Formononetin attenuates psoriasiform inflammation by regulating interferon signaling pathway.

BACKGROUND: Psoriasis is a long-lasting, inflammatory, continuous illness caused through T cells and characterized mainly by abnormal growth and division of keratinocytes. Currently, corticosteroids are the preferred option. However, prolonged use of traditional topical medication can lead to adverse reactions and relapse, presenting a significant therapeutic obstacle. Improved alternative treatment options are urgently required. Formononetin (FMN) is a representative component of isoflavones in Huangqi (HQ) [Astragalus membranaceus (Fisch.) Bge.]. It possesses properties that reduce inflammation, combat oxidation, inhibit tumor growth, and mimic estrogen. Although FMN has been shown to ameliorate skin barrier devastation via regulating keratinocyte apoptosis and proliferation, there are no reports of its effectiveness in treating psoriasis. OBJECTIVE: Through transcriptomics clues and experimental investigation, we aimed to elucidate the fundamental mechanisms underlying FMN's action on psoriasis. MATERIALS AND METHODS: Cell viability was examined using CCK8 assay in this study. The results of analysis of differentially expressed genes (DEGs) between FMN-treated HaCaT cells and normal HaCaT cells using RNA-sequencing (RNA-seq) were presented on volcano plots and heatmap. Enrichment analysis was conducted on DEGs using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO), and results were validated through RT-qPCR verification. After 12 days of FMN treatment in psoriasis mouse model, we gauged the PASI score and epidermis thickness. A variety of techniques were used to assess FMN's effectiveness on inhibiting inflammation and proliferation related to psoriasis, including RT-qPCR, HE staining, western blot, and immunohistochemistry (IHC). RESULTS: The findings indicated that FMN could suppress the growth of HaCaT cells using CCK8 assay (with IC50 = 40.64 uM) and 20 uM FMN could reduce the level of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) to the greatest extent. FMN-treated HaCaT cells exhibited 985 up-regulated and 855 down-regulated DEGs compared to normal HaCaT cells. GO analysis revealed that DEGs were linked to interferon (IFN) signaling pathway. Furthermore, FMN improved pathological features, which encompassed decreased erythema, scale, and thickness scores of skin lesions in psoriasis mouse model. In vivo experiments confirmed that FMN down-regulated expression of IFN-α, IFN-ß, IFN-γ, decreased secretion of TNF-α and IL-17 inflammatory factors, inhibited expression of IFN-related chemokines included Cxcl9, Cxcl10, Cxcl11 and Cxcr3 and reduced expression of transcription factors p-STAT1, p-STAT3 and IFN regulatory factor 1 (IRF1) in the imiquimod (IMQ) group. CONCLUSIONS: In summary, these results suggested that FMN played an anti-inflammatory and anti-proliferative role in alleviating psoriasis by inhibiting IFN signaling pathway, and FMN could be used as a potential therapeutic agent.

Accurate network pharmacology and novel ingredients formula of herbal targeting estrogen signaling for psoriasis intervention.

ETHNOPHARMACOLOGICAL RELEVANCE: As a common chronic inflammatory skin disease, psoriasis is incompletely understood and brings a lot of distress to patients. The estrogen signaling pathway has been implicated in its pathogenesis, making it a potential therapeutic target. Si Cao Formula (SCF) has demonstrated promise in treating psoriasis clinically. However, its molecular mechanisms concerning psoriasis remain largely unexplored. AIM OF THE STUDY: To elucidate the underlying mechanisms of the action of SCF on psoriasis. MATERIALS AND METHODS: Active ingredients were identified by LC-MS/MS. After the treatment with SCF, the exploration of differentially expressed proteins (DEPs) were conducted using tandem mass tag (TMT)-based quantitative proteomics analysis. By GO/KEGG, WikiPathways and network pharmacology, core signaling pathway and protein targets were explored. Consequently, major signaling pathway and protein targets were validated by RT-qPCR, immunoblotting and immunofluorescence. Based on Lipinski's Rule of Five rules and molecular docking, 8 active compounds were identified that acted on the core targets. RESULTS: 41 compounds of SCF and 848 specific targets of these compounds were identified. There were 570 DEPs between IMQ (Imiquimod) and IMQ + SCF group, including 279 up-regulated and 304 down-regulated proteins. GO/KEGG, WikiPathways and network pharmacology revealed estrogen signaling pathway as the paramount pathways, through which SCF functioned on psoriasis. We further show novel ingredients formula of SCF contributes to estrogen signaling intervention, including liquiritin, parvisoflavone B, glycycoumarin, 8-prenylluteone, licochalcone A, licochalcone B, oxymatrine, and 13-Hydroxylupanine, where targeting MAP2K1, ILK, HDAC1 and PRKACA, respectively. Molecular docking proves that they have good binding properties. CONCLUSION: Our results provide an in-depth view of psoriasis pathogenesis and herbal intervention, which expands our understanding of the systemic pharmacology to reveal the multiple ingredients and multiple targets of SCF and focus on one pathway (estrogen signaling pathway) may be a novel therapeutic strategy for psoriasis treatment of herbal medicine.

Qinzhuliangxue mixture ameliorates psoriasis by restraining apoptosis in psoriasis via downregulating the MDA-5 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Psoriasis is characterized by hyperkeratosis that produces the classic silvery scales, and the pathogenesis of psoriasis involves abnormal proliferation of keratinocytes. Emerging evidence supports that apoptosis regulates keratinocyte proliferation and formation of stratum corneum, which maintains the homeostasis of the skin. Qinzhuliangxue mixture (QZLX) is a representative formula for the treatment of psoriasis, which was earliest recorded in the classic Chinese medicine book Xia's Surgery. In our previous clinical studies, QZLX demonstrated 83.33% efficacy with few side effects in the treatment of psoriasis. Furthermore, our published basic research has also proved that the QZLX mixture effectively inhibits the hyperproliferation of keratinocytes, thus exerting therapeutic effects on psoriasis. However, whether QZLX mixture can regulate keratinocytes apoptosis requires further clarification. OBJECTIVE OF THE STUDY: To investigate the mechanism of QZLX in the treatment of psoriasis from the perspective of keratinocyte apoptosis. MATERIALS AND METHODS: First, psoriasis-like mice with imiquimod (IMQ)-induced were given QZLX intragastric administration and Psoriasis Area Severity Index (PASI) scores were recored for 11 consecutive days to appraise the efficacy. Then, tissue samples were collected for transcriptome analysis. The DEseq2 method detected significantly differentially expressed genes (DEGs), Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway databases were used to analyze the functions and pathway enrichment of DEGs. After that, the therapeutic mechanisms of QZLX in intervening with psoriasis were explored using TUNEL, immunohistochemical staining, and western blotting. RESULTS: QZLX ameliorated the symptoms and pathological characteristics of IMQ-induced psoriasis in mice. The epidermal cell hyperplasia in the skin was inhibited, in accordance with the suppressed expression of PCNA and Ki67 after treatment. Transcriptome sequencing showed that melanoma differentiation associated gene-5 (MDA-5) was downregulated. GO and KEGG enrichment analysis of the signaling pathways indicated that the differentially expressed genes were significantly enriched in apoptosis pathways. Besides, QZLX treatment decreased the apoptosis of keratinocyte as shown by reduced TUNEL-positive cells. As MDA-5 protein levels decreased, so did the expression of the downstream protein Caspase-8, which indicates that the apoptotic pathway was triggered. Furthermore, QZLX therapy might also help to balance the apoptotic Bcl-2 family expression. CONCLUSION: QZLX restrains the apoptosis of keratinocyte in psoriasis-like mice by downregulating the MDA-5 pathway. The restoration of the balance between cell apoptosis and proliferation in the skin may lead to considerable psoriasis relief. Our study reveals the possible molecular processes behind the effects of QZLX therapy on the skin lesions of psoriasis, and lends support to its clinical efficacy.

KGRT peptide incorporated hydrogel with antibacterial activity for wound healing by optimizing cellular functions via ERK/eNOS signaling.

Bacterial infected wounds, which is characterized by easy infection, multiple inflammation and slow healing, is a complex symptom, resulting from metabolic disorder of the wound microenvironment. In this study, a series of self-healing double-network hydrogels based on KGRT peptide (Lys-Gly-Arg-Thr) with antibacterial, anti-inflammatory and optimizing cellular functions were designed to promote the healing of infected wounds with full-thickness skin defects. Moreover, the dextran hydrogelintroduces a large number of side chains, which are entangled with each other in the Schiff base network to form an interpenetrating structure. The hydrogel might regulate cell metabolism, differentiation and vascular endothelial growth factor (VEGF) function. Importantly, both in vitro and in vivo data showed that hydrogel not only has good antibacterial properties (99.8 %), but also can eradicate bacterial biofilm, effectively reduce inflammation (down-regulated IL-1ß, TNF-α and ROS) and accelerate chronic wound healing process by speeding-up wound closure, increasing granulation tissue thickness, collagen deposition, angiogenesis (up-regulated CD31). The hydrogel could up-regulate mRNA expression of PI3K, AKT, ERK, eNOS, HIF-1α and VEGF, which were correlated with wound healing. Consistently, the hydrogel could promote infected wounds healing and inhibit inflammation through ERK/eNOS signaling pathway. Collectively, hydrogel has excellent clinical application potential for promoting infected wound healing.

The therapeutic efficacy and mechanism action of Si Cao formula in the treatment of psoriasis: A pilot clinical investigation and animal validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Psoriasis is a chronic inflammation and relapsing disease that affected approximately 100 million individuals worldwide. In previous clinical study, it was observed that the topical application of Si Cao Formula (SCF) ameliorated psoriasis skin lesions and reduced the recurrence rate of patients over a period of three months. However, the precise mechanism remains unclear. AIM OF THE STUDY: The objective of this study was to assess the effectiveness and safety of SCF in patients diagnosed with psoriasis and explore the molecular mechanisms that contribute to SCF's therapeutic efficacy in psoriasis treatment. MATERIALS AND METHODS: A randomized, controlled, and pilot clinical study was performed. This study assessed 30 individuals diagnosed with mild to moderate plaque psoriasis. 15 of them underwent local SCF treatment, the others received calcipotriol intervention. The outcome measure focused on Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI), and recurrence rate. In addition, IMQ-induced psoriasis-like mice model were used to assess the impact of SCF on ameliorating epidermal hyperplasia, suppressing angiogenesis, and modulating immune response. Furthermore, we performed bioinformatics analysis on transcriptome data obtained from skin lesions of mice model. This analysis allowed us to identify the targets and signaling pathways associated with the action of SCF. Subsequently, we conducted experimental validation to confirm the core targets. RESULTS: Our clinical pilot study demonstrated that SCF could ameliorate skin lesions in psoriasis patients with comparable efficacy of calcipotriol in drop of PASI and DLQI scores. SCF exhibited a significantly reduced recurrence rate within 12 weeks (33.3%). Liquid Chromatography Mass Spectrometry (LC-MS) identified 41 active constituents of SCF (26 cations and 15 anions). Animal experiments showed SCF ameliorates the skin lesions of IMQ-induced psoriasis like mice model and suppresses epidermal hyperkeratosis and angiogenesis. There were 845 up-regulated and 764 down-regulated DEGs between IMQ and IMQ + SCF groups. GO analysis revealed that DEGs were linked to keratinization, keratinocyte differentiation, organic acid transport epidermal cell differentiation, and carboxylic acid transport interferon-gamma production. KEGG pathway analysis showed that SCF may play a vital part through IL-17 and JAK/STAT signaling pathway. In addition, SCF could reduce the number of positive cells expressing PCNA, CD31, pSTAT3, CD3, and F4/80 within the epidermis of psoriatic lesions, as well as the expression of Il-17a and Stat3 in IMQ-induced psoriasis mice. CONCLUSIONS: Our research suggests that SCF serves as a reliable and efficient local approach for preventing and treating psoriasis. The discovery of plausible molecular mechanisms and therapeutic targets associated with SCF may support its broad implementation in clinical settings.

Loss of ORP3 induces aneuploidy and promotes bladder cancer cell invasion through deregulated microtubule and actin dynamics.

We have recently shown that loss of ORP3 leads to aneuploidy induction and promotes tumor formation. However, the specific mechanisms by which ORP3 contributes to ploidy-control and cancer initiation and progression is still unknown. Here, we report that ORP3 is highly expressed in ureter and bladder epithelium while its expression is downregulated in invasive bladder cancer cell lines and during tumor progression, both in human and in mouse bladder cancer. Moreover, we observed an increase in the incidence of N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced invasive bladder carcinoma in the tissue-specific Orp3 knockout mice. Experimental data demonstrate that ORP3 protein interacts with γ-tubulin at the centrosomes and with components of actin cytoskeleton. Altering the expression of ORP3 induces aneuploidy and genomic instability in telomerase-immortalized urothelial cells with a stable karyotype and influences the migration and invasive capacity of bladder cancer cell lines. These findings demonstrate a crucial role of ORP3 in ploidy-control and indicate that ORP3 is a bona fide tumor suppressor protein. Of note, the presented data indicate that ORP3 affects both cell invasion and migration as well as genome stability through interactions with cytoskeletal components, providing a molecular link between aneuploidy and cell invasion and migration, two crucial characteristics of metastatic cells.

Targeting upregulation of the immunosuppressive activity of MDSCs with indirubin as a novel strategy to alleviate psoriasis.

BACKGROUND: Psoriasis is a chronic and incurable skin disorder that causes inflammation. There is an urgent clinical need for new treatments. We identified the natural compound indirubin as a potential potent agent for the treatment of psoriasis, but it's therapeutic effect and underlying mechanisms were not well understood. METHODS: Peripheral blood and skin tissues from psoriasis patients and healthy individuals were collected. Bioinformatics analysis was performed to investigate LAT1 expression and associated signal pathways in psoriasis skin lesions. A mouse model of psoriasis was established. Indirubin was administered separately or in combination with MDSCs depletion or adoptively transferred MDSCs. JPH203, rapamycin, siRNA, and NV5138 were further used to investigate the potential mechanism by which indirubin regulates MDSCs. RESULTS: Psoriasis patients had increased numbers of MDSCs in their blood and skin lesions, with high expression of Lat1. The upregulation of LAT1 expression and the arginine synthesis pathway was observed in psoriasis skin lesions. The number of MDSCs was increased, while their inhibitory effect on psoriatic T cells was decreased. Indirubin decreased Lat1 expression on the surface of MDSCs, inhibited mTOR pathway activation, upregulated Arg1 expression in MDSCs, and enhanced the immunosuppressive activity of MDSCs while inhibiting CD4+CCR6+ T cells. CONCLUSION: This study demonstrates indirubin's pharmacological and therapeutic effects, providing a basis for future clinical application in treating psoriasis.

CRISPR-based quantum dot nanobead lateral flow assay for facile detection of varicella-zoster virus.

Varicella-zoster virus (VZV) infects more than 90% of the population worldwide and has a high incidence of postherpetic neuralgia in elderly patients, seriously affecting their quality of life. Combined with clustered regularly interspaced short palindromic repeats (CRISPR) system, we develop a quantum dot nanobeads (QDNBs) labeled lateral flow assay for VZV detection. Our assay allows the identification of more than 5 copies of VZV genomic DNA in each reaction. The entire process, from sample preparation to obtaining the results, takes less than an hour. In 86 clinical vesicles samples, the test shows 100% concordance with quantitative real-time PCR for VZV detection. Notably, when vesicles are present in specific areas, such as the genitals, our method outperforms clinical diagnosis. Compared to traditional detection methods, only a minute amount of blister fluid is required for accurate detection. Therefore, we anticipate that our method could be translated to clinical applications for specific and rapid VZV detection. KEY POINTS: • CRISPR/Cas12a and quantum dot nanobead-based lateral flow assay achieved 5 copies per reaction for VZV detection • Specific identification of VZV in atypical skin lesions • Results read by the naked eye within one hour.

Therapeutic effects and mechanisms of Ku-Gan formula on atopic dermatitis: A pilot clinical study and modular pharmacology analysis with animal validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Atopic dermatitis (AD) is a persistent, recurrent inflammatory skin disorder with a rapid upward trend worldwide. The first-line treatment for AD consists of topical medicines such as topical corticosteroids (TCSs). However, long-term use of conventional topical medicine results in side effects and recurrence, presenting therapeutic challenges for the management of AD. Ku-Gan formula (KG) has been extensively used to treat skin diseases since the Song dynasty. In particular, topical administration of the KG alleviates the cutaneous symptoms of AD and reduces recurrence rates with a good safety profile; however, the mechanisms of the KG's action remain unknown. AIM OF THE STUDY: The current study aimed to evaluate the efficacy and safety of KG in AD patients and to investigate the molecular mechanisms that underlie the efficacy of KG in the treatment of AD. MATERIALS AND METHODS: A single-arm prospective pilot study with historical controls was conducted. This study evaluated 11 patients with mild to moderate AD, who underwent topical KG treatment. The primary outcome was the change in local eczema area and severity index (EASI) scores. The secondary outcomes included the recurrence rate and safety. The recurrence rate were compared to those of a matched historical control group. Secondly, modular pharmacology analysis was used to elucidate the therapeutic mechanism of KG in AD treatment by identifying the hub genes and kernel pathways. Moreover, we evaluated treatment effects and verified modular pharmacology-based findings using the calcipotriol (MC903)-induced mouse model and bioinformatics analysis. RESULTS: Our clinical pilot study demonstrated that the KG wet wrapping could effectively ameliorate skin lesions in AD patients with a significant drop from 4.18 to 1.63 in local EASI. Compared to the historical controls, KG had a reduced recurrence rate (36%) and a longer median time to relapse (>12 weeks). Modular pharmacology analysis identified the hub genes including IL6, IL1B, VEGFA, STAT3, JUN, TIMP1 and ARG1, and kernel pathway including IL-17 signaling pathway of KG. Pharmacodynamic results suggested that KG ameliorated skin symptoms and demonstrated no less efficacy than halcinonide (HC) in MC903-induced AD-like mice. In addition, KG regulated the mRNA expression of hub genes as well as the related genes involved in IL-17 signaling pathway including Il25, Il17a,Traf3ip2, and Traf6, in skin lesions of AD-like mice. CONCLUSION: These results showed that KG is a safe and effective topical treatment for AD with low recurrence. In addition, our study identified potential molecular pathways and therapeutic candidate targets of the KG formula, providing evidence for its clinical applicability in AD.

Electroacupuncture for relieving itching in atopic eczema: study protocol for a multicenter, randomized, sham-controlled trial.

Background: Atopic eczema (AE) is a common atopic inflammatory skin disease affecting 2.1-4.9% of the population in different countries. Pruritus, one of the most burdensome symptoms, is often underestimated for the problems it can cause, creating a vicious loop of itching, scratching, and lichenification. Therefore, further research into practical and safe treatments that relieve itchy symptoms and enhance skin protection is key to overcoming AE. Acupuncture, with or without electrical stimulation, is one of the most commonly used therapeutic measures to treat AE. This trial aimed to objectively evaluate the efficacy and safety of the electroacupuncture (EA) antipruritic technique in AE pruritus and obtain high-level clinical evidence for the popularization and application of EA for AE. Methods and analysis: This multicenter, single-blinded, randomized controlled trial is planned to transpire from April 15, 2023, to June 30, 2025. We will recruit 132 participants with AE (44 per group). Participants will be assigned randomly to three equal-sized groups: EA, sham electroacupuncture, and sham acupuncture. Treatment will be administered three times a week during the 2-week intervention phase. The primary outcome measure is the Visual Analog Scale, with a numeric rating scale to evaluate pruritus. Secondary outcome measures include the Eczema Area and Severity Index and Dermatology Life Quality Index. Other outcome measures include physical examination, serum IgE, and safety evaluation. The number, nature, and severity of adverse events will be carefully recorded. Trial registration: ClinicalTrials.gov, 22Y11922200. Registered 3 September 2022, https://register.clinicaltrials.gov.

Clinical Feature, Lifestyle Behavior and Non-Communicable Diseases Comorbidities Among Psoriasis Patients in Shanghai: Gender Disparity Analysis Based on a Cross-Sectional Study.

Background: Gender difference is prevalent in clinical feature, disease severity for noncommunicable diseases (NCD), but studies on gender disparity in clinical feature, disease severity and NCD comorbidity among psoriasis patients are limited. This cross-sectional study explores gender differences in clinical feature, lifestyle behavior and NCD comorbidity among psoriasis patients. Methods: Psoriasis patients were recruited through cluster survey method in two hospitals, and questionnaire interviews were applied to collect the demographic feature, lifestyle habits, clinical feature and NCD among patients. Results: A total of 2102 psoriasis patients included 1332 males (63.4%), 70% were over 35 years old and approximately 50% of them were overweight or obesity. The median value for psoriasis initiation age and disease duration was 33 years old (34 for male and 32 for female) and 9 years (10 for male and 7 for female), respectively. The psoriasis recurrence was mainly in winter (73.4%) and autumn (34.2%) both for patients. The prevalence of tobacco smoking and alcohol drinking was 31.2% and 12.6%. Male patients had higher prevalence of tobacco smoking (odds ratio (OR) = 13.26, 95% confidence interval (CI): 9.54-18.44) and alcohol drinking (OR = 14.44, 95% CI: 7.90-26.40). The prevalence of diabetes, hypertension, hyperlipidemia, and metabolic syndrome were 13.2%, 28.5%, 23.4% and 21.5%, respectively. Male patients had higher prevalence of diabetes (OR = 1.53, 95% CI: 1.16-2.02), hypertension (OR = 1.87, 95% CI: 1.52-2.30), hyperlipidemia (OR = 2.34, 95% CI: 1.85-2.95) and metabolic syndrome (OR = 2.06, 95% CI: 1.63-2.62) than female patients. The proportions for 4 types of NCDs diagnosed after psoriasis onset were over 58%, which were also higher in males than females. Conclusion: Female patients had shorter disease duration and with less NCD, and male patients had more body weight issue, with fewer sleep time and higher prevalence of tobacco smoking and alcohol drinking and NCDs. We recommend that dermatologist should notice the gender disparity in psoriasis patients, which is helpful for the disease diagnosis and treatment.

The estimated influence of assumed physicians' advice for tobacco smoking cessation among current smokers in Shanghai, China: A cross-sectional study.

INTRODUCTION: Evidence indicates that physicians' smoking cessation advice is significant for tobacco control, which is an impetus to encourage smoking cessation among smokers, but the estimated influence of physicians' smoking cessation advice on smokers' intention to quit is limited in Shanghai, China. METHODS: We enrolled 1104 participants who were current smokers in the SJ (Songjiang) and FX (Fengxian) districts in Shanghai in 2021. An electronic questionnaire was used to collect data and SAS 9.4 was used for data analysis. Univariate and multivariate logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) to estimate the influence of the assumed physicians' advice for smoking cessation on current smokers' smoking cessation plan. RESULTS: A total of 1104 participants provided information of which 914 were male smokers (82.8%) and 190 (17.2%) were female smokers. Multivariate logistic regression demonstrated that female smokers (OR=2.47; 95% CI: 1.66-3.68), smokers with at least 1 type of non-communicable disease (OR=2.09; 95% CI: 1.42-3.07), smoking intensity <20 cigarettes/day (OR=1.64; 95% CI: 1.22-2.17), with personal tobacco burden less than 20% (OR=1.52; 95% CI: 1.10-2.13), exposed to secondhand smoke (OR=1.99; 95% CI:1.44-2.76), and previous smoking cessation attempt (OR=4.43; 95% CI: 3.23-6.08), were more likely to report an intent to quit smoking. Moreover, approximately 50% of participants without a plan to quit in a year had also reported their intention to quit smoking with the presumption that the physicians would advise them to quit, irrespective of their sex, age, NCD status and secondhand tobacco smoke exposure. CONCLUSIONS: Physicians' cessation advice could promote smokers to consider stopping smoking. The reported cessation intention was higher among female smokers, and smokers with NCD, lower smoking intensity and burden, with smoking cessation attempts, all of which could be incorporated into the implementation of tobacco control measures in the future in Shanghai.

Case report: Going through pregnancy safely after twice partial nephrectomy for bilateral kidneys with HLRCC-associated RCC.

Background: HLRCC-associated RCC (hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinoma) caused by germline mutations of the fumarate hydratase (FH) gene is a rare autosomal dominant genetic renal cancer. At present, there are no reports of bilateral kidneys with HLRCC-associated RCC, let alone safe pregnancy after twice partial nephrectomy for bilateral kidney HLRCC-associated RCC. Case presentation: We report a 25-year-old woman with bilateral renal tumors detected by ultrasound screening during a routine checkup. CT revealed a soft tissue mass in the parenchyma of the left kidney and a nodular soft tissue mass in the lower pole of the right kidney. She underwent robot-assisted laparoscopic left partial nephrectomy and underwent laparoscopic right partial nephrectomy 3 months after the first surgery. Heterozygous mutation in the FH gene on the patient's tumor tissue was detected by genetic testing. Combined with the patient's medical history, microstructure and immunohistochemical staining of tumor tissue, and genetic test results, the pathological reports after two operations concluded HLRCC-associated RCC. Then, she was injected with interferon and nivolumab as a preventative treatment against tumor recurrence. Up to 38 months after surgery, having given birth to a baby, till now there was no tumor progression. Conclusions: This is a clinically significant case, as it provides a reference for pregnancy in patients undergoing partial nephrectomy for bilateral kidneys with HLRCC-associated RCC and may indicate an effective approach to preventing tumor recurrence by nivolumab in patients with HLRCC-associated RCC.

Discovering Novel Biomarkers Associated with the Pathogenesis of Psoriasis: Evidence from Bioinformatic Analysis.

Objective: This study aimed to investigate key biomarkers and their molecular pathogenesis in psoriasis. Methods: Differentially expressed genes (DEGs) of datasets (GSE13355, GSE30999, and GSE106992) obtained from Gene Expression Omnibus (GEO) were identified using Venn diagram. Function and pathway enrichment analyses were performed. Protein-protein interaction (PPI) network and the hub genes were constructed. The correlation between normal tissue and infiltrating immune cells was analyzed by CIBERSORT. ROC analysis was performed to distinguish between skin lesion samples and skin non-lesion samples. Analyze the highest expression of single gene in the whole body within the Human Protein Atlas (HPA) database. Effect of CXCL8 expression level on proliferation, invasion, migration and apoptosis of HaCat cells was detected by qPCR. Results: A total of 239 pairs of normal and lesional skin samples were downloaded. PPI network revealed a tight interaction among 197 DEGs. The GO enrichment analysis showed that these genes were markedly enriched in the "defense response to virus", "type I interferon signaling pathway", and "cell response to type I interferon" categories. The KEGG pathway analysis showed that the DEGs were mainly in the NOD-like receptor axis, interaction between cytokine and cytokine receptor and the IL-17 axis. PPI analysis showed that CXCL8 was the novel hub gene of psoriasis and correlated to 22 types of infiltrating immune cells. 6 miRNAs were predicted to be related to CXCL8. CXCL8 was most widely distributed in lymphoid tissues and plays a role in psoriatic inflammatory lesions by promoting cell proliferation, migration, and anti-apoptosis. Conclusion: CXCL8 plays a key role in psoriasis development. This study provided new insights into the exploration of molecular mechanisms and therapeutic targets of psoriasis.

Tobacco smoking was positively associated with metabolic syndrome among patients with psoriasis in Shanghai: A cross-sectional study.

INTRODUCTION: A number of studies have reported a high correlation between psoriasis and metabolic syndrome (MetS), and tobacco smoking is one independent risk factor accounting for the increased prevalence both for psoriasis and MetS. However, few studies have been conducted to assess the effects of tobacco smoking on co-morbidities of psoriasis and MetS. METHODS: We conducted a cross-sectional study with 1014 psoriasis patients recruited from January to May 2021. Patients were recruited with a cluster survey method in Yueyang Hospital (affiliated with Shanghai University of Traditional Chinese Medicine) and Shanghai Skin Diseases Hospital (affiliated with Tongji University). Data were collected by face-to-face questionnaire interviews which included basic information, personal life habits, medical history, and clinical examinations. SPSS 24.0 was used for data analysis and a p<0.05 was considered statistically significant. RESULTS: The 1014 psoriasis patients were predominantly males (65.58%), with an average age of 45.98 years (IQR: 34.00-57.00). Of these, 25.74% (261) of psoriasis had MetS and 31.85% (323) were tobacco smokers. Male psoriasis patients had higher tobacco smoking prevalence than female patients. With increasing age and BMI, the prevalence of tobacco smoking among psoriasis patients increased dramatically (p<0.01). Logistic regression indicated that psoriasis patients with tobacco smoking had 1.78 times (95% CI: 1.21-2.60) the probability to have MetS than those without tobacco smoking, even adjusting for potential confounding factors. Moreover, smoking psoriasis patients with MetS consumed more cigarettes per day, with longer smoking duration, but with an older age of smoking initiation. CONCLUSIONS: The prevalence of tobacco smoking and MetS among psoriasis patients was high in Shanghai, and tobacco smoking was positively associated with the MetS among psoriasis patients. Clinicians should recommend psoriasis patients to abstain from tobacco smoking and provide tobacco cessation assistance regularly.

Integrated bioinformatic analysis of key biomarkers and signalling pathways in psoriasis.

BACKGROUND AND AIMS: Psoriasis is a relatively common autoimmune inflammatory skin disease with a chronic etiology. Since psoriasis is still incurable, it is necessary to identify the molecular mechanisms of psoriasis. The present study was designed to detect novel biomarkers and pathways associated with psoriasis incidence, and provide new insights into treatment of psoriasis. METHODS AND RESULTS: Differentially expressed genes (DEGs) associated with psoriasis in the Gene Expression Omnibus (GEO) database were identified, and their functional roles and interactions were then annotated and evaluated through GO, KEGG, and gene set variation (GSVA) analyses. In total 197 psoriasis-related DEGs were identified and found to primarily be associated with the NOD-like receptor, IL-17, and cytokine-cytokine receptor interaction signalling pathways. GSVA revealed significant differences between normal and lesional groups (P < 0.05), while PPI network analyses identified CXCL10 as the hub gene with the highest degree value, whereas IRF7, IFIT3, OAS1, GBP1, and ISG15 were promising candidate genes for the therapeutic treatment of psoriasis. CONCLUSION: The findings of the present integrated bioinformatics may enhance our understanding of the molecular events occurring in psoriasis, and these candidate genes and pathways together may prove to be therapeutic targets for psoriasis.

Spinal Cord Stimulation and Treatment of Peripheral or Central Neuropathic Pain: Mechanisms and Clinical Application.

Spinal cord stimulation (SCS) as an evidence-based interventional treatment has been used and approved for clinical use in a variety of pathological states including peripheral neuropathic pain; however, until now, it has not been used for the treatment of spinal cord injury- (SCI-) induced central neuropathic pain. This paper reviews the underlying mechanisms of SCS-induced analgesia and its clinical application in the management of peripheral and central neuropathic pain. Evidence from recent research publications indicates that nociceptive processing at peripheral and central sensory systems is thought to be modulated by SCS through (i) inhibition of the ascending nociceptive transmission by the release of analgesic neurotransmitters such as GABA and endocannabinoids at the spinal dorsal horn; (ii) facilitation of the descending inhibition by release of noradrenalin, dopamine, and serotonin acting on their receptors in the spinal cord; and (iii) activation of a variety of supraspinal brain areas related to pain perception and emotion. These insights into the mechanisms have resulted in the clinically approved use of SCS in peripheral neuropathic pain states like Complex Regional Pain Syndrome (CRPS) and Failed Back Surgery Syndrome (FBSS). However, the mechanisms underlying SCS-induced pain relief in central neuropathic pain are only partly understood, and more research is needed before this therapy can be implemented in SCI patients with central neuropathic pain.

Identification and biological characteristics of clear cell renal cell carcinoma associated urine-derived stem cells.

Urine-derived stem cells (USC) are isolated from voided urine and have demonstrated potential for use in tissue engineering and regenerative medicine therapies. Clear cell renal cell carcinoma (ccRCC) is a common urological malignancy that originates in the kidney. Since USC also originate in the kidney, the objective of this study was to investigate any biological differences between USC isolated from healthy patients and those isolated from ccRCC patients (rc-USC). We found that USC can be isolated from the voided urine of ccRCC patients (rc-USC) and have a morphology and function similar to those isolated from healthy donors. However, the rc-USC showed greater proliferation and invasion capacity than USC, and possessed some features of cancer cells; but the rc-UC were not able to form xenografts when implanted in vivo. We further performed RNA sequencing of rc-USC and USC and found several differentially expressed lncRNAs and mRNAs; however subsequent GO and KEGG enrichment analysis showed few pathway differences between these cells. Bioinformatic analyses and RT-PCR showed the expression of several known ccRCC-related genes in rc-USC expressed, as compared to USC derived from healthy donors. This study demonstrates that rc-USC displayed several cellular and genetic features of ccRCC cells, which suggests that this population of cells could provide a non-invasive approach for for the diagnosis, predication, disease modeling and therapeutic strategies targeting ccRCC.

Research on the effects of soil petroleum pollution concentration on the diversity of natural plant communities along the coastline of Jiaozhou bay.

This study examines the 4 typical natural plant communities at the coastal waterfront of Jiaozhou Bay. Based on field survey and sampling, laboratory analysis, application of classical statistical methods and the requirements for urban ecological preservation and data restoration in IoT engineering technology, this study investigates the diversity pattern of the 4 natural plant communities, i.e. Phragmitesaustralis, Suaeda salsa, Setariaviridis and Conyzacanadensis, analyzes the characteristics of the petroleum pollution suffered by these 4 natural plant communities and the soil at the coastal waterfront of Jiaozhou Bay. By investigating the impact on the natural regulation ability of the natural ecosystem, species and habitat, this study provides the basis for protection of the natural plant communities in the petroleum polluted area and for the design of plants arrangement in ecological restoration in the site and provides the support for application of IoT technology in urban ecosystem establishment and urban ecological restoration. Findings: (1) During investigation of 30 quadrats of the plant communities in the petroleum polluted area at coastal waterfront of Qingdao, 74 plant species have been discovered.They belong to 12 families, where Chenopodiaceae, Poaceae and Compositae are dominant families and account for 9.09%, 20.45% and 38.63% respectively; Phragmitesaustralis, Suaeda salsa, Conyza canadensis and Setariaviridis communities are all herbosa, their species composition is quite simplex and most of them are in monodominant community patch; (2) The Conyzacanadensis community has the largest Shannon-Wiener diversity index, Patrick richness index and Simpson dominance index, which are 2.115, 1.930 and 1.228 respectively; in terms Pielou evenness index, the rank is Phragmitesaustralis > Conyzacanadensis > Setariaviridis > Suaeda salsa, which are 1.056, 0.907, 0.877 and 0.661; (3) According to the result of data analysis, the petroleum polluted area at coastal waterfront of Jiaozhou Bay has average total salt content 0.626%, average PH 8.067 and average petroleum hydrocarbons content 69.306 mg/kg.According to the result of difference examination of different plant communities, the total salt, PH and petroleum hydrocarbons content in the soil at the coastal waterfront Jiaozhou Bay are the main factors that affect the distribution of plant communities in that area (P < 0.05), and the petroleum hydrocarbons content in the soil has significant impact on the distribution of the communities (P < 0.01).(4) In this study, the petroleum hydrocarbon tolerance degrees of the 4 typical tolerant plant communities are ranked as Conyzacanadensis > Suaeda salsa > Setariaviridis > Phragmitesaustralis.In the soil environment with light (Level Ⅰ) and severe (Level Ⅳ) petroleum hydrocarbon pollution, the indexes of Suaeda salsa and Conyzacanadensis are optimal among the communities; the indexes of Phragmitesaustralis and Setariaviridis are optimal in the soil environment with Level Ⅱ and Level Ⅲ petroleum hydrocarbon pollution and can grow better in that environment.