Skin is a coated barrier that protects internal organs from harsh environments. This barrier is essential for maintaining the homeostasis of body fluids, controlling temperature, and protecting the body from infection. The skin also has immunological, nervous, and metabolic functions (1, 2), devastating issues that affect such a barring ability (3). According to a study, wounds account for 30% of the total emergency caseload in veterinary healthcare centers (4). Animals (especially pets) with severe burns need immediate access to professional facilities. Such modern resuscitation and emergency burn therapies are designed to mitigate systemic changes caused by the sudden destruction of skin barriers, but unfortunately, these facilities are not available in the developing countries of Asia and Africa. The majority of burns is unintentional that occurred at veterinary clinics, relating to the use of adjunct heat to reduce the risk of developing hypothermia. Veterinarians often encounter burns that are <20% of the animal's body surface. Thus, severe metabolic disturbances, such as electrolyte levels imbalances, red blood cells destruction, and high susceptibility toward systemic infection, might not be seen (5). But the use of such animals as a model is still a viable option in overall healthcare in translational medical studies (6). A list of medicines to treat burns, i.e., Nitrofurazone and silver sulfadiazine, is available in the markets. But due to the high cost of these medicines, most people cannot afford them. Hence, more traditional herbal products have been used in African and Asian middle-class families (7). According to the WHO statistics, 265,000 deaths annually occur due to burning, most of which happen in these regions (8). The herbal products used by these people seem moderately effective, less toxic, and less expensive than other market products. Honey has been used in folk medicine for a long time, but it has only recently been discovered by medical researchers that it can be used to treat both acute and long-term wounds.

Traditionally, honey has been used to treat burns (9) due to its antimicrobial properties, especially to cover up burn wounds. It has been shown to inhibit a wide spectrum of bacteria and is as efficient against antibacterial drugs resistant bacteria (10–12). Interestingly, one of the earliest experiments of honey's efficiency against antibiotic-resistant was conducted, using Manuka honey to treat a hydroxyurea-induced leg ulcer colonized by methicillin-resistant Staphylococcus aureus (MRSA). This research established that honey has antibacterial capabilities against resistant bacteria and may also aid in the healing process of wounds (13). Such antibacterial action of honey is due to its acidity, hydrogen peroxide contents, osmotic effects, nutritional and antioxidant contents, stimulation of immunity, and unidentified compounds (14). Generally, honey has glucose, maltose, sucrose, fructose, water, and a few other things, such as amino acids, organic acids, proteins, vitamins, acetylcholine, and flavonoids (15). Many scientific studies have been urged on its medicinal properties in Ayurvedic, Chinese and Roman traditions (14). Manuka honey is the purest form of unifloral honey that is derived from Manuka trees and Leptospermum scoparium, belongs to the family Myrtaceae in New Zealand and the Eastern region of Australia (16). It is dark honey as compared to other honey types. It contains the highest concentration of phenolic and flavonoid compounds (pinobanksin, pinocembrin, and chrysin) that have been identified as having potent reactive oxygen species (ROS) scavenging activity (17). Flavonoids polyphenolic compound is a group of secondary metabolites that naturally occur in the plant kingdom that possesses numerous pharmacological activities (18).

Nitrofurazone (C6H6N4O4) is a commercially available product used as an antimicrobial agent on different wounds, especially burn wounds (19). It has been reported to show bactericidal activity against many gram-positive and gram-negative bacteria, inhibiting bacterial enzymes involved in carbohydrate metabolism. It exhibits bactericidal activity against most pathogens that commonly cause surface skin infections (20). But Nitrofurazone (NT) therapy has a limit on its low aqueous solubility. The poor solubility of NT urges a slow-release rate, causing less penetration of an effective drug concentration into the skin. Moreover, due to its high permeability through the skin, NT remains for a limited time at the applied area (21). Others include sensitivity, itching, contact dermatitis, and longer time period (8).

The current experimental study explored the effects of topical application of Manuka honey ointment on full-thickness burns, in comparison with commercially available Nitrofurazone at the thoracoabdominal regions of rabbits. The evaluation parameters, such as healing time, contraction rate, hematological, and histopathological assessment, were compared with untreated thermally injured rabbits.

The skin is the largest organ in the body that performs many important functions, e.g., homeostasis, body temperature, immunity, nervous sensations, and metabolism. The skin also acts as a physical barrier against infections (29). If this barrier is damaged, pathogens can penetrate directly into the body. Several studies have shown that burns are the leading cause of death with severe burns. Therefore, many researchers have sought to develop appropriate treatments to reduce the risk of wound infection and reduce the duration of treatment for burn injuries. These treatments include topical antimicrobials that effectively reduce mortality (30, 31), with low toxicity and sensitivity (32, 33). However, the occurrence of reactions related to allergies, toxicity, and irritation reduces skin regeneration ability, which can minimize their efficacy (29, 34). For example, the Nitrofurazone is one of the commonly used antimicrobial agents against gram-positive and gram-negative bacteria. As a consequence of its action, Nitrofurazone breaks down ribosomal proteins and some other macromolecules, which slow down the production of proteins, DNA, and RNA and stop the cellular proliferation. Additionally, it may impair bacterial cells' aerobic metabolism and carbohydrate metabolism activities (35). Meanwhile, oxidative processes produce reactive superoxide and hydroxyl radicals (36). Despite the fact that these actions take place in milliseconds or less, they have the potential to be harmful if left uncontrolled (34). As a result, the second choice is to employ natural products, which have been used since ancient times. These products are less toxic and cheaper than synthetic drugs. It has been shown that many plants and plant products effectively heal wounds. Nowadays, most drugs are a mixture of several plants or herbs, but these traditional ointments are not scientific. Using medicinal herbs has been noticed in the therapy of wounds from the very beginning due to its reduced financial load and its medical effects. Our study results are in line with the results of Bischofberger et al. (37). Where Manuka honey provided a protective barrier over the wound in preventing microbial infection. Its immunological activity accelerates wound repair and anti-inflammatory effects (38). Some other factors and bioactive components have also been involved that trigger the direct and indirect actions against the bacteria in wound repair (14). A 5.8 kDa bioactive component of Manuka honey has been identified as responsible for stimulating monocyte activity by activating the toll-like receptor 4 (TLR4). Activation of TLR4 and subsequently the intracellular signaling pathway nuclear factor kappaB (NF-κB) enhance the production of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), which are important in regulating the inflammatory response (39) (Figure 7).

Besides being able to reduce Cyclooxygenases 1 (COX-2) expression, Manuka honey can also have an antioxidant effect by changing the production of ROS and phenolic compounds (17). This is because of the production of ROS and other compounds.

Methylglyoxal is another active antibacterial ingredient of Manuka honey, which has been reported to react with lysine, arginine, and cysteine residues of structural proteins, such as collagen. Further it gives genesis to advanced glycation end products (AGEs). It promotes fibrosis in chronic tissue infections, impairs immune response microcirculation, promotes atherosclerosis and neovascularization, induces endothelial cell dysfunction, and impairs wound closure (40). Our study results are in line with the results of Bischofberger et al. (37), in which Manuka honey was found effective in experimental equine wounds in minimizing the wound area by decreasing retraction and overall healing time. The mechanism p38 is evolved during wound repair through Manuka honey. This mechanism mediates the stimulation of locomotion and proliferation by plate derivative growth factor (PDGF), the main growth factor in the early phases of wound healing (41). Our study is also in line with study of Moore et al. (42), who reviewed previous randomized controlled trials comparing honey with different treatments. Moore et al. concluded that honey is a useful treatment for burns.

The results of this study give a free hand to the companies to start the formation of medicines in the form of ointments or creams. We hope that a new burn ointment or cream can be used with herbal medicines, which will help to decrease the healing period and hypertrophic scar rate.

Manuka honey ointment may provide an alternative medication for managing extensive burns. However, there are some regulatory barriers to introducing a new product containing just honey. Therefore, changing attitudes toward clinical practice might take longer due to these barriers. Such prominent factors may decrease the acceptability of such treatment option. Hence, to address such acceptability concerns, the therapeutic options must be in combination with allopathic medications. It would place more emphasis on promoting the acceptability and would be helpful in providing a better option throughout the globe. Moreover, further research with randomized prospective is also needed to fully elucidate MO's effect on burns.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

The animal study was reviewed and approved by Departmental Ethical Committee.

MK: methodology and writing original draft. KA and AA: supervision. MS, MN, and IS: reagents, materials, and analysis tools. ZB, SS, HH, and MK: writing review and editing. AC, MA, and RH: visualization. KD, YW, and KL: conceptualization, funding, and resources. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

This study was supported by the Start-up fund of Nanjing Agricultural University (804131) and the Start-up Fund for Distinguished Scholars of Nanjing Agricultural University (80900219).

KD is employed by China Tobacco Henan Industrial Co., Ltd., China. The remaining authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.