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Background Skin, as a crucial external defense organ, is more vulnerable to oxidative stress (OS) insult, reactive oxygen species (ROS)-mediated OS in particular. OS results from a redox imbalance caused by various extrinsic stimuli and occurs once the oxidants production overwhelming the antioxidants capacity, through mediating in DNA damage, lipid peroxidation (LPO), protein oxidation and a serial of signaling pathways activation/inactivation, thereby offering favorable conditions for the occurrence and development of numerous diseases especially some dermatoses, e.g. psoriasis, vitiligo, skin photodamage, skin cancer, systemic sclerosis (SSc), chloasma, atopic dermatitis (AD), pemphigus, etc. Targeting OS molecular mechanism, a variety of anti-OS agents emerge, in which flavonoids, natural plant extracts, stand out. Objectives To discuss the possible mechanisms of OS mediating in dermatoses and summarize the properties of flavonoids as well as their applications in OS-related skin disorders. Methods Published papers on flavonoids and OS-related skin diseases were collected and reviewed via database searching on PubMed, MEDLINE and Embase, etc. Results It has been confirmed that flavonoids, belonging to polyphenols, are a class of plant secondary metabolites widely distributed in various plants and possess diverse bioactivities especially their potent antioxidant capacity. Moreover, flavonoids benefit to suppress OS via eliminating free radicals and mediating the corresponding signals, further excellently working in the prevention and management of OS-related skin diseases. Conclusion Flavonoids have the potential therapeutic effects on oxidative stress-related dermatoses. However, more studies on specific mechanism as well as the dosage of flavonoids are needed in future.

Background. Skin photodamage is associated with ultraviolet- (UV-) induced reactive oxygen species (ROS) overproduction and nuclear factor erythroid 2-related factor 2 (Nrf2) inactivation. In our previous study, skin-derived precursors (SKPs) were shown to ameliorate a UV-induced damage in mice, probably through Nrf2 activation and ROS scavenging. Objective. To clarify the mechanism underlying the photoprotective effect of SKPs against UV-induced damage in a three-dimensional (3D) skin model. Methods. The Nrf2 gene in SKPs was modified using lentiviral infection, and 3D skin models were reconstructed with keratinocytes and fibroblasts on the basis of type I collagen. Subsequently, these models were divided into the following six groups: normal, model, overexpressed, control, silenced, and negative control groups. Prior to irradiation, respective SKPs were injected into the last four groups. Next, all groups except the normal group were exposed to UVA+UVB. Lastly, the pathological and molecular-biological techniques were employed to determine the parameters. Additionally, LY294002, a PI3K inhibitor, was used to investigate the roles of PI3K/Akt and Nrf2/hemeoxygenase-1 (HO-1) in SKP photoprotection. Results. Normal 3D skin models appeared as milky-white analogs with a clear, well-arranged histological structure. After the skin was exposed to irradiation, it exhibited cell swelling and a disorganized structure and developed nuclear condensation with numerous apoptotic cells. The expressions of cellular protective genes and Nrf2/HO-1/PI3K/Akt proteins remarkably decreased, which were accompanied by increased oxidative stress and decreased antioxidants (P<0.05). However, these phenomena were reversed by nrf2-overexpressing SKPs. The 3D skin in the overexpressed group showed mild swelling, neatly arranged cells, and few apoptotic cells. Cellular protective genes and Nrf2/HO-1/PI3K/Akt proteins were highly expressed, and the oxidative biomarkers were remarkably ameliorated (P<0.05). Nevertheless, the expression of these proteins decreased after LY294002 pretreatment regardless of SKP treatment or not. Meanwhile, there were increases in both UV-induced apoptotic cells and ROS level accompanied with SOD and GPX decrease in the presence of LY294002. Conclusions. Evidence from the 3D skin model demonstrates that the protection of SKPs against UV-mediated damage is primarily via the PI3K/Akt-mediated activation of the Nrf2/HO-1 pathway, indicating that SKPs may be a promising candidate for the treatment of photodermatoses.

Angiogenesis is the process of new vessel formation, which sprouts from preexisting vessels. This process is highly complex and primarily involves several key steps, including stimulation of endothelial cells by growth factors, degradation of the extracellular matrix by proteolytic enzymes, migration and proliferation of endothelial cells, and capillary tube formation. Currently, it is considered that multiple cytokines play a vital role in this process, which consist of proangiogenic factors (e.g., vascular endothelial growth factor, fibroblast growth factors, and angiopoietins) and antiangiogenic factors (e.g., endostatin, thrombospondin, and angiostatin). Angiogenesis is essential for most physiological events, such as body growth and development, tissue repair, and wound healing. However, uncontrolled neovascularization may contribute to angiogenic disorders. In physiological conditions, the above promoters and inhibitors function in a coordinated way to induce and sustain angiogenesis within a limited period of time. Conversely, the imbalance between proangiogenic and antiangiogenic factors could cause pathological angiogenesis and trigger several diseases. With insights into the molecular mechanisms of angiogenesis, increasing reports have shown that a close relationship exists between angiogenesis and oxidative stress (OS) in both physiological and pathological conditions. OS, an imbalance between prooxidant and antioxidant systems, is a cause and consequence of many vascular complains and serves as one of the biomarkers for these diseases. Furthermore, emerging evidence supports that OS and angiogenesis play vital roles in many dermatoses, such as psoriasis, atopic dermatitis, and skin tumor. This review summarizes recent findings on the role of OS as a trigger of angiogenesis in skin disorders, highlights newly identified mechanisms, and introduces the antiangiogenic and antioxidant therapeutic strategies.

Hemangioma, the most common benign vascular tumor, not only affects the appearance and psychology but also has a life-threatening potential. It is considered that clonal vascular endothelial cell proliferation and excessive angiogenesis are responsible for hemangioma pathogenesis, in which abnormal cytokines/pathways are closely implicated, primarily including high expression of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) as well as their downstream pathways, especially phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt). These further stimulate the migration and proliferation of vascular endothelial cells and promote the formation of new vessels, ultimately leading to the occurrence and development of hemangioma. Proanthocyanidins are naturally active substance from plants and fruits. They possess multiple functions like antiproliferation, antiangiogenesis, and antitumor. It has been demonstrated that proanthocyanidins effectively work in various diseases via inhibiting the expression of various factors, e.g., HIF-1α, VEGF, PI3K, and Akt. Considering the pathogenesis of hemangioma and the effect of proanthocyanidins, we hold a hypothesis that proanthocyanidins would be applied in hemangioma via downregulating cytokine/pathway expression, suppressing vascular cell proliferation and arrest abnormal angiogenesis. Taken together, proanthocyanidins may be a potential novel way for the treatment of hemangioma.

Macrophages, a kind of innate immune cells, derive from monocytes in circulation and play a crucial role in the innate and adaptive immunity. Under the stimulation of the signals from local microenvironment, macrophages generally tend to differentiate into two main functional phenotypes depending on their high plasticity and heterogeneity, namely, classically activated macrophage (M1) and alternatively activated macrophage (M2). This phenomenon is often called macrophage polarization. In pathological conditions, chronic persistent inflammation could induce an aberrant response of macrophage and cause a shift in their phenotypes. Moreover, this shift would result in the alteration of macrophage polarization in some vascular dermatoses; e.g., an increase in proinflammatory M1 emerges from Behcet’s disease (BD), psoriasis, and systemic lupus erythematosus (SLE), whereas an enhancement in anti-inflammatory M2 appears in infantile hemangioma (IH). Individual polarized phenotypes and their complicated cytokine networks may crucially mediate in the pathological processes of some vascular diseases (vascular dermatosis in particular) by activation of T cell subsets (such as Th1, Th2, Th17, and Treg cells), deterioration of oxidative stress damage, and induction of angiogenesis, but the specific mechanism remains ambiguous. Therefore, in this review, we discuss the possible role of macrophage polarization in the pathological processes of vascular skin diseases. In addition, it is proposed that regulation of macrophage polarization may become a potential strategy for controlling these disorders.

Objectives Currently, innovative methods to prevent photoaging are needed. Skin-derived precursors (SKP) have been shown to play a crucial role in resisting UVB-induced apoptosis in vitro. The objective of this study was to explore the effect of SKP on preventing skin photoaging in vivo. Methods Skin-derived precursors from neonatal BALB/c mice were isolated, identified and intradermally transplanted with a PKH26 label to track their survival. These were then injected at different concentrations into the buttock dermis of nude mice at 2-weekly intervals before UV irradiation. Photographs, assessment of live skin surface, histology with quantitative real-time polymerase chain reaction and immunohistochemistry were used to evaluate the impact of SKP on wrinkles and other relevant indicators of skin photoaging. Results SKP exhibited a sphere-like structure and could survive for at least 2 weeks after intradermal transplantation. A large dose of SKP transplantation (105 SKP +UV) at 2-weekly intervals were able to ameliorate coarse UV-induced wrinkles. Moreover, the skin smoothness value, dermal thickness and collagen percentage were significantly increased in mice that received a large dose of SKP (105 SKP +UV). UV radiation induced the mRNA expression of MMP-13 and decreased the mRNA and protein expression of TβRII, but these effects were diminished by SKP transplantation. The transplantation of SKP could increase the mRNA of TIMP-1. Conclusions We found that transplanted SKP exert a beneficial impact on preventing UV-induced wrinkles in vivo, suggesting that SKP transplantation is a promising candidate for preventing photoaging.

Psoriasis is a common, chronic, inflammatory skin disease that affects 2%–4% of the global population. Recent studies have shown that increased oxidative stress (OS) and T-cell abnormalities are central to the pathogenesis of this disease. The resulting reactive oxygen species (ROS) induces proliferation and differentiation of Th17/Th1/Th22 cells and inhibits the anti-inflammatory activities of regulatory T lymphocytes (Treg). Subsequent secretions of inflammatory cytokines, such as interleukin (IL)-17, IL-22, tumor necrosis factor alpha (TNF-α), and interferon-gamma (IFN-γ), and vascular endothelial growth factor (VEGF), stimulate keratinocyte proliferation and angiogenesis. Proanthocyanidins are a class of flavonoids from plants and fruits, and have various antioxidant, anti-inflammatory, and anti-angiogenic properties. Numerous reports have demonstrated therapeutic effects of proanthocyanidins for various diseases. Among clinical activities, proanthocyanidins suppress cell proliferation, prevent OS, and regulate Th17/Treg cells. Because the pathogenesis of psoriasis involves OS and T cells dysregulation, we reviewed the effects of proanthocyanidins on OS, Th17 and Treg cell activities, and keratinocyte proliferation and angiogenesis. Data from multiple previous studies warrant consideration of proanthocyanidins as a promising strategy for the treatment of psoriasis.

Diffuse large B-cell lymphoma (DLBCL) is a clinically aggressive B-cell non-Hodgkin’s lymphoma (NHL) with high treatment difficulty and high relapse rate. The bromodomain and extra-terminal (BET) proteins play significant roles in supporting the transcription of known DLBCL oncogene MYC, which provides a way for the development of targeted therapeutic agents to address this kind of malignant tumor. Here, we reported a novel benzoxazinone derivative YLT-LL-11 as potential BRD4 inhibitor and further investigated the biological activities against DLBCL. The results suggested that YLT-LL-11 inhibited cell growth against a panel of human hematopoietic malignancies cell lines in a dose- and time-dependent manner. In addition, flow cytometry and Western blotting assays showed that YLT-LL-11 inhibited the proliferation of a DLBCL cell line OCI-LY10 via inducing G0/G1 cell cycle arrest with regulation of the cyclin-dependent kinases (CDKs) expression. Furthermore, YLT-LL-11 facilitated OCI-LY10 cell apoptosis by up-regulation of pro-apoptotic protein BAX and down-regulation of anti-apoptotic protein Bcl-2. Taken together, these results revealed that BRD4 inhibitor YLT-LL-11 can down-regulate growth-associated transcription factors MYC in DLBCL thus resulted in cell growth inhibition and apoptosis.

Strategies to battle malignant tumors have always been a dynamic research endeavour. Although various vehicles (e.g., chemotherapeutic therapy, radiotherapy, surgical resection, etc.) are used for skin cancer management, they mostly remain unsatisfactory due to the complex mechanism of carcinogenesis. Increasing evidence indicates that redox imbalance and aberrant reactive oxygen species (ROS) are closely implicated in the oncogenesis of skin cancer. When ROS production goes beyond their clearance, excessive or accumulated ROS could disrupt redox balance, induce oxidative stress, and activate the altered ROS signals. These would damage cellular DNA, proteins, and lipids, further leading to gene mutation, cell hyperproliferation, and fatal lesions in cells that contribute to carcinogenesis in the skin. It has been known that ROS-mediated skin carcinogenesis involves multiple ways, including modulating related signaling pathways, changing cell metabolism, and causing the instability of the genome and epigenome. Nevertheless, the exact role of ROS in skin cancer has not been thoroughly elucidated. In spite of ROS inducing skin carcinogenesis, toxic-dose ROS could trigger cell death/apoptosis and, therefore, may be an efficient therapeutic tool to battle skin cancer. Considering the dual role of ROS in the carcinogenesis and treatment of skin cancer, it would be essential to clarify the relationship between ROS and skin cancer. Thus, in this review, we get the related data together to seek the connection between ROS and skin carcinogenesis. Besides, strategies basing on ROS to fight skin cancer are discussed.

Pruritus, the most common cutaneous symptom, is widely seen in many skin complaints. It is an uncomfortable feeling on the skin and sometimes impairs patients’ quality of life. At present, the specific mechanism of pruritus still remains unclear. Antihistamines, which are usually used to relieve pruritus, ineffectively work in some patients with itching. Recent evidence has suggested that, apart from histamine, many mediators and signaling pathways are involved in the pathogenesis of pruritus. Various therapeutic options for itching correspondingly have been developed. In this review, we summarize the updated pathogenesis and therapeutic strategies for pruritus.

Proanthocyanidins (PCs) are naturally occurring polyphenolic compounds abundant in many vegetables, plant skins (rind/bark), seeds, flowers, fruits, and nuts. Numerousin vitroandin vivostudies have demonstrated myriad effects potentially beneficial to human health, such as antioxidation, anti-inflammation, immunomodulation, DNA repair, and antitumor activity. Accumulation of prooxidants such as reactive oxygen species (ROS) exceeding cellular antioxidant capacity results in oxidative stress (OS), which can damage macromolecules (DNA, lipids, and proteins), organelles (membranes and mitochondria), and whole tissues. OS is implicated in the pathogenesis and exacerbation of many cardiovascular, neurodegenerative, dermatological, and metabolic diseases, both through direct molecular damage and secondary activation of stress-associated signaling pathways. PCs are promising natural agents to safely prevent acute damage and control chronic diseases at relatively low cost. In this review, we summarize the molecules and signaling pathways involved in OS and the corresponding therapeutic mechanisms of PCs.

Background Skin photodamage is associated with UV-induced overproduction of reactive oxygen species (ROS) and the inactivation of NF-E2-related factor 2 (Nrf2). Skin-derived precursor cells (SKPs), a population of dermal stem cells, are considered to be involved in wound repair and skin regeneration through the activation of Nrf2. However, no reports concentrate on the treatment of skin photodamage with SKPs. Objective To investigate the photoprotective role of SKPs against UV-induced damage in mice. Methods Fifty Balb/c hairless mice were divided into five groups (n = 10), namely, normal (no intervention), model, prevention, treatment, and control groups. The latter four groups were dorsally exposed to UVA + UVB irradiation over a 2-week period. Mice in the prevention group received weekly SKP injections for 2 weeks the day before irradiation. Mice in the treatment and Hanks groups received a two-time injection of SKPs and Hanks, respectively, after irradiation. One week after final intervention, skin appearance, pathological alterations, and oxidative indicators were evaluated by enzyme-linked immunosorbent assay, immunohistochemical analysis, and western blotting. Results After irradiation, lesions were observed on the dorsal skin of mice, including erythema, edema, scales, and wrinkles; however, these were significantly ameliorated by subcutaneous SKP injection. Hyperkeratosis, acanthosis, and spongiosis in the epidermis, as well as dermal papillae edema and inflammatory cell infiltration, were observed in both model and control groups; however, these conditions resolved with either pretreatment or posttreatment with SKPs. In addition, SKPs increased Nrf2, heme oxygenase-1, glutathione peroxidase, superoxide dismutase, catalase, and gluthathione expression, while decreasing levels of ROS, MDA, and H 2 O 2 . Conclusions These findings suggest that SKPs have a photoprotective role against UV-induced damage in mice, which may be associated with their ability to scavenge photo-oxidative insults and activate Nrf2.

In their article, [Helwa et al. (2017)][1] show the effect of monomethylfumarate (MMF) in the treatment of psoriasis through enhancing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and aquaporin-3 (AQP3). In our opinion, however, there are some doubts about the results of

Bcl-2 and Nrf2 are critical factors in protecting cells against UVB-induced apoptosis. Hair-follicle-bulge stem cells could resist ionization through Bcl-2 upregulation. Skin-derived precursors (SKPs) dwelling on the bulge may be against UVB irradiation. Initially, SKPs were isolated and identified. Then, SKPs were exposed to UVB and grew in medium for 24 hours. CCK-8 assay, TUNEL, and Ki67 staining evaluated cells apoptosis/proliferation, while SA-βgal staining evaluated cells senescence and pH2AX immunostaining evaluated DNA damage. Meanwhile, Bcl-2, Nrf2, HO-1, Bax, and Bak expressions were assessed by qRT-PCR and western blot. Two weeks later, floating spheres appeared and were identified as SKPs. After UVB radiation, SKPs maintained spherical colonies and outnumbered unirradiated ones, showing high Ki67 expression and low TUNEL, SA-βgal, and pH2AX expression. Fibroblasts (FBs), however, displayed deformation, senescence, and reduction, with increased TUNEL, SA-βgal, and pH2AX expression. Moreover, Bcl-2 and Nrf2 mRNA expression were significantly higher than Bak and Bax in irradiated SKPs. Conversely, Bcl-2 and Nrf2 mRNA levels greatly decreased compared with Bax and Bak in irradiated FBs. Interestingly, SKPs showed higher protein levels of Bcl-2, Nrf2, and HO-1 than FBs. SKPs exert a beneficial effect on resisting UVB-induced apoptosis, which may be associated with Bcl-2 and Nrf2 upregulation.

Behcet's disease (BD) involves oxidative stress (OS) aggression and imbalanced oxidant/antioxidant status. Owing to its antioxidant property, allicin is proposed for treating BD. In this study, we aimed to investigate the efficacy and safety of allicin on patients with BD with mucocutaneous involvement. Twenty patients with active BD were treated with allicin for 12 weeks and followed up to 16 weeks. A clinical manifestations index and scoring system was the primary technique for efficacy evaluation at baseline and Week 4, 12, 16. The secondary efficacy variables were OS-related biomarkers determined at first and final visit. Side effects were assessed at each visit. By the end of study, 18 patients completed the trail. Allicin was effective in decreasing ulcer and cutaneous parameters (p

The study objectives were to evaluate the efficacy and safety of Tripterygium hypoglaucum Hutch (THH) in adult with severe chronic urticaria (CU) by performing a randomized, double-blind, placebo-controlled clinical trial.Seventy-eight (78) adult patients with severe CU, 21-58 years of age, responding poorly to antihistamines alone, were randomly divided into two groups: the therapeutic group with THH 3 tablets 3 times daily (n = 40) and the control group with placebo 3 tablets 3 times daily (n = 38). Meanwhile, all patients jointly received cetirizine hydrochloride (HCl) 10 mg once daily throughout the study period. The efficacy of THH was assessed by the scoring system of 4-point scale and the subject's global assessment of relief.Sixty-nine (69) of 78 patients (37 in the therapeutic group, 32 in the control group) completed the study. By the end of the fourth week, there was a 67% improvement of total effective rate (TER) with THH compared with a 28% improvement with placebo by per-protocol analysis (χ(2) = 10.68, p = 0.0011), while by intention-to-treat analysis, 63% and 24% improvements of TER were respectively observed in the therapeutic group and the control group (χ(2) = 11.36, p = 0.001). THH with cetirizine showed statistical superiority to placebo with cetirizine during each study week for changes in total severity scores (p ≤ 0.001). In weekly analyses, THH was also statistically superior to placebo in reducing the mean pruritus scores during each study week (p ≤ 0.005).This study shows that the therapeutic effect of THH with cetirizine is predominant over that of cetirizine alone in adult CU. THH with cetirizine may play an important role in the therapy of CU and be a useful treatment for CU.

Skin photoaging, the most common skin damage, is caused by chronic UV irradiation. It is involved in the reduction, aging and apoptosis of fibroblasts (FBs) as well as the blockage of transforming growth factor-beta (TGF-β)/Smad and p38 mitogen-actived protein kinase (MAPK) signaling pathways. Dermal multipotent stem cells (dMSCs) are a population of adult stem cells derived from dermis in recent years. It has been confirmed that dMSCs can activate or differentiate into FBs to participate in wound healing by producing and expressing TGF-β and other cytokines. Considering the mechanism of skin photoaging and the role of dMSCs, we hold a hypothesis that dMSCs may be applied in skin photoaging by activating TGF-β/Smad and p38 MAPK signaling pathways, and then stimulating FBs to secrete and synthesize collagen or elastin, heightening the extracellular matrix, finally eliminating wrinkles and strengthening skin elasticity. These would provide a novel approach for anti-skin photoaging.