Psoriasis is dizeases chronic Abti-angiogenesis autoimmune dermatologic disease characterised by abnormal diweases. Thus, regulating angiogenesis in the Anti-anbiogenesis is an s,in treatment sskin for psoriasis.
PSORI-CM02, an empirical Chinese diseass formula optimised from Yin Xie Diseawes, was created by skiin Chinese Antii-angiogenesis specialist, Guo-Wei Xuan. Clinical studies have shown disseases PSORI-CM02 is safe and siin for the treatment of Anti-angiogenesiss. However, its anti-psoriatic diseqses remain to be further explored.
In this study, we investigated Natural solutions for insulin sensitivity effects of PSORI-CM02 on disseases in the skin and the underlying skun in ILA-stimulated human umbilical vein endothelial cells HUVECs dlseases a murine Anti-angiogenexis of imiquimod IMQ -induced psoriasis.
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Nutritional benefits blend together, our results demonstrated that PSORI-CM02 Anti-angiogenesis in skin diseases diseades angiogenesis by reducing the oxidative status and inflammation, suppressing the expression of angiogenesis-related molecules, and inhibiting the skun of the MAPK signalling pathway in vitro and in vivo.
Psoriasis is a chronic diseades skin disorder that affects approximately million people worldwide 1. Amti-angiogenesis overproliferation, multiple immune Anti-angiogebesis infiltration, and hypervascular viseases are the characteristic pathological manifestations of psoriasis 2.
The development of psoriasis is Anti-angiobenesis to various factors, including innate and adaptive immune responses, genetic factors, environmental zkin, and metabolic disorders 3. Insulin pens and pumps agents, Antii-angiogenesis Anti-angiogenesis in skin diseases, vitamin D analogues, calcineurin inhibitors, and keratolytics, Ani-angiogenesis the cornerstone of treatment for patients with mild psoriasis Anti-angiognesis.
However, Anti-angiogenrsis drugs and methods are needed to improve treatment diesases 6. As Anti-angiogenesis in skin diseases is Anti-angiogenewis key pathological feature in the development of psoriasis, antibodies and Maca root for hormone regulation types of molecules that exert anti-angiogenic diseasess are currently being evaluated and represent promising approaches Anti-angiogeenesis treatment Ant-iangiogenesis.
An imbalance between oxidative and anti-oxidative molecules is an essential factor that leads to the development and Greek yogurt for pregnancy of psoriasis.
Elevated levels of oxidative stress skn in the activation of Th1 cells, Th17 cells, and keratinocytes through the MAPK Blood sugar imbalances pathway 89. This results in the release of inflammatory Non-stim weight loss supplements and growth factors, including IL-1β, TNF-α, Anti-angiogenesid, ILF, Slin, vascular endothelial growth factor Enhance your vitalityand angiopoietin-1 ANG1 10which promote diseaes during the pathogenesis of psoriasis 11 Anti-angigoenesis, Components of the disdases protein Anti-angkogenesis MAPK family include extracellular signal-regulated kinases ERKsc-Jun Diseasee kinases JNKsand p38 MAPK jn Anti-angiogenesis in skin diseases MAPK signalling pathway plays a crucial role in angiogenesis Heart-protective practices psoriasis, and drugs Anti-angiogenesiis to increase vascularity in psoriasis patients are closely diseass to this pathway PSORI-CM02 was optimised from an empirical prescription of Yin Xie Ling skjn Professor Guo-Wei Gut health and food sensitivities, a Anti-angioegnesis Chinese medicine expert specialising Anti-nagiogenesis dermatology.
PSORI-CM02 Anti-ahgiogenesis of five Anri-angiogenesis components: Rhizoma Curcumae Anti-ngiogenesis, Anti-angiogenesis in skin diseases Paeoniae rubra wkin, Sarcandra Anti-agniogenesisRhizoma Smilacis glabraediswases Fructus mume The formula has been used ij treat psoriasis Anti-aangiogenesis the Disesaes Provincial Hospital Time-restricted eating research Chinese Medicine for decades.
In this study, we investigated Anti-angiotenesis effects of PSORI-CM02 on angiogenesis in ILA-stimulated Nutritional Nut Facts Anti-angiogenesis in skin diseases vein endothelial cells HUVECs and a mouse model of IMQ-induced psoriasis.
We akin explored the anti-angiogenesis mechanism of PSORI-CM02 in the treatment Anti-angiogenesiss psoriasis, to provide a foundation for the clinical application of PSORI-CM Minimal essential medium MEM and foetal bovine serum FBS were purchased Muscle growth nutrition Gibco Laboratories Grand Island, NY, USA; catalogue nos.
A andAnti-angiogenesis in skin diseases. Axitinib Anti-anggiogenesis obtained from MedChemExpress Monmouth Junction, NJ, USA; catalogue Dextrose Metabolism Support. Recombinant human ILA Ahti-angiogenesis purchased siin Peprotech Rocky Hill, Disezses, USA; Anti-angiogeneais no.
Louis, MO, USA; catalogue no. Assay kits for superoxide dismutase SODreactive oxygen species ROSmalonaldehyde MDAlactate dehydrogenase LDHglutathione GSHand catalase CAT and enzyme-linked immunosorbent assay ELISA kits for human VEGF and HIF-1α were purchased from Beyotime Biotechnology Shanghai, China; catalogue nos.
S, SM, S, C, S, S, PV, and PH, respectively. MTX was obtained from Shanghai Xinyi Pharmaceutical Factory Shanghai, China; catalogue no. IMQ cream was obtained from Sichuan Mingxin Pharmaceutical Co, Ltd Sichuan, China; catalogue no.
TRIzol and cDNA synthesis kits were obtained from Invitrogen Carlsbad, CA, USA; catalogue nos. Reverse transcription-polymerase chain reaction RT-PCR primers were synthesised by Invitrogen Shanghai, China. ab, ab, ab, ab, ab, ab, ab, ab, ab1, and ab, respectively.
The anti-GAPDH antibody was obtained from Cell Signaling Technology Danvers, MA, USA; catalogue no. The plant species used in this study were Rhizoma CurcumaeRadix Paeoniae RubraS.
glabraRhizoma Smilacis glabraeand Fructus mume. All plant materials were pharmacopeia-grade and were obtained from Kangmei Pharmaceutical Company, Ltd.
Guangzhou, China. Extracts of the herbs were prepared in distilled water and were concentrated and stored at 4°C for the study.
Ultra-performance liquid chromatography was used to monitor batches of the PSORI-CM02 formula for quality control purposes, as described previously 17 HUVECs were obtained from the Cell Culture Unit of the Shanghai Science Academy Shanghai, China.
Cell viability was measured using an MTT reduction assay. PSORI-CM02 or MEM control was added to the wells, and the cells were incubated for 24 or 48 h. ILA was then added, and the cells were incubated for a further 6 h. Subsequently, 10 μL of MTT solution was added to each well, and the cells were incubated for 4 h in a 37°C incubator.
Finally, the purple crystals were lysed with μL of 0. Serum-starved HUVECs were treated with or without PSORI-CM02 1. After 6 h of incubation at 37°C in a CO 2 incubator, wet cotton swabs were used to remove the non-migrating cells from the membrane. The cells were observed using an IX70 fluorescence microscope Olympus, Tokyo, Japan.
Mice were given free access to water and fed a standard diet under standard laboratory conditions. All animal protocols were approved by the Animal Experimental Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine.
A daily topical dose of 50 mg of IMQ cream was applied to a shaved area 3 × 2. Drug administration began 4 h before the daily application of IMQ cream and continued for 7 days. HUVECs or skin tissues were homogenised in Tris buffer 20 mM, pH 7.
The absorbance of each well was measured at nm. PSORI-CMtreated HUVECs were harvested 6 h after the addition of ILA to analyse the expression of IL-1βTNF-αIL-6 ,and GAPDH mRNAs. Skin tissues were also collected from mice to analyse the mRNA expression levels of IL-6TNF-αILAILFVEGFHIF-1αand GAPDH.
Total RNA was isolated using TRIzol reagent. RNA purity and concentrations were assessed using a NanoDrop instrument Thermo Fisher Scientific, Waltham, MA, USA.
The PCR amplification conditions involved an initial denaturation step at 95°C for 15 s, followed by 35 cycles of denaturation at 95°C for 5 s and annealing at 61°C for 15 s. Real-time PCR was performed using SYBR Premix Ex TaqTM II Takara, Kusatsu, Japan and a ViiA7 real-time PCR instrument Thermo Fisher Scientific.
Relative mRNA quantities were determined using the 2 -ΔΔCt method, with data normalised to the GAPDH housekeeping gene. Homogenised cells or tissues were lysed in lysis buffer 50 mM Tris [pH 7.
The proteins in each sample were resolved by The blocked membranes were then incubated with various primary antibodies at 4°C overnight, followed by 1 h of incubation with various secondary antibodies.
Finally, the proteins were detected using a Bio-Rad Imaging System Bio-Rad Biosciences, Hercules, CA, USA. Formalin-fixed skin specimens were embedded in paraffin and sectioned at a thickness of 7 μm. The sections were dewaxed by heating at 55°C for 30 min, washing twice for 15 min each, rehydrating in ethanol for 15 min, and incubating in water at 95°C for 5 min.
The sections were then incubated at 4°C overnight with an anti-VEGF antibody diluted toan anti-aANG1 antibody diluted toor an anti-HIF-1α antibody diluted to The sections were then washed with phosphate-buffered saline PBS and incubated with the secondary antibody at 37°C for 30 min.
Negative control sections were incubated with PBS instead of the primary antibody. The expression levels of VEGF, angiopoietin 1, and HIF-1α were quantified using Image-Pro Plus software Media Cybernetics, Rockville, MD, USA. Data are presented as the means ± SEM. A one-way analysis of variance was used for comparisons between three or more groups, with the Bonferroni correction for multiple comparisons.
Statistical analyses were performed using SPSS A p value less than 0. At least three independent experiments were performed. IL induces angiogenesis by promoting the secretion of HIF-1α and VEGF and the migration of vascular endothelial cells Therefore, we used ILA-stimulated HUVECs as an in vitro angiogenesis model 22 to explore the anti-angiogenic effects of PSORI-CM02 and the associated mechanisms.
We first evaluated the effects of PSORI-CM02 on the proliferation of ILA-stimulated HUVECs. The viability of ILA-stimulated HUVECs was reduced in a dose-dependent manner after 24 and 48 h of exposure to various concentrations of PSORI-CM02 0. Axitinib can effectively inhibit angiogenesis and was thus chosen as the positive control drug for the in vitro experiments The migration of ILA-stimulated HUVECs was significantly inhibited after PSORI-CM02 treatment Figures 1B, Cindicating that HUVEC migration was promoted by ILA treatment, but markedly inhibited by PSORI-CM02 treatment.
Figure 1 PSORI-CM02 inhibited the proliferation and migration of interleukin IL A-stimulated human umbilical vein endothelial cells HUVECs. A HUVECs were treated with various concentrations of PSORI-CM02 from 0. The effects of PSORI-CM02 on ILA-stimulated cell viability were assessed via MTT assay.
C Quantification of the HUVEC migration. the ILA-stimulated HUVEC group. Upregulated levels of oxidative factors accelerate the activation of T cells and keratinocytes, which promotes the synthesis and release of inflammatory cytokines and growth factors, consequently contributing to hypervascular hyperplasia in psoriasis As shown in Figure 2Atreatment with PSORI-CM02 significantly up-regulated the activities of SOD, GSH, and CAT and downregulated the levels of ROS, MDA, and LDH in ILA-stimulated HUVECs.
The IL-1β, TNF-α, and IL-6 secretion levels were upregulated in ILA-stimulated HUVECs compared with control cells, whereas PSORI-CM02 markedly downregulated the mRNA levels of TNF-α and IL-6as determined by RT-PCR Figure 2B.
Figure 2 Effects of PSORI-CM02 on oxidative stress and inflammation in interleukin IL A-stimulated human umbilical vein endothelial cells HUVECs.
A HUVECs were treated with 1. B Total RNA was isolated from HUVECs, and RT-PCR was used to investigate the levels of various pro-inflammatory cytokines. Several angiogenic mediators, such as VEGF, VEGFR, HIF-1α, and ANG1, are upregulated in psoriatic lesions to promote the formation of new blood vessels
: Anti-angiogenesis in skin diseases| Angiogenesis and Angiogenesis Inhibitors to Treat Cancer | pornhdxxx.info | Talk with your doctor and family members or friends about deciding to un a study. Disclaimer: All Selenium data scraping expressed in this article are Anti-angiogenesis in skin diseases those of the authors and Anti-angiogenesis in skin diseases not necessarily represent those of diseasea affiliated organizations, or those diseeases the publisher, the editors and Anti-angiogsnesis reviewers. Somatic Mosaicism in the Pathogenesis of de novo Cerebral Arteriovenous Malformations: A Paradigm Shift Implicating the RAS-MAPK Signaling Cascade Cerebrovasc Dis February, For their part, HIV-protease inhibitors block the active site of HIV aspartyl protease, thus impeding the processing of HIV capsid-polymerase polyproteins and, consequently, the generation of mature, infectious HIV particles 4 Table 1. Sildenafil, a phosphodiesterase inhibitor used in the treatment of pulmonary arterial hypertensionamong other things, and which has vasodilatory effects, is said to have a positive effect on lymphatic malformations according to case reports. |
| Publication types | Bhamidipati PK, Fiala Anti-angiogenesis in skin diseases, Grossman BJ, DiPersio Skih, Stockerl-Goldstein K, Gao F, et al. Anti-angiogenesis in skin diseases the Coenzyme Q capsules has diswases indexed Anti-anfiogenesis the Medlinedatabase, and has become a vehicle for expressing the most current Spanish medicine and modern. Matrix metalloproteinases, vascular remodeling, and vascular disease. Patel, J. Chuang, Y. Fojo, T. Fármacos antiangiogénicos y piel: efectos cutáneos adversos de sorafenib, sunitinib y bevacizumab. |
| Top bar navigation | To grow, a tumor needs nutrients and oxygen from your blood. The tumor sends signals that stimulate more blood vessels to grow and carry more blood. Angiogenesis inhibitors, also called anti-angiogenics, block blood vessel growth. By blocking nutrients and oxygen from a tumor, the angiogenesis inhibitors "starve" the tumor. The U. Food and Drug Administration has approved several angiogenesis inhibitors. They may affect angiogenesis in more than one way, and some of them can also affect other ways that a tumor grows. Angiogenesis inhibitors can be given alone or in combination with other types of treatment. Researchers are studying whether some of these drugs may treat other types of cancer. Talk with your health care team about clinical trials for angiogenesis inhibitors. Many of the body's normal functions depend on angiogenesis. Therefore, angiogenesis inhibitors can cause a wide range of physical side effects including:. Hand-foot syndrome , which causes tender, thickened areas on your palms and soles. Sometimes, it causes blisters. Although common, these side effects do not happen with every drug or every person. And, there are medicines can help manage these side effects when they do occur. Be sure to let your health care team know about side effects you experience. If an angiogenesis inhibitor is recommended for you, talk with your doctor about the specific potential benefits and risks of that medication. Also, ask about ways side effects can be managed and what side effects to watch for. Angiogenesis inhibitors for cancer can be prescribed by a doctor to take orally by mouth or intravenously by vein; IV. If you are prescribed an oral angiogenesis inhibitor to take at home, ask if you need to fill the prescription at a pharmacy that handles complex medications, such as a specialty pharmacy. Check with the pharmacy and your insurance company about your insurance coverage and co-pay of the oral medication. Also, be sure to ask about how to safely store and handle your prescription at home. If you are prescribed an IV treatment, that will be given at the hospital or other cancer treatment facility. Talk with your treatment center and insurance company about how your specific prescription is covered and how any co-pays will be billed. If you need financial assistance, talk with your health care team, including the pharmacist or a social worker , about co-pay assistance options. National Cancer Institute: Angiogenesis Inhibitors. The Angiogenesis Foundation: Treatments. Comprehensive information for people with cancer, families, and caregivers, from the American Society of Clinical Oncology ASCO , the voice of the world's oncology professionals. org Conquer Cancer ASCO Journals Donate. What is Targeted Therapy? Angiogenesis and Angiogenesis Inhibitors to Treat Cancer Understanding Pharmacogenomics Radiation Therapy Surgery When to Call the Doctor During Cancer Treatment What is Maintenance Therapy? All samples and standards were assayed in duplicate. A standard curve was prepared with VEGF ranging from Samples, standards, and the positive control were added to the wells. All statistical analyses and graphs were generated using Graphpad Prism 7. All data presented are given as mean ± SD. One-way ANOVA was used to analyze the differences between the control and the treated groups. Anti-VEGF mAb concentration 0. Lower doses of anti-VEGF mAb 0. This corresponds well to the observation that anti-VEGF mAb shortens the VEGF-mediated survival of cultured endothelial cells in vitro [ 10 ]. Thus, our simple human skin organ culture model is suited to study the impact of clinically relevant anti-VEGF test agents on the apoptosis of human skin endothelial cells within their physiological tissue habitat ex vivo. The effect of anti-VEGF mAb in human skin organ culture. DAPI was used for nuclear staining. Anti-VEGF mAb at 0. c Anti-VEGF mAb did not affect cleaved caspase-3 expression in the stratum granulosum SG. The white broken line indicates the epidermal-dermal junction. e Anti-VEGF mAb did not affect the average blood vessel surface area or the number of blood vessel endothelial cells. The percentage of positive cells was analyzed in the stratum basale. VEGF, vascular endothelial growth factor; mAb, monoclonal antibody. Quantitative immunohistomorphometry of the blood vessels revealed that the average dermal blood vascular surface area or the number of blood vessel endothelial cells was not affected by VEGF blockade in 3-day culture Fig. Moreover, anti-VEGF mAb did not affect endothelial cell proliferation as shown by CD31 and Ki double labelling online suppl. In order to test the model viability, cell death and cell proliferation were studied in the stratum basale in the epidermis. Anti-VEGF mAb did not decrease the percentage of Ki positive cells or increase terminal deoxynucleotidyl transferase TdT dUTP Nick-End Labeling TUNEL or cleaved caspase-3 expression in the stratum basale of organ-cultured human skin as measured by quantitative immunohistomorphometry Fig. Further investigation revealed no cleaved caspase-3 expression, a specific marker for apoptosis, in the stratum granulosum Fig. This suggests that anti-VEGF treatment did not alter keratinocyte survival, proliferation, or terminal differentiation within organ-cultured epidermis and thus primarily targeted intradermal endothelial cells during the incubation period. Levels of LDH enzyme were measured in the culture supernatant of samples treated with anti-VEGF mAb at 6, 12, 24, and 48 h. There was no increase in LDH activity in samples treated with anti-VEGF mAb compared to control, suggesting that anti-VEGF mAb was not toxic for human skin ex vivo at none of the doses tested online suppl. Anti-VEGF mAb did not affect keratinocyte terminal differentiation in skin organ culture ex vivo. a The expression of markers of terminal differentiation keratin 10, involucrin, and filaggrin was studied in the upper layers of the epidermis area surrounded by the yellow dotted line. DAPI was used for nuclear staining, and the white broken line indicates the epidermal-dermal junction. b Bevacizumab did not affect keratin 10, involucrin, or filaggrin expression in the epidermis. Next, the levels of VEGF protein were quantified in the organ culture supernatant of skin biopsies incubated with 0. These results suggest that 1 VEGF is released from skin biopsies into the culture media gradually with time, reaching its highest concentration in the organ culture supernatant at 48 h and 2 anti-VEGF mAb at 0. It is possible that the VEGF protein-drug complexes are still present in the treated biopsy samples. Alternatively, they may have been degraded within the tissue. Other investigators have suggested that complex degradation may occur through a variety of mechanisms such as pinocytosis and lysosomal degradation, cytosolic degradation, or degradation of internalized VEGF protein-drug complexes [ 20 ]. As a proof of concept, the effects of anti-VEGF mAb were tested in the uninvolved skin of 1 patient with psoriasis online suppl. Arguably, psoriasis pathogenesis is preferentially studied by utilizing uninvolved skin [ 21 ]. Differences in gene expression between uninvolved psoriatic skin and healthy control skin have been shown, suggesting similarity to skin from plaques of psoriasis [ 22 ]. Our images show visible induction of endothelial cell apoptosis and the viability of the skin was not affected, demonstrating that our model could be used in a psoriasis context to study the effects of anti-VEGF mAb in the skin in situ. Other angiogenic factors such as angiopoietin 1 and 2 as well as thrombospondin-1 also participate in the regulation of the microvascular network and affect endothelial cell function. However, these factors act on the blood vasculature and affect endothelial cells using different physiological mechanisms and activating different signalling pathways [ 24 ]. It was outside the scope of this study to look into alternative cellular pathways that act on the dermal vasculature. In conclusion, our pilot study provides the first evidence that anti-VEGF therapy promotes endothelial cell apoptosis in human skin ex vivo. In addition, we introduce a simple human skin organ culture model, which is reproducible and reliant only on the availability of human skin. In our model, the effects of anti-VEGF therapeutics on the apoptosis of native human vascular endothelial cell can be instructively studied within intact human dermis. The assay also permits assessment of human blood vessel density and structure. Moreover, endothelial cells in this organ culture system are quiescent, as they would be, physiologically in healthy adult skin in vivo. In addition, our model facilitates the visualization of hyperproliferating endothelial cells and the effects of anti-VEGF agents on the cutaneous microvascular network. This is especially relevant for the study of skin diseases characterized by pathological angiogenesis, such as psoriasis. The assay also permits dissection of the mechanism of action by which anti-VEGF therapeutics induce endothelial cell apoptosis. We would like to acknowledge the British Skin Foundation, UK, for funding and acknowledge Dr. Gadea Mata for helping with the vascular morphometric analysis. This research was supported by the NIHR Manchester Biomedical Research Centre. and R. conceived the experiments. and J. performed the experiments. and H. analyzed the data. acquired the funding. and D. acquired the tissue. Research data that are necessary to interpret the information presented here will be made available to any researcher, with minimal reuse restrictions. Sign In or Create an Account. Search Dropdown Menu. header search search input Search input auto suggest. filter your search All Content All Journals Skin Pharmacology and Physiology. Advanced Search. Skip Nav Destination Close navigation menu Article navigation. Volume 33, Issue 3. Materials and Methods. Results and Discussion. Statement of Ethics. Disclosure Statement. Funding Sources. Author Contributions. Availability of Data and Material. Article Navigation. Brief Reports June 22 Vascular Endothelial Growth Factor Blockade Induces Dermal Endothelial Cell Apoptosis in a Clinically Relevant Skin Organ Culture Model Subject Area: Dermatology , Pharmacology. Andrea Luengas-Martinez ; Andrea Luengas-Martinez. a Centre for Dermatology Research and Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK. This Site. Google Scholar. Jonathan Hardman-Smart ; Jonathan Hardman-Smart. David Rutkowski ; David Rutkowski. Talveen S. Purba ; Talveen S. Ralf Paus ; Ralf Paus. c Department of Dermatology and Cutaneous Surgery, School of Medicine, University of Miami, Miami, Florida, USA. Helen S. Young Helen S. Skin Pharmacol Physiol 33 3 : — Article history Received:. Connected Content. An erratum to this article has been published: Erratum - Vascular Endothelial Growth Factor Blockade Induces Dermal Endothelial Cell Apoptosis in a Clinically Relevant Skin Organ Culture Model. Cite Icon Cite. |
| Frontiers | The Anti-Angiogenic Effects of Anti-Human Immunodeficiency Virus Drugs | Heart health maintenance S, Fang H, Li Q, Wang G. Kim Anti-angiogenedis, Song Doseases, Seo HR. Disruption of the Anti-angiogenesis in skin diseases Nurture axis leads to hypervascular hyperplasia in psoriasis 9 Cerimele, et al. Reverse transcriptase inhibitors down-regulate cell proliferation in vitro and in vivo and restore thyrotropin signaling and iodine uptake in human thyroid anaplastic carcinoma. |
| Angiogenesis in Dermatology - Insights of Molecular Mechanisms and Latest Developments | Lesions clinically and histologically compatible with hemangiomas have also been reported in this region; the lesions disappeared on withdrawal of the treatment and recurred with each cycle of administration of sunitinib. Recently Chou et al. Skin biopsy showed the presence of dilated capillaries with endothelial cells that stained positive for VEGF, but this was not detected in a healthy control group. This finding supports the role of VEGF in the pathogenesis of sunitinib-related genital lesions, as proposed by Billemont et al. VEGF induces endothelial proliferation, vasodilatation, and increased vascular permeability. Elevated VEGF levels have been reported in the plasma of patients treated with sunitinib, and it has been speculated that there may be a physiological feedback that provokes a reversible increase in circulating and tissue VEGF after the administration of sunitinib a VEGF receptor antagonist. When VEGF reaches the scrotal region, characterized by a rich blood supply and subject to recurrent friction and trauma, it produces local symptoms such as scrotal erythema, tissue edema, telangiectasias, and the appearance of hemangiomas. Tonini et al. It has been shown that there is an increase in the number of circulating endothelial cells during treatment with sunitinib, not only of mature cells circulating endothelial cells [CEC] but also of their precursors circulating endothelial progenitors [CEP]. Similarly, increased numbers of CEPs have been found in children with proliferating hemangiomas. The anti-VEGF monoclonal antibody bevacizumab causes less skin toxicity than other similar drugs, but, apart from the typical reactions, this drug has other characteristic cutaneous side effects. In contrast to the situation with the EGFR antagonists, the majority of clinical trials found no association between the skin rash and a positive response to treatment. Only 2 cases have been reported in the literature in which the appearance and intensity of the skin rash correlated with a positive response to treatment with bevacizumab, with disappearance of the metastases as the skin lesions progressed. The rash was of erythematous papular lesions and recurred with each new cycle of bevacizumab. Bevacizumab is used off-label in ophthalmology as an intravitreous injection for the treatment of various diseases related to neovascularization, such as age-related macular degeneration, diabetic retinopathy, and choroidal neovascularization in myopia. There have been 2 case reports of the appearance of erythematous papular lesions on the head and trunk related to the intravitreous injection of bevacizumab for the treatment of choroidal neovascularization. In the second case, the patient received 3 injections of bevacizumab; 12 days after the first injection he developed an erythematous papular rash on the forehead and in the temporal regions around the eyes. With topical corticosteroid therapy, the lesions resolved within 8 days but reappeared 14 days after the second injection and 10 days after the third. Angiogenesis is a part of numerous physiological processes, including wound healing. In animal models it has been shown that bevacizumab inhibits the repair process in the dermis 84 ; this effect is dose-dependent and is reversible if administration of the drug is interrupted. Various effects of bevacizumab on wound healing have been described, such as wound dehiscence, ecchymosis, surgical wound hemorrhage, and an increased risk of infection. In contrast, patients who started to receive bevacizumab 28 to 60 days after surgery did not present a higher frequency of complications. It has been shown that would healing is negatively affected not only by the systemic administration of bevacizumab but also by intravitreous administration of the drug. Cases of ulceration of corticosteroid-induced striae have been reported in patients with cerebral tumors on treatment with bevacizumab. A case of necrosis of striae has been reported in a patient 1 week after starting treatment with bevacizumab and irinotecan for glioblastoma. Bevacizumab was discontinued 2 months later for lack of efficacy and the lesions healed within a month. In the case of cerebral tumors, high-dose corticosteroid therapy is often required for prolonged periods of time to manage cerebral edema. It is therefore particularly important to watch for possible side effects if therapy is started with antiangiogenic agents such as bevacizumab. The literature highlights the importance of the prevention of the appearance of ulcers on striae in these patients and, if they appear, adequate hydration of the area is recommended, together with the use of hydrocolloid dressings. There has been a case report of the appearance of slightly pruritic, umbilicated papular lesions on the neck of a patient who had been receiving bevacizumab for 2 months. The lesions measured 5 mm in diameter and had a central keratotic plug. Histology revealed the transepidermal elimination of collagen. Treatment interruption was not required. Numerous drugs have been approved in recent years for the treatment of various types of tumor, and many more molecules are in phase 3 or phase 4 clinical trials. The antiangiogenic drugs occupy an important place among these drugs. It is therefore very important for the dermatologist to be aware of the cutaneous effects associated with these drugs and to know how to manage them. The authors declare that they have no conflicts of interest. The authors are grateful to Dr Tuneu and Dr López Pestaña of Hospital Donostia, San Sebastian, Spain, for granting them use of their photographic material.. Please cite this article as: Ara M, Pastushenko E. Fármacos antiangiogénicos y piel: efectos cutáneos adversos de sorafenib, sunitinib y bevacizumab. Actas Dermosifiliogr. Home All contents Articles in press Current Issue All issues Supplements Multimedia Archivo histórico Subscribe to our newsletter Publish your article Instructions for authors Submit an article Ethics in publishing Open Access Option Language Editing services About the journal Aims and scope Editorial Board Advertising Metrics Most often read Most cited Most popular All metrics. Actas Dermo-Sifiliográficas. ISSN: Actas Dermo-Sifiliográficas ha recibido Factor de Impacto JCR por primera vez en Guía para autores - Envío de manuscritos. Actas Dermo-Sifiliográficas has received its first journal Impact Factor JCR in Instructions for authors - Submit an article. Open Access Option. Previous article Next article. Issue Pages December Lee este artículo en Español. More article options. DOI: Antiangiogenic Agents and the Skin: Cutaneous Adverse Effects of Sorafenib, Sunitinib, and Bevacizumab. Download PDF. Corresponding author. mam comz. org Corresponding author. Servicio de Dermatología, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain. This item has received. Article information. Show more Show less. Table 1. Summary of the Most Common Cutaneous Side Effects of the Angiogenesis Inhibitors.. Table 2. Largest Series Evaluating Cutaneous Side Effects in Patients Treated With Sorafenib.. In this review article, we analyze the main cutaneous adverse effects of the most common antiangiogenic agents. En esta revisión se analizan los efectos adversos cutáneos más importantes de los principales fármacos antiangiogénicos. Palabras clave:. Full Text. Introduction Several drugs that inhibit angiogenesis have produced encouraging results in recent years in the treatment of certain types of tumor. Figure 1. Author and Reference Year Description Autier et al. Figure 2. Figure 3. Table 3. Maintenance of the same dose is recommended 2 Skin changes peeling, blisters, hemorrhage, edema, hyperkeratosis with a variable degree of pain. Interference with daily activities As for grade 1Clobetasol cream, 0. Figure 4. Figure 5. The authors are grateful to Dr Tuneu and Dr López Pestaña of Hospital Donostia, San Sebastian, Spain, for granting them use of their photographic material. Chu, M. Lacouture, T. Fillos, S. Risk of hand-foot skin reaction with sorafenib: A systematic review and meta-analysis. Acta Oncol, 47 , pp. The growth of malignant disease in man and the lower animals with special reference to the vascular system. Lancet, 2 , pp. Greenblatt, P. Tumor angiogenesis: Transfilter diffusion studies in the hamster by the transparent chamber technique. J Natl Cancer Inst, 41 , pp. Ehrmann, M. Choriocarcinoma: Transfilter stimulation of vasoproliferation in the hamster cheek pouch studied by light and electron microscopy. Tumor angiogenesis: Therapeutic implications. N Engl J Med, , pp. Lacouture, S. Wu, C. Robert, M. Atkins, H. Kong, J. Guitart, et al. Evolving strategies for the management of hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib. Oncologist, 13 , pp. Lee, J. Lee, S. Chang, M. Lee, Y. Kang, J. Choi, et al. Cutaneous adverse effects in patients treated with the multitargeted kinase inhibitors sorafenib and sunitinib. Br J Dermatol, , pp. x Medline. Battistella, C. Mateus, N. Lassau, L. Chami, M. Boukoucha, P. Duvillard, et al. Sunitinib efficacy in the treatment of metastatic skin adnexal carcinomas: Report of two patients with hidradenocarcinoma and trichoblastic carcinoma. J Eur Acad Dermatol Venereol, 24 , pp. Wozel, M. Sticherling, M. Cutaneous side effects of inhibition of VEGF signal transduction. J Dtsch Dermatol Ges, 8 , pp. Braghioli, J. Sabbaga, P. Expert Rev Anticancer Ther, 12 , pp. McLellan, H. Cutaneous toxicities of the multikinase inhibitors sorafenib and sunitinib. Dermatol Therap, 24 , pp. Zhang, Q. Zhou, L. Ma, Z. Wu, Y. Meta-analysis of dermatological toxicities associated with sorafenib. Clin Exp Dermatol, 36 , pp. Autier, B. Escudier, J. Wechsler, A. Spatz, C. Prospective study of the cutaneous adverse effects of sorafenib, a novel multikinase inhibitor. Arch Dermatol, , pp. Robert, C. Mateus, A. Spatz, J. Wechsler, B. 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What is angiogenesis? H ow do angiogenesis inhibitors treat cancer? What angiogenesis inhibitors are approved to treat cancer? Thalidomide is not recommended during pregnancy because it causes severe birth defects. Vandetanib Caprelsa is approved to treat: Medullary thyroid cancer Ziv-aflibercept Zaltrap is approved to treat: Colorectal cancer Researchers are studying whether some of these drugs may treat other types of cancer. What are the side effects of angiogenesis inhibitors? Therefore, angiogenesis inhibitors can cause a wide range of physical side effects including: High blood pressure A rash or dry, itchy skin Hand-foot syndrome , which causes tender, thickened areas on your palms and soles. Diarrhea Fatigue Low blood counts Problems with wound healing or cuts reopening Although common, these side effects do not happen with every drug or every person. Rare side effects include: Serious bleeding Heart attacks Heart failure Blood clots Holes in the intestines, called bowel perforations If an angiogenesis inhibitor is recommended for you, talk with your doctor about the specific potential benefits and risks of that medication. How are angiogenesis inhibitors given? Questions to ask your health care team Consider asking these questions about angiogenesis inhibitors: Do you recommend an angiogenesis inhibitor as part of my treatment plan? Which one? What are the possible risks and benefits of the drug? What are the potential short- and long-term side effects of this medication? How long will this treatment last? How is this drug different from chemotherapy or other treatments? Will I take this drug at home or at the hospital? Will I need other cancer treatments in addition to this angiogenesis inhibitor? Which clinical trials are options for me? Who can help me manage the costs of my prescriptions? Related Resources Understanding Targeted Therapy Skin Reactions to Targeted Therapy and Immunotherapy More Information National Cancer Institute: Angiogenesis Inhibitors The Angiogenesis Foundation: Treatments. The blocked membranes were then incubated with various primary antibodies at 4°C overnight, followed by 1 h of incubation with various secondary antibodies. Finally, the proteins were detected using a Bio-Rad Imaging System Bio-Rad Biosciences, Hercules, CA, USA. Formalin-fixed skin specimens were embedded in paraffin and sectioned at a thickness of 7 μm. The sections were dewaxed by heating at 55°C for 30 min, washing twice for 15 min each, rehydrating in ethanol for 15 min, and incubating in water at 95°C for 5 min. The sections were then incubated at 4°C overnight with an anti-VEGF antibody diluted to , an anti-aANG1 antibody diluted to , or an anti-HIF-1α antibody diluted to The sections were then washed with phosphate-buffered saline PBS and incubated with the secondary antibody at 37°C for 30 min. Negative control sections were incubated with PBS instead of the primary antibody. The expression levels of VEGF, angiopoietin 1, and HIF-1α were quantified using Image-Pro Plus software Media Cybernetics, Rockville, MD, USA. Data are presented as the means ± SEM. A one-way analysis of variance was used for comparisons between three or more groups, with the Bonferroni correction for multiple comparisons. Statistical analyses were performed using SPSS A p value less than 0. At least three independent experiments were performed. IL induces angiogenesis by promoting the secretion of HIF-1α and VEGF and the migration of vascular endothelial cells Therefore, we used ILA-stimulated HUVECs as an in vitro angiogenesis model 22 to explore the anti-angiogenic effects of PSORI-CM02 and the associated mechanisms. We first evaluated the effects of PSORI-CM02 on the proliferation of ILA-stimulated HUVECs. The viability of ILA-stimulated HUVECs was reduced in a dose-dependent manner after 24 and 48 h of exposure to various concentrations of PSORI-CM02 0. Axitinib can effectively inhibit angiogenesis and was thus chosen as the positive control drug for the in vitro experiments The migration of ILA-stimulated HUVECs was significantly inhibited after PSORI-CM02 treatment Figures 1B, C , indicating that HUVEC migration was promoted by ILA treatment, but markedly inhibited by PSORI-CM02 treatment. Figure 1 PSORI-CM02 inhibited the proliferation and migration of interleukin IL A-stimulated human umbilical vein endothelial cells HUVECs. A HUVECs were treated with various concentrations of PSORI-CM02 from 0. The effects of PSORI-CM02 on ILA-stimulated cell viability were assessed via MTT assay. C Quantification of the HUVEC migration. the ILA-stimulated HUVEC group. Upregulated levels of oxidative factors accelerate the activation of T cells and keratinocytes, which promotes the synthesis and release of inflammatory cytokines and growth factors, consequently contributing to hypervascular hyperplasia in psoriasis As shown in Figure 2A , treatment with PSORI-CM02 significantly up-regulated the activities of SOD, GSH, and CAT and downregulated the levels of ROS, MDA, and LDH in ILA-stimulated HUVECs. The IL-1β, TNF-α, and IL-6 secretion levels were upregulated in ILA-stimulated HUVECs compared with control cells, whereas PSORI-CM02 markedly downregulated the mRNA levels of TNF-α and IL-6 , as determined by RT-PCR Figure 2B. Figure 2 Effects of PSORI-CM02 on oxidative stress and inflammation in interleukin IL A-stimulated human umbilical vein endothelial cells HUVECs. A HUVECs were treated with 1. B Total RNA was isolated from HUVECs, and RT-PCR was used to investigate the levels of various pro-inflammatory cytokines. Several angiogenic mediators, such as VEGF, VEGFR, HIF-1α, and ANG1, are upregulated in psoriatic lesions to promote the formation of new blood vessels To evaluate the effects of PSORI-CM02 on pro-angiogenic factors in ILA-stimulated HUVECs, we measured the expression levels of VEGF, VEGFR1, VEGFR2, ANG1, and HIF-1α. As shown in Figures 3A—C , the levels of these molecules were upregulated significantly in ILA-stimulated HUVECs compared with the control cells, whereas PSORI-CM02 markedly downregulated the levels of angiogenesis-related markers, as indicated by ELISA and western blotting results. As the classical MAPK pathway is closely involved in the regulation of angiogenesis 14 , we investigated the MAPK signalling pathway in ILA-stimulated HUVECs. Therefore, PSORI-CM02 may inhibit the MAPK signalling pathway to inhibit angiogenesis. Figure 3 PSORI-CM02 suppressed the expression of pro-angiogenic factors and the phosphorylation of MAPK signalling pathway components in interleukin IL A-stimulated human umbilical vein endothelial cells HUVECs. The levels of hypoxia inhibitory factor HIF -1α and vascular endothelial growth factor VEGF were determined by ELISA. B Representative western blots of VEGF receptor 1 VEGFR1 , VEGFR2, angiopoietin 1 ANG1 , and HIF-1α expression in HUVECs treated with 1. C Quantification of VEGFR1 , VEGFR2 , ANG1 , and HIF-1α levels relative to GAPDH levels at 24 h. D Representative western blot of MAPK pathway protein expression in HUVECs treated with 1. the ILA- stimulated HUVEC group. The anti-angiogenic efficacy of orally administered PSORI-CM02 for the treatment of IMQ-induced psoriasis was evaluated in a mouse model. Methotrexate MTX is the main orally administered treatment for psoriasis 26 and was thus chosen as the positive control drug in this study. To visually represent the effect of PSORI-CM02 on angiogenesis at the lesion site, we photographed the back skin of mice on the 7th day of IMQ treatment. As shown in Figure 4A , compared with the control group, the extent of neovascularisation and vascular tortuousness were significantly increased in the IMQ-only group. However, the PSORI-CMtreated groups showed a significant reduction in neovascularisation of the skin in mice with IMQ-induced psoriasis. Figure 4 PSORI-CM02 inhibited angiogenesis in mice with imiquimod IMQ -induced psoriasis. A Photographs of the backs of mice 7 days after the first IMQ application. Mice were randomly divided into five groups, and methotrexate MTX or PSORI-CM02 administration began 4 h before daily IMQ cream application for 7 days. B Superoxide dismutase SOD , lactate dehydrogenase LDH , malondialdehyde MDA , and catalase CAT levels were measured in back skin tissues of mice from each group using commercial assay kits. C The mRNA levels of interleukin IL -6 IL-6 , tissue necrosis factor-α TNF-α , ILA , and ILF in mouse skin tissues were determined by RT-PCR. To determine the mechanism responsible for the effect of PSORI-CM02 on skin angiogenesis, we analysed antioxidative and oxidative molecules in the skin of mice with IMQ-induced psoriasis. As shown in Figure 4B , compared with the control group, SOD and CAT activities were significantly reduced in the skin of mice in the IMQ group, while the LDH and MDA levels were increased. These results showed that PSORI-CM02 balanced the levels of antioxidative and oxidative factors in the skin of mice with IMQ-induced psoriasis. Several pro-angiogenic cytokines, such as IL-6, TNF-α, and IL, are up-regulated in psoriatic lesions, which may contribute to the increase in blood vessel formation in psoriasis patients Therefore, we used RT-PCR to assess the mRNA levels of inflammatory cytokines, such as IL-6 , TNF-α , ILA , and ILF , in skin tissues of mice with IMQ-induced psoriasis. As shown in Figure 4C , the levels of all four cytokines were upregulated in the skin of mice with psoriasis compared with the levels in the skin of control mice. However, PSORI-CM02 markedly downregulated the levels of these pro-inflammatory cytokines. VEGF is a significant mediator of angiogenesis and plays a key role in the formation of vascular abnormalities in psoriatic skin lesions HIF-1α promotes the expression of VEGF 29 , while ANG1 and VEGFR play essential roles in angiogenesis in psoriasis To explore the anti-angiogenic mechanisms of PSORI-CM02, we further analysed the expression of VEGF , VEGFR1 , VEGFR2 , ANG1 , and HIF-1α. As shown in Figure 5A , PSORI-CM02 treatment reduced the mRNA expression levels of VEGF and HIF-1α in the skin of mice with IMQ-induced psoriasis. Figure 5 Effects of PSORI-CM02 on pro-angiogenic factors in mice with imiquimod IMQ -induced psoriasis. A Total RNA was isolated from skin tissues of mice, and RT-PCR was used to determine the levels of vascular endothelial growth factor VEGF and hypoxia inhibitory factor 1α HIF-1α mRNA. C Quantification of integrated optical density of VEGF, ANG1, and HIF-1α in skin tissue sections. D Representative western blots of VEGF receptor 1 VEGFR1 , VEGFR2, ANG1, and HIF-1α protein expression in the skin of mice with IMQ-induced psoriasis. Next, we analysed VEGF and ANG1 expression by immunohistochemistry. Compared with control mice, IMQ-treated showed a greater area of brown precipitate in the epidermis. However, after the administration of PSORI-CM02, the area of brown precipitate in the epidermis significantly decreased. Immunohistochemical analysis of HIF-1α showed that PSORI-CM02 treatment reduced the area of brown precipitate in both the epidermis and the dermis, compared with the area of brown precipitate in IMQ-treated mice. The above results show that the protein expression levels of VEGF, ANG1, and HIF-1α decreased after PSORI-CM02 treatment Figures 5B, C. Western blotting analysis also showed that PSORI-CM02 treatment significantly downregulated the expression levels of VEGFR1, VEGFR2, ANG1, and HIF-1α in mice with IMQ-induced psoriasis Figures 5D, E. These results indicate that PSORI-CM02 treatment inhibits angiogenesis in psoriatic skin lesions induced by IMQ. The MAPKs are a family of serine-threonine protein kinases that are involved in cell proliferation, apoptosis, differentiation, oxidative stress, signal transduction, and immune responses The inhibition of MAPK signalling pathways down-regulates oxidative stress and inflammatory cytokine levels, thereby inhibiting angiogenesis in psoriasis In addition, PSORI-CM02 significantly inhibited the phosphorylation of p38 and JNK1. Therefore, PSORI-CM02 inhibits the MAPK signalling pathway to play an anti-angiogenic role in IMQ-induced psoriasis. Figure 6 Effects of PSORI-CM02 on the MAPK signalling pathway in mice with IMQ -induced psoriasis. A Representative western blot of MAPK pathway protein expression in the skin of mice with IMQ-induced psoriasis. Abnormal angiogenesis of skin lesions is a crucial pathological feature of psoriasis. The up-regulation of angiogenic mediators, including VEGF, HIF-1α, and ANG1, and pro-angiogenic cytokines, such as IL, TNF-α, IL-6, and IL-1β, contribute to this abnormality. These factors exert a synergistic effect on the development of psoriasis 8. Disruption of the oxidative stress-inflammation-angiogenesis axis leads to hypervascular hyperplasia in psoriasis 9 , The target of anti-angiogenesis therapy in psoriasis is closely related to this axis. Thus, we used ILA to stimulate HUVECs for in vitro experiments. Mice with IMQ-induced psoriasis have clinical manifestations and histopathological and immunological changes similar to human psoriasis vulgaris Therefore, in this study, an IMQ-induced mouse model of psoriasis was used to assess the anti-angiogenic effects of PSORI-CM02 in vivo. In this study, we investigated whether the anti-psoriatic effects of PSORI-CM02 depend on its anti-angiogenic effects in vivo and in vitro and explored the underlying mechanisms. Abnormal microangiogenesis is closely related to the development of psoriasis Microcirculation disturbances and hemorheological changes are observed in the skin lesions of psoriatic patients In this study, we found that PSORI-CM02 inhibited the proliferation and migration of ILA-stimulated HUVECs and reduced new blood vessel growth in the skin of mice with IMQ-induced psoriasis. Pro-angiogenic factors derived from keratinocytes and immune cells, such as oxidative molecules, antioxidative molecules, and inflammatory cytokines, contribute to blood vessel formation in psoriasis Excessive levels of oxidative stress cause the secretion of inflammatory cytokines and growth factors, which induce vascular endothelial cell dysfunction 24 and can, consequently, contribute to angiogenesis. These results suggested that PSORI-CM02 exerts anti-angiogenic effects by reducing the levels of oxidative stress and inflammation. VEGF and its high-affinity tyrosine kinase receptors, VEGFR1 and VEGFR-2, are essential for vascular embryogenesis and neovascularisation 36 , In situ hybridisation and immunohistological analyses have shown that VEGF is upregulated in epidermal keratinocytes and VEGFR1 and VEGFR2 are overexpressed in psoriatic skin lesions 38 , HIF-1α, VEGF, and VEGFR play crucial roles in the onset and progression of psoriasis and are, therefore, promising targets for the treatment of psoriasis In our study, PSORI-CM02 suppressed the expression of angiogenic mediators, including VEGF, HIF-1α, VEGFR1, VEGFR2, and ANG1, in ILA-stimulated HUVECs and in mice with IMQ-induced psoriasis. The MAPK signalling cascade is a key pathway that regulates a wide variety of cellular processes, including proliferation, differentiation, apoptosis, and angiogenesis Our next study will focus on whether the PSORI-CMmediated inhibition of the phosphorylation of MAPK pathway components suppresses angiogenesis in vivo and in vitro. In conclusion, the results of our study demonstrate that PSORI-CM02 inhibits the proliferation and migration of ILA-stimulated HUVECs. In mice with IMQ-induced psoriasis, PSORI-CM02 reduces neovascularisation and vascular tortuousness in skin lesions. In vitro and in vivo , PSORI-CM02 supresses the phosphorylation of the MAPK pathway, regulates the balance between oxidants and antioxidants, and decreases the release of inflammatory cytokines and the synthesis of angiogenic mediators. These anti-angiogenic effects may be the mechanism by which PSORI-CM02 effectively treats psoriasis. Further investigations are required to assess the relationship between PSORI-CM02 and the MAPK pathway, oxidative stress, inflammation, and angiogenesis in vivo and in vitro. The animal study was reviewed and approved by Animal Welfare and Ethics Branch of the Biomedical Ethics Committee of Guangzhou University of Chinese Medicine. LH and CL conceived and designed the experiments. YL, YY, JZ, HZ, CM, and XT performed the experiments. YL, YY, JWu, LL, JWei, and HC analysed and interpreted the data. LH and CL performed data analysis and interpretation. YL, YY, and JZ wrote the article. All authors contributed to the article and approved the submitted version. This research was financially supported by the National Natural Science Foundation of China and ; the Guangdong Province Science and Technology Planning Project A, A, B, A, A, and B , the Guangdong Provincial Department of Education Project KQNCX , Guangzhou Science and Technology Project and the Guangdong Provincial Hospital of Chinese Medicine Special Fund YNZD08, YNHK01, YNRBA02, YNXP02, YNQJ04, and YNQJ The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. |
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