crucial metastasis-related signals,tumor-promoting inflammatory pathways,and pro-angiogenic factors,have been systemically reviewed and discussed.Subsequently,we outline current progresses in therapies targeting mutated driver genes and immune checkpoi nts,as well as the mecha nisms underlying the treatment resista nee.Finally,the prospects and challe nges in the developme nt of mela noma therapy,especially immu no therapy and related ongoing din ical trials,are summarized and discussed.
基金National Natural Science Foundation of China(No.81703113)。
文摘Antimicrobial peptides(AMPs)are small molecules produced by a myriad of cells and play important roles not only in protecting against infections and sustaining skin barrier homeostasis but also in contributing to immune dysregulation under pathological conditions.Recently,increasing evidence has indicated that AMPs,including cathelicidin(LL-37),humanβ-defensins,S100 proteins,lipocalin 2,and RNase 7,are highly expressed in psoriatic skin lesions.These peptides broadly regulate immunity by interacting with various immune cells and linking innate and adaptive immune responses during the progression of psoriasis.In this review,we summarize the recent findings regarding AMPs in the pathogenesis of psoriasis with a main focus on their immunomodulatory abilities.
基金This work was supported by the National Natural Science Foundation of China[grant number 81773307]a research grant from Chongqing Science and Technology Commission[grant number cstc2018jcyjAX0195].
文摘Secreted frizzled-related protein 5(SFRP5)plays a pivotal role in regulating the development of many tissues and organs,however,as an inhibitor of Wnt signaling,the role of SFRP5 in vitiligo remains unknown.Hence,we speculated that SFRP5 might be associated with melanogenesis in melanocytes by regulating Wnt signaling in vitiligo.In this study,we found that SFRP5 was overexpressed in the skin lesions of patients with vitiligo.Compared with that in normal epidermal melanocytes(PIG1),the expression of SFRP5 was increased in vitiligo melanocytes(PIG3V).To investigate the effect of SFRP5 on melanin synthesis,PIG1 cells were infected with recombinant SFRP5 adenovirus(AdSFRP5),and PIG3V cells were infected with recombinant siSFRP5 adenovirus(AdsiSFRP5).The results showed that SFRP5 overexpression inhibited melanin synthesis in PIG1 cells through downregulation of microphthalmia-associated transcription factor(MITF)and its target proteins via suppression of the Wnt/b-catenin signaling pathway.Accordingly,SFRP5 silencing increased melanin synthesis and activated the Wnt signaling pathway in PIG3V cells.Moreover,SFRP5 overexpression also downregulated the transcriptional activity of T cell factor/lymphoid enhancer factor(TCF/LEF)in PIG1 cells.Furthermore,this inhibitory effect of SFRP5 on melanin synthesis was reversed by treatment with the b-catenin agonist,SKL2001.The inhibitory action of SFRP5 in pigmentation was further confirmed in vivo using a nude mouse model.Hence,our results indicate that SFRP5 can inhibit melanogenesis in melanocytes.Additionally,our findings showed that SFRP5 plays a vital role in the development of vitiligo,and thus may serve as a potential therapeutic target for vitiligo.
基金Supported by Grants from the National Natural Science Foundation(No.81130035,81071545,and 30971192)the National Basic Research Program of China(No. 2012CB518102)
文摘Objective: To observe the effects of Xuebijing Injection (血必净注射液) on dendritic cells (DCs) and T lymphocytes, and the potential mechanisms of its therapeutic effect on systemic lupus erythematosus (SLE). Methods: A widely used mouse model, SLE-prone BLLF1 mice aged 8-10 weeks, was employed. Mice were randomly divided into 4 groups: a normal group, a model group and two treatment groups treated with Xuebijing Injection with a dose of 6.4 mL/kg via intraperitoneal administration for SLE-prone BLLF1 mice aged 8 weeks (treatment A group) and 10 weeks (treatment B group). Renal tissue sections were stained with Masson's trichrome and periodic acid-silver methenamine. Histopathological changes in the kidney were evaluated by a light microscopy. The capacity of the DCs isolated from the spleen to stimulate the T cell proliferation in response to concanavalin A (Con A) was determined. Results: Compared with the model group, levels of anti-dsDNA antibodies in the two treatment groups decreased remarkablely (P〈0.01, P〈0.05), and levels of serum creatinine and blood urea nitrogen increased (P〈0.01, P〈0.05). Pathological changes were found in the kidney in the model group. Histopathological abnormalities were alleviated in the two treatment groups. Treatment with Xuebijing injection also significantly upregulated the expression of CD80, CD86 and major histocompatibility class Ⅱ by DCs compared with the model group (P〈0.05). When splenic T lymphocytes from BLLF1 mice were co-cultured with DCs at ratios of 1:100, 1:150 and 1:200 for 3 and 5 days, the proliferation of T lymphocytes was suppressed compared with the normal group (P〈0.05), but this was restored by Xuebijing Injection under the same conditions. In the model group, levels of tumor necrosis factor (TNF)-α in supernatants were significantly elevated compared with the normal group (P〈0.01), interleukin-2 levels decreased (P〈0.05), while these changes were significantly alleviated in the Xuebijing treatment groups. Conclusions: Xuebijing Injection alleviated renal injury in SLE-prone BLLF-1 mice. The mechanism might be through influencing T cell polarization mediated by DCs, and Xuebijing Injection might be a potential drug that suppresses immune dysfunction in patients with SLE.
基金National Natural Science Foundation of China(Nos.81803125 and 81903192)。
文摘Background:Psoriasis is a common chronic inflammatory skin disease with 2%to 3%prevalence worldwide and a heavy social-psychological burden for patients and their families.As the exact pathogenesis of psoriasis is still unknown,the current treatment is far from satisfactory.Thus,there is an urgent need to find a more effective therapy for this disease.Keratin 17(K17),a type I intermediate filament,is overexpressed in the psoriatic epidermis and plays a critical pathogenic role by stimulating T cells in psoriasis.Therefore,we hypothesized that inhibiting K17 may be a potential therapeutic approach for psoriasis.This study aimed to investigate the therapeutic effect of K17-specific small interfering RNA(siRNA)on mice with imiquimod(IMQ)-induced psoriasis-like dermatitis.Methods:Eight-week-old female BALB/c mice were administered a 5%IMQ cream on both ears to produce psoriatic dermatitis.On day 3,K17 siRNA was mixed with an emulsion matrix and applied topically to the left ears of the mice after IMQ application every day for 7 days.The right ears of the mice were treated in parallel with negative control(NC)siRNA.Inflammation was evaluated by gross ear thickness,histopathology,the infiltration of inflammatory cells(CD3+T cells and neutrophils)using immunofluorescence,and the expression of cytokine production using real-time quantitative polymerase chain reaction.The obtained data were statistically evaluated by unpaired t-tests and a one-way analysis of variance.Results:The severity of IMQ-induced dermatitis on K17 siRNA-treated mice ears was significantly lower than that on NC siRNA-treated mice ears,as evidenced by the alleviated ear inflammation phenotype,including decreased ear thickness,infiltration of inflammatory cells(CD3+T cells and neutrophils),and inflammatory cytokine/chemokine expression levels(interleukin 17[IL-17],IL-22,IL-23,C-X-C motif chemokine ligand 1,and C-C motif chemokine ligand 20)(P<0.05 vs.the Blank or NC siRNA groups).Compared to the NC siRNA treatment,the K17 siRNA treatment resulted in increased K1 and K10 expression,which are characteristic of keratinocyte differentiation(vs.NC siRNA,K17 siRNA1 group:K1,t=4.782,P=0.0050;K10,t=3.365,P=0.0120;K17 siRNA2 group:K1,t=4.104,P=0.0093;K10,t=4.168,P=0.0042;siRNA Mix group:K1,t=3.065,P=0.0221;K10,t=10.83,P<0.0001),and decreased K16 expression,which is characteristic of keratinocyte proliferation(vs.NC siRNA,K17 siRNA1 group:t=4.156,P=0.0043;K17 siRNA2 group:t=2.834,P=0.0253;siRNA Mix group:t=2.734,P=0.0250).Conclusions:Inhibition of K17 expression by its specific siRNA significantly alleviated inflammation in mice with IMQ-induced psoriasis-like dermatitis.Thus,gene therapy targeting K17 may be a potential treatment approach for psoriasis.
基金This work was supported by a grant from the National NaturalScience Foundation of China (No.39570656)
文摘Background Heat shock protein 70 (HSP70) is expressed highly in epithelial tumours associated closely with human papillomavirus 16 (HPV16) infections. However, evidence about the direct relationship between HSP70 expression and HPVs infections are still lacking. In the present study, we examined the expression of HSP70 in keratinocytes introduced with HPV16 E6/E7 oncogenes. Methods Stable transfected cells were established by transfection of the plasmids pLXSN16E6/E7 into cultured primary keratinocytes and subsequently selected by plasmid specific selection antibiotic (G418) at the required concentration. The expression of HSP70 in pLXSN16E6/E7 transfected keratinocytes was determined by Western blot. The correlation of HSP70 expression and E6/E7 transfeetion was further confirmed by doubly labelled immunofluorescent staining. Results Compared to non-transfected keratinocytes, there was a significant trend for higher levels of HSP70 in pLXSN16E6/E7 transfected keratinocytes. Doubly labelled immunofluorescent staining experiment showed that the co-localization of HPV16 E6/E7 and HSP70 in transfeeted keratinoeytes was observed and increased expression of HSP70 was strongly associated with the transfection of HPV16 E6/E7. Conclusions Our studies demonstrated increased levels of HSP70 proteins in keratinocytes stably transfected by HPV16 E6/E7 oncogenes. It suggests that the expression of HSP70 is modulated by HPV16 E6/E7 proteins, which may be involved in HPV16 E6/E7 induced immortalization.
基金National Natural Science Foundation of China(No.81703116,No.81703125,and No.81903208)。
文摘To the Editor:Bullous pemphigoid(BP)is an autoimmune blistering disease that is caused by autoantibodies and is associated with complement activation.[1]Autoantibody-mediated complement activation is involved in BP pathogenesis.Complement-regulatory proteins(CRPs)including CD35,CD46,CD55,and CD59 comprise an important class of regulatory proteins in the complement system that control the enzyme cascades,assembly of the membrane-attack complex,and complement system homeostasis.[2]Classically,both CD55 and CD46 negatively regulate complement system activation by inhibiting the production of new C3 and C5 convertases and accelerating the degradation of those already formed,thereby protecting cells from complement activation-induced damage.