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 Curcumae , Radix Paeoniae Rubra , S. glabra , Rhizoma Smilacis glabrae , and 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-1β , TNF-α , IL-6 ,and GAPDH mRNAs. Skin tissues were also collected from mice to analyse the mRNA expression levels of IL-6 , TNF-α , ILA , ILF , VEGF , HIF-1α , and 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 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.

HUVECs, human umbilical vein endothelial cells; IMQ, imiquimod; MTX, methotrexate; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; ANG1, angiopoietin-1; HIF-1α, hypoxia-inducible factor-1 alpha; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; SOD, superoxide dismutase; GSH, glutathione; CAT, catalase; ROS, reactive oxygen species; MDA, malonaldehyde; LDH, lactate dehydrogenase.

Armstrong AW, Read C. Pathophysiology, Clinical Presentation, and Treatment of Psoriasis: A Review. JAMA 19 — doi: PubMed Abstract CrossRef Full Text Google Scholar. Boehncke WH, Schön MP. Lancet — Dand N, Mahil SK, Capon F, Smith CH, Simpson MA, Barker JN.

Psoriasis and Genetics. Acta Derm Venereol 3 :adv Tokuyama M, Mabuchi T. New Treatment Addressing the Pathogenesis of Psoriasis. Int J Mol Sci 21 20 CrossRef Full Text Google Scholar. Kamata M, Tada Y. Safety of Biologics in Psoriasis.

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In addition to pro-angiogenic growth factors, pro-inflammatory cytokines also contribute to this process by activating endothelial cells and exerting pro-angiogenic action as well. Angiogenesis, in psoriasis display a close association of vascular endothelium activation, angiogenesis, inflammation and lesional skin, as is demonstrated by in vivo models.

Objective: The present review discusses angiogenesis as the central process in the evolution of psoriasis and summarizes various angiogenic mediators and their respective roles in the development of psoriasis. Conclusion: Anti-angiogenic therapies targeting vasoproliferation may represent a valid approach for the development of anti-psoriatic drugs and further development in this field can pave way to new fields of treatment.

Such therapies could be at par to those directly targeting inflammation. Keywords: Angiogenesis; angiopoietins; hyperproliferation; keratinocytes; psoriasis; vascular endothelial growth factor..

Copyright© Bentham Science Publishers; For any queries, please email at epub benthamscience. Abstract Background: Psoriasis is a chronic disease of inflammatory nature.

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