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Skin wound healing and regeneration is very challenging across the world as simple or acute wounds can be transformed into chronic wounds or ulcers due to foreign body invasion, or diseases like diabetes or cancer. The study was designed to develop a novel bioactive scaffold, by loading aloesin to chitosan-coated cellulose scaffold, to cure full-thickness skin wounds. The physiochemical characterization of the scaffold was carried out using scanning electron microscopy (SEM) facilitated by energy-dispersive spectrophotometer (EDS), atomic force microscopy (AFM), and Fourier transform infrared spectroscopy (FTIR). The results indicated the successful coating of chitosan and aloesin on cellulose without any physical damage. The drug release kinetics confirmed the sustained release of aloesin by showing a cumulative release of up to 88 % over 24 h. The biocompatibility of the aloesin-loaded chitosan/cellulose (AlCsC Fp ) scaffold was evaluated by the WST-8 assay that confirmed the significantly increased adherence and proliferation of fibroblasts on the AlCsC Fp scaffold. The in vivo wound healing study showed that both 0.05 % and 0.025 % AlCsC Fp scaffolds have significantly higher wound closure rates (i.e. 88.2 % and 95.6 % approximately) as compared to other groups. This showed that novel composite scaffold has a wound healing ability. Furthermore, histological and gene expression analysis demonstrated that the scaffold also induced cell migration, angiogenesis, re-epithelialization, collagen deposition, and tissue granulation formation. Thus, it is concluded that the aloesin-loaded chitosan/cellulose-based scaffold has great therapeutic potential for being used in wound healing applications in the clinical setting in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Timely repair of damaged skin is very important to maintain the integrity and homeostasis of skin, but the wound healing process is compromised in diabetic patients due to several extrinsic and intrinsic factors thus lead to leg amputation and death eventually. Sirtuins, a family of seven conserved proteins are known to be associated with pathophysiological processes of the skin. The most important among them are sirt1and sirt3 involved in cell regeneration and cell survival. Naphthoquinone derivatives have a wide range of therapeutic properties, but the potential diabetic wound healing activity of lapachol has not been identified yet. The present study thus aimed to investigate the wound healing effects of lapachol in a diabetic mouse model. Diabetic wounded mice were divided into 3 groups; vehicle, lapachol 0.05%, and lapachol 0.1%. Skin samples collected from diabetic wounded mice on different time points after treatment for 10 consecutive days were subjected to downstream analysis by western blot, ELISA and histology. Lapachol treatment was found to enhance the expression of sirt1/sirt3 and other proteins involved in cell migration and blood vessel formation. The tissue development rate was increased by lapachol treatment with better collagen deposition. Interestingly, lapachol treatment also gave rise to a high concentration of growth factors resulting in speedy and timely recovery of injured skin. In summary, our findings suggest that lapachol promotes efficient wound healing in a diabetic mouse model by increasing the expression of sirt1 and sirt3 and other proteins related to wound repair and skin regeneration including α-PAK, RAC1/CDC42, VEGF and growth factors viz PDGF and VEGF. This research work finds a novel potential activator of sirtuins in the form of lapachol and depicts the role of activated sirtuins in diabetic wound healing.

The pandemic coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a great threat to public health. Currently, no potent medicine is available to treat COVID-19. Quest for new drugs especially from natural plant sources is an area of immense potential. The current study aimed to repurpose stilbenoid analogs, reported for some other biological activities, against SARS-CoV-2 spike protein and human ACE2 receptor complex for their affinity and stability using molecular dynamics simulation and binding free energy analysis based on molecular docking. Four compounds in total were probed for their binding affinity using molecular docking. All of the compounds showed good affinity (> -7 kcal/mol). However, fifty nanoseconds molecular dynamic simulation in aqueous solution revealed highly stable bound conformation of resveratrol to the viral protein: ACE2 receptor complex. Net free energy of binding using MM-PBSA also affirmed the stability of the resveratrol-protein complex. Based on the results, we report that stilbene based compounds in general and resveratrol, in particular, can be promising anti-COVID-19 drug candidates acting through disruption of the spike protein. Our findings in this study are promising and call for further in vitro and in vivo testing of stiblenoids, especially resveratrol against the COVID-19. [Formula: see text] Communicated by Ramaswamy H. SarmaHighlightsStilbenoid analogs could be potential disruptors of SARS-CoV-2 spike protein and human ACE2 receptor complex.In particular, resveratrol revealed highly stable conformation to the viral protein: ACE2 receptor complex.The strong interaction of resveratrol is affirmed by molecular dynamic simulation studies and better net free energies.

Objectives: Lapachone is a natural naphthoquinone-derived compound found in Tabebuia avellanedae . It is well-known for its analgesic, anti-inflammatory, anti-microbial, diuretic, and anti-cancerous effects. However, the wound-healing effects of this compound are not known yet. The aim of this study was to investigate the wound healing activity of naphthoquinones (α-lapachone and β-lapachone) from Handroanthus impetiginosus ., Materials and Methods: Expression of Sirt3, migration-related proteins (Rac1, Cdc42, α-Pak) and angiogenesis-related protein of vascular endothelial growth factor (VEGF) was monitored using western blot analysis. Blood vessel formation and tissue development were monitored by angiogenesis assay and hematoxylin & eosin (H & E) staining, respectively on mouse skin tissue samples. Both α-lapachone and β-lapachone increased Sirt3 expression in vivo , but only β-lapachone increased Sirt3 expression in vitro., Results: Both the compounds accelerated wound healing in cultured skin cells as well as mouse skin; however, β-lapachone was more effective at lower concentrations. Both of the compounds increased the expression of migration-related proteins both in vitro and in vivo . Similarly, α-lapachone and β-lapachone increased VEGF expression, tissue development and blood vessel formation in mouse skin., Conclusion: These findings indicated that α-lapachone and β-lapachone are novel Sirt3 activators, and Sirt3 has a role in wound healing. Thus, Sirt3 and its regulators come out as a novel target and potential drug candidates, respectively in the important field of cutaneous wound healing.

Exposure to environmental toxicants such as Bisphenol A (BPA) has raised serious health issues globally particularly in developing countries. It is ubiquitously used in the manufacturing of canned food and feeding bottles. BPA generated reactive oxygen species can lead to several diseases including cardiotoxicity. However, the endpoints stimulated in BPA cardiotoxicity yet need to be investigated. The current study was aimed to investigate the underlying molecular pathways which may contribute in revealing the protective effects of Pistacia integerrima against BPA induced oxidative stress. The dose of 100 µg/kg BW of BPA, 200 mg/kg BW P. integerrima, and 4 mg/kg BW melatonin was administered to Sprague Dawley rats. Present results of western blotting and qRT-PCR showed the increased expression of p53, PUMA and Drp1, while downregulation of Ubc13 in heart tissues of BPA treated group whereas the levels were reversed upon treatment with P. integerrima. The role of BPA in heart tissue apoptosis was further confirmed by the increased level of P-p53, cytochrome C and disrupted cellular architecture whereas the P. integerrima has shown its ameliorative potential by mitigating the adverse effects of BPA. Moreover, the oxidant, antioxidant, lipid, and liver markers profile has also revealed the therapeutic potential of P. integerrima by maintaining the levels in the normal range. However, melatonin has also manifested the normalized expression of apoptotic markers, biochemical markers, and tissue architecture. Conclusively, the data suggest that P. integerrima may be a potential candidate for the treatment of BPA induced toxicity by neutralizing the oxidative stress through Ubc13/p53 pathway.

Skin hyperpigmentation is generally characterized by increased synthesis and deposition of melanin in the skin. UP256, containing bakuchiol, is a well-known medication for acne vulgaris. Acne sometimes leaves dark spots on the skin, and we hypothesized that UP256 may be effective against hyperpigmentation-associated diseases. UP256 was treated for anti-melanogenesis and melanocyte dendrite formation in cultured normal human epidermal melanocytes as well as in the reconstituted skin and zebrafish models. Western blot analysis and glutathione S-transferase (GST)-pull down assays were used to evaluate the expression and interaction of enzymes related in melanin synthesis and transportation. The cellular tyrosinase activity and melanin content assay revealed that UP256 decreased melanin synthesis by regulating the expression of proteins related on melanogenesis including tyrosinase, TRP-1 and -2, and SOX9. UP256 also decreased dendrite formation in melanocytes via regulating the Rac/Cdc42/α-PAK signaling proteins, without cytotoxic effects. UP256 also inhibited ciliogenesis-dependent melanogenesis in normal human epidermal melanocytes. Furthermore, UP256 suppressed melanin contents in the zebrafish and the 3D human skin tissue model. All things taken together, UP256 inhibits melanin synthesis, dendrite formation, and primary cilium formation leading to the inhibition of melanogenesis.

Cutaneous wound healing is a highly complex biological process involving major events such as cell migration, angiogenesis, and tissue development. Sirtuin 1 (Sirt1) and its regulators have been suggested to play a role in cell migration and tissue repair. The aim of the present study was to determine the effects of a novel Sirt1 activator, the piper amide derivative (E)‑3‑(2,4‑dichlorophenyl)‑N‑phenylacrylamide, also known as NED416, on cutaneous wound healing. The effects of NED416 on Sirt1 activity, Sirt1 expression, and angiogenesis were measured in skin and endothelial cells (epidermal keratinocytes, dermal fibroblasts and vascular endothelial cells) using a Sirt1 activity assay kit, western blot analysis and tube formation assays, respectively. The effects of NED416 on the rate of wound closure and collagen deposition were measured via H&E staining and Masson's trichrome staining, respectively. Levels of migration‑related [Rac1, cell division cycle 42 (Cdc42) and α‑p21‑activated kinase] and mitogen‑activated protein kinase (MAPK) signaling pathway proteins were measured in hairless mice via western blot analysis. NED416 significantly increased Sirt1 activity in dermal fibroblasts and epidermal keratinocytes to a greater extent than resveratrol, leading to increased cell migration and angiogenesis through Rac1/Cdc42 and ERK/JNK activation. Furthermore, NED416 accelerated wound closure, macrophage infiltration, and epithelium and collagen formation in vivo. The present study demonstrated a role of Sirt1 in cutaneous wound healing, and suggested that NED416 as a Sirt1 activator is more potent than resveratrol in promoting wound healing through Rac1/Cdc42 and MAPK signaling without toxicity, thus serving as a promising candidate for treatment.

[This corrects the article DOI: 10.1155/2017/8379539.].

Background: Lespedeza species have been used as a traditional medicine to treat nephritis, azotemia, inflammation, energy depletion, diabetes, and diuresis., Purpose: The purpose of this study is to screen the most potent Lespedeza species against methylglyoxal (MGO)-induced glucotoxicity, and to elucidate the mechanisms of action. Also, we will attempt to identify small chemical metabolites that might be responsible for such anti-glucotoxicity effects., Methods: Firstly, the protective effect of 26 different Lespedeza species against MGO-induced toxicity in human umbilical vein endothelial cells was investigated. The chemical metabolites of the most potent species (Lespedeza bicolor 1 (LB1) were identified by high pressure liquid chromatography quadrupole time-of-flight tandem mass spectrometry (HPLC-Q-TOF-MS/MS), then quantified by HPLC. The effects of LB1 on MGO-induced apoptosis were measured by annexin V-FITC staining and western blot. Inhibitory effects of LB1 on MGO-induced ROS generation, and effect of LB1 on advanced glycation end products (AGEs) inhibitor or a glycated cross-link breaker are also measured., Results: Among different Lespedeza species, LB1 extract was shown to reduce intracellular reactive oxidative species, exhibit anti-apoptotic effects, strongly inhibit all the mitogen-activated protein kinase signals, inhibit MGO-induced AGEs formation, and break down preformed AGEs. We tentatively identified 17 chemical constituents of LB1 by HPLC-Q-TOF-MS/MS. Among those, some components, such as genistein and quercetin, significantly reduced the AGEs formation and increased the AGEs-breaking activity, resulting in the reduction of glucotoxicity., Conclusion: LB1 extract has shown to be effective in preventing or treating MGO-induced endothelial dysfunction., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Background: Cutaneous wound healing is a complex process involving various regulatory factors at the molecular level. Aloe vera is widely used for cell rejuvenation, wound healing, and skin moisturizing., Hypothesis/purpose: This study aimed to investigate the effects of aloesin from Aloe vera on cutaneous wound healing and mechanisms involved therein., Study Design: This study consisted of both in vitro and in vivo experiments involving skin cell lines and mouse model to demonstrate the wound healing effects of aloesin by taking into account several parameters ranging from cultured cell migration to wound healing in mice., Methods: The activities of Smad signaling molecules (Smad2 and Smad3), MAPKs (ERK and JNK), and migration-related proteins (Cdc42, Rac1, and α-Pak) were assessed after aloesin treatment in cultured cells (1, 5 and 10µM) and mouse skin (0.1% and 0.5%). We also monitored macrophage recruitment, secretion of cytokines and growth factors, tissue development, and angiogenesis after aloesin treatment using IHC analysis and ELISAs., Results: Aloesin increased cell migration via phosphorylation of Cdc42 and Rac1. Aloesin positively regulated the release of cytokines and growth factors (IL-1β, IL-6, TGF-β1 and TNF-α) from macrophages (RAW264.7) and enhanced angiogenesis in endothelial cells (HUVECs). Aloesin treatment accelerated wound closure rates in hairless mice by inducing angiogenesis, collagen deposition and granulation tissue formation. More importantly, aloesin treatment resulted in the activation of Smad and MAPK signaling proteins that are key players in cell migration, angiogenesis and tissue development., Conclusion: Aloesin ameliorates each phase of the wound healing process including inflammation, proliferation and remodeling through MAPK/Rho and Smad signaling pathways. These findings indicate that aloesin has the therapeutic potential for treating cutaneous wounds., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

The skin is the outermost protective barrier between the internal and external environments in humans. Chronic exposure to ultraviolet (UV) radiation is a major cause of skin aging. UVB radiation penetrates the skin and induces ROS production that activates three major skin aging cascades: matrix metalloproteinase- (MMP-) 1-mediated aging; MAPK-AP-1/NF- κ B-TNF- α /IL-6, iNOS, and COX-2-mediated inflammation-induced aging; and p53-Bax-cleaved caspase-3-cytochrome C-mediated apoptosis-induced aging. These mechanisms are collectively responsible for the wrinkling and photoaging characteristic of UVB-induced skin aging. There is an urgent requirement for a treatment that not only controls these pathways to prevent skin aging but also avoids the adverse effects often encountered when applying bioactive compounds in concentrated doses. In this study, we investigated the efficacy of genetically modified normal edible rice (NR) that produces the antiaging compound resveratrol (R) as a treatment for skin aging. This resveratrol-enriched rice (RR) overcomes the drawbacks of R and enhances its antiaging potential by controlling the abovementioned three major pathways of skin aging. RR does not exhibit the toxicity of R alone and promisingly downregulates the pathways underlying UVB-ROS-induced skin aging. These findings advocate the use of RR as a nutraceutical for antiaging purposes.

Skin cell regeneration and wound healing are key processes in the recovery from skin injuries. Rapid cell migration and regeneration of skin cells lead to faster and better healing of wounded skin. In the present study, we aimed to investigate the wound healing potential of juglone, a naturally occurring Pin1 inhibitor found in walnuts. Cultured skin cells (NHDF and HaCaT) and hairless mice were treated with juglone after wound creation to examine its effects on cell migration and wound healing rate. The expressions of cell migration related proteins (Rac1, Cdc42, and α-PAK), collagen deposition, and angiogenesis were analyzed. Juglone treatment resulted in faster rate of growth and migration and recovered cell morphology, particularly at a concentration of 5 µM, in skin cells compared to the untreated group. In vivo experiments showed that mice treated with juglone showed faster wound healing rate with better skin morphology and collagen deposition than the vehicle group. Furthermore, juglone increased the activation and/or expression of Cdc42, Rac1, and α-pak in HaCaT cells, and resulted in enhanced angiogenesis in endothelial cells (HUVECs). Juglone also activated MAPKs signaling by activation of ERK, JNK, and p38 proteins. Taken together, these data suggest that juglone may be a potential candidate for wound healing and skin regeneration which ameliorates wound healing mainly by promoting skin cell migration through Rac1/Cdc42/PAK pathway., (© 2016 by the Wound Healing Society.)

A series of novel aryl carbamate derivatives of metronidazole (MNZ) were designed, synthesized, and screened for antiamoebic activity. As compared to MNZ, most of the derivatives exhibited moderate to excellent activity against the HM1:IMSS strain of Entamoeba histolytica. Compounds 7, 14, 16, 19, and 21 exhibited the most promising antiamoebic activity with IC50 values of 0.24, 0.08, 0.26, 0.26, and 0.15 μM, respectively, compared to that of MNZ (1.78 μM). Moreover, from the toxicological studies of these compounds on human melanocytes, the melan-a cell line revealed that the potent compounds are nontoxic at concentrations ranging from 2.5 to 50 μM.