Submitted:
02 December 2024
Posted:
03 December 2024
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Abstract
Background. Psoriasis is a chronic autoimmune disease marked by excessive skin cell growth and inflammation, driven by the overexpression of certain key genes. Advances in omics have revealed genes pivotal to psoriasis, while natural substances offer the potential for gene modulation. By combining omics data with large language models (LLMs) driven by artificial intelligence (AI), this study aimed to identify natural substances that can downregulate overexpressed genes, providing a novel approach to treat psoriasis. Method. We retrieved psoriasis microarray data from the National Institutes of Health Gene Expression Omnibus repository (series GSE30999), consisting of 170 skin biopsy samples from 85 patients with moderate-to-severe psoriasis who were not undergoing active treatment at the time of collection. For natural substance recommendations, we utilized two LLMs, ChatGPT from OpenAI and Gemini from Google. Results. Our results identified the top 10 overexpressed genes in psoriasis, including S100A12, SERPINB3, S100A7A, and KYNU, using gene expression data from psoriatic skin samples. By integrating these omics data with AI-driven recommendations from LLMs, we were able to propose several natural substances that may target these genes. Notable suggestions included quercetin for S100A12, resveratrol for SERPINB4, and curcumin for S100A7A, though our analysis revealed a lack of direct evidence linking these substances to specific gene modulation. Both ChatGPT and Gemini offered overlapping recommendations, such as curcumin, green tea extract, and resveratrol, suggesting consistency in their potential therapeutic benefits. Additional substances like aloe vera, bromelain, astragalus, omega-3 fatty acids, and ginger were also proposed for their broader anti-inflammatory and dermatological effects. Conclusions. Our study underscores the potential of combining omics data with LLM-driven insights to explore natural treatments for psoriasis. While the proposed natural substances exhibit promise due to their known bioactive properties, a critical need remains for direct evidence linking these substances to specific gene targets. Future research should focus on validating these interactions in experimental settings, which could pave the way for more targeted and effective natural therapies for psoriasis.
Keywords:
Psoriasis
; chronic autoimmune disease
; excessive skin cell growth
; inflammation
; overexpressed genes
; omics
; gene modulation
; large language models (LLMs)
; artificial intelligence (AI)
; natural substances
; psoriasis treatment
; microarray data
; gene expression
Introduction
Psoriasis is a chronic inflammatory skin disease driven by keratinocyte hyperproliferation, immune dysregulation, and complex genetic factors, making effective treatment challenging due to incomplete responses, side effects, and disease recurrence. Recent advances in genomics and transcriptomics have provided new insights into the molecular underpinnings of psoriasis, highlighting overexpressed genes that play a critical role in its pathology. Omics technologies now allow researchers to explore gene expression profiles in unprecedented detail, revealing opportunities for more precise, gene-targeted therapies. However, traditional drug discovery is slow and costly, prompting the need for innovative solutions. Large language models (LLMs), trained on vast biomedical literature, offer a novel approach by identifying potential therapeutic agents based on molecular targets, and natural substances, known for their pharmacological properties, emerge as promising candidates. This study integrated omics data with LLM capabilities to discover natural substances that can downregulate overexpressed genes in psoriasis, offering a new, efficient pathway to treatment by combining artificial intelligence (AI) and the therapeutic potential of natural substances.
Data
We retrieved psoriasis microarray data from the National Institutes of Health Gene Expression Omnibus repository (series GSE30999). This dataset included gene expression profiles from skin biopsy samples of patients with moderate-to-severe psoriasis. A total of 170 skin biopsy samples were collected from 85 patients at baseline, all of whom had moderate-to-severe psoriasis and were not undergoing active treatment at the time of sample collection (Figure 1).
Overexpressed Genes in Psoriasis and LLM-Guided Natural Treatments
Table 1 and Table 2 highlight the top 10 overexpressed genes in psoriasis and the corresponding natural substances proposed to regulate their activity. Each gene is associated with a specific natural substance known for its anti-inflammatory, antioxidant, or immune-modulating effects. Among the S100 proteins, S100A12 (S100 calcium binding protein A12) has shown the closest association with disease activity and therapeutic response and may therefore be a valuable biomarker for psoriasis [1]. SERPINB3 and SERPINB4 are known to be overexpressed in epidermal cells of psoriatic skin, as the serpin-derived protein Pso p27 (an autoantigen in psoriasis and other chronic inflammatory diseases) is proteolytically derived from SERPINB3 and SERPINB4 through non-canonical cleavage in mast cells by chymase [2]. S100A7A (S100 calcium binding protein A7A), as an antimicrobial protein, is overexpressed in the epidermis of psoriatic lesions, where it mediates inflammation as a chemoattractant for immune cells [3]. TCN1 (transcobalamin 1) is involved in pathways related to cobalamin (vitamin B12) transport and metabolism, as well as the functioning of the innate immune system. KYNU (kynureninase) contributes to the pathogenesis of psoriasis through promoting inflammation [4]. Strong VNN3P (vanin 3) expression is found in the stratum spinosum of the skin [5]. TMPRSS11D (transmembrane serine protease 11D) may be related to a known defect in the regulation of epidermal proteases in psoriasis [6]. Playing a regulatory role, SPRR2C (small proline rich protein 2C) is involved in the PI3K/AKT/mTOR signaling pathway in psoriatic keratinocytes, which may provide a potential diagnostic and therapeutic target in psoriasis [7]. Finally, OASL (2'-5'-oligoadenylate synthetase like) has been shown to contribute to epidermal keratinocyte proliferation by regulating the cell cycle and augmenting the IFN-1‒induced Jak1‒signal transducer and activator of transcription 1 phosphorylation in psoriasis [8].
In the next step, we asked both ChatGPT and Google Gemini the following:
“For the given overexpressed genes in psoriasis, recommend as a naturopathic specialist the natural substances that may downregulate these genes. One substance for one gene.”
For each gene, ChatGPT suggested a natural substance along with its proposed mechanism of action (Table 1). However, despite an extensive online search, we found no evidence linking the recommended substances to their respective genes. For example, ChatGPT recommended quercetin for S100A12, noting its anti-psoriatic effects through antioxidant and anti-inflammatory improvements [9], but no direct association between quercetin and S100A12 was found. For SERPINB4, ChatGPT suggested resveratrol, known for its wide-ranging health benefits, including against cancer, aging, bacteria, inflammation, and oxidation that may influence the pathways involved in inflammatory skin disorders [10]. Curcumin, the active substance in turmeric, was recommended for S100A7A, as it plays a significant role in improving symptoms of psoriasis and reducing inflammation [11]. For TCN1, essential vitamins such as folic acid and vitamin B12 were suggested. Systemic folinate calcium (a folic acid derivative) and topical vitamin B12 have shown efficacy in treating psoriasis [12]. Finally, green tea extract was recommended for KYNU due to its inhibitory effect on psoriasis and potential as a nutritional supplement for managing skin inflammation [13]. Omega-3 fatty acid supplementation complements topical psoriasis treatments, leading to significant reduction in the Psoriasis Area and Severity Index (PASI) and Nail Psoriasis Severity Index (NPASI) scores, improvement in Dermatological Life Quality Index (DLQI), and noticeable relief from symptoms like scalp lesions, itching, redness, scaling, and skin infiltration in the treated areas [14]. N-acetylcysteine is known to modulate inflammation and may influence serine protease activity. Boswellia (from which frankincense is extracted), known for its anti-inflammatory properties, has proven to be an effective anti-psoriatic agent [15]. Additionally, milk thistle extract, rich in silymarin, has demonstrated potent anti-psoriatic effects comparable to standard cortisone treatment [16]. Finally, fatty acids derived from ashwagandha seeds have shown strong anti-inflammatory properties and significant therapeutic potential for psoriasis-like skin conditions [17].
Table 2 presents the top 10 overexpressed genes in psoriasis along with the corresponding natural substances proposed by Gemini. Among the recommended natural substances, curcumin, green tea extract, boswellia, quercetin, and resveratrol overlap with ChatGPT’s suggestions. Other substances such as vitamin B6 (pyridoxine) in high dose showed strong anti-inflammatory properties in lipopolysaccharide-stimulated monocytes [18]. Ginger can be used as both a topical treatment and a dietary supplement to alleviate the discomfort caused by psoriasis [19]. Bromelain, a proteolytic enzyme, dissolves protein bonds that bind excess dead skin cells, a hallmark of scalp psoriasis [20]. In addition, a study found that a 0.5% aloe vera extract in a hydrophilic cream was more effective than placebo, with no reported toxicity or side effects [21]. Finally, astragalus has also been shown to alleviate chronic inflammatory skin conditions through its antioxidant and anti-inflammatory effects, modulating intracellular reactive oxygen species production; NF-κB, JAK/STAT, and PI3/Akt signaling pathways; and immune responses [22].
Discussion
The integration of omics data and AI, specifically LLMs, offers a novel approach for identifying potential natural therapies for complex diseases like psoriasis. Our study successfully identified the top 10 overexpressed genes in psoriasis using gene expression data, and we leveraged the capabilities of LLMs to suggest natural substances that could potentially target these dysregulated genes. This approach combines the precision of molecular profiling with the therapeutic potential of natural substances, providing a promising pathway for treatment.
The genes identified—including S100A12, SERPINB3, S100A7A, and KYNU—are closely tied to the inflammatory and immune processes that drive the pathology of psoriasis. Traditional treatments for this disease often come with limitations, such as incomplete responses and adverse effects. Thus, the search for more natural, gene-targeted therapies has gained interest. However, despite LLMs providing logical recommendations for natural substances based on their known bioactivity, our analysis revealed a significant gap in the direct evidence linking these substances to specific gene modulation.
Two examples include quercetin and resveratrol. Quercetin was suggested for S100A12 due to its known antioxidant and anti-inflammatory properties, which are relevant in psoriasis management. However, no specific studies support a direct interaction between quercetin and S100A12. Similarly, resveratrol, suggested for SERPINB4, has known broad-spectrum benefits for skin health, yet lacks direct evidence of modulating this gene in psoriatic pathways. These findings highlight the current limitations in our understanding of natural substance-gene interactions and the need for more focused research in this area.
Interestingly, both ChatGPT and Gemini suggested overlapping natural substances, such as curcumin, green tea extract, and resveratrol. These substances are well-documented for their anti-inflammatory and antioxidant effects, which support their proposed roles in mitigating the symptoms of psoriasis. The consensus between LLMs regarding these substances strengthens the case for their therapeutic potential. Nevertheless, further experimental validation is required to establish their efficacy in directly downregulating the overexpressed genes identified in our study.
Several natural substances—such as aloe vera, bromelain, and astragalus—have also been recommended based on their broader dermatological benefits. Aloe vera has been shown to improve psoriatic skin without notable side effects, while bromelain’s proteolytic activity can reduce the excess dead skin cells associated with scalp psoriasis. Astragalus, through its modulation of inflammatory pathways like NF-κB and JAK/STAT, offers potential therapeutic benefits for inflammatory skin diseases, though direct evidence in the context of psoriasis remains scarce.
The potential of omega-3 fatty acids, ginger, boswellia, and other substances highlights the versatility of natural substances in addressing various aspects of psoriasis, including inflammation, immune dysregulation, and keratinocyte hyperproliferation. Their broad range of bioactivities positions them as complementary agents to standard treatments, though their specific mechanisms of action on overexpressed genes in psoriasis warrant further investigation.
Summary
Our study integrated omics data and AI to identify potential natural therapies for psoriasis. By analyzing overexpressed genes and utilizing LLMs, we suggested natural substances like quercetin and resveratrol that could target these genes. Although these substances have known benefits for psoriasis, direct evidence linking them to gene modulation remains limited. Despite this limitation, several natural substances—including omega-3 fatty acids, ginger, and boswellia—show promise in positively impacting psoriasis in various ways. Further research is needed to validate their efficacy and understand their specific mechanisms of action on overexpressed genes.
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Table 1.
Top 10 overexpressed genes in psoriasis and the recommended natural substances by ChatGPT.
| Overexpressed Genes in Psoriasis and Natural Treatments by ChatGPT | ||
| Gene | Natural substance | Mechanism of Action |
| S100A12 | Quercetin | A flavonoid with strong anti-inflammatory effects, known to inhibit the S100 family of proteins |
| SERPINB4 | Resveratrol | Known for its anti-inflammatory and antioxidant properties, which may downregulate serpin family proteins |
| S100A7A | Curcumin | The active component of turmeric, which has anti-inflammatory effects and modulates S100 protein activity |
| TCN1 | Folic Acid and Vitamin B12 | Both vitamins, important for modulating the immune system, have been linked to psoriasis management |
| KYNU | Green Tea Extract | Epigallocatechin gallate from green tea inhibits kynurenine pathways and reduces inflammation |
| VNN3P | Omega-3 Fatty Acids | Fish oil has anti-inflammatory properties and may influence genes involved in immune responses |
| TMPRSS11D | N-Acetylcysteine | Known to modulate inflammation and may influence serine protease activity |
| SERPINB3 | Boswellia | Shown to reduce inflammation by modulating immune pathways, potentially affecting serpin expression |
| SPRR2C | Milk Thistle | Known for its anti-inflammatory and antioxidant properties, which may influence skin barrier-related genes |
| OASL | Ashwagandha | An adaptogen that modulates the immune system and reduces stress, potentially influencing OASL expression |
Table 2.
Top 10 overexpressed genes in psoriasis and the recommended natural substances by Gemini.
| Overexpressed Genes in Psoriasis and Natural Treatments by Gemini | ||
| Gene | Natural substance | Mechanism of Action |
| S100A12 | Curcumin | Found in turmeric, with anti-inflammatory and antioxidant properties that may downregulate S100A12 expression |
| SERPINB4 | Green tea extract | Rich in epigallocatechin gallate, this extract has been shown to inhibit SERPINB4 expression in vitro |
| S100A7A | Boswellia serrata | An Ayurvedic herb, boswellia serrata contains boswellic acids that have anti-inflammatory effects and may reduce S100A7A expression |
| TCN1 | Quercetin | A flavonoid found in onions, apples, and berries, quercetin has antioxidant and anti-inflammatory properties that may downregulate TCN1 expression |
| KYNU | Vitamin B6 | A cofactor for enzymes involved in tryptophan metabolism, which can regulate KYNU expression |
| VNN3P | Ginger | Ginger contains gingerols, which have anti-inflammatory and antioxidant properties that may reduce VNN3P expression |
| TMPRSS11D | Resveratrol | A polyphenol found in grapes and red wine, resveratrol has been shown to inhibit TMPRSS11D expression in vitro |
| SERPINB3 | Bromelain | An enzyme found in pineapple, bromelain has anti-inflammatory and fibrinolytic properties that may downregulate SERPINB3 expression |
| SPRR2C | Aloe vera | Aloe vera contains aloin, which has anti-inflammatory and wound-healing properties that may reduce SPRR2C expression |
| OASL | Astragalus | An adaptogenic herb, astragalus contains saponins that have antioxidant and immune-modulating properties that may downregulate OASL expression |
Figure 1.
GSE30999 contained 85 non-lesion and 85 psoriasis lesion skin biopsies.
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