Kushen herpes tincture confront senile herpes zoster by inhibiting STAT3 and EGFR
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Dan Deng
,
Sijie Du
,
Ni Wen
,
Lingling Yang
,
Xiaoguo Zhang
,
Jinping Kang
,
Min You
and
Yuanming Bai
Abstract
Objectives
The study aimed to explore the potential mechanism of Kushen Herpes Tincture in treating herpes zoster in aging people based on network pharmacology.
Methods
Four herbs in Kushen Herpes Tincture were screened for transdermal active ingredients by TCMSP and HERB databases. Topological Polar Surface Area (TPSA) smaller than 60 Å square (Å2) was used to screen the good at cell membrane-penetrating compounds. Potential targets of compounds were gathered from TCMSP, HERB, and SwissTargetPrediction. GeneCards and DisGeNET databases were used to screen herpes zoster-related targets. The targets were analyzed for protein interactions and KEGG enrichment. Among the top 20 targets, STAT3 and EGFR were subjected to cell experiment validation.
Results
Kushen Herpes Tincture was predicted to act on 51 herpes zoster-related targets. These targets were retraced to 103 cell membrane-penetrating compounds. Protein interactions proposed STAT3 and EGFR as two among the top 10 targets. The key KEGG pathway contained C-type lectin receptor signaling pathway, PI3K-Akt signaling pathway, etc. STAT3 and EGFR were upregulated in human keratinocyte and human epithelial cells after varicella-zoster virus infection, while decreased by Kushen Herpes Tincture treatment. Kushen Herpes Tincture restricted varicella-zoster virus replication in vitro.
Conclusions
Kushen Herpes Tincture may exert its therapeutic effect on aging herpes zoster through multi-component action on multi-targets and multi-pathways, including STAT3 and EGFR.
Introduction
Herpes zoster is also known as shingles. It is often caused by a latent varicella zoster virus (VZV) [1], 2]. More often than primary infections, viral reactivations are symptomatic [3]. The latent virus can reactivate in the body years later when immunity declines and causes herpes zoster, a neurocutaneous disease. In addition to shingles, viral reactivation syndrome encompasses severe and painful postherpetic neuralgia and many other neurologic conditions [4]. The disease is intensely painful and is an extremely agonizing illness that may last for weeks or months [4]. Pooled postherpetic neuralgia risk was 12.6 % in China [5]. Since herpes zoster is secondary to chickenpox, its incidence increases with age. Aging of the body is often accompanied by a decrease in cellular immunity, which makes older people susceptible to shingles. Age is a major risk factor for developing herpes zoster [6]. The global population is aging, with the older people expected to double by 2050 [7]. The use of vaccine prophylaxis is a key strategy in the fight against herpes zoster, but there are challenges in using the vaccine in an older population with compromised immune function [8]. Antiherpesviral drugs with novel pharmacologic mechanisms should be introduced with a view to advancing the treatment of herpes zoster.
Currently, herpes zoster can seek herbal remedies to relieve symptoms. These herbal remedies usually include topical application or oral administration of herbs. One study reveals that Chuanjin Qinggan decoction can lead to reduced pain and improved sleep quality in depressed patients with herpes zoster [9]. Hydrocotyle sibthorpioides Lam. has been used by different tribes around the world to treat patients with shingles infections [10]. In several Asian countries, many Gynura species have been regarded as effective herbal remedies for shingles infections [11]. Aqueous extract of Sophorae Flavescentis Radix showed significant antiviral activity [12]. Kushen Herpes Tincture is based on Sophorae Flavescentis Radix as the main herb, additionally supplemented with Erigeron Breviscapus, Cortex Moutan, and Apis mellifera ligustica. Sophorae Flavescentis Radix has antiviral activity and positive effect on liver biochemistry in chronic hepatitis B [13]. Sophorae Flavescentis Radix can mediate CFHR2 expression and inhibit the inflammatory response of macrophages [14]. It is widely used in pruritus treatment, especially histamine-independent intractable itching [15]. Erigeron Breviscapus has neuroprotective effects [16]. Cortex Moutan is an herbal remedy with a wide range of pharmacological activities such as anti-inflammatory, antioxidant, neuroprotective, and hepatoprotective effects [17]. A. mellifera ligustica has a role in regulating inflammation to homeostasis and anti-inflammation [18]. Kushen Herpes Tincture can clear heat and detoxify, remove heat from the blood, and alleviate pain. It is mainly used to treat herpes zoster in China.
The concept of “network pharmacology” was first introduced in 2007 to analyze the interrelationships between drugs, diseases, and targets using a biological network approach [19]. Based on the integration of systems biology, bioinformatics and computational network science, this method can analyze the complex biological relationship between drugs and the human body from the perspective of “multi-target, multi-pathway” [20]. This integrated approach plays a key role in guiding the development and clinical practice of traditional Chinese medicine.
Therefore, this study used network pharmacology to predict the main active components, potential targets, and mechanism of action of Kushen Herpes Tincture. To validate the predicted key targets, cell culture experiments were conducted.
Materials and methods
Ethical statement
An ethics statement was not required for this study since no human or animal subjects or materials were used.
Screening of transdermal active ingredients in kushen herpes tincture
Sophorae Flavescentis Radix, Erigeron Breviscapus, and Cortex Moutan were searched in TCMSP database (https://www.tcmsp-e.com/#/database) under ‘Herb name’ as keywords for the constituents of each herb. Raphani Semen was searched in the HERB database (http://herb.ac.cn/) under the ‘Herb’ item. Polar surface area is the sum of the areas of the polar parts of the surface of a molecule, which can reflect the molecular surface properties. Topological Polar Surface Area (TPSA) is a physicochemical property that describes the polarity of a molecule, and TPSAs smaller than 60 Å square (Å2) are usually good at penetrating cell membranes [21]. As a topical formulation, TPSA less than 60 Å2 was selected as a screening parameter to obtain the active ingredient of Kushen Herpes Tincture. TPSAs were collected from PubChem chemistry database (https://pubchem.ncbi.nlm.nih.gov/).
Collection of the targets for transdermal active ingredients
The targets of the available components were collected in TCMSP, and the HERB database was used as a complementary target library. For compositions for which targets could not be retrieved, after obtaining ‘Isomeric SMILES’ in the Pubchem database, we predicted them in SwissTargetPrediction (http://www.swisstargetprediction.ch/) and used Probability greater than 0 as inclusion criteria to obtain potential targets. The UniprotKB database (https://www.uniprot.org/), a universal protein knowledgebase, was used to annotate and standardize the collected targets.
Construction of ‘Herb-Active Ingredient-Target’ network for kushen herpes tincture
The ‘Herbal-Transdermal-Active Ingredient-Target’ network for Kushen Herpes Tincture was constructed using Cytoscape 3.9.1.
Search for aging herpes zoster-related targets
Potential targets of herpes zoster were searched from GeneCards (https://www.genecards.org/) and DisGeNET (https://www.disgenet.org/) databases using ‘herpes zoster’ as the keyword. The results were combined to remove duplicates and normalized in the Uniprot database to obtain aging herpes zoster-related targets.
Construction of the ‘herb-component-disease target’ network
The disease targets were interacted with the targets for transdermal active ingredients. Cytoscape 3.9.1 software was introduced for the construction of the herb-component-disease-target network.
Protein-protein interaction (PPI) network for identification of key targets
For the construction of the protein-protein interaction (PPI) network model, the overlapping targets were imported into the STRING database. The network was reconstructed by Cytoscape 3.9.1 software, with topology analyzed. Degree values were used to screen the top 20 targets.
KEGG pathway enrichment analysis
Targets were annotated using Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses using OmicShare Tools with p<0.01 setting. The enriched GO entries were sorted by p-value from low to high, and secondary analyses were performed. And the top 20 enriched pathways were visualized.
Cell line culture and virus infection
HaCaT cells (Shanghai Institute of Biochemistry and Cell Biology (SIBCB), China) and ARPE-19 Cells (SIBCB, China) were maintained in respective mediums, Dulbecco’s modified Eagle’s medium (DMEM) and DMEM/F12 (1:1), which supplemented with 10 % fetal bovine serum (FBS). VZV (P-Oka strain) recombinant virus (Wuhan Institute of Virology, China) was infected HaCaT or ARPE-19 cells were co-cultivated with uninfected cells at a 1:5 ratio [22]. Virus titration was performed on HaCaT or ARPE-19 cells in triplicate. A concentration of 5 mg/mL in DMEM or DMEM/F12 (1:1) was selected as the non-cytotoxic concentration of Kushen Herpes Tincture for HaCaT cells base on our preliminary studies. The full-length STAT3 plasmid (pcDNA.STAT3), full-length EGFR plasmid (pcDNA.EGFR) and their control (pcDNA.NC) were synthesized by Genepharma (Shanghai, China). Cell transfection was performed using Lipofectamine 3,000 (Invitrogen, USA).
Western blotting
To analyze phosphorylated STAT3, phosphorylated EGFR, IE62 and ORF11 protein expression, confluent monolayers of HaCaT or ARPE-19 cells were grown in 25 cm2 flasks and infected with VZV. In some determination, cells were transfected with full-length STAT3 plasmid (pcDNA.STAT3), full-length EGFR plasmid (pcDNA.EGFR) and its control (pcDNA.NC) (all from Genepharma, China) using Lipofectamine 3,000 (Invitrogen). Cells were then scraped in ice-cold PBS, pelleted by centrifugation and lysed. Supernatants of the cell lysates after centrifugation were subjected for protein quantification using Pierce BCA Protein Assay Kit (Thermo Fisher Scientific. USA). 30 mg of cell lysates were separated by SDS-Page and transferred to Immobilon-FL PVDF membranes (Merck). After blocked with 5 % (w/v) skim milk, the membrane was stained with primary antibodies overnight at 4 °C, followed by another incubation with the secondary antibodies. The bands on the membrane were analyzed using LI-COR Odyssey Infrared Imaging System.
Statistical analysis
All statistical analyses were performed with Graphpad Prism software, using the statistical tests indicated in each figure legend. When p<0.05, the difference was significant. No indication mean that the difference was not significant.
Results
Targets of kushen herpes tincture against aging herpes zoster
Kushen Herpes Tincture belongs to the category of externally applied remedies. After screening by TPSA parameters, a total of 97 active ingredients were obtained, of which 35 from Sophorae Flavescentis Radix, 18 from Erigeron Breviscapus contained, 20 from Cortex Moutan, and 26 from A. mellifera ligustica (Supplementary Table 1). After target prediction, these ingredients targeted a total of 698 targets (Supplementary Figure 1). Fifty-one targets against aging herpes zoster were obtained in Kushen Herpes Tincture by taking intersection with disease targets (Figure 1). Compositional and herbal backtracking of these targets revealed that 56 components in four herbs of Kushen Herpes Tincture could be associated (Supplementary Figure 2). The constructed network had 111 nodes and 212 edges. After analyzing the network, the components with the highest degree values were (6aS, 11aS)-homopterocarpin (HBIN012233), 5-methoxyflavanone (HBIN011752), (6aS, 11aS)-medicarpin (HBIN012234), (3 S)-7-O-methylvestitol (HBIN009696), pimaric acid (HBIN039936), neoabietic acid (HBIN036539), 14,15-dinor-13-oxo-8 (17)-labden-19-oic acid (HBIN001321), Dimethylallylumbelliferone (MOL006633), Paeonol (MOL000874), and Formononetin (MOL000392).
Network diagram of “herbs-transdermal active ingredients-herpes zoster targets” in kushen herpes tincture. Different colors and shapes of nodes represent different entries, where pink ovals represent herbs, green diamonds represent transdermal active ingredients, and yellow squares represent targets.
PPI network and pathway enrichment analyses of targets
The 51 common targets were imported into the String database to obtain the PPI network diagram, which was visualized using Cytoscape 3.9.1 software and then displayed according to the degree value (Figure 2A). By enrichment analysis of the above 51 key targets, KEGG enrichment results showed a total of 144 signaling pathways were enriched. Kaposi sarcoma-associated herpesvirus infection, Human T-cell leukemia virus one infection, C-type lectin receptor signaling pathway, PI3K-Akt signaling pathway ranked among the top 20 pathways (Figure 2B).
Target annotation. (A) Protein-protein interaction (PPI) of targets. (B) A bioinformatics resource for linking genomes to life and the environment-kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis was conducted and depicted to be a bubble diagram.
Kushen herpes tincture downregulated STAT3 and EGFR in VZV-infected cells
After analyzing the network topology, the top 20 genes according to degree value were IL6, GAPDH, AKT1, TNF, IL1B, STAT3, EGFR, TP53, INS, JUN, MAPK3, MTOR, ESR1, IFNG, PTEN, IL2, IL4, JAK2, ICAM1, and CD44 (Figure 3A). It is believed that signal transducer and activator of transcription 3 (STAT3) may exhibit proviral functions in VZV infection [23]. Furthermore, a prominent role for the transduction axis of epidermal growth factor receptor (EGFR) signaling in VZV infection has been identified [24]. To investigate the effect of Kushen Herpes Tincture on expression levels of STAT3 and EGFR, cell culture experiments in vitro were performed. We found Kushen Herpes Tincture reduced the upregulation of p-STAT3 (Figure 3B) and p-EGFR (Figure 3C) in HaCaT cells caused by VZV infection. Similarly, Kushen Herpes Tincture reduced the increase in p-STAT3 (Figure 3D) and p-EGFR (Figure 3E) caused by VZV infection in ARPE-19 cells.
Kushen herpes tincture downregulated STAT3 and EGFR in VZV-infected cells. (A) Top 20 hub genes sorted by degree value. (B) and (C) relative protein levels of p-STAT3 and EGFR in HaCaT cells. (D) and (E) relative protein levels of p-STAT3 and EGFR in ARPE-19 cells. Data were analyzed by one-way analysis of variance (multiple comparisons using Turkey test). ∗∗∗ indicated significance when compared with control group. ### Indicated significance when compared with VZV infection group. &&& indicated significance when compared with pcDNA.NC group.
Kushen herpes tincture restricted varicella-zoster virus replication in vitro through STAT3 and EGFR
To establish biological relevance, we investigated the consequences of treatment with Kushen Herpes Tincture on VZV-infected cells in vitro. The mean VZV titer was significantly decreased in VZV-infected ARPE-19 cells in the presence of Kushen Herpes Tincture, while overexpression of STAT3 or EGFR increased the VZV titer (Figure 4A). Impaired VZV replication in the presence of Kushen Herpes Tincture was further confirmed by decreased expression of VZV proteins IE62 and ORF11, which was restored by overexpression of STAT3 or EGFR (Figure 4B and C). VZV titers in VZV-infected HaCaT cells decreased in the presence of Kushen Herpes Tincture (Figure 4D). VZV proteins IE62 and ORF11 in Kushen Herpes Tincture-treated HaCaT cells were also much more restricted (Figure 4E and F).
Kushen herpes tincture restricted varicella-zoster virus replication in vitro through STAT3 and EGFR. (A) Infectious virus yields were determined by titration on ARPE-19 cells. (B) and (C) expression of VZV proteins was assessed in VZV-infected ARPE-19 cells using Western blotting (D) infectious virus yields were determined by titration on HaCaT cells. (E) and (F) expression of VZV proteins was assessed in VZV-infected HaCaT cells using Western blotting. Data were analyzed by one-way analysis of variance (multiple comparisons using Turkey test). ### Indicated significance when compared with VZV infection group. && or &&& indicated significance when compared with pcDNA.NC group.
Discussion
Herpes zoster is a disease caused by the reactivation of the herpes virus that is latent in the body and is more common in older people [25]. Kushen Herpes Tincture can detoxify and relieve pain, commonly used in China for herpes zoster caused by dampness-heat of liver channel. In this study, network pharmacology was applied to analyze and predict the potential active ingredients and corresponding targets and signaling pathways of Kushen Herpes Tincture against aging herpes zoster. The network pharmacology approach yielded 97 transdermal active ingredients in Kushen Herpes Tincture, targeting a total of 698 targets, of which 56 ingredients could act on 51 herpes zoster disease genes.
By analyzing the network topology of “Herb-Active Ingredient-Target” of Kushen Herpes Tincture, it was found that (6aS, 11aS)-homopterocarpin (HBIN012233), 5-methoxyflavanone (HBIN011752), (6aS, 11aS)-medicarpin (HBIN012234), 14,15-dinor-13-oxo-8 (17)-labden-19-oic acid (HBIN001321), Dimethylallylumbelliferone, 0- (MOL006633), Paeonol (MOL000874), and Formononetin (MOL000392) corresponded to a large number of targets, which are potential pivotal active ingredients for the treatment of herpes zoster (6aS, 11aS)-homopterocarpin, also known as 3,9-Dimethoxypterocarpan, Baphinitone, (−)-Homopterocarpin, has antifungal and antimicrobial activities [26], 27]. Monoamine oxidase B inhibitor can ameliorate paclitaxel-induced peripheral neuropathy [28] (6aS, 11aS)-medicarpin has a role in cell protection through the promotion of NRF2 transcriptional activity [29]. Herpes simplex virus one infection enhances the degradation of nuclear factor E2-related factor 2 (Nrf2) [30]. Upregulation of Nrf2 represses the replication of herpes simplex virus type 1 [31]. Paeonol can inhibit several virus infections [32]. Formononetin can inhibit enterovirus 71 replication by regulating COX-2/PGE2 expression, and exhibit significant anti-herpes simplex virus activity in vitro [33].
Based on PPI network analysis and pathway analysis, STAT3 and EGFR were found to be the core targets of Kushen Herpes Tincture for the treatment of aging herpes zoster. In this study, we found VZV infection increased the level of p-STAT3, which was in line with the results from Buckingham’s study [34]. We also found Kushen Herpes Tincture can reduced the p-STAT3 level in VZV-infected cells. IL-6 has been identified to act as a pro-autophagy cytokine within the IL-6-STAT3 pathway, which lead STAT3 involve in autophagy during VZV infection [35]. VZV-activated STAT3 contributes to the formation of skin lesions after viral infection, suggesting that p-STAT3 regulation is a potential target against VZV infection [36]. STAT3 is known to be a regulator of genes involved in wound healing, the anagen phase of the hair cycle, and migration of keratin-forming cells. STAT3 has been reported as a transcription factor gene which is mediated by resveratrol in VZV infection [37]. We found that Kushen Herpes Tincture inhibited p-STAT3 levels after VZV infection. Previous studies have shown that VZV can alter the basal program of infected follicular stem cells by activating STAT3 in newly infected follicular stem cells, accelerates the delivery of VZV to the epidermal site where lesions begin to form and can accelerate keratinocyte growth leading to hyperkeratosis [36]. We found that overexpression of p-STAT3 counteracted the anti-VZV effect of Kushen Herpes Tincture. These suggest that Kushen Herpes Tincture may exert anti-aging herpes zoster effects by targeting STAT3. An important role for EGFR signalling in VZV infection has been demonstrated by analysis of the viral and host proteomes of VZV-infected human epithelial cells. EGFR stimulation and inhibition resulted in an increase and decrease, respectively, in viral replication [24]. Myricetin has potential to target cellular EGFR/PI3K/Akt pathway and inhibit herpes simplex virus [38]. Here, we found Kushen Herpes Tincture can inhibit the p-EGFR level in VZV-infected cells and suppress VZV replication.
Conclusions
In summary, this study applied network pharmacology to predict the active ingredients, potential targets, and regulatory pathways of Kushen Herpes Tincture for the treatment of aging herpes zoster and theoretically demonstrated the inhibitory effect of Kushen Herpes Tincture on herpes zoster. Kushen Herpes Tincture may inhibit the p-EGFR and p-STAT3 level in VZV-infected cells and suppress VZV replication. This study highlights the “multi-target and multi-pathway” manner of Kushen Herpes Tincture in treating herpes zoster, providing an effective approach for exploring the mechanisms of Kushen Herpes Tincture in the treatment of herpes zoster.
Funding source: This work was funded by Hangzhou Medicine and Health Science and Technology Program
Award Identifier / Grant number: Project Number: B20210569
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Research ethics: An ethics statement was not required for this study type since no human or animal subjects or materials were used.
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Informed consent: N/A.
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Author contributions: All authors contributed to the study conception and design. Material preparation and data collection were performed by Dan Deng, Sijie Du, Ni Wen, Lingling Yang, Xiaoguo Zhang, and Jinping Kang, Yuanming Bai. Data analysis was conducted by Dan Deng, Sijie Du, Ni Wen and Min You. The first draft of the manuscript was written by Ni Wen and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Use of Large Language Models, AI and Machine Learning Tools: None.
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Conflict of interest: None.
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Research funding: This work was funded by Hangzhou Medicine and Health Science and Technology Program, Project Number: B20210569.
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Data availability: All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.
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