Current Peer Reviewed Research Studies on the Health Benefits of Serrapeptase
Biotechnol Rep (Amst). 2020 Dec; 28: e00544.
Serratiopeptidase: Insights into the therapeutic applications
Swati B. Jadhav
aNutrient Awarding and Development Laboratory, Advanced Enzymes Technologies Ltd., Louiswadi, Thane, (w)-400604, India
Neha Shah
bPulmonary Fibrosis Now! Chino, CA, 91710, United States
Ankit Rathi
aFood Application and Development Laboratory, Avant-garde Enzymes Technologies Ltd., Louiswadi, Thane, (due west)-400604, Republic of india
cSpecialty Enzymes and Probiotics, Yorba Ave, Chino, CA, 91710, United States
Vic Rathi
aNutrient Awarding and Development Laboratory, Advanced Enzymes Technologies Ltd., Louiswadi, Thane, (w)-400604, India
cSpecialty Enzymes and Probiotics, Yorba Ave, Chino, CA, 91710, United States
Abhijit Rathi
aFood Awarding and Development Laboratory, Advanced Enzymes Technologies Ltd., Louiswadi, Thane, (w)-400604, India
Received 2020 Aug 12; Revised 2020 Sep 29; Accepted 2020 Oct xv.
Abstract
Therapeutic applications of enzymes have been widely accepted in clinical practices for decades. Proteolytic enzymes in particular, have been used for the treatment of diseases and disorders. Serratiopeptidase is a proteolytic enzyme having immense applications in therapeutic areas which have been validated past several in vitro, in vivo, and clinical studies equally well as through anecdotal evidences. These applications are attributable to its versatile properties including anti-inflammatory, anti-biofilm, analgesic, anti-edemic, and fibrinolytic furnishings. The pregnant impact of serratiopeptidase reported needs to be backed past more scientific data. This review encompasses the details of therapeutic applications of serratiopeptidase based on available in vitro, in vivo, and clinical studies. We found some strong evidences regarding the efficacy of serratiopeptidase. Still data on safety, tolerability, and its mechanism of action need detailing. This review aims to farther explore the available literature on serratiopeptidase as well as provide scientific details for existing applications.
Keywords: Serratiopeptidase, Therapeutic application, Anti-inflammatory, Anti-biofilm, Clinical report
ane. Introduction
Enzymes are an essential part of well-nigh metabolic processes and are straight or indirectly of import for the normal functioning of the human torso. They control many physiological functions such as digestion, metabolism, immune function, reproduction, and respiration. Enzymes are obtained from plant, creature, and microbial sources and currently used in clinical practices for the handling and management of diverse diseases and disorders. Enzyme-based therapeutics is recently gaining more attention due to its selectivity, efficiency, and safety contour. The therapeutic efficacy of various enzymes including trypsin, chymotrypsin, papain, and bromelain has been proven [ane]. Serratiopeptidase (serralysin/ serratia-protease/serrapeptidase) is a widely used proteolytic enzyme in therapeutic applications. It has shown significant anti-inflammatory, anti-edemic, and analgesic effects in various areas including surgery, orthopaedics, otorhinolaryngology, gynaecology, and dentistry [2]. It is well known amongst researchers for its caseinolytic (proteolytic) and fibrinolytic properties.
Serratiopeptidase is a zinc containing metalloprotease of molecular weight 45–60 kDa. The enzyme has an EC number 3.4.24.forty and belongs to the group Serralysin. It is originally obtained from Serratia marcescens isolated from the intestine of the silkworm Bombyx mori L. Extensive review on analytical techniques used in the qualitative and quantitative assay of serratiopeptidase has been published by [3], where the authors pointed out a need for selective and specific techniques for the quantification of serratiopeptidase. A detailed review of existing evidences for serratiopeptidase has been reported by [4]. The major role of this enzyme against inflammation is well mapped in the review written past [1]. Other applications of serratiopeptidase in clinical practices majorly include breast illness, atherosclerosis, Alzheimer's illness, sinusitis, hepatitis, lung disorders, and uterine fibroids [5].
This review is a comprehensive report of the therapeutic potential of serratiopeptidase also equally its regulatory status. Nosotros take included in vitro, in vivo, and clinical study reports equally well equally some unconcluded studies from dissimilar therapeutic areas to our best capacity. This review helps to elucidate the potential of serratiopeptidase as well every bit identify lacunas in using it to its full extent and hence, identify areas of future research (Fig. 1).
Properties of serratiopeptidase contributing to its wide applications in therapeutics.
2. Role of enzymes in therapeutics
In 1964, de Duve commencement suggested employ of enzymes as replacement therapy for genetic disorders [vi]. With the emergence of novel diseases and failure of conventional treatments in certain atmospheric condition, enzyme-based therapeutics is playing an important role in the current century. Target specificity and multiple quick substrate conversion are two main properties which have made enzymes successful and popular over non-enzymatic drugs in therapeutic areas. Enzymes are widely used to treat cancer, cardiovascular diseases, digestive disorders, wound debridement, lysosomal storage disease, inflammatory reaction, genetic disorders, and bleeding disorders [7,8]. Several enzymes have been cited in literature for their therapeutic potential including collagenase, proteases, streptokinase, lysostaphin, laccase, glutaminase, and lipase [9]. Specifically, serine proteases have been used to treat blood vascular disorders; fifty-asparaginase and 50,50-glutaminase have shown efficacy in the handling of acute lymphoblastic leukemia; and caspases have been used for treating cancer and many classes of viruses [1].
Some obstacles in using enzymes in therapeutic applications include their big size making information technology difficult for distribution in the body, immunogenicity, short half-life, and impurities. Due to these factors, very few enzymes have been canonical by the FDA despite their proven efficacy. Enzymes including altephase, reteplase, tenecteplase, urokinase, streptokinase, and anistreplase are FDA approved for the handling of cardiovascular diseases [eight]. Few enzymes with notable divergent properties include serratiopeptidase, superoxide dismutase, adenosine deaminase, phenylalanine ammonia lyase, dornase, and rasburicase [8]. Our review highlights the therapeutic molecule serratiopeptidase and its wide clinical applications.
three. Serratiopeptidase
Conventionally, serratiopeptidase is produced from Serratia marcescens, a Gram negative opportunistic pathogen in nutrient rich growth medium. The details of production process and media optimization were explained in earlier review [five]. It has been shown to accept maximum activity at pH 9.0 and temperature 40 °C and is inactivated at 55 °C in 15 min [2]. It is stable in a wide range of pH (pH iii–10) as revealed in the circular dichroism written report, where it showed stable secondary construction [10]. The factor encoding serratiopeptidase is made up of 470 amino acids, devoid of sulfur containing amino acids. The enzyme is produced, purified, characterized and modeled using SWISS-MODEL by [eleven] where authors take authenticated the structure past assessing the Ramachandran plot using PROCHECK server.
Presently, the demand of serratiopeptidase for the industry and pharmaceuticals is being satisfied by wild or mutant strains of Serratia marcescens. Still, the pathogenic nature of the organism and chance associated with the majority biomass released after fermentation necessitates the inquiry on the development of recombinant molecule. Attempts have been carried out to limited serratiopeptidase genes in Escherichia coli using suitable vectors [five]. The failure of many of the attempts attributed to the unregulated intracellular expression of proteases causing cell lysis, growth inhibition, instability of the expression plasmids, lack of poly peptide expression, or degradation of the proteins into non-functional misfolded aggregates [12]. Recently, [12] have demonstrated a production of recombinant serratiopeptidase in Escherichia coli successfully. Further, [xiii] have elucidated the optimized growth media and process weather condition for the large scale product of the recombinant serratiopeptidase.
4. Application of serratiopeptidase in therapeutics
Serratiopeptidase has been used past healthcare professionals in Japan and Europe for therapeutic applications for decades. Recently the clinical use of serratiopeptidase lonely or in combination with other drugs is increasing worldwide.
4.ane. Serratiopeptidase equally an anti-inflammatory agent
Inflammation serves as a defense mechanism against injury and infection. The immune organisation responds quickly to any foreign substances as well as tissue injury by recruiting immune cells and inflammatory mediators to the target site. Hence, inflammation is considered to be the cleaning process of the trunk leading to maintenance of homeostasis [14]. Based on the pathologic conditions of the tissue and intensity of the trigger, inflammation tin be astute or chronic. Though acute inflammation is a protective measure against injury or infection, failure of its resolution leads to chronic inflammation. Inflammatory disorders such as arthritis, sinusitis, bronchitis, fibrocystic breast disease, and carpal tunnel syndrome etc. are common worldwide. Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) alone or in combination with other drugs are prescribed to combat acute inflammation, whereas steroidal drugs are combined with NSAIDs to treat chronic inflammation [one]. The enormous limitations of these drugs take necessitated research on other possible treatments, including natural molecules. Hence, enzyme-based drugs are at present popular in many therapeutic areas including inflammation.
Serine proteases are commonly used in therapeutic areas including inflammation. They were establish to accept high affinity for cyclooxygenases (COX-I and COX-2), key enzymes in the production of different inflammatory mediators. Serratiopeptidase was first used for its anti-inflammatory effects in Japan in 1957 [1]. Further, many researchers have evaluated the potential of serratiopeptidase against inflammation in different therapeutic areas. Information technology has also been used along with other NSAIDs to reach a combined effect. Though serratiopeptidase has been proven to be an constructive anti-inflammatory molecule in many studies, efforts are needed to optimize its dose based on the application. The concentration of serratiopeptidase in the plasma was institute to vary with body mass. Hence, validated cross over studies and optimization are necessary steps to be taken before recommending and prescribing serratiopeptidase [xv].
4.one.1. Pre-clinical and clinical studies
[16] compared the anti-inflammatory result of serratiopeptidase with aspirin and other proteolytic enzymes trypsin and chymotrypsin in albino rats against carrageenan induced paw edema. Serratiopeptidase showed better anti-inflammatory activity alone as well equally showed a synergistic effect with aspirin in both acute and subacute models of inflammation in rats. Another pocket-size pre-clinical study past [17] on 16 Charles Foster albino rats evaluated the anti-inflammatory consequence of serratiopeptidase against diclofenac sodium. Serratiopeptidase at (10−twenty mg/kg of body weight) showed comparable results to that of diclofenac sodium (0.v mg/kg) in inhibiting astute besides equally chronic inflammation in paw edema. The dosage of serratiopeptidase required was college equally compared to diclofenac. This may exist due to the low bioavailability of serratiopeptidase, which tin can be improved using a suitable delivery style (explained in advisable department of this review).
Ulcerative colitis is an inflammatory bowel disease caused by overstimulation or inadequate regulation of the mucosal immune system, affecting rectal and colonic mucosa. [18] conducted an impactful study to test the potential of serratiopeptidase on acerb acid-induced ulcerative colitis in mice. Several inflammatory markers including C-reactive protein, myeloperoxidase, glutathione, and nitric oxide were examined, forth with histopathological test. Serratiopeptidase reduced the disease activity index and prevented colonic shortening, spleen enlargement, glutathione depletion, lipid peroxidation, and nitric oxide production every bit compared to the command group. Further, there was significant reduction in C-reactive protein level in serratiopeptidase treated mice as compared to command. Moreover, myeloperoxidase, an important enzyme marker of inflammation was reduced by serratiopeptidase treatment. These results confirm the anti-inflammatory potential of serratiopeptidase.
There is much clinical data available on the anti-inflammatory effects of serratiopeptidase on pain, swelling, and trismus, details of which are shown in Table 1.
Table 1
Clinical studies in diverse therapeutic areas to evaluate efficiency of serratiopeptidase as an anti-inflammatory agent.
| Type of Inflammation | Treatment method (Drug(southward) taken along with oral administration of serratiopeptidase) | Duration of treatment | Result | Adverse effect reported (Yes/No) | Reference |
|---|---|---|---|---|---|
| Knee osteoarthritis | Metformin | v months | -Reduced pain score -Low level of Tumor necrosis factor alpha (TNF-α), interleukin ane beta (IL-1ß) and interleukin eight (IL-8) | No | Ateia et al. [xix] |
| Acne vulgaris | Doxycycline with retin A foam awarding and panoxyl gel | 5 months | Combined therapy showed significantly rapid improvement in acne appearance | – | Mikhael and Mohammed [20] |
| Postoperative pain, swelling and trismus after surgical removal of mandibular third molars | Methylprednisolone | 5 days | Serratiopeptidase showed moderate analgesic activity but effective control of swelling and trismus compared to methylprednisolone | – | Chappi et al. [21] |
| Postoperative pain, swelling and trismus after surgical extraction of mandibular third molars | – | 7 days | Significant reduction in the occurrence of post-surgical swelling and pain, but no effect on postoperative trismus | No | Ai-Khateeb and Nusair [15] |
| Astute and chronic inflammation of otorhinolaryngology | – | 7−8 days | Rapid issue with a significant improvement in symptoms | No | Mazzone et al. [22] |
| Swelling of the talocrural joint produced by supination trauma | – | 5 months | -Swelling decreased past 50 % on the 3rd post-operative day, which was faster than the command group -Serratiopeptidase treated group was apace pain free compared to the control grouping | – | Esch et al. [23] |
| Postoperative buccal swelling (Caldwell-luc antrotomy) | – | 5 days | Serratiopeptidase treated patients showed lesser caste of swelling than placebo-treated patients at every point of observation | No | Tachibana et al. (1984) |
| Postoperative pain, swelling and trismus after surgical removal of mandibular 3rd molars | – | 3 days | Serratiopeptidase showed good effect on trismus but not on swelling and hurting | – | Murugesan et al. [24] |
Withal, some reports on paw showed comparatively lesser result of serratiopeptidase. In a written report past [25] the efficacy and rubber of serratiopeptidase and seaprose S in the treatment of venous inflammatory disease were compared. Seaprose S had a college efficacy as compared to serratiopeptidase (85 % vs 65 %) with no adverse furnishings. Farther, in this study, one out of 20 patients that received serratiopeptidase showed balmy gastrointestinal disturbance. [26] institute comparatively lesser analgesic and anti-inflammatory outcome of serratiopeptidase every bit compared to Betamethasone and Ibuprofen. Further, a combination of trypsin and chymotrypsin had a higher efficacy in wound management as compared to serratiopeptidase in a 75 patient study [27]. Contradictory results were observed in two independent studies washed on a rat mitt edema model. In a written report by [28] comparison serratiopeptidase with diclofenac, serratiopeptidase handling (5.iv mg/kg of body weight) did not result in significant improvement in the inflammation of paw edema. These results are not in agreement with those of [17] where serratiopeptidase (10 mg/kg of body weight) showed promising anti-inflammatory activity. The different dosages used in these 2 studies make it difficult to draw determination.
Overall, serratiopeptidase tin can exist seen every bit a promising candidate in modernistic medicine when used either alone or in combination with other agents, particularly in situations where NSAIDs do not bear witness satisfactory results (Table 2, Tabular array three).
Table ii
In vitro studies of a combination of serratiopeptidase and antibiotics for biofilm treatment.
| Serratiopeptidase combinations with the antibiotics | Biofilms | Results | Reference |
|---|---|---|---|
| Ofloxacin | Staphylococcus epidermidis Pseudomonas aeruginosa | -Serratiopeptidase enhanced the activity of ofloxacin and inhibited biofilm formation | Selan et al. [29] |
| Azithromycin | Bacterial biofilms growing on vascular graft surface | - Combination of serratiopeptidase and azithromycin was constitute to exist very effective against Stayphalococcus strains by showing less minimum inhibitory concentration (MIC) compared to other antibiotic treatments | Thaller et al. [xxx] |
| Ciprofloxacin | Staphylococcus aureus | - Combination of serratiopeptidase (50 μg/mL) and ciprofloxacin at sub-MIC concentration cleared biofilm on catheter. | Gupta and Nagarsenke (2015) |
| Vancomycin and rifampicin | Methicillin resistant and methicillin susceptible strains of S. aureus | - Effective in dispersing biofilm contained of the strain of organism. | Hogan et al. [31] |
| Levofloxacin | Staphylococcus aureus | - Eradicated >90 % of the preformed biofilm - Combination showed synergistic activity | Gupta et al. [32] |
Table 3
Mode of commitment of serratiopeptidase for different applications.
| Fashion of commitment (Entrapement/carrier) | Results | Reference |
|---|---|---|
| Serratiopeptidase loaded albumin nanoparticles | Entrapment efficiency and percentage drug release was found to be 85 % and 79.3 % respectively | Kaur and Singh [33] |
| Encapsulation in liposome | Serratiopeptidase encapsulated in liposome forth with antibody levofloxacin helps in biofilm irradiation in S. aureus infected rat | Gupta et al. [32] |
| Clove oil emulsified buccal patch of serratiopeptidase | Significant entrapment efficiency was obtained forth with controlled released for 24h | Shende et al. [34] |
| Poly(D,L-lactic-co-glycolic acid) microspheres of serratiopeptidase and gentamicin entrapped into polyvinyl alcohol-gelatin hydrogel | -The developed delivery organisation is effective in promoting natural debridement past hydrating necrotic tissue -It provides directly sustained release of antibiotics and serratiopeptidase for better and faster wound healing | Singh and Singh [35] |
| Serratiopeptidase loaded chitosan nanoparticles | -Sustained release upto 24h -Prolonged anti-inflammatory action upto 32h | Mali et al. [36] |
| Microsphere of serratiopeptidase in polymer Eudragit RS100 | Prolonged release of serratiopeptidase for sustained therapeutic effect | Hire et al. [37] |
| Liposomal formulations of serratiopeptidase | -A maximum entrapment efficiency of 86 % was found -Liposomal formulation of serratiopeptidase improved its permeability every bit revealed past an in vitro study using PAMPA and caco-2 model | Sandhya et al. [38] |
| Serratiopeptidase transdermal patch by lipid-based transfersomes | -Entrapment efficiency was 96.76 % -In vitro and in vivo release was controlled and steady | Shende et al. [39] |
| Serratiopeptidase niosomal gel | -Maximum entrapment efficiency was 54.82 % with a consistent release design -Anti-inflammatory activity was comparable to that of diclofenac gel as revealed past in vivo efficacy report | Shinde and Kanojiya [40] |
| Serratiopeptidase and metronidazole loaded on alginate microspheres past emulsification | -Good loading efficiency -Improved wound healing as observed in in vivo testing in rabbits | Rath et al. [41] |
| Serratiopeptidase immobilized on amino-functionalized magnetic nanoparticles | -Immobilization increased permeation through the membrane as observed in in vitro studies -Immobilization reduced the dose of serratiopeptidase for anti-inflammatory effect as studied in a rat edema model | Kumar et al. [42] |
4.2. Serratiopeptidase as an anti-biofilm agent
Bacterial biofilms are multicellular structures of dense and highly hydrated communities of microorganisms embedded within a matrix of self-synthesised polymeric or proteinaceous fabric [43,44]. They tin can exist attached to biotic or abiotic surfaces. I of the characteristic backdrop of biofilms is high resistance to the adaptive and innate immune systems also as tolerance to high concentrations of antibiotics/antimicrobial agents. This leads to persistent infection, making these entities a medical and economical nuisance [31]. They are associated with a variety of infections including urinary tract infections, chronic lung infections, endocarditis, osteomyelitis, chronic otitis media etc. [44]. Biofilms unremarkably develop on implants and medical devices like catheters, pacemakers, prosthetic joints, tooth surfaces, and various host tissue surfaces leading to chronic infections [44]. They are virtually 100 times more than resistant to antimicrobial agents as compared to private bacterial colonies, thus leading to antibody treatment failure.
Various strategies to provide a suitable solution to biofilm associated health bug including inhibition, dispersal, and utilize of biofilm eradicating agents (antibiotics) accept been attempted. Surface proteins and secreted proteins accept found to play an important role in biofilm formation, stability, and regulation [44]. Hence, proteases were hypothesized to be a potential treatment of biofilms, which was further supported by scientific studies. Proteases purified from different organisms accept tested successfully against biofilm, with metalloproteases in detail, playing an important role [45]. Moreover, commercial proteases have likewise been successful in the eradication of biofilms [46,47]. Serratiopeptidase, a commercially bachelor bacterial metalloprotease has proven to be effective against a variety of biofilm-associated medical conditions due to the following reasons:
-
1
It can modify the virulent phenotype of leaner in biofilms [48,49]
-
2
It is effective against mature biofilms [49]
-
3
Information technology enhances the bactericidal effect of antibiotics confronting bacterial biofilms [50].
4.two.1. In vitro studies
Various in vitro studies prove a positive impact of serratiopeptidase confronting biofilms. It affects a discrete number of proteins involved in fundamental mechanisms associated with bacterial virulence, such equally adhesion, invasion, and biofilm germination [51]. Serratiopeptidase reduces cell surface proteins Ami4b, autolysin, internalinB, and ActA and hence reduces the ability of Listeria monocytogenes to form biofilms and to invade host cells. This leads to the prevention of initial adhesion of Listeria monocytogenes to the human gut [52]. [48] tested the part of three serine proteases (proteinase G, trypsin, and chymotrypsin) and 2 metalloproteases (serratiopeptidase and carboxypeptidase) confronting biofilm germination and in human cell invasion processes using different strains of Staphylococcus aureus and Staphylococcus epidermidis. Among all the proteases tested, simply serratiopeptidase was constitute to inhibit the action of all the tested strains. It slightly affected the adhesion efficiency (20 %) just drastically reduced the invasion efficiency (200-fold) of Staphylococcus aureus. Serratiopeptidase neither afflicted bacterial viability nor showed whatever cytotoxic effects on the eukaryotic cell lines, alluding to its safe.
A study of the anti-infective adequacy of serratiopeptidase against Staphylococcus aureus revealed its effects on a discrete number of surface proteins [49]. One such protein is At1 which helps in internalization of staphylococcus in host cells, confirming that serratiopeptidase modulates adhesins and autolysins in Staphylococcus aureus. Farther, the action of serratiopeptidase is not only restricted to initial bacterial attachment on abiotic surface but is also effective on mature biofilms. The writer emphasised that serratiopeptidase hinders the entry of pathogens in human tissue as well as impairs adhesion of pathogens to prostheses, catheters, and medical devices.
[53] developed a mutant class of serratiopeptidase with no proteolytic activity. The developed mutant was found to maintain anti-biofilm holding, suggesting that this property is independent of the proteolytic activity of serratiopeptidase. They concluded that serratiopeptidase is a potential antipathogenic agent with or without proteolytic activity and prevents the formation of biofilms on medical devices [53]. Further, authors suggested the demand for enquiry to identify the machinery of activity of serratiopeptidase in biofilm regulation that is unrelated to proteolytic activity. Recently, [54] evaluated the anti-biofilm ability of serratiopeptidase against Staphalococcus aureus infection on osteoblastic MG-63 cells. The pro-inflammatory chemokine MCP-ane was used as an immunological marker. Serratiopeptidase impaired the invasion adequacy of Staphylococcus aureus in the osteoblastic cells and lowered the secretion of MCP-i. It is worthwhile to note that serratiopeptidase did not affect the viability or proliferation of the osteoblastic cells, indicating its condom in the handling of os infection.
Further, combined treatment of serratiopeptidase with antibiotics is a novel approach in the handling against bacterial biofilm infection. The combination has been shown to have synergistic effects. Serratiopeptidase is thought to work like a biological "nanodrill" and disrupt the bacterial biofilm membrane, thus paving the way for antibiotics to human activity [32]. Serratiopeptidase was likewise shown to be more constructive as compared to other proteases [29].
iv.2.ii. Pre-clinical and clinical studies
In an in vivo study on 60 Sprague-Dawley rats, serratiopeptidase eradicated periprosthetic infection caused by Staphylococcus epidermis [55]. Histological and microbiological testing revealed that 5.half dozen % of rats showed infection in the serratiopeptidase + antibody treated group vs 37.5 % in the antibiotic alone treated group. The authors ended that the anti-biofilm holding of serratiopeptidase enhances the efficacy of antibiotics. The study reported adverse furnishings on articulation cartilage and synovial tissue attributable to serratiopeptidase. However, the authors believe that serratiopeptidase use is safety equally shown in previous studies and commented that a lower dose may not prove this adverse event. Hence, enzyme dosage and application sites should exist carefully considered before using an enzyme-antibiotic combination handling.
Clinical studies of peri-implantitis are important, given the large number of implant surgeries being performed worldwide. Early diagnosis of peri-implantitis is difficult due to initial balmy or no symptoms too every bit lack of proper diagnostic tests. Antibody resistance is some other obstruction in its treatment. Colonization of leaner occurs at the surface of the implant, forming a biofim which causes severe inflammation of the peri-implant tissue and damages the implant supporting bone. In a controlled study of 64 adults, [l] evaluated the combined effect of serratiopeptidase with antibiotics in peri-implantitis. The combined treatment significantly improved clinical, microbiological, and inflammatory parameters as compared to the command group. The authors concluded that serratiopeptidase enhanced the efficacy of antibiotics by increasing tissue concentration of the antibiotics [56,57]. A retrospective study in 544 patients was conducted by [58] on partially edentulous patients treated for peri-implantitis by evaluating clinical charts. The study indicated that serratiopeptidase helps in the repair of bone lesions and speeds upwards the clinical healing process. The authors strongly believe that the co-administration of serratiopeptidase with antibiotics to exist a preferred pick in peri-implantitis handling.
iv.3. Other applications
The analgesic effect of serratiopeptidase is widely known and has been reported in clinical studies. The ability of serratiopeptidase to hydrolyse bradykinin, histamine, and serotonin contributes to its analgesic activity. Serratiopeptidase was institute to salve hurting in patients with root culvert treatment [59] and control toothache when emulsified with clove oil [34]. The analgesic activity of serratiopeptidase has likewise been proven in cases of surgical extraction of mandibular third molars reported by Al-Khateeb and Nusair, 2008.
A clinical trial by [lx] on 70 patients with chest engorgement demonstrated that serratiopeptidase treatment resulted in moderate to marked improvement in breast pain, swelling, and induration with no adverse events reported. A prospective trial to explore the application of serratiopeptidase in the handling of carpel tunnel syndrome showed clinical improvement in 65 % of the patients [61]. Serratiopeptidase has been widely used in Japan as an anti-inflammatory and mucolytic agent. Airway mucus is a viscoelastic gel important for the airway defense system. Still, in chronic airway disease, increased secretion of mucus and decreased clearance causes its accumulation. [62] evaluated the effect of serratiopeptidase on viscosity and elasticity of nasal mucus in patients with chronic sinusitis. Serratiopeptidase was constitute to reduce viscosity but not elasticity of the mucus. Further, study washed by [63] demonstrated that the Serrapeptidase could enhance fungus clearance in patients with chronic airway disease. This effect was attributed to the ability of serratiopeptidase to reduce neutrophil count and modify viscoelasticity of the mucus.
Another innovative and interesting application is in the treatment of Alzheimer'south affliction via reduction of amyloidosis. Serratiopeptidase was institute to be equally effective as nattokinase (an enzyme shown to degrade amyloid coarse) in relieving Alzheimer's affliction pathophysiology in a rat model [64]. Oral administration of an enzyme decreased brain acetylcholinesterase activity, as well every bit levels of transforming growth factor ß, Fas, and interleukin-6, all of which were significantly increased in patients with Alzheimer'south disease. These results were confirmed by histological examination of brain tissue. This written report demonstrates that serratiopeptidase can downwardly-regulate the amyloidogenic pathway due to its proteolytic, anti-oxidant, and anti-amyloidogenic effects. The study was further supported by a recent reports [65,66] showing dissociation of insulin amyloids by serratiopeptidase both in vitro and in vivo. Amyloidosis is a result of misfolding of normal cellular protein to protease resistant β-sheets making insoluble aggregates. These aggregates build upward in the body and their clearance is highly difficult. The amyloid dissociation ability of serratiopeptidase was better than that of the standard amyloid dissociating amanuensis, nattokinase. This novel approach paves the manner to explore the therapeutic potential of serratiopeptidase in different amyloid related disorders.
A combination therapy consisting of enteric coated Vitamin C, extract of Withaferania somnia, and serratiopeptidase has been used to care for thyroid cancer [67]. Consummate remission of thyroid tumor was establish later 18 months of combination therapy. Serratiopeptidase plays an important role in cleaning the dead cells from the target site leading to an increased rate of killing of tumor cells. This written report farther highlights the scope for injecting enzyme directly to the target site of a tumor to enhance efficiency.
5. Mechanism of activity
Despite its wide therapeutic applications, the mechanism of serratiopeptidase activeness has non been well elucidated.
Wound healing: Serratiopeptidase helps to thin the fluids in inflamed areas, thus facilitating drainage. This results in reduction of swelling, pain, and enhances tissue repair. Serratiopeptidase also accelerates the healing procedure due to its unique property of dissolving dead tissue surrounding the injured area without harming living tissue. Further, it hydrolyses bradykinin, histamine, and serotonin which helps to subtract pain and swelling and better microcirculation, which in plow supports the wound healing procedure [68].
Anti-inflammatory: Serratiopeptidase acts every bit an anti-inflammatory agent by regulating inflammatory cytokines and hence the onset of chronic inflammation. It significantly modifies cell adhesion molecules that guide inflammatory cells to the sites of inflammation. It promotes wound healing, repair, and restores the skin temperature at the target inflammation site. It should be noted that serratiopeptidase is more stable and has higher efficacy when used in combination with metal ions like zinc and manganese [1].
Antibiofilm: The anti-biofilm power of serratiopeptidase is accredited to its adequacy of modulating the expression of adhesion molecules and reduces cell surface proteins of bacteria [51]. It prevents biofilm formation too as helps to disperse preformed biofilm. Its anti-biofilm ability helps to enhance the penetration of antibiotics through the resistant biofilm and hence increases susceptibility of biofilms to antibiotics.
Fibrinolytic: Serratiopeptidase is known to dissolve blood clots and artherosclerotic plaques past breaking down fibrin and other dead or damaged tissue [2]. It can likewise remove deposits of fatty substances, cholesterol, and cellular waste inside the arteries. The fibrinolytic property of serratiopeptidase may also help with the problems of thick blood, risk of stroke, and thrombophlebitis [1].
half-dozen. Absorption and safety of serratiopeptidase
Meagre literature is available on the absorption and prophylactic of serratiopeptidase in the human body. Information technology is known that orally taken serratiopeptidase gets captivated through the intestine and transported into the claret. The abdominal absorption of serratiopeptidase has been tested in rats by evaluating its concentration in plasma, lymph, and inflammatory tissue extract using the sandwich enzyme immunoassay technique. The study showed that the concentration of serratiopeptidase in plasma and lymph is dose dependent. Superlative plasma concentration was reached at 0.25−0.5 h later intake and the enzyme was measurable upto 6 h [69]. Further, [lxx] demonstrated that the concentration of serratiopeptidase was college in inflammatory tissue that that of in plasma. The authors proposed that serratiopeptidase is absorbed from the intestine and distributed to inflammatory sites via blood or lymph. Serratiopeptidase forms a circuitous with plasma protease inhibitor alpha-1 macroglobulin in the ratio of i:1 as observed in a rat report [71]. This binding masks its antigenicity with twenty % memory of its original caseinolytic activity. This circuitous helps to send serratiopeptidase via blood to the target sites. The dosage of serratiopeptidase by and large ranges from 10−60 mg per twenty-four hour period (2000/mg Unit of measurement activity). It is highly recommended to get a prescription for serratiopeptidase from health experts considering its dosage requirement varies depending on the application and illness state.
Serratiopeptidase is a natural molecule that is beingness used for decades, hence ordinarily considered every bit safe. The prophylactic of this enzyme in unlike areas of therapeutics is supported by several studies [fifteen,xix,22,48,54,72] in which no side effects or adverse events were reported. Notwithstanding, some studies have reported adverse effects of this molecule, simply at a rare frequency. The explanation of the aforementioned has been provided above in the respective department of this review. Further, Stevens-Johnson syndrome [73] and buccal infinite abscess [74] have besides been reported as side effects of this molecule. These side effects may be dose dependent or possibly due to a combination outcome when used with other drugs. Detailed, scientifically designed controlled clinical studies need to be conducted to further examine the prophylactic profile.
seven. Mode of delivery of serratiopeptidase
Common problems associated with drug delivery are poor solubility, toxicity, instability, incompatibility, and poor penetration [75]. Each drug needs a suitable commitment organization depending on its characteristics. Serratiopeptidase suffers high gamble of enzymatic degradation in the gastrointestinal tract due to its proteinacious nature. Further, its hydrophilic nature causes low permeability through the intestinal membrane. These factors impose the use of a very high dosage for significant effects. Controlled and sustained released of serratiopeptidase is vital approach to subtract the frequency of dosing and to improve patient compliance. Hence, different delivery modes have been studied including magnetic nanoparticles, microspheres, encapsulation in liposomes, and emulsification. In vitro release profiles and in vivo efficacy are important parameters demand to be studied to develop suitable commitment modes.
New modes of commitment take been evaluated in cases of dentistry and wound healing. Novel effective biocompatible moist system for consummate wound management was studied by [35]. Poly(D,L-lactic-co-glycolic acid) microspheres of serratiopeptidase and gentamicin were entrapped into polyvinyl alcohol-gelatin hydrogel. In vitro and in vivo studies showed the direct sustained release of serratiopeptidase along with antibiotics at the wound site leading to a amend and faster healing process. [76] adult a topical conception of serratiopeptidase in the grade of an ointment and a gel and evaluated its anti-inflammatory effects. The authors highlighted that topical awarding circumvents the drawbacks of oral delivery including anorexia, nausea, and GI disturbance, if any. An optimized formulation was evaluated for in vitro release profile and in vivo anti-inflammatory action where it showed satisfactory inhibition of ear edema in a rat study. The absence of whatever allergic reaction in rats supports the safety profile of the serratiopeptidase formulation. Enteric dispersion of serratiopeptidase with the polymer Eudragit has shown promising results for controlled release of the drug [37,77].
8. Regulatory aspects
Though serratiopeptidase is widely used in clinical practice around the globe, its regulatory condition varies in unlike countries. The marketing and use of this molecule in whatever intended country needs approval by designated regulatory bodies. Background authoritative, chemical science, pre-clinical and clinical data are needed for blessing where quality, efficacy, and safety are important parameters to be considered. Serratiopeptidase has been approved in Canada for use as an ingredient in dietary supplements to reduce pain and swelling [78]. In India, it is approved equally a pharmaceutical ingredient for the treatment of acute pain in combination with other drugs [80]. Regulatory authorities provide approval status for specific applications. However, a few regulatory regime take published approvals for serratiopeptidase to be used every bit a dietary supplement or equally an active pharmaceutical ingredient as listed in Table four.
Table 4
Regulatory status of serratiopeptidase in major global markets.
| Country | Regulatory Agency | Approval status | Details | References |
|---|---|---|---|---|
| United states of america | U.S. Food & Drug Administration | New Dietary Ingredient Notification (NDIN) | NDIN# 6 was filed by Specialty Enzymes & Probiotics | Dietary supplement health and education act (DSHEA) [81] |
| Drug Master file (DMF) | DMF# 23,557 filed by Specialty Enzymes & Probiotics and DMF# 27,172 filed by Newgen Biotech | 21 Code of federal regulations (CFR) part- 314 | ||
| Canada | Health Canada | Natural health product (NHP) | -Enteric coated version is immune. Can be used for reduction in pain and swelling and to combat throat infections | NHP Ingredients Database: Serrapeptase [78] |
| Europe | European committee (EC) | Novel Nutrient | Serratiopeptidase is considered as Novel Food. Safety evaluation is needed under 2015/2283 regulation | Regulation (EU) No. 2015/2283 |
| India | Central Drug Standard Command Organisation (CDSO) | Approved as active pharmaceutical ingredient (API) | Serratiopeptidase is widely available. It is generally sold in combination with other APIs. | The Drug and Corrective Human activity [80] |
Besides, in Japan, proprietor, Takeda has voluntarily withdrew serratiopeptidase in 2011 then subsequently, Singapore regime has taken decision to stage out serratiopeptidase containing preparations equally medicinal products due to some controversial results of the trials and lack of substantive scientific evidences [79].
Label/health merits guidelines demand to be followed for products containing serratiopeptidase equally a dietary ingredient or pharmaceutical ingredient. The big claiming for articles and distributors is to understand the assortment of label claims that are allowed to be used for serratiopeptidase containing products. In the United States, dietary supplements can make structure/office statements [81]. However, regulatory agencies in Europe and Canada have special provisions to allow broader health claims. Those are canonical under regulation (EC) no. 1924/2006 in Europe and Food and Drugs human activity (section 30(j)) in Canada. Manufacturers need detailed case past case evaluation of the approved claims in each country before marketing serratiopeptidase.
9. Conclusion
The proteolytic enzyme serratiopeptidase is beingness widely used in the treatment of many diseases and disorders for decades across the world. In vitro studies, controlled, uncontrolled pre-clinical and clinical studies, and some anecdotal reports highlight its potential in the therapeutics. However, negative and controversial results obtained also equally some reports of mild to moderate side effects cannot exist overlooked. Hence, more research is needed to ostend its therapeutic potential, elucidate the mechanism(south) of action as well as safety of different doses and formulations. Well designed in vitro, in vivo, and clinical studies volition assist to establish the apply of serratiopeptidase in various therapeutic areas.
Author contribution statement
The conception and blueprint of the written report: Southward. J and Abhijit R; acquisition of data, analysis, and estimation of data: South. J, Ankit R, and N. S; Drafting the article: South. J, N. South, and Ankit R; revising the commodity critically for important intellectual content: N. S, S. J and V. R; final approval of the version to be submitted: 5. R and Abhijit R.
Declaration of Competing Involvement
The authors study no declarations of interest.
Acknowledgements
Authors are grateful to Advanced Enzymes Technologies Ltd., India for support.
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