Fig 1.
Workflow of the study.
Fig 2.
Structures of dereplicated compounds from Cystoseira algae.
Fig 3.
Mesenchymal stem cell infusion on skin wound healing of hydrocortisone-immunosuppressed Wistar rats.
Progress of skin wound healing over 16 days of observation. The table columns show the experimental groups, with the control group (I), hydrocortisone group (II), Mebo® ointment Market group (III), hydrocortisone-treated with mesenchymal stem cells group (IV), hydrocortisone-treated with Cystoseira sp. extract group (V) and hydrocortisone-treated with Cystoseira sp. extract + mesenchymal stem cell group (VI).
Fig 4.
(A) Wound closure rates over time post-injury in all experimental groups, (B) the wound aspect ratio was calculated to describe observed changes in the shape and direction of wound contraction between the groups (length: width).
Fig 5.
Flow cytometric analysis showed that cultured immunophenotype of BMMSC displayed negative expression of CD34 and CD 45, also highlighting positive expression of CD90 (98.21%) and CD105 (97.1%) antibodies staining.
Fig 6.
(A) (Group I) showing the mature epidermis with keratinization (red arrow), subepidermal and upper dermal layers with dermal collagen (red arrowhead), skin adnexa (yellow star), and hair follicle (blue star), 200x; (B) (Group II) showing discontinuous epidermal skin layers covered with necrotic tissue slough and blood clots (red arrow), dermal layers with mild edema (red arrowhead) and inflammatory cellular infiltrated macrophages (red star), 200x; (C) (Group III) showing epidermal skin layer with thin keratinization (red arrow), dermal layer with thick wavy compactly organized collagen bundles (red arrowhead) and folliculosebaceous unit of skin adnexa (red star). 200x; (D) (Group IV) section showing normal mature epidermal skin layer with keratinization (red arrow). Dermal layer shows compactly organized collagen bundles (red arrowhead) with mature folliculosebaceous unit of skin adnexa (red star). Mild subepidermal edema was also noticed (yellow star) 200x; (E) (Group V) section displayed a normal mature epidermal skin layer with keratinization (red arrow). Dermal layer showing mature organized wavy collagen bundles (red arrowhead) with scattered mature folliculosebaceous unit of skin adnexa (red star), 200x; (F) (Group VI) showing normal mature epidermal skin layer with keratinization (red arrow), dermal layer showing compactly organized mature thick collagen bundles (red arrowhead) with multiple mature folliculosebaceous of skin adnexa (red star), 200x.
Fig 7.
(A) mRNA expression of COX-I and COX-II; (B) mRNA expression of IL-1β and TNF-α; (C) mRNA expression of INF-γ and NF-KB; (D) mRNA expression of TGF-β and IL-10 by quantitative RT-PCR. The data reflect fold change relative to the relative gene expression in the normal control group after being normalized to glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The mean ± standard deviation is represented by bars and the significant difference among the groups is examined by a one-way ANOVA test, where: *p < 0.001 compared with those of the untreated group on the respective day and #p < 0.001 compared with those of the Mebo® group on the corresponding day.
Fig 8.
(A) Human cancer PPI network. This network consists of 201 nodes and 202 edges with an average node degree of 2.01. The top-interacting nodes were colored red (7.9%, 38 proteins of all interacting nodes, namely, hub protein). (B) The top interacting nodes (4.4%, ten proteins of all interacting nodes, namely, hub protein). Cystalgerone was predicted to interact with one of the hub proteins (viz., MMP9).
Fig 9.
(A) Wound healing-relevant network categorized into 5 different subnetworks. These subnetworks represent the first 5 key pathways involved in the wound-healing process. Red nodes cluster represents the remodeling extracellular matrix pathway; Blue nodes cluster represents the PI3K-Akt signaling pathway; Green nodes cluster represents the proteasome signaling pathway; Cyan nodes cluster represents the apoptosis signaling pathway; Yellow nodes cluster represents the TNF signaling pathway. (B) the cluster of remodeling extracellular matrix proteins.
Fig 10.
(A) Binding modes of cystalgerone (brick red-colored structure) in alignment with the co-crystallized inhibitors (cyan-colored structures) inside the active site of MMP9 (PDB ID: 6ESM). (B) RMSD profiles of both cystalgerone and the co-crystallized inhibitor inside the active site of MMP9 over the course of 100 ns-long MD simulation.
Fig 11.
The probable role of cystalgerone in diabetic wound healing process.