Safety assessment of Paeonia lactiflora root extract for a cosmetic ingredient employing the threshold of toxicological concern (TTC) approach.

Botanical extracts, widely used in cosmetics, pose a challenge to safety assessment due to their complex compositions. The threshold of toxicological concern (TTC) approach, offering a safe exposure level for cosmetic ingredients, proves to be a promising solution for ensuring the safety of cosmetic ingredients with low exposure level. We assessed the safety of Paeonia lactiflora root extract (PLR), commonly used in skin conditioning products, with the TTC. We identified 50 constituents of PLR extract from the USDA database and literature exploration. Concentration of each constituent of PLR extract was determined with the information from USDA references, literature, and experimental analysis. The genotoxicity of PLR and its constituents was assessed in vitro and in silico respectively. Cramer class of the constituents of the PLR extract was determined with Toxtree 3.1 extended decision tree using ChemTunes®. Systemic exposure of each constituent from leave-on type cosmetic products containing PLR at a 1% concentration was estimated and compared with respective TTC threshold. Two constituents exceeding TTC threshold were further analyzed for dermal absorption using in silico tools, which confirmed the safety of PLR extract in cosmetics. Collectively, we demonstrated that the TTC is a useful tool for assessing botanical extract safety in cosmetics.

Analysis of particulate matter-induced alteration of genes and related signaling pathways in the respiratory system.

Airborne particulate matter (PM) is a global environmental risk factor threatening human health and is a major cause of cardiovascular and respiratory disease-associated death. Current studies on PM exposure have been limited to large-scale cohort and epidemiological investigations, emphasizing the need for detailed individual-level studies to uncover specific differentially expressed genes and their associated signaling mechanisms. Herein, we revealed that PM exposure significantly upregulated inflammatory and immune responses, such as cytokine-mediated signaling pathways, complement system, and the activation and migration of immune cells in gene set enrichment analysis of our RNA sequencing (RNAseq) data. Remarkably, we discovered that the broad gene expression and signaling pathways mediated by macrophages were predominantly expressed in the respiratory system following PM exposure. Consistent with these observations, individual PMs, classified by aerodynamic size and origin, significantly promoted macrophage recruitment to the lungs in the mouse lung inflammation model. Additionally, we confirmed that RNAseq observations from the respiratory system were reproduced in murine bone marrow-derived macrophages and the alveolar macrophage cell line MH-S after individual PM exposure. Our findings demonstrated that PM exposure augmented broad inflammatory and immune responses in the respiratory system and suggested the reinforcement of global strategies for reducing particulate air pollution to prevent respiratory diseases and their exacerbation.

RAB25 coordinates filaggrin-containing keratohyalin granule maturation and affects atopic dermatitis severity.

BACKGROUND: Keratohyalin granules (KHGs) supply the critical epidermal protein constituents such as filaggrin for maintaining skin barrier function during epidermal differentiation; however, their regulating mechanism remains largely unelucidated. METHODS: To investigate the role of Ras-related protein Rab-25 (RAB25) expression in skin disease, we utilized skin specimens of patients with moderate-to-severe atopic dermatitis (AD) and healthy controls. To investigate the susceptibility of Rab25 knockout mice to AD, we established an oxazolone-induced AD model. RESULTS: We investigated the role of RAB25 in KHG maturation and AD. RAB25-deficient mice showed a disrupted stratum corneum along with skin barrier dysfunction, decreased KHG production, and abnormal KHG processing. Consistently, in the human keratinocyte cell line HaCaT, RAB25 co-expressed with filaggrin-containing KHG and RAB25 silencing impaired KHG formation, which was attributable to abnormal actin dynamics. Most importantly, RAB25 expression was severely downregulated in the skin lesions of patients with AD, which was strongly correlated with disease severity scores. CONCLUSIONS: RAB25 coordinates KHG homeostasis by regulating actin dynamics and is critical for epidermal differentiation and the pathophysiology of AD.

Safety assessment of Cnidium officinale rhizome extract in cosmetics using the Threshold of Toxicological Concern (TTC) approach.

Cosmetics often contain botanical extracts, which present a challenge for safety assessors due to their complex composition. The threshold of toxicological concern (TTC) approach is considered as a solution for the safety assessment of botanical extracts in cosmetics as part of next-generation risk assessment. In this study, we applied the TTC approach to evaluate the safety of Cnidium officinale rhizome extract (CORE), a widely used botanical extract in skin conditioning products. We identified 32 components of CORE through the USDA database and literature and determined the content of each component through literature or actual analysis where an authentic standard was available. Macro- and micronutrients were also analyzed to exclude them as safe components. The Toxtree® software was used to identify the Cramer class of remaining components. We estimated the systemic exposure of each component from leave-on type cosmetic products containing CORE at a 1% concentration and compared the results to TTC thresholds. All components of CORE had a systemic exposure below the TTC threshold. While batch variations and presence of unknown chemicals in individual CORE materials should be considered, this study demonstrated that the TTC approach can be a useful tool for the safety assessment of botanical extracts in cosmetics.

Tiered human health risk assessment of antibacterial quaternary ammonium compounds (QACs) in dishwashing detergents.

Quaternary ammonium compounds (QACs) are widely used in consumer products because of their unique antibacterial properties, and dishwashing detergents are a major source of exposure through oral, inhalation, and dermal routes. The three classes of QACs, including benzalkonium chloride (BAC), n-alkyldimethylethylbenzylammonium chloride (ADEBAC), and di-n-alkyldimethylammonium chloride (DDAC), in spray and non-spray types of dishwashing detergents were quantified by high-performance liquid chromatography-mass spectrometry. A tiered risk assessment approach was also considered. In the Tier 1 assessment, the mean and worst-case exposure were estimated to screen for rough exposure and risk levels. In the Tier 2 assessment, mean and upper-tail exposure levels were calculated based on the exposure parameters of Korean consumers using Monte Carlo simulation. QACs had a low frequency of detection of up to 20% in dishwashing detergents, and the contents of detected QACs varied depending on the individual samples. Based on the results of the Tier 1 assessment, BACs and DDACs posed potential health risks via inhalation and dermal routes. Tier 2 assessment suggested that the current level of oral and dermal exposure of Korean consumers to QACs in dishwashing detergents is unlikely to pose a health risk, even for upper-tail exposure groups. However, the present results suggest that spray-type DDACs may pose a health risk in the upper-tail inhalation exposure group, and further investigation is required to clarify this risk.

Improved Wound Healing and Skin Regeneration Ability of 3,2'-Dihydroxyflavone-Treated Mesenchymal Stem Cell-Derived Extracellular Vesicles.

Flavonoids enhance the self-renewal and differentiation potential of mesenchymal stem cells (MSCs) and have therapeutic activities, including regenerative, anti-oxidative, and anti-inflammatory effects. Recent studies have revealed that MSC-derived extracellular vesicles (MSC-EVs) have therapeutic effects on tissue regeneration and inflammation. To facilitate further research on the therapeutic potential of MSC-EVs derived from flavonoid-treated MSCs, we surveyed the production of EVs and their therapeutic applications in wound regeneration. MSCs treated with flavonoids enhanced EV production twofold compared with naïve MSCs. EVs produced by MSCs treated with flavonoids (Fla-EVs) displayed significant anti-inflammatory and wound-healing effects in vitro. The wound-healing capacity of EVs was mediated by the upregulation of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling. Interestingly, the protein level of p-ERK under inhibition of MEK signals was maintained in Fla-EV-treated fibroblasts, suggesting that Fla-EVs have a higher therapeutic potential than naïve MSC-EVs (Cont-EVs) in wound healing. Moreover, the in vivo wound closure effect of the Fla-EVs showed significant improvement compared with that of the flavonoid-only treatment group and the Cont-EVs. This study provides a strategy for the efficient production of EVs with superior therapeutic potential using flavonoids.

The Orphan GPR50 Receptor Regulates the Aggressiveness of Breast Cancer Stem-like Cells via Targeting the NF-kB Signaling Pathway.

The expression of GPR50 in CSLC and several breast cancer cell lines was assessed by RT-PCR and online platform (UALCAN, GEPIA, and R2 gene analysis). The role of GPR50 in driving CSLC, sphere formation, cell proliferation, and migration was performed using shGPR50 gene knockdown, and the role of GPR50-regulated signaling pathways was examined by Western blotting and Luciferase Assay. Herein, we confirmed that the expression of G protein-coupled receptor 50 (GPR50) in cancer stem-like cells (CSLC) is higher than that in other cancer cells. We examined that the knockdown of GPR50 in CSLC led to decreased cancer properties, such as sphere formation, cell proliferation, migration, and stemness. GPR50 silencing downregulates NF-kB signaling, which is involved in sphere formation and aggressiveness of CSLC. In addition, we demonstrated that GPR50 also regulates ADAM-17 activity by activating NOTCH signaling pathways through the AKT/SP1 axis in CSLC. Overall, we demonstrated a novel GPR50-mediated regulation of the NF-κB-Notch signaling pathway, which can provide insights into CSLC progression and prognosis, and NF-κB-NOTCH-based CSLC treatment strategies.

WFDC2 Promotes Spasmolytic Polypeptide-Expressing Metaplasia Through the Up-Regulation of IL33 in Response to Injury.

BACKGROUND & AIMS: WAP 4-disulfide core domain protein 2 (WFDC2), also known as human epididymis protein 4, is a small secretory protein that is highly expressed in fibrosis and human cancers, particularly in the ovaries, lungs, and stomach. However, the role of WFDC2 in carcinogenesis is not fully understood. The present study aimed to investigate the role of WFDC2 in gastric carcinogenesis with the use of preneoplastic metaplasia models. METHODS: Three spasmolytic polypeptide-expressing metaplasia (SPEM) models were established in both wild-type and Wfdc2-knockout mice with DMP-777, L635, and high-dose tamoxifen, respectively. To reveal the functional role of WFDC2, we performed transcriptomic analysis with DMP-777-treated gastric corpus specimens. RESULTS: Wfdc2-knockout mice exhibited remarkable resistance against oxyntic atrophy, SPEM emergence, and accumulation of M2-type macrophages in all 3 SPEM models. Transcriptomic analysis revealed that Wfdc2-knockout prevented the up-regulation of interleukin-33 (IL33) expression in the injured mucosal region of SPEM models. Notably, supplementation of recombinant WFDC2 induced IL33 production and M2 macrophage polarization, and ultimately promoted SPEM development. Moreover, long-term treatment with recombinant WFDC2 was able to induce SPEM development. CONCLUSIONS: WFDC2 expressed in response to gastric injury promotes SPEM through the up-regulation of IL33 expression. These findings provide novel insights into the role of WFDC2 in gastric carcinogenesis.

Transcriptome-metabolome-wide association study (TMWAS) in rats revealed a potential carcinogenic effect of DEHP in thyroid associated with eicosanoids.

The incidence of thyroid cancer (TC) has increased considerably in the last few decades. Environmental factors, including plasticizers, are recognized as potential risks leading to thyroid cancer in humans. In this study, we used a transcriptome-metabolome-wide association study to find the unidentified carcinogenic mechanism of di-2-ethylhexyl phthalate (DEHP) in thyroid and biomarkers for non-invasive diagnosis. Rats were treated with different doses of DEHP (0, 0.3, 3, 30, 150 mg DEHP/kg bw/day) for 13 weeks. Then, the thyroids were processed for Ki67 staining and RNA-seq. Also, 17-h urine samples were collected for high-resolution metabolomics analysis. After a high dose of DEHP exposure, the terminal body weights and the thyroid and parathyroid glands weights were not altered. However, the liver weights and numbers of Ki67-positive cells were increased. Further, multivariate statistical analysis revealed that metabolic shifts were considerably altered above 30 mg DEHP/kg bw/day. In RNA-seq analysis, some cancer-related genes were altered, including 18 upregulated and 9 downregulated transcripts. These cancer transcripts and whole metabolome data were integrated to uncover thyroid cancer-related metabolic pathways, which revealed that cancer-related transcripts had a network structure linked to eicosanoids such as leukotriene D4 and prostaglandin. In brief, our study demonstrated that DEHP can induce thyroid hyperplasia through the eicosanoid-associated pathway, providing further insight into the mechanism of DEHP-associated thyroid cancer.

Deoxyvasicinone with Anti-Melanogenic Activity from Marine-Derived Streptomyces sp. CNQ-617.

The tricyclic quinazoline alkaloid deoxyvasicinone (DOV, 1) was isolated from a marine-derived Streptomyces sp. CNQ-617, and its anti-melanogenic effects were investigated. Deoxyvasicinone was shown to decrease the melanin content of B16F10 and MNT-1 cells that have been stimulated by α-melanocyte-stimulating hormone (α-MSH). In addition, microscopic images of the cells showed that deoxyvasicinone attenuated melanocyte activation. Although, deoxyvasicinone did not directly inhibit tyrosinase (TYR) enzymatic activity, real-time PCR showed that it inhibited the mRNA expression of TYR, tyrosinase-related protein 1 (TRP-1), and tyrosinase-related protein 2 (TRP-2). In the artificial 3D pigmented skin model MelanodermTM, deoxyvasicinone brightened the skin significantly, as confirmed by histological examination. In conclusion, this study demonstrated that the marine microbial natural product deoxyvascinone has an anti-melanogenic effect through downregulation of melanogenic enzymes.

Comparison of surgical outcomes between 3-dimensional and 2-dimensional laparoscopy of ovarian cyst (LOOC): a randomised controlled trial.

The purpose of this study was to compare the surgical outcomes and efficacy of 3-dimensional (3D) versus 2-dimensional (2D) imaging systems for the treatment of ovarian cyst. A total of 46 patients undergoing a laparoscopic ovarian cystectomy were randomly assigned to either the 3D or 2D laparoscopy group. The primary outcome measure was the operative blood loss. The secondary outcome measure was visually induced motion sickness (VIMS), task efficacy during laparoscopy, and postoperative complication. There were no differences in baseline demographics between the two groups. The operative blood loss was significantly smaller in the 3D groups (28.7 ± 11.6 mL) than in the 2D groups (46.5 ± 24.4 mL) (p = .012). VIMS score was significantly higher in the 3D groups than the 2D groups (p < .001). 3D laparoscopy was superior to 2D in terms of the task efficacy of ovarian cyst enucleation (p < .001), adhesiolysis or dissection (p < .001), and ovarian suturing (p = .008). None of the patients in both groups developed operative complications. In conclusion, a 3D imaging system showed a more favourable surgical outcome and improved task efficacy than 2D in laparoscopic ovarian cystectomy. However, 3D laparoscopy tends to cause more frequent VIMS in surgeons.Impact statementWhat is already known on this subject? Several studies examining the possible benefits and drawbacks of a 3D imaging system versus 2D in laparoscopic surgery have brought about conflicting results. However, there have been few studies comparing the surgical outcomes of 3D and 2D laparoscopic ovarian cystectomy.What do the results of this study add? 3D laparoscopy showed favourable surgical outcomes and improved task efficacy than 2D laparoscopy in ovarian cystectomy.What are the implications of these findings for clinical practice and/or further research? More complex procedures, such as suturing and adhesiolysis, might be easier to perform with 3D laparoscopy than with 2D laparoscopy. Therefore, further large studies of 3D gynaecologic laparoscopy with different complexities and for surgeons with different surgical skills are needed.

Titanium dioxide nanoparticles enhance thrombosis through triggering the phosphatidylserine exposure and procoagulant activation of red blood cells.

BACKGROUND: Expanding biomedical application of anatase titanium dioxide (TiO2) nanoparticles (NPs) is raising the public concern on its potential health hazards. Here, we demonstrated that TiO2 NPs can increase phosphatidylserine (PS) exposure and procoagulant activity of red blood cells (RBCs), which may contribute to thrombosis. RESULTS: We conducted in vitro studies using RBCs freshly isolated from healthy male volunteers. TiO2 NPs exposure (≦ 25 µg/mL) induced PS exposure and microvesicles (MV) generation accompanied by morphological changes of RBCs. While ROS generation was not observed following the exposure to TiO2 NPs, intracellular calcium increased and caspase-3 was activated, which up-regulated scramblase activity, leading to PS exposure. RBCs exposed to TiO2 NPs could increase procoagulant activity as measured by accelerated thrombin generation, and enhancement of RBC-endothelial cells adhesion and RBC-RBC aggregation. Confirming the procoagulant activation of RBC in vitro, exposure to TiO2 NPs (2 mg/kg intravenously injection) in rats increased thrombus formation in the venous thrombosis model. CONCLUSION: Collectively, these results suggest that anatase TiO2 NPs may harbor prothrombotic risks by promoting the procoagulant activity of RBCs, which needs attention for its biomedical application.

In silico prediction of the full United Nations Globally Harmonized System eye irritation categories of liquid chemicals by IATA-like bottom-up approach of random forest method.

As an alternative to in vivo Draize rabbit eye irritation test, this study aimed to construct an in silico model to predict the complete United Nations (UN) Globally Harmonized System (GHS) for classification and labeling of chemicals for eye irritation category [eye damage (Category 1), irritating to eye (Category 2) and nonirritating (No category)] of liquid chemicals with Integrated approaches to testing and assessment (IATA)-like two-stage random forest approach. Liquid chemicals (n = 219) with 34 physicochemical descriptors and quality in vivo data were collected with no missing values. Seven machine learning algorithms (Naive Bayes, Logistic Regression, First Large Margin, Neural Net, Random Forest (RF), Gradient Boosted Tree, and Support Vector Machine) were examined for the ternary categorization of eye irritation potential at a single run through 10-fold cross-validation. RF, which performed best, was further improved by applying the 'Bottom-up approach' concept of IATA, namely, separating No category first, and discriminating Category 1 from 2, thereafter. The best performing training dataset achieved an overall accuracy of 73% and the correct prediction for Category 1, 2, and No category was 80%, 50%, and 77%, respectively for the test dataset. This prediction model was further validated with an external dataset of 28 chemicals, for which an overall accuracy of 71% was achieved.

Skin Epidermis and Barrier Function.

The skin epidermis is the outermost epithelial tissue that protects the body from the external environment [...].

Anti-Pigmentary Natural Compounds and Their Mode of Action.

Hyper-activated melanocytes are the major cause of skin hyper-pigmentary disorders, such as freckles and melasma. Increasing efforts have been made to search for materials with depigmenting activity to develop functional cosmetics. As a result, numerous materials have been reported to have depigmenting activity but some of them are known to cause unwanted side effects. Consequently, anti-pigmentary natural compounds without concern of toxicity are in great demand. Virtually all sorts of natural sources have been investigated to find anti-pigmentary natural compounds. This review summarizes recently reported anti-pigmentary natural compounds and their mode of action from the ocean, plants, and bacteria.

A Commonly Used Biocide 2-N-octyl-4-isothiazolin-3-oneInduces Blood-Brain Barrier Dysfunction via Cellular Thiol Modification and Mitochondrial Damage.

Isothiazolinone (IT) biocides are potent antibacterial substances commonly used as preservatives or disinfectants, and 2-n-Octyl-4-isothiazolin-3-one (OIT; octhilinone) is a common IT biocide that is present in leather products, glue, paints, and cleaning products. Although humans are exposed to OIT through personal and industrial use, the potentially deleterious effects of OIT on human health are still unknown. To investigate the effects of OIT on the vascular system, which is continuously exposed to xenobiotics through systemic circulation, we treated brain endothelial cells with OIT. OIT treatment significantly activated caspase-3-mediated apoptosis and reduced the bioenergetic function of mitochondria in a bEnd.3 cell-based in vitro blood-brain barrier (BBB) model. Interestingly, OIT significantly altered the thiol redox status, as evidenced by reduced glutathione levels and protein S-nitrosylation. The endothelial barrier function of bEnd.3 cells was significantly impaired by OIT treatment. OIT affected mitochondrial dynamics through mitophagy and altered mitochondrial morphology in bEnd.3 cells. N-acetyl cysteine significantly reversed the effects of OIT on the metabolic capacity and endothelial function of bEnd.3 cells. Taken together, we demonstrated that the alteration of the thiol redox status and mitochondrial damage contributed to OIT-induced BBB dysfunction, and we hope that our findings will improve our understanding of the potential hazardous health effects of IT biocides.

Ex Vivo Live Full-Thickness Porcine Skin Model as a Versatile In Vitro Testing Method for Skin Barrier Research.

Since the European Union (EU) announced their animal testing ban in 2013, all animal experiments related to cosmetics have been prohibited, creating a demand for alternatives to animal experiments for skin studies. Here, we investigated whether an ex vivo live porcine skin model can be employed to study the safety and skin barrier-improving effects of hydroxyacids widely used in cosmetics for keratolytic peels. Glycolic acid (1-10%), salicylic acid (0.2-2%), and lactobionic acid (1.2-12%) were used as representative substances for α-hydroxyacid (AHA), ß-hydroxyacid (BHA), and polyhydroxyacid (PHA), respectively. When hydroxyacids were applied at high concentrations on the porcine skin every other day for 6 days, tissue viability was reduced to 50-80%, suggesting that the toxicity of cosmetic ingredients can be evaluated with this model. Based on tissue viability, the treatment scheme was changed to a single exposure for 20 min. The protective effects of a single exposure of hydroxyacids on skin barrier function were evaluated by examining rhodamine permeability and epidermal structural components of barrier function using immunohistochemistry (IHC) and immunofluorescence (IF) staining. Lactobionic acid (PHAs) improved skin barrier function most compared to other AHAs and BHAs. Most importantly, trans-epidermal water loss (TEWL), an important functional marker of skin barrier function, could be measured with this model, which confirmed the significant skin barrier-protective effects of PHAs. Collectively, we demonstrated that the ex vivo live full-thickness porcine skin model can be an excellent alternative to animal experiments for skin studies on the safety and efficacy of cosmetic ingredients.

The Protective Effects of EMF-LTE against DNA Double-Strand Break Damage In Vitro and In Vivo.

With the rapid growth of the wireless communication industry, humans are extensively exposed to electromagnetic fields (EMF) comprised of radiofrequency (RF). The skin is considered the primary target of EMFs given its outermost location. Recent evidence suggests that extremely low frequency (ELF)-EMF can improve the efficacy of DNA repair in human cell-lines. However, the effects of EMF-RF on DNA damage remain unknown. Here, we investigated the impact of EMF-long term evolution (LTE, 1.762 GHz, 8 W/kg) irradiation on DNA double-strand break (DSB) using the murine melanoma cell line B16 and the human keratinocyte cell line HaCaT. EMF-LTE exposure alone did not affect cell viability or induce apoptosis or necrosis. In addition, DNA DSB damage, as determined by the neutral comet assay, was not induced by EMF-LTE irradiation. Of note, EMF-LTE exposure can attenuate the DNA DSB damage induced by physical and chemical DNA damaging agents (such as ionizing radiation (IR, 10 Gy) in HaCaT and B16 cells and bleomycin (BLM, 3 µM) in HaCaT cells and a human melanoma cell line MNT-1), suggesting that EMF-LTE promotes the repair of DNA DSB damage. The protective effect of EMF-LTE against DNA damage was further confirmed by attenuation of the DNA damage marker γ-H2AX after exposure to EMF-LTE in HaCaT and B16 cells. Most importantly, irradiation of EMF-LTE (1.76 GHz, 6 W/kg, 8 h/day) on mice in vivo for 4 weeks reduced the γ-H2AX level in the skin tissue, further supporting the protective effects of EMF-LTE against DNA DSB damage. Furthermore, p53, the master tumor-suppressor gene, was commonly upregulated by EMF-LTE irradiation in B16 and HaCaT cells. This finding suggests that p53 plays a role in the protective effect of EMF-LTE against DNA DSBs. Collectively, these results demonstrated that EMF-LTE might have a protective effect against DNA DSB damage in the skin, although further studies are necessary to understand its impact on human health.

Arsenic induces platelet shape change through altering focal adhesion kinase-mediated actin dynamics, contributing to increased platelet reactivity.

Arsenic, an environmental contaminant in drinking water worldwide is well-established to increase cardiovascular diseases (CVDs) in humans. Of these, thrombotic events represent a major adverse effect associated with arsenic exposure, for which an abundance of epidemiological evidence exists. Platelet aggregation constitutes a pivotal step in thrombosis but arsenic alone doesn't induce aggregation and the mechanism underlying arsenic-induced thrombosis still remains unclear. Here we demonstrated that arsenic induces morphological changes of platelets, i.e., contraction and pseudopod projection, the primal events of platelet activation, which can increase platelet reactivity. Arsenite induced prominent platelet shape changes in a dose-dependent manner in freshly isolated human platelets. Of note, arsenite suppressed focal adhesion kinase (FAK) activity, which in turn activated RhoA, leading to altered actin assembly through LIMK activation, and subsequent cofilin inactivation. Arsenic-induced platelet shape change appeared to increase the sensitivity to thrombin and ADP-induced aggregation. Supporting this, latrunculin A, an inhibitor of actin-dynamics abolished it. Taken together, we demonstrated that arsenic induces cytoskeletal changes and shape changes of platelets through FAK-mediated alteration of actin dynamics, which renders platelets reactive to activating stimuli, ultimately contributing to increased thrombosis.

Loss of Rab25 promotes the development of skin squamous cell carcinoma through the dysregulation of integrin trafficking.

Rab25 can function as both a tumor suppressor and a tumor promoter across different tissues. This study sought to clarify the role of Rab25 as a tumor suppressor in skin squamous cell carcinoma (SCC). Rab25 loss was closely associated with neoplastic transition in both humans and mice. Rab25 loss was well correlated with increased cell proliferation and poor differentiation in human SCC. While Rab25 knockout (KO) in mice did not induce spontaneous tumor formation, it did significantly accelerate tumor generation and promote malignant transformation in a mouse two-stage skin carcinogenesis model. Xenografting of a Rab25-deficient human keratinocyte cell line, HaCaT, also elicited neoplastic transformation. Notably, Rab25 deficiency led to dysregulation of integrins ß1, ß4, and α6, which matched well with increased epidermal proliferation and impaired desmosome-tight junction formation. Rab25 deficiency induced impairment of integrin recycling, leading to the improper expression of integrins. In line with this, significant attenuation of integrin ß1, ß4, and α6 expression was identified in human SCCs where Rab25 was deficient. Collectively, these results suggest that loss of Rab25 promotes the development and neoplastic transition of SCC through dysregulation of integrin trafficking. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.