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Cureus Nov 2023The spike protein of SARS-CoV-2 has been found to exhibit pathogenic characteristics and be a possible cause of post-acute sequelae after SARS-CoV-2 infection or... (Review)
Review
The spike protein of SARS-CoV-2 has been found to exhibit pathogenic characteristics and be a possible cause of post-acute sequelae after SARS-CoV-2 infection or COVID-19 vaccination. COVID-19 vaccines utilize a modified, stabilized prefusion spike protein that may share similar toxic effects with its viral counterpart. The aim of this study is to investigate possible mechanisms of harm to biological systems from SARS-CoV-2 spike protein and vaccine-encoded spike protein and to propose possible mitigation strategies. We searched PubMed, Google Scholar, and 'grey literature' to find studies that (1) investigated the effects of the spike protein on biological systems, (2) helped differentiate between viral and vaccine-generated spike proteins, and (3) identified possible spike protein detoxification protocols and compounds that had signals of benefit and acceptable safety profiles. We found abundant evidence that SARS-CoV-2 spike protein may cause damage in the cardiovascular, hematological, neurological, respiratory, gastrointestinal, and immunological systems. Viral and vaccine-encoded spike proteins have been shown to play a direct role in cardiovascular and thrombotic injuries from both SARS-CoV-2 and vaccination. Detection of spike protein for at least 6-15 months after vaccination and infection in those with post-acute sequelae indicates spike protein as a possible primary contributing factor to long COVID. We rationalized that these findings give support to the potential benefit of spike protein detoxification protocols in those with long-term post-infection and/or vaccine-induced complications. We propose a base spike detoxification protocol, composed of oral nattokinase, bromelain, and curcumin. This approach holds immense promise as a base of clinical care, upon which additional therapeutic agents are applied with the goal of aiding in the resolution of post-acute sequelae after SARS-CoV-2 infection and COVID-19 vaccination. Large-scale, prospective, randomized, double-blind, placebo-controlled trials are warranted in order to determine the relative risks and benefits of the base spike detoxification protocol.
PubMed: 38024037
DOI: 10.7759/cureus.49204 -
PloS One 2023Colorectal cancer (CRC) is one of the most lethal cancers worldwide. Long-term survival is not achieved in metastatic CRC despite the current multidisciplinary...
BACKGROUND
Colorectal cancer (CRC) is one of the most lethal cancers worldwide. Long-term survival is not achieved in metastatic CRC despite the current multidisciplinary therapies. Bromelain, a compound extracted from the pineapple plant, has multiple functions and anticancer properties. Previously, bromelain has been chromatographically separated into four fractions. Fraction 3 (F3) exhibits the highest proteolytic activity. The anticancer effects of F3 bromelain in CRC cells is unknown.
METHODS
In vitro cytotoxicity was verified through a sulforhodamine B assay. Apoptosis in CRC cells induced by unfractionated or F3 bromelain was examined using Annexin V-FITC/PI staining and Western blot analysis. ROS status, autophagy and lysosome formation were determined by specific detection kit.
RESULTS
The cytotoxicity of F3 bromelain in CRC cells was found to be comparable to that of unfractionated bromelain. F3 bromelain induces caspase-dependent apoptosis in CRC cells. Treatment with unfractionated or F3 bromelain increased superoxide and oxidative stress levels and autophagy and lysosome formation. ATG5/12 and beclin-1 were upregulated, and the conversion of LC3B-I to LC3B-II was increased significantly by treatment with F3 bromelain. Treated CQ, autophagy inhibitor, with unfractionated or F3 bromelain enhances the cytotoxic effects. Finally, the combination of unfractionated and F3 bromelain with a routine chemotherapeutic agent (5-fluourouracil, irinotecan, or oxaliplatin) resulted in synergistically higher cytotoxic potency in CRC cells.
CONCLUSION
Unfractionated and F3 bromelain inhibits CRC cell proliferation in vitro, and the cytotoxic effects of unfractionated bromelain are equivalent to F3 bromelain. F3 bromelain may be a potential and potent drug for clinical use due to its anticancer efficacy and high synergistic cytotoxicity when combined with a routine chemotherapeutic agent for CRC.
Topics: Humans; Bromelains; Cell Line, Tumor; Antineoplastic Agents; Irinotecan; Colonic Neoplasms; Apoptosis; Cell Proliferation; Colorectal Neoplasms
PubMed: 37262048
DOI: 10.1371/journal.pone.0285970 -
Scientific Reports Jul 2023Papain (aka C1A) family proteases, including bromelain enzymes, are widespread across the plant kingdom and play critical regulatory functions in protein turnover during...
Papain (aka C1A) family proteases, including bromelain enzymes, are widespread across the plant kingdom and play critical regulatory functions in protein turnover during development. The proteolytic activity exhibited by papain family proteases has led to their increased usage for a wide range of cosmetic, therapeutic, and medicinal purposes. Bromelain enzymes, or bromelains in short, are members of the papain family that are specific to the bromeliad plant family. The only major commercial extraction source of bromelain is pineapple. The importance of C1A family and bromelain subfamily proteases in pineapple development and their increasing economic importance led several researchers to utilize available genomic resources to identify protease-encoding genes in the pineapple genome. To date, studies are lacking in screening bromelain genes for targeted use in applied science studies. In addition, the bromelain genes coding for the enzymes present in commercially available bromelain products have not been identified and their evolutionary origin has remained unclear. Here, using the newly developed MD2 v2 pineapple genome, we aimed to identify bromelain-encoding genes and elucidate their evolutionary origin. Orthologous and phylogenetic analyses of all papain-family proteases encoded in the pineapple genome revealed a single orthogroup (189) and phylogenetic clade (XIII) containing the bromelain subfamily. Duplication mode and synteny analyses provided insight into the origin and expansion of the bromelain subfamily in pineapple. Proteomic analysis identified four bromelain enzymes present in two commercially available bromelain products derived from pineapple stem, corresponding to products of four putative bromelain genes. Gene expression analysis using publicly available transcriptome data showed that 31 papain-family genes identified in this study were up-regulated in specific tissues, including stem, fruit, and floral tissues. Some of these genes had higher expression in earlier developmental stages of different tissues. Similar expression patterns were identified by RT-qPCR analysis with leaf, stem, and fruit. Our results provide a strong foundation for future applicable studies on bromelain, such as transgenic approaches to increase bromelain content in pineapple, development of bromelain-producing bioreactors, and studies that aim to determine the medicinal and/or therapeutic viability of individual bromelain enzymes.
Topics: Bromelains; Ananas; Papain; Phylogeny; Proteomics
PubMed: 37463972
DOI: 10.1038/s41598-023-38907-y -
Foods (Basel, Switzerland) Nov 2023Plant proteases, including actinidin, papain and bromelain, have been widely used in the food industry but with limited application in dairy systems. This research aimed...
Plant proteases, including actinidin, papain and bromelain, have been widely used in the food industry but with limited application in dairy systems. This research aimed to establish and compare operational parameters (kinetics, temperature, enzyme type, time and thermodynamics) relevant to the applications of these enzymes in the hydrolysis of whey protein isolates (WPI), whey protein concentrates (WPC) or milk protein concentrates (MPC). The degree of hydrolysis (DH) increased with the rise in temperature, and the maximum DH was achieved at 60 °C for all three dairy systems. The addition of papain resulted in a greater %DH of whey proteins in comparison to bromelain. The cleavage of proteins was clearly time-dependent ( < 0.05), while the pH did not change significantly ( > 0.05) during this time. PAGE analysis revealed that all three enzymes mainly acted on α-lactalbumin and α-casein in WPI and MPC, respectively. Kinetic parameters from the Lineweaver-Burk plot at 60 °C using WPC and MPC as a substrate varied widely, establishing that WPC hydrolysis was characterised by a lower KM, higher kcat, kcat/KM and Vmax compared to MPC in the case of all three enzymes. The difference in kcat/KM values amongst all enzymes (actinidin > papain > bromelain) indicated the difference in the strength of substrate binding sites. The thermodynamic parameters of these enzymes with MPC and WPC were also determined at a temperature range of 15-60 °C, and the results indicate the potential application of papain and actinidin in the dairy industry.
PubMed: 38231667
DOI: 10.3390/foods12234248 -
Journal of Clinical Medicine Nov 2023Diabetic retinopathy (DR) is one of the most severe diabetes-related complications, and macular edema stands as the primary contributor to the loss of central vision in...
Diabetic retinopathy (DR) is one of the most severe diabetes-related complications, and macular edema stands as the primary contributor to the loss of central vision in individuals diagnosed with diabetes mellitus. The purpose of this study was to investigate the anatomical and functional effects of the oral administration of bromelain and curcugreen in patients controlled by therapy with non-proliferative DR presenting focal edema. Patients were enrolled and divided into two groups: group A (n = 18) received two tablets a day of bromelain and curcugreen (Retinil Forte) orally, and group B (n = 15) underwent observation. The protocol included four visits: the screening visit (T0) and follow-up checks every 3 months up to 12 months (T3-T6-T9-T12). Best-corrected visual acuity (BCVA), central macular thickness (CMT) measured by optical coherence tomography (OCT) and vascular perfusion (VP) in superficial capillary plexus (SCP) and the deep capillary plexus (DCP) measured by optical coherence tomography angiography (OCTA) were analyzed. A mixed-design ANOVA was calculated to determine whether the change in BCVA, CMT, VP in SCP and DCP over time differed according to the consumption of Retinil Forte. The results indicated that the interaction between time and treatment on the CMT and VP in DCP were significant, with F (4, 124) = 6.866 ( < 0.0001) and F (4, 124) = 3.263 ( = 0.0140), respectively. Conversely, the interaction between time and treatment was not significant on BCVA and VP in SCP with F (4, 124) = 1.121 ( = 0.3496) and F (4, 124) = 1.473 ( = 0.2146), respectively. In conclusion, our results suggest a protective role of the oral administration of bromelain and curcugreen in patients with DR and focal edema, in terms of the improvement of baseline CMT and VP in DCP over time.
PubMed: 38068370
DOI: 10.3390/jcm12237318 -
Frontiers in Immunology 2023In the present study, the impact of BromAc®, a specific combination of bromelain and acetylcysteine, on the SARS-CoV-2-specific inflammatory response was evaluated.
INTRODUCTION
In the present study, the impact of BromAc®, a specific combination of bromelain and acetylcysteine, on the SARS-CoV-2-specific inflammatory response was evaluated.
METHODS
An in vitro stimulation system was standardized using blood samples from 9 healthy donors, luminex assays and flow cytometry were performed.
RESULTS AND DISCUSSION
BromAc® demonstrated robust anti-inflammatory activity in human peripheral blood cells upon SARS-CoV-2 viral stimuli, reducing the cytokine storm, composed of chemokines, growth factors, and proinflammatory and regulatory cytokines produced after short-term in vitro culture with the inactivated virus (iSARS-CoV-2). A combined reduction in vascular endothelial growth factor (VEGF) induced by SARS-CoV-2, in addition to steady-state levels of platelet recruitment-associated growth factor-PDGFbb, was observed, indicating that BromAc® may be important to reduce thromboembolism in COVID-19. The immunophenotypic analysis of the impact of BromAc® on leukocytes upon viral stimuli showed that BromAc® was able to downmodulate the populations of CD16+ neutrophils and CD14+ monocytes observed after stimulation with iSARS-CoV-2. Conversely, BromAc® treatment increased steady-state HLA-DR expression in CD14+ monocytes and preserved this activation marker in this subset upon iSARS-CoV-2 stimuli, indicating improved monocyte activation upon BromAc® treatment. Additionally, BromAc® downmodulated the iSARS-CoV-2-induced production of TNF-a by the CD19+ B-cells. System biology approaches, utilizing comprehensive correlation matrices and networks, showed distinct patterns of connectivity in groups treated with BromAc®, suggesting loss of connections promoted by the compound and by iSARS-CoV-2 stimuli. Negative correlations amongst proinflammatory axis and other soluble and cellular factors were observed in the iSARS-CoV-2 group treated with BromAc® as compared to the untreated group, demonstrating that BromAc® disengages proinflammatory responses and their interactions with other soluble factors and the axis orchestrated by SARS-CoV-2.
CONCLUSION
These results give new insights into the mechanisms for the robust anti-inflammatory effect of BromAc® in the steady state and SARS-CoV-2-specific immune leukocyte responses, indicating its potential as a therapeutic strategy for COVID-19.
Topics: Humans; SARS-CoV-2; COVID-19; Vascular Endothelial Growth Factor A; Anti-Inflammatory Agents
PubMed: 38193087
DOI: 10.3389/fimmu.2023.1308477 -
Scientific Reports Dec 2023Enzyme therapy can be an appropriate treatment option for celiac disease (CeD). Here, we developed Bromelain-Loaded Nanocomposites (BLNCs) to improve the stability and...
Enzyme therapy can be an appropriate treatment option for celiac disease (CeD). Here, we developed Bromelain-Loaded Nanocomposites (BLNCs) to improve the stability and retention of bromelain enzyme activity. After the characterization of BLNCs, the cytotoxicity of BLNCs was determined on the Caco-2 cell line. The effect of BLNCs on gliadin degradation and the production of pro-inflammatory cytokines and anti-inflammatory molecules in peripheral blood mononuclear cells (PBMCs) obtained from celiac patients were assessed. Furthermore, the expression of CXCR3 and CCR5 genes was measured in CaCo-2 cells treated with gliadin, gliadin-digested with BLNCs, and bromelain. Our study demonstrated that the Bromelain entrapment efficiency in these nanoparticles was acceptable, and BLNCs have no toxic effect on cells. SDS-PAGE confirmed the digestion effect of bromelain released from nanocomposites. When Caco-2 cells were treated with gliadin digested by free bromelain and BLNCs, the expression of CXCR3 and CCR5 genes was significantly decreased. PBMCs of celiac patients treated with Bromelain and BLNCs decreased inflammatory cytokines (IL-1β, IL-6, TNF-α, and IFN-γ) production compared to untreated PBMCs. This treatment also increased IL-10 and CTLA-4 in PBMCs of CeD patients. According to the promising results of this study, we can hope for the therapeutic potential of BLNCs for CeD.
Topics: Humans; Caco-2 Cells; Gliadin; Leukocytes, Mononuclear; Bromelains; Cytokines; Celiac Disease
PubMed: 38040898
DOI: 10.1038/s41598-023-48460-3 -
BMC Complementary Medicine and Therapies Oct 2023Diabetic foot ulcers often affect tendon tissue. Consequently, the infection may spread proximally along the tendon, leading to amputation or even the death of patients....
Combination of Shengji ointment and bromelain in the treatment of exposed tendons in diabetic foot ulcers: study protocol for a non-blind, randomized, positive control clinical trial.
BACKGROUND
Diabetic foot ulcers often affect tendon tissue. Consequently, the infection may spread proximally along the tendon, leading to amputation or even the death of patients. Exposed, degenerated, and necrotic tendons are key factors affecting the healing of diabetic foot ulcers. The effective treatment of the tendon involvement may positively affect the prognosis. In clinical practice, treatment with Shengji ointment and bromelain induces islands of granulation tissue on the denatured tendon surface, which gradually grows and merges. Ideally, the exposed tendon is covered entirely by granulation tissue. This trial aims to assess the effect of a combined treatment regime of Shengji ointment, which has been shown to regenerate muscle tissue and pineapple protease in preventing the loss of function and amputation caused by tendon necrosis. This trial will provide high-quality evidence for the effectiveness of this combination in healing diabetic ulcers with tendon necrosis.
METHODS
The sample size will be 180 patients who will be randomly assigned 1:1 to a treatment group (90 patients) using Shengji ointment combined with bromelain and a control group (90 patients) using hydrocolloid dressing. Both groups will continue their conventional treatments, such as blood glucose and blood pressure medication, lipid regulation, antiplatelets, and others. The primary outcome will be the wound coverage with granulation tissue. Secondary outcomes will be the wound healing rate, amputation extent (where needed), time to granulation, and the Maryland Foot Score. Other efficacy outcomes will be the time to debridement of necrotic tendon tissue and granulation tissue score.
DISCUSSION
This study will treat patients with diabetic foot ulcers with exposed, degenerated, and necrotic tendons with Shengji ointment and bromelain. The trial aims to promote regeneration and healing, to preserve the limb and its function, and to develop a comprehensive and effective protocol that can be applied to promote the healing of exposed tendons in diabetic foot wounds.
TRIAL REGISTRATION
ChiCTR2000039327 ; date of registration: 2020-10-23.
Topics: Humans; Diabetic Foot; Bromelains; Tendons; Necrosis; Diabetes Mellitus; Randomized Controlled Trials as Topic
PubMed: 37817236
DOI: 10.1186/s12906-023-04128-z -
International Journal of Health Sciences 2023Inflammatory bowel diseases (IBDs) are a multiple inflammatory status in small intestines and colon. Bromelain and Papain were cysteine proteases enzymes extracted from...
OBJECTIVES
Inflammatory bowel diseases (IBDs) are a multiple inflammatory status in small intestines and colon. Bromelain and Papain were cysteine proteases enzymes extracted from pineapple and papaya, and possess antioxidant and anti-inflammatory characteristics. Therefore, this comparative work aimed to examine the anti-inflammatory and antioxidant effect of bromelain and papain in intestinal inflammation of rats and to evaluate the most potent effect of both types of enzymes.
METHODS
Forty rats were used in this study (8 rats/group), G1: control group, G2: (Indo group) intestinal inflammation was induced by two doses of Indomethacin (7.5 mg/kg body weight) apart 24 h. G3: (Indomethacin + Bromelain) intestinal inflamed rats treated by oral dose of bromelain (1000 mg/kg/day). G4: (Indomethacin + Papain) intestinal inflamed rats treated by oral dose of papain (800 mg/kg/day). G5: (Indomethacin + Sulfasalazine) intestinal inflamed rats treated by oral dose of sulfasalazine (500 mg/kg/day). Oxidative stress and inflammatory markers were measured along with histological assessment.
RESULTS
Indomethacin-induced intestinal inflammation (in both Jejunum and Ileum) characterized by increased oxidative stress biomarkers: Xanthine oxidase, Catalase, Glutathione reductase, and Protein carbonyl and Inflammatory biomarkers: Tumor necrosis factor-α, Interleukin-10, Monocyte chemoattractant protein-1, Nuclear factor-kappa β, C-reactive protein, and Prostaglandin E2, as compared to control rats. On the other hand, administering either bromelain or Papain would effectively decrease symptoms of intestinal inflammation and modulate biomarkers of oxidative stress and pro-inflammatory cytokines.
CONCLUSION
Comparing results revealed that bromelain showed the most potent protective effect and possesses an apparent role in protection against the development of intestinal inflammation.
PubMed: 37692988
DOI: No ID Found