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Hidradenitis suppurativa (HS) is a chronic, inflammatory skin condition that poses a significant diagnostic and therapeutic challenge for clinicians, as the underlying etiology and pathogenesis remains unclear. The host of genetic mutations and immune dysfunction has been identified to be involved in the pathogenesis of HS during recent years. These genetic defects, including monogenetic mutations altering subunits of γ-secretase, a protease that functions through Notch signaling to maintain skin appendages, promote epithelial stability, suppress/terminate innate immune responses (ie, Toll-receptors), further have the propensity to induce aberrant cytokine responses that create to a proinflammatory environment, consequently induce hyperkeratosis and promote expression of pro-inflammatory, locally destructive matrix metalloproteinases. Cytokine-driven inflammation propagates the disease state of HS and contributes to the formation of painful subcutaneous nodules, abscesses, and eventually, fistulas and draining sinus tracts. A closer look at genetic mutations linked to the disease may explain the immune perturbations seen in HS. An understanding of the immune cells and inflammatory markers expressed in affected individuals provides insight into disease pathogenesis and can help identify therapeutic targets.

Ultraviolet (UV) B irradiation of the skin induces acute inflammation, as characterized by erythema, edema, and immunosuppression, and is subsequently linked to the progression of skin cancer. Toll-like receptor 4 (TLR4), a component of innate immunity, has been shown to play an important role in cancer. To elucidate the role of TLR4 in UVB-induced tumor development, TLR4-proficient (C3H/HeN) and TLR4-deficient (C3H/HeJ) mice were exposed to multiple doses of UVB radiation (200 mJ/cm2 ) for 40 weeks. Photocarcinogenesis was retarded in terms of tumor incidence, and tumor latency, in mice deficient in TLR4 compared with TLR4-proficient mice, whereas significantly greater numbers of tumors occurred in TLR4-proficient mice. There was significant upregulation of inflammatory markers like COX-2, PGE2 , S100A8, and S100A9 in the skin of TLR4-proficient mice than the skin of TLR4-deficient mice. Furthermore, we found that TLR4-proficient mice had a significantly higher number of Gr1+CD11b+ myeloid cells CD4+CD25+ regulatory T-cells than TLR4-deficient mice. Furthermore, the levels of interferon (IFN)-γ cytokine was increased and the levels of interleukin (IL)-4, IL-10, and IL-17 cytokines were decreased in serum, skin, and tumor lysates of TLR4-deficient mice in comparison with samples from TLR4-proficient mice. Together, our data indicate that TLR4-mediated inflammation may cause suppression of antitumor responses and trigger the development of UVB-induced skin cancers. Thus, strategies to inhibit TLR4-mediated immune suppression may allow us to develop preventive and therapeutic approaches for the management of UVB-induced cutaneous tumors.

Some chemicals act as human carcinogens in various organ systems including the skin. Mice have been an ideal model to study a wide variety of chemical carcinogens because the pathogenesis in that species often mirrors that in humans. However, different mouse strains vary in their susceptibility to these agents. Thus, reliance on a single strain may lead to inaccurate findings. 2-Ethylhexyl acrylate (2-EHA) is an acrylate used as a co-monomer in the production of polymer resins for adhesives, latex paints, cross-linking agents, finishes for textiles and leather, and paper coatings. Monomer exposure may occur in occupational settings where it is produced or used; the only exposure that may occur to consumers or construction personnel is trace amounts in the final polymer product. There are no reports of cancer in humans caused by exposure to 2-EHA. However, 2-EHA has been reported to cause cancer in one strain of mice. This is an important issue since recommendations about its safety in humans depend, in part, on information derived from animal studies. We reviewed the literature on the preclinical effects of acrylates on skin carcinogenesis in C3H/HeJ mice, which can be criticized because of peculiarities in the immunological composition of that strain, the lack of rigorous histopathologic characterization of tumors that developed, the high doses of 2-EHA that were used for evaluation, and the lack of reproducibility in a second strain of mice. The C3H/HeJ mouse model is not ideal as it has a mutation in Toll-like receptor 4 (TLR4) that impairs its innate and adaptive immune responses. Inconsistencies in the histological evaluation of tumors induced in C3H/HeJ mice provide further evidence that the tumorigenic effect of 2-EHA was strain specific, a result of chronic inflammation during the promotion stage and/or a skewed immune response caused by the TLR4 mutation. In conclusion, 2-EHA has not convincingly been demonstrated to have skin carcinogenic activity to date. More relevant mouse models that mimic human squamous cell carcinoma, basal cell carcinoma, and melanoma with amounts that do not exceed a maximum tolerated dose are needed to assess the carcinogenic effects of 2-EHA.

Type I interferons (IFNs) are important enhancers of immune responses which are downregulated in human cancers, including skin cancer. Solar ultraviolet (UV) B radiation is a proven environmental carcinogen, and its exposure contributes to the high prevalence of skin cancer. The carcinogenic effects of UV light can be attributed to the formation of cyclobutane pyrimidine dimers (CPD) and errors in the repair and replication of DNA. Treatment with a single dose of UVB (100 mJ/cm2) upregulated IFNα and IFNβ in the skin of C57BL/6 mice. IFNα and IFNβ were predominantly produced by CD11b+ cells. In mice lacking the type I IFN receptor 1 (IFNAR1), the repair of CPD following cutaneous exposure to a single dose of UVB (100 mJ/cm2) was decreased. UVB induced the expression of the DNA repair gene xeroderma pigmentosum A (XPA) in wild-type (WT) mice. In contrast, such treatment in IFNAR1 (IFNAR1-/-) mice downregulated XPA. A local UVB regimen consisting of UVB radiation (150 mJ/cm2) for 4 days followed by sensitization with hapten 2,4, dinitrofluorobenzene (DNFB) resulted in significant suppression of immune responses in both WT and IFNAR1-/- mice. However, there were significantly higher CD4+CD25+Foxp3+ regulatory T-cells in the draining lymph nodes of IFNAR1-/- mice in comparison to WT mice. Overall, our studies reveal a previously unknown action of type I IFNs in the repair of photodamage and the prevention of UVB-induced immune suppression.

Gynecological cancers are the most commonly diagnosed malignancies in females worldwide. Despite the advancement of diagnostic tools as well as the availability of various therapeutic interventions, the incidence and mortality of female-specific cancers is still a life-threatening issue, prevailing as one of the major health problems worldwide. Lately, alternative medicines have garnered immense attention as a therapeutic intervention against various types of cancers, seemingly because of their safety profiles and enhanced effectiveness. Isothiocyanates (ITCs), specifically sulforaphane, benzyl isothiocyanate, and phenethyl isothiocyanate, have shown an intriguing potential to actively contribute to cancer cell growth inhibition, apoptosis induction, epigenetic alterations, and modulation of autophagy and cancer stem cells in female-specific cancers. Additionally, it has been shown that ITCs plausibly enhance the chemo-sensitization of many chemotherapeutic drugs. To this end, evidence has shown enhanced efficacy in combinatorial regimens with conventional chemotherapeutic drugs and/or other phytochemicals. Reckoning with these, herein, we discuss the advances in the knowledge regarding the aspects highlighting the molecular intricacies of ITCs in female-specific cancers. In addition, we have also argued regarding the potential of ITCs either as solitary treatment or in a combinatorial therapeutic regimen for the prevention and/or treatment of female-specific cancers. Hopefully, this review will open new horizons for consideration of ITCs in therapeutic interventions that would undoubtedly improve the prognosis of the female-specific cancer clientele. Considering all these, it is reasonable to state that a better understanding of these molecular intricacies will plausibly provide a facile opportunity for treating these female-specific cancers.

Major epigenetic alterations, such as chromatin modifications, DNA methylation, and miRNA regulation, have gained greater attention and play significant roles in oncogenesis, representing a new paradigm in our understanding of cancer susceptibility. These epigenetic changes, particularly aberrant promoter hypermethylation, abnormal histone acetylation, and miRNA dysregulation, represent a set of epigenetic patterns that contribute to inappropriate gene silencing at every stage of cancer progression. Notably, the cancer epigenome possesses various HDACs and DNMTs, which participate in the histone modifications and DNA methylation. As a result, there is an unmet need for developing the epigenetic inhibitors against HDACs and DNMTs for cancer therapy. To date, several epigenetically active synthetic inhibitors of DNA methyltransferases and histone deacetylases have been developed. However, a growing body of research reports that most of these synthetic inhibitors have significant side effects and a narrow window of specificity for cancer cells. Targeting tumor epigenetics with phytocompounds that have the capacity to modulate abnormal DNA methylation, histone acetylation, and miRNAs expression is one of the evolving strategies for cancer prevention. Encouragingly, there are many bioactive phytochemicals, including organo-sulfur compounds that have been shown to alter the expression of key tumor suppressor genes, oncogenes, and oncogenic miRNAs through modulation of DNA methylation and histones in cancer. In addition to vitamins and microelements, dietary phytochemicals such as sulforaphane, PEITC, BITC, DADS, and allicin are among a growing list of naturally occurring anticancer agents that have been studied as an alternative strategy for cancer treatment and prevention. Moreover, these bioactive organo-sulfur compounds, either alone or in combination with other standard cancer drugs or phytochemicals, showed promising results against many cancers. Here, we particularly summarize and focus on the impact of specific organo-sulfur compounds on DNA methylation and histone modifications through targeting the expression of different DNMTs and HDACs that are of particular interest in cancer therapy and prevention.

Abstract: Cervical cancer is the fourth leading cause of cancer death among women worldwide. Due to cervical cancer's high incidence and mortality, there is an unmet demand for effective diagnostic, therapeutic, and preventive agents. At present, the preferred treatment strategies for advanced metastatic cervical cancer include surgery, radiotherapy, and chemotherapy. However, cervical cancer is gradually developing resistance to chemotherapy, thereby reducing its efficacy. Over the last several decades, phytochemicals, a general term for compounds produced from plants, have gained attention for their role in preventing cervical cancer. This role in cervical cancer prevention has garnered attention on the medicinal properties of fruits and vegetables. Phytochemicals are currently being evaluated for their ability to block proteins involved in carcinogenesis and chemoresistance against cervical cancer. Chemoresistance to cancer drugs like cisplatin, doxorubicin, and 5-fluorouracil has become a significant limitation of drug-based chemotherapy. However, the combination of cisplatin with other phytochemicals has been identified as a promising alternative to subjugate cisplatin resistance. Phytochemicals are promising chemo-preventive and chemotherapeutic agents as they possess antioxidant, anti-inflammatory, and anti-proliferative potential against many cancers, including cervical cancer. Furthermore, the ability of the phytochemicals to modulate cellular signaling pathways through up and down regulation of various proteins has been claimed for their therapeutic potential. Phytochemicals also display a wide range of biological functions, including cell cycle arrest, apoptosis induction, inhibition of invasion, and migration in cervical cancer cells. Numerous studies have revealed the critical role of different signaling proteins and their signaling pathways in the pathogenesis of cervical cancer. Here, we review the ability of several dietary phytochemicals to alter carcinogenesis by modulating various molecular targets.

The majority of melanomas carry an oncogenic BRAF mutation (BRAF(V600E)), which results in constitutive kinase activity driving melanoma proliferation. While inhibitors of BRAF(V600E) (BRAFi) effectively lead to rapid tumor shrinkage, most patients treated with BRAFi develop acquired resistance. Identification of factors as regulators of melanoma growth and as potential sources of resistance is thus crucial for the design of improved therapies to treat advanced melanoma with more durable responses. Here, we show that KH-type splicing regulatory protein (KSRP) is critical for proliferation of melanoma cells without and with acquired resistance to vemurafenib. Silencing KSRP reduces cell proliferation and augments the growth suppressive effects of vemurafenib. We identify killin (KLLN), a p53-regulated DNA replication inhibitor, as a downstream effector of growth inhibition by KSRP silencing and demonstrate that KSRP promotes decay of KLLN mRNA through an RNA-protein interaction. Using heterologous mRNA reporters, we show that a U-rich element within the 3′ untranslated region of KLLN is responsible for KSRP-dependent mRNA decay. These findings implicate that KSRP is an important regulator of melanoma cell growth in part through controlling KLLN mRNA stability.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that is clinically defined by lesions ranging from painful, deep seated nodules to abscesses, draining sinus tracts, and ultimately, irreversible fibrotic scars. While the etiology remains unclear, a number of mechanisms ranging from genetics to aberrations of the immune system have been proposed. In addition, HS has a number of associations and may occur in conjunction with several diseases that span a host of medical specialties. The estimated prevalence ranges are from 1% to 4%; however, a large degree of under-reporting and misdiagnosis of this condition likely underestimates its true clinical significance. The debilitating consequences of missed diagnoses or improper management leads to severe pain and irreversible cutaneous manifestations (i.e., fistulae, sinus tracts, disfiguring scarring). HS has been found to significantly impair patients' quality of life to a greater degree when compared with other skin conditions. Early recognition and treatment are critical for a favorable prognosis, and diagnostic delays may be related to variable presentations within numerous comorbidities. Here we provide an in-depth, clinical-based review of HS, highlighting the clinical presentation, pathophysiology, grading systems, epidemiology, and comorbidities, in hopes of shedding light on an often misunderstood disease and ultimately moving closer to a more conclusive understanding of its various presentations and association.

The tumor microenvironment (TME), which assists in the development, progression, and metastasis of malignant cells, is instrumental in virtually every step of tumor development. While a healthy TME can protect against malignancy, in an unhealthy state, it can result in aberrant cellular behavior and augment tumor progression. Cytokines are one component of the TME, therefore, understanding the composition of the cytokine milieu in the tumor microenvironment is critical to understand the biology of malignant transformation. One cytokine, interleukin (IL)-23, has received particular scrutiny in cancer research because of its ability to manipulate host immune responses, its role in modulating the cells in TME, and its capacity to directly affect a variety of premalignant and malignant tumors. IL-23 belongs to the IL-12 cytokine family, which is produced by activated dendritic cells (DC) and macrophages. IL-23 acts by binding to its receptor consisting of two distinct subunits, IL-12Rβ1 and IL-23R. This, in turn, leads to janus kinase (JAK) activation and signal transducer and activator of transcription (STAT) 3/4 phosphorylation. There have been contradictory reports of pro- and antitumor effects of IL-23, which likely depend on the genetic background, the type of tumor, the causative agent, and the critical balance of STAT3 signaling in both the tumor itself and the TME. Clinical trials of IL-12/23 inhibitors that are used to treat patients with psoriasis, have been scrutinized for reports of malignancy, the most common being nonmelanoma skin cancers (NMSCs). Continued investigation into the relationship of IL-23 and its downstream pathways holds promise in identifying novel targets for the management of cancer and other diseases.

American Cancer Society acknowledges that most skin cancers result from exposure to ultraviolet (UV) rays in sunlight. UVB radiation induces mutant cells as well as immune suppression. Tumors only occur when mutant cells are in an immune suppressive environment. The mechanisms for UVB induced immune suppression are yet to be fully elucidated. The goal of this work is to explore new mechanisms for UVB induced immune suppression and skin carcinogenesis by using advanced technology. Analysis of UVB exposed mouse (Nanostring) and human (RNAseq) skin shows that triggering receptor expressed on myeloid cells (TREM)-1 signal pathway is the top canonic pathway increased by UVB. TREM-1 has roles in inflammatory diseases and cancers. However, its role in UVB induced immune suppression and skin cancers is not understood. We have found by using multi-color flow cytometry that UVB induces TREM-1 expression in a subset of conventional dendritic cell type 2 (cDC2) in the draining lymph nodes (LN). TREM-1+ cDC2 cells are barely detected in normal LN and express a high level of the co-inhibitory molecule PD-L1. In functional assays, treatment of mice with a specific TREM-1 blocking peptide LP-17 significantly diminishes UVB-induced suppression of contact hypersensitivity responses that are mediated by T cells. Further, mice treated with this peptide show decreased incidence of photocarcinogenesis and reduced number of tumors. In summary, our findings demonstrate that UVB induces the development of a novel TREM-1+ cDC2 cell subset and that TREM-1 has an important role in UVB induced immune suppression and skin carcinogenesis. Importantly, our study implies new strategies for targeting TREM-1 in the prevention and treatment of UVB induced skin cancers. Supported by grants from NIH (R01AR072213 and R01AI154842)

The tumor microenvironment (TME), which assists in the development, progression, and metastasis of malignant cells, is instrumental in virtually every step of tumor development. While a healthy TME can protect against malignancy, in an unhealthy state, it can result in aberrant cellular behavior and augment tumor progression. Cytokines are one component of the TME, therefore, understanding the composition of the cytokine milieu in the tumor microenvironment is critical to understand the biology of malignant transformation. One cytokine, interleukin (IL)-23, has received particular scrutiny in cancer research because of its ability to manipulate host immune responses, its role in modulating the cells in TME, and its capacity to directly affect a variety of premalignant and malignant tumors. IL-23 belongs to the IL-12 cytokine family, which is produced by activated dendritic cells (DC) and macrophages. IL-23 acts by binding to its receptor consisting of two distinct subunits, IL-12Rβ1 and IL-23R. This, in turn, leads to janus kinase (JAK) activation and signal transducer and activator of transcription (STAT) 3/4 phosphorylation. There have been contradictory reports of pro- and antitumor effects of IL-23, which likely depend on the genetic background, the type of tumor, the causative agent, and the critical balance of STAT3 signaling in both the tumor itself and the TME. Clinical trials of IL-12/23 inhibitors that are used to treat patients with psoriasis, have been scrutinized for reports of malignancy, the most common being nonmelanoma skin cancers (NMSCs). Continued investigation into the relationship of IL-23 and its downstream pathways holds promise in identifying novel targets for the management of cancer and other diseases.

Skin cancer is rising at an alarming rate worldwide. The most common types of skin cancers, melanoma and non-melanoma are often seen in white population in the world. The geographical distribution for these cancers can be seen mainly in countries with this population. Among the non-melanoma skin cancers, basal cell carcinomas (BCC) have the highest incidence followed by squamous cell carcinomas (SCC). The incidence of melanoma is much lower than non-melanoma skin cancers but the mortality is high. Skin cancers cause a huge economic burden on the healthcare system so several countries employ public health measures for their prevention. In this chapter, we have discussed the global impact of melanoma and non-melanoma cancers along with other skin cancers. We have also discussed their etiology and strategies for prevention and treatment.

Melanocytic nevi are benign proliferations of pigment cells that can occasionally develop into melanomas. There is a significant correlation between increased nevus numbers and melanoma development. Our previous reports revealed that 7,12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) induced dysplastic nevi in C3H/HeN mice, with a potential to transform into melanomas. To understand the immune mechanisms behind this transformation, we applied increasing DMBA doses followed by TPA to the skin of C3H/HeN mice. We observed that increased doses of DMBA correlated well with increased numbers of nevi. The increased DMBA dose induced diminished immune responses and promoted the expansion of regulatory T cells (Treg) that resulted in increased IL10 and reduced IFNγ levels. Mice with increased nevus numbers had loss of p16 expression. These mice had increased migration of melanocytic cells to lymph nodes (LN) and a greater percent of LNs produced immortalized melanocytic cell lines. DMBA-induced immunosuppression was lost in CD4-knockout (KO) mice. Lymphocytes in the CD4KO mice produced less IL10 than CD8KO mice. Furthermore, CD4KO mice had significantly reduced nevus numbers and size compared with wild-type and CD8KO mice. These results suggest that Tregs play a vital role in the incidence of nevi and their progression to melanoma. Prevention Relevance: There has been little progress in developing novel strategies for preventing premalignant dysplastic nevi from becoming melanomas. In this study in mice, regulatory-T cells enhanced progression of benign nevi to malignant melanomas; and by inhibiting their activity, melanomas could be retarded. The findings identify new possibilities for melanoma prevention in high risk individuals.

Doxorubicin (DOX) is a widely used drug for cancer treatment as a chemotherapeutic agent. However, the cellular and integrative mechanism of DOX-induced immunometabolism is unclear. Two-month-old male C57BL/6J mice were divided into high- and low-dose DOX-treated groups with a maintained saline control group. The first group was injected with a high dose of DOX (H-DOX; 15 mg·kg−1·wk−1), and the second group was injected with 7.5 mg·kg−1·wk−1 as a latent low dose of DOX (LL-DOX). H-DOX treatment led to complete mortality in 2 wk and 70% survival in the LL-DOX group compared with the saline control group. Therefore, an additional group of mice was injected with an acute high dose of DOX (AH-DOX) and euthanized at 24 h to compare with LL-DOX and saline control groups. The LL-DOX and AH-DOX groups showed obvious apoptosis and dysfunctional and structural changes in cardiac tissue. Splenic contraction was evident in AH-DOX- and LL-DOX-treated mice, indicating the systems-wide impact of DOX on integrative organs of the spleen, which is essential for cardiac homeostasis and repair. DOX dysregulated splenic-enriched immune-sensitive lipoxygenase and cyclooxygenase in the spleen and left ventricle compared with the saline control group. As a result, lipoxygenase-dependent D- and E-series resolvin precursors, such as 16HDoHE, 4HDoHE, and 12-HEPE, as well as cyclooxygenase-mediated PG species (PGD2, PGE2, and 6-keto-PG2α) were decreased in the left ventricle, suggestive of defective immunometabolism. Both AH-DOX and LL-DOX induced splenic contraction and expansion of red pulp with decreased CD169+ metallophilic macrophages. AH-DOX intoxicated macrophages in the spleen by depleting CD169+ cells in the acute setting and sustained the splenic macrophage loss in the chronic phase in the LL-DOX group. Thus, DOX triggers a vicious cycle of splenocardiac cachexia to facilitate defective immunometabolism and irreversible macrophage toxicity and thereby impaired the inflammation-resolution program. NEW & NOTEWORTHY Doxorubicin (DOX) triggered splenic mass loss and decreased CD169 with germinal center contraction in acute and chronic exposure. Cardiac toxicity of DOX is marked with dysregulation of immunometabolism and thereby impaired resolution of inflammation. DOX suppressed physiological levels of cytokines and chemokines with signs of splenocardiac cachexia.

UVA irradiation is known to cause photoaging via production of reactive oxygen species (ROS) and activation of inflammatory processes. Previously, we have demonstrated that baicalin, a plant-derived flavonoid possessing both antioxidant and anti-inflammatory activity, protects mouse keratinocytes against damage from UVB irradiation. However, the role of baicalin in vivo has not been well studied, particularly in the setting of UVA irradiation. To explore the protective effects and mechanisms of baicalin treatment in mice after UVA irradiation, mice were exposed to acute and chronic doses of UVA irradiation with or without baicalin or vehicle. Skin samples were collected for histological staining, RNA isolation, flow cytometry, and protein extraction. Our results demonstrate the protective effect of baicalin against UVA-induced oxidative damage and inflammation in mouse skin. These effects are likely mediated via the TLR4 pathway, which may serve as a target for photochemoprevention against skin inflammation.

Immune cells and cytokines play an important role in the pathogenesis of psoriasis. Interleukin‐12 (IL‐12) and IL‐23 promote cellular responses mediated by T cells, which contribute to an inflammatory loop responsible for the induction and maintenance of psoriatic plaques. Antibodies that inhibit IL‐12/23 or IL‐23 are key treatment options for patients with psoriasis. IL‐12 and IL‐23 also play a key role in immune responses to infections and tumors. A growing body of information from clinical trials, cohort studies, postmarketing reports, genetic studies and animal models provides insights into the potential biological relationships between IL‐12/23 inhibition and malignancies. We summarize this information in tables and provide some context for the interpretation of these data with the goal of informing dermatologists who are using IL‐12/23 or IL‐23 inhibitors to treat patients with psoriasis.

Aim: Fenofibrate, a PPAR-α inhibitor used for treating dyslipidemia, has well-documented anti-inflammatory effects that vary between individuals. While DNA sequence variation explains some of the observed variability in response, epigenetic patterns present another promising avenue of inquiry due to the biological links between the PPAR-α pathway, homocysteine and S-adenosylmethionine – a source of methyl groups for the DNA methylation reaction. Hypothesis: DNA methylation variation at baseline is associated with the inflammatory response to a short-term fenofibrate treatment. Methods: We have conducted the first epigenome-wide study of inflammatory response to daily treatment with 160 mg of micronized fenofibrate over a 3-week period in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n = 750). Epigenome-wide DNA methylation was quantified on CD4+ T cells using the Illumina Infinium HumanMethylation450 array. Results: We identified multiple CpG sites significantly associated with the changes in plasma concentrations of inflammatory cytokines such as high sensitivity CRP (hsCRP, 7 CpG sites), IL-2 soluble receptor (IL-2sR, one CpG site), and IL-6 (4 CpG sites). Top CpG sites mapped to KIAA1324L (p = 2.63E-10), SMPD3 (p = 2.14E-08), SYNPO2 (p = 5.00E-08), ILF3 (p = 1.04E-07), PRR3, GNL1 (p = 6.80E-09), FAM50B (p = 3.19E-08), RPTOR (p = 9.79e-07) and several intergenic regions (p

Psoriasis is a chronic inflammatory skin disease affecting 2.5–6 million patients in the United States. The cause of psoriasis remains unknown. Previous human and animal studies suggest that patients with a susceptible genetic background and some stimulus, such as barrier disruption, leads to a coordinated signaling events involving cytokines between keratinocytes, endothelial cells, T cells, macrophages and dendritic cells. Ceramides are endogenous skin lipids essential for maintaining skin barrier function and loss of ceramides may underlie inflammatory and premalignant skin. Ceramides act as a double-edged sword, promoting normal skin homeostasis in the native state, but can be metabolized to sphingosine-1-phosphate (S1P), linked to inflammation and tumorigenesis. To overcome this difficulty, we synthesized solenopsin analogs which biochemically act as ceramides, but cannot be metabolized to S1P. We assess their in vivo bioactivity in a well-established mouse model of psoriasis, the KC-Tie2 mouse. Topical solenopsin derivatives normalized cutaneous hyperplasia in this model, decreased T cell infiltration, interleukin (IL)-22 transcription, and reversed the upregulation of calprotectin and Toll-like receptor (TLR) 4 in inflamed skin. Finally, they stimulated interleukin (IL)-12 production in skin dendritic cells. Thus suggesting barrier restoration has both a biochemical and physical component, and both are necessary for optimal barrier restoration.

Basal cell carcinomas (BCCs) account for majority of skin malignancies in the United States. The incidence of BCCs is strongly associated with exposure of ultraviolet (UV) radiation. Nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasome plays an important role in innate immune responses. Different stimuli such as toxins, microorganisms and particles released from injured cells activate the NLRP3 inflammasome. Activated NLRP3 results in activation of caspase-1, which cleaves pro-IL-1β to active IL-1β. In this study, we have shown that NLRP3 is expressed in human basal cell carcinomas. The proximal steps in activation of NLRP3 inflammasome are not well understood. Here, we have attempted to elucidate a critical role for Ca2+ mobilization in activation of the NLRP3 inflammasome by UVB exposure using HaCaT keratinocytes. We have demonstrated that UVB exposure blocks Ca2+ mobilization by downregulating the expression of sarco/endoplasmic reticulum Ca2+ -ATPase (SERCA2), a component of store-operated Ca2+ entry that leads to activation of the NLRP3 inflammasome.

IMPORTANCE: Studies have begun to investigate the complex relationship between host and microorganism in non-infectious pathologies such as acne, atopic dermatitis, and psoriasis. Though the skin is continuously exposed to environmental stressors such as ultraviolet radiation (UVR), no studies exist examining the effects of UVR on the skin microbiome. OBJECTIVE: To test the effect of UVA and UVB on human skin microbiome. DESIGN: This study was a pilot observational study completed in 2015 and data was analyzed in 2016. SETTING: The study was conducted in a multicenter setting, utilizing the Henry Ford Hospital and UAB facilities. PARTICIPANTS: At the Henry Ford Hospital, individuals with Fitzpatrick types I and II were recruited and consented to the study. Participants were all men (n=6) age 19-35 with no skin disease, photosensitivity, use of photosensitizing medications, antibiotics, or NSAIDs. Participants with tanning bed exposure in the last 6 months were also excluded, and topical medications were not allowed at the site of UVR. EXPOSURE(S) (FOR OBSERVATIONAL STUDIES): Varying doses of UVA1 and UVB were administered at the Henry Ford Hospital to the skin of the left upper back or midback. The individual minimal erythema dose was determined for both UVA1 and UVB. Control swab samples were taken from non-irradiated skin on the midback. Swab samples were collected prior to, immediately after, and 24 hours after UVR exposure. The swabs were frozen and shipped to UAB. Amplification was done on the V4 region of the 16S rDNA and sequencing was performed at UAB. Various statistical analyses were then conducted on the data to study the population changes. MAIN OUTCOME(S) AND MEASURE(S): The primary study outcome measurements were statistical changes in the microorganism population as determined by the operational taxonomic unit (OTU) abundance. RESULTS: There was vast intra- and inter-subject variation immediately and 24 hours following UVR. Specific observation include an increase in the phylum Cyanobacteria and a decrease in the families Lactobacillaceae and Pseudomonadaceae. The responsiveness of microbes to UVR and their re-colonization potential following exposure differed in UVA vs. UVB. CONCLUSIONS AND RELEVANCE: The results demonstrate that UVR has profound qualitative and quantitative influences on the composition of the skin microbiome, possibly influencing cutaneous disease in which UVR is a factor.

Conjugation of bioactive targeting molecules to nano- or micrometer-sized drug carriers is a pivotal strategy to improve their therapeutic efficiency. Herein, we developed pH- and redox-sensitive hydrogel particles with a surface-conjugated cancer cell targeting ligand for specific tumor-targeting and controlled release of the anticancer drug doxorubicin. The poly(methacrylic acid) (PMAA) hydrogel cubes of 700 nm and 2 μm with a hepsin-targeting (IPLVVPL) surface peptide are produced through multilayer polymer assembly on sacrificial cubical mesoporous cores. The direct peptide conjugation to the disulfide-stabilized hydrogels through a thiol-amine reaction does not compromise the structural integrity, hydrophilicity, stability in serum or the pH/redox sensitivity, but affects the internalization by cancer cells. The cell uptake kinetics and the ultimate extent of internalization is controlled by the cell type and hydrogel size. The peptide modification significantly promotes the uptake of the 700 nm hydrogels by hepsin-positive MCF-7 cells due to ligand-receptor recognition but has a negligible effect on the uptake of 2-μm PMAA hydrogels. The selectivity of 700-nm IPLVVPL-PMAA hydrogel cubes to hepsin-overexpressing tumor cells is further confirmed by a 3- to 10-fold higher particle internalization by hepsin-positive MCF-7 and SK-OV-3 compared to hepsin-negative PC-3 cells. This work provides a facile method to fabricate enhanced tumor-targeting carriers of submicrometer size and improves the general understanding of particle design parameters for targeted drug delivery.