INTRODUCTION:

Chronic inflammatory skin conditions affect approximately one-third of the global population, leading to significant healthcare challenges¹. The pathophysiology of the disease reflects overactive immune responses, scaly plaques, and chronic inflammation. Pro-inflammatory cytokines like interleukin-4 (IL-4), IL-6, IL-17A, TNF-α, and IL-23 play pivotal roles in driving the disease pathology. Besides pro-inflammatory markers, glucose transporter 1 (GLUT-1) significantly aggravates chronic inflammatory skin conditions. In psoriasis, there is an increased demand for glucose by activated immune cells and rapidly dividing skin cells within psoriatic plaques. GLUT-1 facilitates glucose uptake into these cells, providing them with the necessary energy to sustain their heightened metabolic and proliferative activities. Research has shown that GLUT-1 expression is elevated in psoriatic skin lesions, particularly in the epidermal layer, where abnormal keratinocyte proliferation occurs. This upregulation of GLUT-1 is believed to be part of the metabolic changes associated with psoriasis and may contribute to the sustained inflammation and hyperproliferation of skin cells seen in this condition. Understanding the role of GLUT-1 in psoriasis could potentially lead to novel therapeutic approaches targeting glucose metabolism to manage the disease^2,3. Targeting cytokine production and modulating the GLUT-1 regulation will be a strategic approach towards effectively managing psoriasis⁴. Despite extensive efforts, chronic inflammatory skin conditions still lack effective treatments, and the idea of personalized medicine has not made significant progress in this field. Besides, the poor pharmacodynamic behaviours of existing drug molecules (anticancer drug: methotrexate, immunosuppressive agent; cyclosporine, etc.) with severe adverse effects. Overcoming challenges associated with the current treatment, suitable, potent anti-inflammatory lead compounds from natural origins may be convenient for managing chronic inflammation skin diseases like psoriasis. In the traditional practice, medicinal herbs such as Betula utilis D.Don, Curcuma longa L., Embelia ribes Burm.f., Fumaria officinalis L., Argemone mexicana L., Gelsemium elegans (Gardner and Chapm.) Benth., Podophyllum peltatum L., etc., are a first-hand account of their effectiveness in preventing and treating various dermal inflammatory conditions.

These plant-based therapeutics, derived from different parts of plants such as leaves, roots, and fruits, offer a range of benefits in the form of anti-inflammatory, antioxidant, wound healing, antimicrobial action, moisturization, UV protection, and immune modulation properties⁵. Screening for the most potent herbal source for targeting the immune-based skin inflammation condition remains a critical challenge. Over the past 100 years, researchers have consistently tested the hypotheses using traditional pharmacology tools such as in vivo and in vitro models. Identifying and performing the activities for all active phytochemicals is difficult. To mitigate such issues, an integrated computational screening approach is now being employed to identify the molecular interactions of the lead compounds with the target moieties and evaluate their thermodynamic stability in the biological mimetic environment. The advancements in technology, computer power, and artificial intelligence provide an opportunity to investigate the molecular interactions of interest⁶. In this manuscript, the primary objective of our research is to develop a computational-based screening method and employ a comprehensive evaluation of the anti-inflammatory activity by utilizing various in-vitro and In-vivo models.

MATERIALS AND METHODS:

Materials:

Natural Science Technologies provided the standards betulin, lupeol, betulinic acid (99% purity), HPLC grade solvents such as acetonitrile, ethanol, methanol, and water are available from Merck Life Science Private Limited, an affiliate of Merck KGaA, Darmstadt, Germany. Sigma Aldrich Pvt. Ltd. provide sodium hydroxide, hematoxylin, and eosin, while ELISA kits (IL-6, IL-17, IL-4, and TNF- α) are purchased from Thermo Fisher Scientific Pvt. Ltd. Milli-Q water was used throughout the experiment, and most chemical reagents and solvents were analytical-grade.

Molecular docking:

n this study, proteins were obtained from the Protein Data Bank (PDB) and subjected to refinement procedures to address conformational details. Specifically, IL-6 (PDB ID: 1P9M), TNF-α (PDB ID: 1A8M), TNF-α receptor (PDB ID: 1FT4), GLUT-1 (PDB ID: 6THA), and IL-17, PDB ID: 4HR9) were utilized. Protein refinement was conducted using the Maestro protein preparation Wizard within the Schrödinger Suite, incorporating polar hydrogen atoms, optimizing hydrogen bonds, removing water molecules, realigning conformers, and introducing formal charges. Energy minimization was performed using the OPLS3e force field. Functional binding sites were identified using the SiteMap tool, considering factors like pocket morphology and amino acid exposure. Receptor grids were generated within chosen binding sites. Ligand preparation involved utilizing the LigPrep tool with the OPLS3e force field, and molecular docking was carried out using GLIDE in XP mode, with evaluation based on the G-Score as shown in Table 1⁷.

In vivo anti-inflammatory activity:

Experimental animals:

The animal experiment adhered to the ARRIVE guidelines (Animal Research: Reporting of in vivo experiments) to ensure rigorous methodology and obtain reproducible results. Ethical approval was secured from the Institutional Animal Ethics Committee (IAEC) under license no. IAEC/SPS/SOA/21/2020. The study involved 36 Wistar albino rats, including males and females, with weights ranging from 150 to 200g and ages 6-8 weeks. These stringent conditions were meticulously upheld when assessing the methanolic extract's anti-inflammatory activity of Betula utilis D. Don using the carrageenan-induced paw edema model.

Carrageenan‑induced paw oedema assay:

The evaluation of MEB's anti-inflammatory activity was conducted using the carrageenan-induced paw edema method in rats, as outlined by Li et al. in 2005. To induce paw inflammation and edema, 0.1mL of a freshly prepared 1% carrageenan suspension was injected into the right hind footpad of all rat groups. The untreated left hind paw served as a control for assessing changes in paw thickness. Carrageenan administration resulted in noticeable redness and significant swelling, well-established by the 3-hour mark and persisted throughout the experiment. Paw edema progression was measured at 0, 1, 2, 3, 4, and 5-hour intervals using a Vernier digital caliper. The previously acclimated animals were divided into six groups, each with six rats (n = 6). One hour before carrageenan injection, the animals in the first four groups were pretreated with MEB at 50, 100, 200, and 400 mg/kg, respectively. The remaining two groups received either distilled water (10mL/kg) as the vehicle control or diclofenac (10mg/kg) as a reference drug. The following formula was employed to determine the percentage of edema inhibition compared to the vehicle control groups⁸.

(Change in control – Change in treatment)

%Inhibition= –––––––––––––––––––––––––––––––––––×100

Change in control

where the change of paw thickness values was calculated from the difference between the left and the right paw volumes.

Evaluation of pro-inflammatory cytokines level (TNF-α, IL-17, IL-4 and IL-6):

Evaluation of the cytokines TNF-α, IL-17, IL-4, and IL-6 within paw tissue samples was conducted using enzyme-linked immunosorbent assay (ELISA), adhering to the protocol delineated by Karim et al. Samples were procured five hours post-inflammation induction, weighed, and preserved at -20°C until further analysis. The subcutaneous tissue surrounding the right hind paw and adjacent tarsotibial joints underwent homogenization in a pH 7.4 phosphate-buffered saline solution. The homogenates were then centrifuged at 10,000rpm and 4°C for a duration of 10 minutes. The supernatants extracted post-centrifugation were analyzed for TNF-α, IL-17, IL-4, and IL-6 levels via ELISA, in accordance with the kit instructions provided by the manufacturer.

Statistical analysis:

The statistical analysis was performed with the software GraphPad Prism of Version 5. Data are expressed in the form of means and standard deviations. To analyze the difference, a student's t-test, one-way ANOVA test (post hoc test), and variations with a *P< 0.05, **P< 0.01, ***P < 0.001 were measured to be significant.

RESULT AND DISCUSSION:

Molecular docking:

BE, a major triterpenoid phytoconstituent of B. utilis D.Don fits well into the three-dimensional binding pocket of geometrical coordinates x=586.58, y= -29.16, and z=208.15 of GUT-1 protein target. The docking score of BE was found to be -6.412, which is higher than other phytocomponents as shown in Table 1. The docking score was comparable with the reference standard nonyl beta-D-glucopyranoside of D-score -7.896. The hydroxy group attached to the C-28 carbon skeleton of the BE form a hydrogen bond (H-bond) with a bond length of 2.40Å with the non-polar neutral amino acid Gly157, as shown in Figure 1. The low RMSD value of 0.782 of the BE-6THA docked complexes indicates better reliability and agreement between the predicted and reference structures, suggesting a more accurate docking result. Hindering the glucose uptake to keratinocytes through inhibiting GLUT-1 may improve the psoriatic condition. Hodeib and coworkers investigated GLUT-1 expression in psoriasis with a sample size of 40 psoriasis patients and 20 healthy individuals, analyzing GLUT-1 antibody and mRNA expression. The results showed increased GLUT-1 expression in psoriasis lesions compared to non-lesioned and normal skin, correlating with disease severity and histopathological parameters. This suggests that GLUT-1 may contribute to the development and progression of psoriasis by facilitating epidermal hyperproliferation, inflammation, and angiogenesis⁹. BE fits well into the three-dimensional binding pocket of geometrical coordinates x=12.26, y= -31.97, and z=-0.39 of target protein IL-6. The docking score of BE was found to be -5.347, higher than other phytocomponents except for curcumin, which has a docking score of -5.813, as mentioned in Table 1. The docking score was comparable with the reference standard L(+)-tartaric acid of d-score -6.986. BE forms three H-bonds with hydrophilic amino acids, such as Glu42, 106, and Ser107. C-3 hydroxy group of the BE structure is the key anchoring point for all these three H-bonds with bond lengths of 2.62Å with Glu42, 2.39Å with Glu106, and 2.6Å with Ser107 cited in Figure 1. The low RMSD value of 0.982 of the BE-1P9M docked complexes indicates better reliability and agreement between the predicted and reference structures, suggesting a more accurate docking result. Individuals with psoriasis often exhibit heightened levels of IL-6 in their bloodstream and skin. This elevated IL-6 contributes to the activation of immune cells and the release of other pro-inflammatory cytokines, ultimately leading to skin inflammation and the symptoms of psoriasis. There are FDA-approved drugs that target the IL-6 receptor, including tocilizumab and sarilumab, which have been approved for conditions like rheumatoid arthritis and, in the case of tocilizumab, giant cell arteritis. Other anti-IL-6 antibodies, such as olokizumab and sirukumab, are currently in clinical phase II/III trials for rheumatoid arthritis. However, there have been reports of more deaths among rheumatoid arthritis patients taking sirukumab¹⁰

The third screening target was IL-17. BE fits well into the three-dimensional binding pocket of geometrical coordinates x=79.7, y= -44.02, and z=-45.58. The docking score of BE was found to be -4.390, which is higher than other phytocomponents except for curcumin, which has a docking score of -5.533, as mentioned in Table 1. The docking score was found to be comparable with the reference standard (4S,20R)-7-chloro-N-methyl-4-{[(1-methyl-1H-pyrazol-5-yl)carbonyl]amino}-3,18-dioxo-2,19-diazatetra-cyclo [20.2.2.1~6, 10~.1~11,15~] octacosa 1(24), 6(28), 7, 9, 11(27), 12, 14, 22, 25-nonaene-20-carboxamide of D-score -8.994. BE forms one H-bond with the hydrophobic amino acid Leu-97 of chain B with a bond length of 2.20 Å as shown in Figure 1. The docked complex showed a low RMSD value of 1.123 of the BE-4HR9 docked complexes, indicating better reliability and agreement between the predicted and reference structures, suggesting a more accurate docking result. Targeting IL-17 holds great potential as a therapeutic strategy for addressing psoriasis. Secukinumab, an FDA-approved biologic medication since 2015, is derived from a recombinant human monoclonal antibody of the IgG1 effectively manages moderate-to-severe plaque psoriasis, hypertrophic palmoplantar psoriasis, generalized pustular psoriasis, and active psoriatic arthritis in adult patients¹.

Another screening target was TNF-α. BE fits well into the three-dimensional binding pocket of geometrical coordinates x=-7.89, y= 68.10, and z=20.23. The docking score of BE was found to be -4.927, higher than other phytocomponents except curcumin, which has a docking score of -7.121, as mentioned in Table 3. The docking score was found to be comparable with the reference standard 6, 7-dimethyl-3-[(methyl{2-[methyl ({1- [3-(trifluoromethyl) phenyl]- 1H-indol-3-yl} methyl) amino]ethyl} amino) methyl] -4H-chromen-4-one of D-score -7.873. BE forms one H-bond with the hydrophobic amino acid Gly-121 of chain A with a bond length of 1.95 Å as shown in Figure 1. The docked complex showed a low RMSD value of 0.667 of the BE-1A8M docked complexes, indicating better reliability and agreement between the predicted and reference structures, suggesting a more accurate docking result.

With the screening target, BE finds a similar affinity towards TNF-α receptors. BE fits well into the three-dimensional binding pocket of geometrical coordinates x=-8.29, y= -9.79, and z=0.57. The docking score of BE was found to be -4.993, which is higher in comparison to other phytocomponents except for koumine (-5.305), podophyllotoxin (-5.300), and psoralen (-5.820), as mentioned in Table 1. The docking score was comparable with the reference standard etanercept of D-score -5.553. BE forms three H-bonds with the hydrophilic amino acids Glu-110 and 116 of chain A of bond lengths of 2.17 and 2.75 Å, respectively as shown in Figure 1. BE formed another H bond with basic hydrophilic amino acids like Arg 98 of polypeptide chain B of bond dimension 1.61 Å. For instance, etanercept, a TNF-α inhibitors, a biologic used in treating psoriasis. It blocks its interaction with receptors or TNF-α trimers, even when the binding is weak¹¹.

Figure 1: A two-dimensional interaction between BE with respective targets (a) 6THA, (b)1P9A, (c) 4HR9, (d) 1A8M, and (e) 1FT4

In-vivo anti-inflammatory activity:

Carrageenan-induced paw edema model:

Based upon the Insilico results, MEB was an extra advantage compared to the other seven methanolic extracts. In the carrageenan-induced paw edema model, different animal groups received 50, 100, 200, and 400 mg/kg treatments. The change in the paw thickness was measured in mm, as illustrated in Figure 2. The experiment resulted in a noteworthy reduction (P < 0.05) in paw volume over time. Specifically, the group treated with a 50mg/kg dose of MEB exhibited a 38.12% inhibition of paw edema. The experimental result shows increasing the dosage to 100mg/kg and 200mg/kg led to a significant increase in the inhibition percentage, reaching 58.67% and 83.91%, respectively, by the end of the 5^th-hour post-treatment, as shown in Table 2. The percentage of inhibition of MEB at a dose of 200mg/kg was found to be comparable with the standard reference diclofenac sodium (90.86%). However, at a higher dose of MEB at 400mg/kg, the percentage inhibition was less significant compared with the precursor groups (MEB_200mg/kg). The anti-inflammatory activity of the MEB may be due to the presence of polyphenolic/terpene compounds. Tunon et al. investigated to evaluate the anti-inflammatory properties of an aqueous extract derived from the leaves of Betula pendula to inhibit prostaglandin biosynthesis and suppress platelet-activating factor (PAF)-induced exocytosis at concentrations of 0.2 mg/mL and 0.25 mg/mL, respectively. The findings demonstrated that the leaf extract displayed a 23±2% reduction in prostaglandin synthesis and a 76±4% decrease in PAF-induced exocytosis. The observed effects in the Betula pendula leaf extracts may be ascribed to their rich content of tannins and various polyphenolic compounds¹².

Table 1: List of phytoconstituents from plant source possess Docking score, GLIDE g-score, and GLIDE e-model against molecular target

Botanical name		Rf/CC ligand	RMSD (Å)	*Betula utilis*			*Curcuma* *longa*	*Embelia* *ribe*	*Fumaria officinalis*	*Prickly* *poppy*	*Gelsemium elegans*	*Podophyllum* *peltatum*	*Psoralea corylifolia*
Phytocompound		Rf/CC ligand	RMSD (Å)	BA	BE	LP	CUR	EMB	FA	IQ	KM	PHT	PSL
GLUT-1 inhibitor (6THA)	Docking score	A: -7.896	0.782	-5.544	-6.412	-6.195	-4.618	-4.084	-2.817	-4.193	6.351	-4.684	-6.195
	Glide g-score	A: -7.896		-5.552	-6.412	-6.195	-5.997	-5.573	-2.817	-5.853	6.351	-4.684	-6.195
	Glide e-model	A: -96.223		-30.205	-58.561	-48.399	-47.741	-35.495	-19.075	-30.145	-34.864	-3'8.953	-38.882
IL-6 (1P9M)	Docking score	B: -6.986	0.982	-2.087	-5.347	-2.726	-5.813	-2.019	-1.799	-1.077	-2.797	-2.779	-3.074
	Glide g-score	B: -6.986		-2.095	-5.347	-2.726	-5.813	-2.092	-1.799	-2.737	-2.797	-2.779	-3.074
	Glide e-model	B: -55.345		-31.512	-47.971	-35.353	-51.516	-31.676	-13.237	-27.356	-25.354	-34.513	-26.158
IL-17 (4HR9)	Docking score	C: -8.994	1.123	-3.258	-4.390	NA	-5.533	-0.514	NA	-2.332	-3.245	-2.551	-4.683
	Glide g-score	C: -8.724		-3.266	-4.390	NA	-5.912	-3.001	NA	-3.992	-3.245	-2.551	-4.683
	Glide e-model	C: -99.675		-31.284	-31.966	NA	-55.902	-35.656	NA	-15.096	-22.320	-22.790	-28.160
TNF- α (1A8M)	Docking score	D: -7.873	0.667	-2.234	-4.927	-4.608	-5.742	-1.868	-2.921	-2.033	-6.383	-4.213	-4.147
	Glide g-score	D: -7.873		-4.814	-4.927	-4.608	-7.121	-3.844	-2.921	-3.693	-6.383	-4.213	-4.147
	Glide e-model	D: -67.113		-47.621	-29.101	-47.582	-57.699	-34.298	-17.591	-24.338	-37.734	-39.237	-26.379
TNF- α receptor (1FT4)	Docking score	E: -5.553	-	1.113	-4.993	-2.930	-2.544	-0.433	-2.234	-3.913	-5.305	-5.300	-5.820
	Glide g-score	E: -5.551		-1.467	-4.993	-2.930	-3923	-0.507	-2.234	-5.574	-5.305	-5.300	-5.820
	Glide e-model	E: -67.984		0.125	-32.027	-9.672	-41.835	-32.614	-18.167	-33.532	-38.160	-54.422	-38.235

Abbreviation: A: nonyl beta-D-glucopyranoside, B: L(+)-Tartaric acid, C: (4S,20R)-7-chloro-N-methyl-4-{[(1-methyl-1H-pyrazol-5-yl)carbonyl]amino}-3,18-dioxo-2,19-diazatetra-cyclo [20.2. 2.1~ 6, 10~.1~11,15~] octacosa 1(24), 6(28), 7, 9, 11(27), 12, 14, 22, 25-nonaene-20-carboxamide, D: 6, 7-Dimethyl-3-[(Methyl{2-[Methyl ({1- [3-(Trifluoromethyl) Phenyl]- 1h-Indol-3-Yl} Methyl) Amino]Ethyl} Amino) Methyl] -4h-Chromen-4-One, E: Etanercept, BA: Betulinic acid, BE: Betulin, LP: Lupeol, CUR: Curcumin, EMB: Embelin, FA: Ferulic acid, IQ: Isoquinoline, KM: Koumine, PHT: Podophyllotoxin, PSL: Psoralen

Table 2: Percentage inhibition of paw thickness in the animal group treated with MEB at a concentration range of 50-400mg/kg

Group	Dose (mg/kg)	Change in paw thickness in mm (hours post-treatment)						% Inhibition
Group	Dose (mg/kg)	0	1	2	3	4	5	% Inhibition
Control	10	7.107±0.015	7.807±0.045	8.203±0.121	8.457±0.057	8.357±0.042	8.243±0.042	-
MEB	50	7.207±0.032	7.380±0.010	7.873±0.021	8.223±0.100	7.870±0.020	7.904±0.015	38.12
	100	7.123±0.015	7.240±0.020	7.667±0.015	7.910±0.010	7.497±0.021	7.589±0.020	58.67
	200	7.150±0.010	7.237±0.021	7.387±0.015	7.447±0.021	7.257±0.025	7.331±0.020	83.91
	400	7.080±0.010	7.150±0.010	7.270±0.020	7.393±0.015	7.240±0.010	7.247±0.030	85.18
Diclofenac sod.	10	7.210±0.010	7.327±0.015	7.563±0.025	7.773±0.015	7.563±0.021	7.313±0.025	90.86

CONCLUSION:

In conclusion, chronic skin inflammation conditions like psoriasis represent a significant healthcare burden, necessitating the exploration of novel and effective treatment options. The phyto-based lead molecule from B. utilis D.Don may emerge as a promising candidate with a long history of use in ethnopharmacological practices in the form of poultices to recover from wounds and reduce swellings. With ethnopharmacological significance, this traditional plant has displayed an impressive capacity to significantly diminish heightened pro-inflammatory cytokines and inhibit glucose uptake in hyperactive epidermal (keratinocyte) cells that impede the energy supply necessary for uncontrolled proliferation, potentially arresting disease advancement. Computational-based experimental findings is supported with the comparable In-vivo anti-inflammatory responses of the methanolic extract may offer a therapeutic adjunct more effective and targeted management of psoriasis.

ACKNOWLEDGEMENTS:

The DBT Builder project (BT/INF/22/SP45078/2022) funded the research activity. The authors acknowledge the help of the Department of Biotechnology (DBT), Govt. India.

DISCLOSURE STATEMENT:

The authors reported no potential conflict of interest.

FUNDING:

The Department of Biotechnology, Ministry of Science and Technology, India Builder project funded the research with order no (BT/INF/22/SP45078/2022).

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