Elafin

A prospective cohort study on the association between cervical microenvironmental factors and the efficacy of treating high-risk human papillomavirus infection comorbid with cervical diseases.

Lingyun Ji, Jing Wu, Yang Zhou +6 more

Interferon-based local therapy is an intervention for high-risk human papillomavirus (HR-HPV)-associated low-grade squamous intraepithelial lesions (LSIL) or lower-grade cervical abnormalities. This study sought to delineate the differences in clinical outcomes following interferon-based local drug treatment and elucidate the microenvironmental factors driving these disparities.

Multi-omics approach identifies PI3 as a biomarker for disease severity and hyper-keratinization in psoriasis.

Jingwen Deng, Emmerik Leijten, Yongzhan Zhu +11 more

Psoriasis is an immune-mediated inflammatory skin disease. Psoriasis severity evaluation is important for clinicians in the assessment of disease severity and subsequent clinical decision making. However, no objective biomarker is available for accurately evaluating disease severity in psoriasis.

Role of PDGF-BB in Oral Squamous Cell Carcinoma through PI3/AKT/mTOR Pathway: An Integrated Computational and Real-Time PCR-Based Approach.

Georgia Benitha J, Pratibha Ramani, Selvaraj Jayaraman +2 more

This study investigates the role of PDGF-BB in oral squamous cell carcinoma (OSCC) and its impact on the PI3K/AKT/mTOR pathway. The goal is to elucidate the expression levels analysis of PDGF-BB and signaling molecules in OSCC pathogenesis, potentially identifying novel biomarkers or therapeutic targets.

Role of spexin and DARS2 as potential biomarkers in basal cell carcinoma and cutaneous malignant melanoma diagnosis, and as therapeutic targets.

Mehmet Mustafa Erdoğan, Songül Yerlikaya Kavak

Basal cell carcinoma (BCC) is a slowly progressive, locally aggressive and rarely metastasizing cancer, and although its mortality is low, its morbidity and cost of disease are high. While BCC is more common, cutaneous malignant melanoma (CMM) is significant due to its higher mortality rate. These patients can be treated, but recurrence, metastasis and mortality may occur in such patients. Various environmental, phenotypic and genotypic factors, especially ultraviolet (UV) radiations, play a role in the etiology of BCC and CMM. Histopathological examination continues to be the "gold standard" in their diagnosis. Spexin (SPX) and DARS2 are newly discovered proteins linked to many diseases, including cancer. These proteins may have an effect on the development and expression of skin cancers such as BCC and CMM. In this study, we evaluated the potential of SPX and DARS2 expressions as immunohistochemical biomarkers in the differential diagnosis of BCC and CMM. This study was conducted retrospectively using samples taken from the pathology laboratory. A total of 180 patient samples were used. The control group consisted of healthy skin tissues of the patients, and the other groups consisted of BCC and CMM tissues of the same patients. Tissue samples of all three groups were evaluated immunohistochemically with SPX and DARS2. The immunoreactivity of SPX was found to be higher in BCC and CMM tissue samples than in healthy skin tissues in the control group. DARS2 immunoreactivity was found to be higher in CMM tissues compared to the other two groups, and statistically significant in BCC tissues when compared with healthy control group tissues. SPX can be used as an immunohistochemical biomarker in the diagnosis of BCC and CMM. Since DARS2 expression is statistically more significant in CMM tissues than in BCC tissues, it can be used in differential diagnosis.

Elafin level in lichen planus.

Reham William Doss, Esraa Hatem Ahmed Mohammed, Eman Hamdy Mohamed +1 more

Lichen planus (LP) is a chronic, inflammatory, autoimmune disease that affects the skin, oral mucosa and genital mucosa. Elafin is an epithelial host-defense protein that is absent in normal skin but highly expressed in inflamed skin keratinocytes. Overexpression of Elafin has been reported in various infective, inflammatory skin disorders, such as cellulitis, psoriasis, Behçet's syndrome, and graft versus host disease. The aim of this case- control study is to map the level of Elafin in LP in order to investigate its role in the pathogenesis of LP. This study included 30 LP patients and 30 healthy controls. 10 cc blood samples were withdrawn from study participants to evaluate the serum level of Elafin using enzyme-linked immunosorbent assay (ELISA) technique. Serum Elafin level was significantly higher in LP patients as compared to healthy controls; the mean values were (32.56 vs. 5.60) in LP cases and healthy controls respectively with a statistically significant p-value < 0.001. We conclude that Elafin could be part of the inflammatory autoimmune process in LP.

Concerted actions by MMPs, ADAMTS and serine proteases during remodeling of the cartilage callus into bone during osseointegration of hip implants.

Jean Cassuto, Agnetha Folestad, Jan Göthlin +2 more

Although the number of patients undergoing total hip arthroplasty is constantly on the rise, we only have limited knowledge of the molecular mechanisms necessary for successful osseointegration of implants or the reasons why some fail. Understanding the spatiotemporal characteristics of signaling pathways involved in bone healing of implants is therefore of particular importance for our ability to identify factors causing implants to fail. The current study investigated the role of three families of proteases, i.e. MMPs (matrix metalloproteinases), ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) and serine proteases, as well as their endogenous inhibitors during osseointegration of hip implants that have endured two decades of use without clinical or radiological signs of loosening.

Elafin and its precursor trappin-2: What is their therapeutic potential for intestinal diseases?

Céline Deraison, Chrystelle Bonnart, Philippe Langella +2 more

Elafin and its precursor trappin-2 are known for their contribution to the physiological mucosal shield against luminal microbes. Such a contribution seems to be particularly relevant in the gut, where the exposure of host tissues to heavy loads of microbes is constant and contributes to mucosa-associated pathologies. The expression of trappin-2/elafin has been shown to be differentially regulated in diseases associated with gut inflammation. Accumulating evidence has demonstrated the protective effects of trappin-2/elafin in gut intestinal disorders associated with acute or chronic inflammation, or with gluten sensitization disorders. The protective effects of trappin-2/elafin in the gut are discussed in terms of their pleiotropic modes of action: acting as protease inhibitors, transglutaminase substrates, antimicrobial peptides or as a regulator of pro-inflammatory transcription factors. Further, the question of the therapeutic potential of trappin-2/elafin delivery at the intestinal mucosa surface is raised. Whether trappin-2/elafin mucosal delivery should be considered to ensure intestinal tissue repair is also discussed.

Using biological information to analyze potential miRNA-mRNA regulatory networks in the plasma of patients with non-small cell lung cancer.

Wei Zhang, Qian Zhang, Li Che +6 more

Lung cancer is the most common malignant tumor, and it has a high mortality rate. However, the study of miRNA-mRNA regulatory networks in the plasma of patients with non-small cell lung cancer (NSCLC) is insufficient. Therefore, this study explored the differential expression of mRNA and miRNA in the plasma of NSCLC patients.

Panax notoginseng saponins induce apoptosis in retinoblastoma Y79 cells via the PI3K/AKT signalling pathway.

Jingchen Liu, Chunli Zhang, Baoyun Jia +7 more

This study aimed to investigate the effects of Panax notoginseng saponins (PNS) on the proliferation, apoptosis, and PI3K/AKT signalling pathways of retinoblastoma Y79 cells to explore the possible mechanism of action of PNS on retinoblastoma. The effects of PNS and carboplatin on the proliferation of Y79 cells were examined using cell counting kit-8 assay. And the apoptosis rate, the mRNA and protein levels of apoptosis-related genes and the expression of PI3K/AKT pathway protein were assessed. PNS effectively inhibited the proliferation (P < 0.05) and increased apoptosis of Y79 cells (P < 0.05). Compared with the negative control, the Y79 cells treated with PNS had significantly increased (P < 0.05) mRNA and protein expression of Bax, caspase-3, caspase-8, and caspase-9 and elevated levels of cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9 proteins (P < 0.05). The mRNA and protein expression of the apoptosis suppressor gene Bcl-2 was inhibited (P < 0.05), while the Bax/Bcl-2 values of the cells in the drug group were significantly higher than those in the negative group (P < 0.01). After treatment with PNS, the total protein expression of PI3K and AKT1 in the Y79 cells did not show significant differences compared with the negative group (P > 0.05), although the expression of phosphorylated proteins p-PI3K, p-AKT (Thr308), p-AKT (Ser473), and p-mTOR were significantly reduced (P < 0.05). Meanwhile, the antagonist protein of the pathway phosphatase and tensin homologue deleted on chromosome 10 (PTEN) expression was increased (P < 0.01). Cellular alterations following inhibition of the PI3K/AKT pathway using LY294002 were similar to those of PNS, the proliferation of Y79 cells was also inhibited, and cell apoptosis increased (P < 0.001). The expression of Bax, caspase-3, caspase-8, caspase-9, and activation proteins cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9 was also significantly higher than that in the negative control (P < 0.05). Bcl-2 protein expression was decreased (P < 0.01), and the Bax/Bcl-2 ratio was higher than that in the negative control (P < 0.001). Overall, we demonstrated that PNS effectively inhibited the proliferation and promoted the apoptosis of retinoblastoma Y79 cells. The apoptosis-promoting effect of PNS may involve the inhibition of the PI3K/AKT signalling pathway, which subsequently regulates the expression of apoptosis-related genes.

Severe Pulmonary Arterial Hypertension Is Characterized by Increased Neutrophil Elastase and Relative Elafin Deficiency.

Andrew J Sweatt, Kazuya Miyagawa, Christopher J Rhodes +14 more

Preclinical evidence implicates neutrophil elastase (NE) in pulmonary arterial hypertension (PAH) pathogenesis, and the NE inhibitor elafin is under early therapeutic investigation.

Childhood brain cancer risk from early life exposure to hyperinsulinemia in offspring of diabetic mothers: the exception that proves the rule?

Raffaella Mormile

Upregulation of elafin expression in the fallopian tube of ectopic tubal pregnancies compared to the normal tubes.

Fatemeh Zakizadeh, Hamidreza Mahmoudzadeh-Sagheb, Azam Asemi-Rad +5 more

Ectopic pregnancy is one of the most important causes of maternal deaths and fallopian tubes are the location of 95% of ectopic pregnancies. Elafin is a natural antimicrobial molecule that plays an important role as an anti-inflammatory agent in mucosal surfaces and has been found in the female reproductive tract.

Eugenol-piperine loaded polyhydroxy butyrate/polyethylene glycol nanocomposite-induced apoptosis and cell death in nasopharyngeal cancer (C666-1) cells through the inhibition of the PI3K/AKT/mTOR signaling pathway.

Xiaopeng Sun, Vishnu Priya Veeraraghavan, Krishna Mohan Surapaneni +5 more

Nasopharyngeal cancer is a malignancy developing from the nasopharynx epithelium due to smoking and nitrosamine-containing foods. Nasopharyngeal cancer is highly endemic to Southeast Asia. Eugenol and piperine have shown many anticancer activities on numerous cancer types, like colon, lung, liver, and breast cancer. In this study, we amalgamated eugenol and piperine loaded with a polyhydroxy butyrate/polyethylene glycol nanocomposite (Eu-Pi/PHB-PEG-NC) for better anticancer results against nasopharyngeal cancer (C666-1) cells. In the current study, nasopharyngeal cancer cell lines C666-1 were utilized to appraise the cytotoxic potential of Eug-Pip-PEG-NC on cell propagation, programmed cell death, and relocation. Eu-Pi/PHB-PEG-NC inhibits cellular proliferation on C666-1 cells in a dose-dependent manner, and when compared with 20 µg/ml, 15 µg/ml of loaded mixture evidently restrained the passage aptitude of C666-1 cells, this was attended with a downregulated expression of mitochondrial membrane potential. Treatment with 15 µg/ml Eu-Pi/PHB-PEG-NC suggestively amplified cell apoptosis in the C666-1 cells. Furthermore, its cleaved caspase-3, 8, and 9 and Bax gene expression was augmented and Bcl-2 gene expression was diminished after Eu-Pi/PHB-PEG-NC treatment. Additionally, our data established that the collective effect of Eu-Pi/PHB-PEG-NC loaded micelles inhibited the expansion of C666-1 cells augmented apoptosis connected with the intrusion of PI3K/Akt/mTOR signaling pathway.

Recombinant Human Elafin Ameliorates Chronic Hyperoxia-Induced Lung Injury by Inhibiting Nuclear Factor-Kappa B Signaling in Neonatal Mice.

Kexin Li, Fengmei Zhang, Li Wei +5 more

The study aimed to investigate whether recombinant human elafin can prevent hyperoxia-induced pulmonary inflammation in newborn mice, and to explore the mechanism underlying the inhibitory effects of elafin on nuclear factor-kappa B (NF-κB) signaling pathway. Neonatal C57BL/6J mice were exposed to 85% O2 for 1, 3, 7, 14, or 21 days. Then, elafin was administered daily for 20 days through intraperitoneal injection. After treatment, morphometric analysis, quantitative real-time polymerase chain reaction, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and Western blotting were carried out to determine the key markers involved in inflammatory process and the potential signaling pathways in hyperoxia-exposed newborn mice treated with elafin. In neonatal bronchopulmonary dysplasia (BPD) mice, hyperoxia induced apoptosis by increasing Bcl-2-associated X protein expression, and triggered inflammation by upregulating the expression levels of interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor-α. Moreover, hyperoxia activated NF-κB signaling pathway by promoting the nuclear translocation of p65 in lung tissue. However, all these changes could be inhibited or reversed by elafin at least partially. Elafin reduced apoptosis, suppressed inflammation cytokines, and improved NF-κB p65 nuclear accumulation in hyperoxia-exposed neonatal mice, indicating that this recombinant protein can serve as a novel target for the treatment of BPD.

Evaluation of trappin-2 in cervicovaginal secretions as predictor of spontaneous preterm birth in asymptomatic high-risk women: Nested case-control study.

Deepika Negi, Kiran Guleria, Vipin Tyagi +2 more

To evaluate trappin-2 levels in cervicovaginal secretions for prediction of spontaneous preterm birth (sPTB) and compare it with transvaginal sonography (TVS) cervical length in asymptomatic women at risk of PTB.

Blockade of RANKL/RANK signaling pathway by epigallocatechin gallate alleviates mast cell-mediated inflammatory reactions.

Hee-Yun Kim, Ho-Geun Kang, Sun-Young Nam +2 more

Receptor activator of NF-κB ligand (RANKL) as an osteoclast differentiation factor induces inflammatory reactions via production of thymic stromal lymphopoietin (TSLP). Epigallocatechin gallate (EGCG) is the major and the most active compound in green tea and has anti-inflammatory, anti-cancer, anti-oxidant, and neuroprotective effects. However, the effect and molecular mechanisms of EGCG are still unknown in RANKL-induced inflammatory reactions. Here we investigated the immuno-regulatory effects and its molecular mechanisms of epigallocatechin gallate (EGCG) in RANKL-stimulated human mast cell line, HMC-1 cells. In this study, EGCG prevented expression of PI3 Kinase and phosphorylation of mitogen-activated protein (MAP) Kinases in RANKL-stimulated HMC-1 cells. EGCG prevented caspase-1 activity and decreased transcriptional activity of nuclear factor (NF)-κB by suppressing inhibitory protein κBα phosphorylation in RANKL-stimulated HMC-1 cells. EGCG has been shown to prevent production and mRNA expression of TSLP, interleukin (IL)-1β, IL-6, and IL-8 by RANKL without cytotoxicity. Furthermore, EGCG prevented degranulation of mast cell in RANKL-stimulated HMC-1 cells. Overall, these results suggest that EGCG acts as a natural agent for preventing and treating RANKL-mediated inflammatory diseases by targeting PI3 Kinase, MAP Kinase, caspase-1, and NF-κB signaling cascade in mast cells.

Evaluation of Elafin Immunohistochemical Expression as Marker of Cervical Cancer Severity.

Adhemar Longatto-Filho, José Humberto Fregnani, Allini Mafra da Costa +5 more

The main risk factor for the development of cervical cancer (CC) is persistent infection by human papillomavirus (HPV) oncogenic types. In order to persist, HPV exhibits a plethora of immune evasion mechanisms. PI3/Elafin (Peptidase Inhibitor 3) is an endogenous serine protease inhibitor involved in epithelial protection against pathogens. PI3/Elafin's role in CC is still poorly understood.

Influenza A Virus Pre-Infection Exacerbates Pseudomonas aeruginosa-Mediated Lung Damage Through Increased MMP-9 Expression, Decreased Elafin Production and Tissue Resilience.

Berengère Villeret, Brigitte Solhonne, Marjolène Straube +4 more

Individuals with impaired immune responses, such as ventilated and cystic fibrosis patients are often infected with Pseudomonas aeruginosa (P.a) bacteria, and a co-infection with the Influenza virus (IAV) is often present. It has been known for many years that infection with IAV predisposes the host to secondary bacterial infections (such as Streptococcus pneumoniae or Staphylococcus aureus), and there is an abundance of mechanistic studies, including those studying the role of desensitization of TLR signaling, type I IFN- mediated impairment of neutrophil chemokines and antimicrobial production, attenuation of IL1β production etc., showing this. However, little is known about the mechanistic events underlying the potential deleterious synergy between Influenza and P.a co-infections. We demonstrate here in vitro in epithelial cells and in vivo in three independent models (two involving mice given IAV +/- P.a, and one involving mice given IAV +/- IL-1β) that IAV promotes secondary P.a-mediated lung disease or augmented IL-1β-mediated inflammation. We show that IAV-P.a-mediated deleterious responses includes increased matrix metalloprotease (MMP) activity, and MMP-9 in particular, and that the use of the MMP inhibitor improves lung resilience. Furthermore, we show that IAV post-transcriptionally inhibits the antimicrobial/anti-protease molecule elafin/trappin-2, which we have shown previously to be anti-inflammatory and to protect the host against maladaptive neutrophilic inflammation in P.a infections. Our work highlights the capacity of IAV to promote further P.a-mediated lung damage, not necessarily through its interference with host resistance to the bacterium, but by down-regulating tissue resilience to lung inflammation instead. Our study therefore suggests that restoring tissue resilience in clinical settings where IAV/P.a co-exists could prove a fruitful strategy.

Metabolic Syndrome, Clusterin and Elafin in Patients with Psoriasis Vulgaris.

Drahomira Holmannova, Pavel Borsky, Lenka Borska +9 more

Psoriasis is a pathological condition characterized by immune system dysfunction and inflammation. Patients with psoriasis are more likely to develop a wide range of disorders associated with inflammation. Serum levels of various substances and their combinations have been associated with the presence of the disease (psoriasis) and have shown the potential to reflect its activity. The aim of the present study is to contribute to the elucidation of pathophysiological links between psoriasis, its pro-inflammatory comorbidity metabolic syndrome (MetS), and the expression of clusterin and elafin, which are reflected in the pathophysiological "portfolio" of both diseases.

USP18 promotes cell proliferation and suppressed apoptosis in cervical cancer cells via activating AKT signaling pathway.

Wenjing Diao, Qisang Guo, Caiying Zhu +5 more

The deubiquitinating (DUB) enzyme ubiquitin-specific protease 18 (USP18), also known as UBP43, is an ubiquitin-specific protease linked to several human malignancies. However, USP18's underlying function in human cervical cancer remains unclear. In the current study, we aimed to analyse the role of USP18 and its signalling pathways in cervical cancer.

Cervicovaginal natural antimicrobial expression in pregnancy and association with spontaneous preterm birth.

Natasha L Hezelgrave, Paul T Seed, Evonne C Chin-Smith +3 more

There is much interest in the role of innate immune system proteins (antimicrobial peptides) in the inflammatory process associated with spontaneous preterm birth (sPTB). After promising pilot work, we aimed to validate the association between the antimicrobial peptides/proteins elafin and cathelicidin and sPTB. An observational cohort study of 405 women at high-risk, and 214 women at low-risk of sPTB. Protein concentrations of elafin and cathelicidin, and the enzyme human neutrophil elastase (HNE) were measured in over 1,000 cervicovaginal fluid (CVF) samples (10 to 24 weeks' gestation). Adjusted CVF cathelicidin and HNE concentrations (but not elafin) were raised in high-risk women who developed cervical shortening and who delivered prematurely and were predictive of sPTB < 37 weeks, with an area under the curve (AUC) of 0.75 (95% CI 0.68 to 0.81) for cathelicidin concentration at 14 to 15+6 weeks. Elafin concentrations were affected by gestation, body mass index and smoking. CVF elafin in early pregnancy was modestly predictive of sPTB < 34 weeks (AUC 0.63, 0.56-0.70). Alterations in innate immune response proteins in early pregnancy are predictive of sPTB. Further investigation is warranted to understand the drivers for this, and their potential to contribute towards clinically useful prediction techniques.

High circulating elafin levels are associated with Crohn's disease-associated intestinal strictures.

Jiani Wang, Christina Ortiz, Lindsey Fontenot +5 more

Antimicrobial peptide expression is associated with disease activity in inflammatory bowel disease (IBD) patients. IBD patients have abnormal expression of elafin, a human elastase-specific protease inhibitor and antimicrobial peptide. We determined elafin expression in blood, intestine, and mesenteric fat of IBD and non-IBD patients.

In-depth serum proteomics reveals biomarkers of psoriasis severity and response to traditional Chinese medicine.

Meng Xu, Jingwen Deng, Kaikun Xu +24 more

Serum and plasma contain abundant biological information that reflect the body's physiological and pathological conditions and are therefore a valuable sample type for disease biomarkers. However, comprehensive profiling of the serological proteome is challenging due to the wide range of protein concentrations in serum. Methods: To address this challenge, we developed a novel in-depth serum proteomics platform capable of analyzing the serum proteome across ~10 orders or magnitude by combining data obtained from Data Independent Acquisition Mass Spectrometry (DIA-MS) and customizable antibody microarrays. Results: Using psoriasis as a proof-of-concept disease model, we screened 50 serum proteomes from healthy controls and psoriasis patients before and after treatment with traditional Chinese medicine (YinXieLing) on our in-depth serum proteomics platform. We identified 106 differentially-expressed proteins in psoriasis patients involved in psoriasis-relevant biological processes, such as blood coagulation, inflammation, apoptosis and angiogenesis signaling pathways. In addition, unbiased clustering and principle component analysis revealed 58 proteins discriminating healthy volunteers from psoriasis patients and 12 proteins distinguishing responders from non-responders to YinXieLing. To further demonstrate the clinical utility of our platform, we performed correlation analyses between serum proteomes and psoriasis activity and found a positive association between the psoriasis area and severity index (PASI) score with three serum proteins (PI3, CCL22, IL-12B). Conclusion: Taken together, these results demonstrate the clinical utility of our in-depth serum proteomics platform to identify specific diagnostic and predictive biomarkers of psoriasis and other immune-mediated diseases.

ZNF479 downregulates metallothionein-1 expression by regulating ASH2L and DNMT1 in hepatocellular carcinoma.

Yi-Ju Wu, Bor-Sheng Ko, Shu-Man Liang +6 more

Decreased expression of metallothionein-1 (MT-1) is associated with a poor prognosis in hepatocellular carcinoma (HCC). Here, we found that MT-1 expression was suppressed by 14-3-3ε, and MT-1 overexpression abolished 14-3-3ε-induced cell proliferation and tumor growth. We identified that 14-3-3ε induced expression of ZNF479, a novel potential transcriptional regulator by gene expression profiling and ZNF479 contributed to 14-3-3ε-suppressed MT-1 expression. ZNF479 induced the expression of DNMT1, UHRF1, and mixed-lineage leukemia (MLL) complex proteins (ASH2L and Menin), and increased tri-methylated histone H3 (H3K4me3) levels, but suppressed H3K4 (H3K4me2) di-methylation. ZNF479-suppressed MT-1 expression was restored by silencing of ASH2L and DNMT1. Furthermore, ZNF479 expression was higher in HCC tissues than that in the non-cancerous tissues. Expression analyses revealed a positive correlation between the expression of ZNF479 and DNMT1, UHRF1, ASH2L, and Menin, and an inverse correlation with that of ZNF479, ASH2L, Menin, and MT-1 isoforms. Moreover, correlations between the expression of ZNF479 and its downstream factors were more pronounced in HCC patients with hepatitis B. Here, we found that ZNF479 regulates MT-1 expression by modulating ASH2L in HCC. Approaches that target ZNF479/MLL complex/MT-1 or related epigenetic regulatory factors are potential therapeutic strategies for HCC.

SOX2 protein biochemistry in stemness, reprogramming, and cancer: the PI3K/AKT/SOX2 axis and beyond.

Thorsten Schaefer, Claudia Lengerke

Research of the past view years expanded our understanding of the various physiological functions the cell-fate determining transcription factor SOX2 exerts in ontogenesis, reprogramming, and cancer. However, while scientific reports featuring novel and exciting aspects of SOX2-driven biology are published in near weekly routine, investigations in the underlying protein-biochemical processes that transiently tailor SOX2 activity to situational demand are underrepresented and have not yet been comprehensively summarized. Largely unrecognizable to modern array or sequencing-based technology, various protein secondary modifications and concomitant function modulations have been reported for SOX2. The chemical modifications imposed onto SOX2 are inherently heterogeneous, comprising singular or clustered events of phosphorylation, methylation, acetylation, ubiquitination, SUMOylation, PARPylation, and O-glycosylation that reciprocally affect each other and critically impact SOX2 functionality, often in a tissue and species-specific manner. One recurring regulatory principle though is the canonical PI3K/AKT signaling axis to which SOX2 relates in various entangled, albeit not exclusive ways. Here we provide a comprehensive review of the current knowledge on SOX2 protein modifications, their proposed relationship to the PI3K/AKT pathway, and regulatory influence on SOX2 with regards to stemness, reprogramming, and cancer.

[Biology and signaling pathways involved in the oncogenesis of desmoid tumors].

Sébastien Salas, Frédéric Chibon

Desmoid tumors (TDs) are derived from mesenchymal stem cells and their pathogenesis is strongly linked to the Wingless/Wnt cascade where the deregulation of β-catenin plays a major role. A mutation of the CTNNB1 encoding β-catenin is found in the majority of sporadic TD cases and constitutional mutations of APC have been described in heritable forms in patients with familial adenomatous polyposis (FAP). Estrogens could also play a role in pathogenesis and this is the basis for the use of hormone therapy. Other signaling pathways have been involved in the development of TDs such as Notch, Hedgehog, JAK/STAT, PI3 Kinase/AKT and mTOR. Metalloproteases are expressed in TDs and play a role in invasiveness. TGF-ß, as a growth factor, stimulates the transcriptional activity of β-catenin. Future studies will need to focus on better describing and understanding the immune environment of TDs. One of the major difficulties for the experimental study of TDs is the virtual absence of a preclinical model, either in vitro or in vivo. This is partly why the interactions between the different signaling pathways presented here and their consequences for the development of TDs are still poorly understood.

A novel curcumin-loaded composite dressing facilitates wound healing due to its natural antioxidant effect.

Yong Zhao, Chuanyu Dai, Zheng Wang +5 more

To prepare a novel wound dressing to facilitate cutaneous wound healing.

Inhibition of CD133 Overcomes Cisplatin Resistance Through Inhibiting PI3K/AKT/mTOR Signaling Pathway and Autophagy in CD133-Positive Gastric Cancer Cells.

Ruiqi Lu, Gang Zhao, Yulong Yang +3 more

Cisplatin is widely used as the standard gastric cancer treatment, but the relapse and metastasis are common as intrinsic or acquired drug resistance. CD133 has been widely known to be associated with chemoresistance in various cancer cells. In this study, we focused on investigating the function and mechanism of CD133 underlying cisplatin resistance in gastric cancer cell line KATO-III. We detected CD133 expression by using quantitative real-time polymerase chain reaction and Western blot and found that expression of CD133 was upregulated in cisplatin resistance of KATO-III cells (Cis-KATO-III) compared with KATO-III cells, indicating the role of CD133 in regulating cisplatin resistance of KATO-III cells. Then we sorted the Cis-KATO-III cells into CD133-positive (CD133+) pools and measured the proliferation and apoptosis after the cell is transfected with pc-CD133 and sh-CD133 by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay and flow cytometry. The results showed that the inhibition of CD133 inhibited the cell viability and promoted the cell apoptosis after cisplatin treatment. Furthermore, we found that inhibition of CD133 downregulated the expression of PI3K/AKT and promoted the expression of mammalian target of rapamycin, thus inhibited the autophagic activity in the Cis-KATO-III cells after cisplatin treatment. Besides, we also verified the effects of CD133 in vivo. The results indicated that inhibition of CD133 enhanced the Cis-KATO-III cell sensitivity to cisplatin by regulating PI3K/AKT/mTOR signaling pathway. In summary, our data provide new insight that CD133 activates the PI3K/AKT/mTOR signaling transduction pathway, resulting in activation of autophagy and cisplatin resistance of Cis-KATO-III cells. These results may offer a novel therapeutic target in cisplatin-resistant gastric cancer.

Peptidase inhibitor 3 and chemokine ligand 27 may serve as biomarkers for actinic keratoses in organ transplant recipients.

Alexandra Geusau, Stanislava Tzaneva, Peter Petzelbauer +4 more

Molecular profiling of tissue samples in organ transplant recipients (OTRs) may allow early and minimally invasive identification of actinic keratosis (AK). The aim of this study was to compare mRNA expression profiles of 13 genes, as putative genetic biomarkers of AK, before and after treatment using two different field therapies, and to correlate the results with histological and clinical parameters. For this single-centre prospective randomized intra-patient-controlled study, 10 OTRs with AKs were recruited for field therapy with two cycles of methyl-5-aminolevulinate 16% cream-photodynamic therapy (PDT) at one site and imiquimod 5% cream for four weeks at another site. AKs in the PDT area were reduced significantly at one, two, and six months after completion of the treatment (p < 0.001). The effect of imiquimod was weaker but still significant when evaluated during the same intervals (p < 0.001). By comparing the mRNA expression profiles of various genetic markers before, during, and three months after therapy, we observed specific patterns of expression for skin-derived peptidase inhibitor 3 (PI3) and chemokine ligand 27 (CCL27) in all groups, regardless of the treatment modality. Compared to healthy skin, the expression of PI3 was strongly decreased and that of CCL27 increased in AK lesions before therapy. The expression level of both genes showed a significant convergence to values observed in healthy skin in both groups after therapy. The pattern and level of specific gene expression in actinic keratoses could serve as a biomarker.

The blood proteomic signature of early-onset pediatric atopic dermatitis shows systemic inflammation and is distinct from adult long-standing disease.

Patrick M Brunner, Helen He, Ana B Pavel +11 more

Despite increasing evidence that adults with long-standing atopic dermatitis (AD) have systemic inflammation, little is known about systemic inflammation in recent-onset early pediatric AD.