## 6 Papain Use as an Exfoliant Agent in Cosmetic Applications
### Bromelain, Ficin, and Papain Biochemical Pathways of Action and Relative Properties
Cyclooxygenase (COX)-2 expression, implicated in tumor-inducing prostaglandin E2 (PGE2) synthesis, is also inhibited, as it modulates tumor growth factor \(\upbeta\)'s (TGF-\(\upbeta\)) expression, potentially influencing tumor growth and inflammatory signaling cascades [35, 42, 134]. Thrombin, collagen, adenosine diphosphate (ADP), and TxA\({}_{2}\) synthetase are finally restrained; hence, skin inflammation and pigmenta  
Figure 7: Illustration of the exfoliation and skin renewal step-wise processes of bromelain, ficin, and papain. (Parts of this figure were obtained from the free database [[https://www.freepik.com](https://www.freepik.com)]([https://www.freepik.com](https://www.freepik.com)) (accessed on 30 January 2025)). tion is reduced, by suppressing the nuclear factor-kappa B (NF-\(\kappa\)B) cascade and halting the inflammatory gene's expression (Figure 8) [42]. Additionally, bromelain has displayed vast therapeutic potential against pre-aging and inflammaging induced by advanced glycation end (AGE) products [135]. Similarly to bromelain, ficin reduces pro-inflammatory cytokines activity, aiding in inhibiting post-inflammatory pigmentation, redness and irritation, and soothing the skin, working best for the milder exfoliation of sensitive skin [68; 70; 85]. While being the most aggressive towards keratin bonds and playing a stronger role in deep exfoliation, papain has a weaker, but also notable, anti-inflammatory impact. Specifically, papain reduces inflammation by modulating cytokine expression and decreasing inflammation-associated mediators, helping with decreasing skin irritation (Figure 8) [26; 74; 101; 107]. Bromelain and ficin possess significant antioxidant properties, effectively scavenging reactive oxygen species (ROS) and free radicals, in order to safeguard cells and tissues against oxidative damage and related disorders. Papain exhibited higher antioxidant action than those of bromelain and ficin, both in free radical scavenging and oxidized polar lipids (ox-PLs) peroxidation inhibition [35; 42; 70; 96; 136; 137; 138]. Plus, bromelain peel, stem and crown crude, and purified extracts have been shown to display important antimicrobial activity against \(S\). aureus, followed by the \(P\). _acne_, \(S\). _epidernidis_, \(C\). _diphthe_, and \(E\). _coli_ bacteria, while \(P\). _aeruginosa_ displayed the highest resistance. In the same  
Figure 8: Illustration of the biochemical pathways of bromelain, ficin, and papain. (The red arrows represent that bromelain, ficin, and papain, share similar biochemical cascades and mechanisms of action which only differ in the magnitude of their final impact). (Parts of this figure were obtained from the free database [[https://www.freepik.com](https://www.freepik.com)]([https://www.freepik.com](https://www.freepik.com)) (accessed on 31 January 2025)). clinical trial, a facewash prepared using the above extracts showed high activity against _S. aureus_, followed by _P. acne_, _C. diphtheria_, and _E. coli_ bacteria, in contrast to commercial acne-reducing formulations [23]. Such antimicrobial activity is induced by bromelain's interaction with intestinal secretory signaling cascades, e.g., the adenosine 3:5'-cyclic monophosphate pathway [35,46]. Ficin exhibits strong antimicrobial properties, particularly against _S. aureus_, _S. epidermidis_, _S. gordonii_, and _S. mutans_[139,140], by disrupting bacterial cell walls as a potent alternative to antibiotics in wound care. Ficin also effectively inhibited _C. albicans_ biofilm generation [141]. Papain also had a notable anti-biofilm impact against _S. aureus_, _S. epidermidis_, and _S. jejuni_[142,143], a vast anti-bacterial impact, along with bromelain, against _A. acidoterrstris_[144], and mitochondria dysfunction-related _C. albicans_ inhibition, induced by a papaya seed extract (Figure 8) [145]. In terms of tissue repair and subsequent wound healing, bromelain promotes both via several mechanisms.