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AIM: This study aimed to compare the remineralizing potential of casein phosphopeptide-amorphous calcium phosphate fluoride (CPP-ACPF) varnish alone and CPP-ACPF varnish after applying papain gel, quantitatively using LASER fluorescence readings and qualitatively using scanning electron microscopy (SEM). MATERIALS AND METHODS: A total of 108 permanent teeth with white spot lesions were divided into Group I: papain gel applied before CPP-ACPF varnish and Group II: CPP-ACPF varnish alone. Remineralization was monitored with DIAGNOdent laser fluorescence readings at baseline, 1, 3, 6, and 9 months. In addition, we randomly selected three samples from each Group after treatment for SEM evaluation. RESULTS: Statistical analysis revealed no significant difference in remineralization efficacy between the two groups. However, the percentage reduction in DIAGNOdent readings from baseline to 9 months was significantly higher in Group I than in Group II. SEM analysis supported these findings by showing better surface integrity in Group I samples. CONCLUSION: Although overall remineralization efficacy did not differ significantly between groups, the combination treatment (papain gel + CPP-ACPF varnish) demonstrated increased longevity of preventive outcomes compared to CPP-ACPF varnish alone. The trial was prospectively registered at CTRI under registration number 2020/01/022962.

BACKGROUND: To address the discomfort associated with conventional drilling for caries removal in children, a minimally invasive approach such as chemo-mechanical caries removal was developed. This study aimed to compare the effectiveness of, and patient behavior associated with chemo-mechanical caries removal versus conventional drilling in children aged 6-12 years. METHODS: A split-mouth randomized clinical trial was conducted involving 66 molar teeth. The effectiveness of Papacarie Duo Gel and conventional drilling methods was assessed using colony-forming unit (CFU) counts before and after each treatment. Cavity preparation time and intraoperative patient behavior using the Frankl Behavior Rating Scale were also evaluated. RESULTS: Both methods resulted in a significant reduction in bacterial counts post-treatment. However, conventional drilling showed a greater percentage reduction in bacterial load (82.9 ± 13.9; t = -4.42, p < 0.001) compared to the chemo-mechanical method (68.6 ± 16.6). The mean caries removal time was 692.4 ± 245.9 sec with the chemo-mechanical method, compared to 266.9 ± 101.6 sec with conventional drilling. In terms of behavior, 57.6% of the children exhibited a positive response during chemo-mechanical treatment whereas negative behavior was more commonly observed with conventional drilling. CONCLUSION: While conventional drilling remains the better-established and time-efficient method of caries removal, the chemo-mechanical technique serves as a valuable alternative for managing children, reducing anxiety and promoting greater comfort and cooperation during treatment. TRIAL REGISTRATION: PanAfrican Clinical Trial Registry PACTR202310877678533. Copyright: © 2026 Malami et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

BACKGROUND: The conventional method of removing caries lesions is an anxiety-inducing process that often necessitates the administration of local anesthesia and the extensive removal of tooth structure. Therefore, minimally invasive procedures are required to preserve tooth structure and minimize discomfort. OBJECTIVES: The aim of the study was to compare 3 minimally invasive treatments for the management of dental caries, evaluating factors such as treatment time, the need for anesthesia, reported adverse events, and restorative material follow-up. MATERIAL AND METHODS: A clinical trial was conducted on 45 children aged 7-8 years with active caries in primary molars. The samples were divided into 3 groups based on the applied treatment: 38% silver diamine fluoride (e-SDF®) group; BRIX3000® group; and CeraBur® group. The duration of treatment was recorded using a stopwatch. Adverse events, including tooth pain irritations, lesions, spots, and discolorations, were reported by parents within 2 weeks. The durability of the restorative material, namely glass ionomer cement (GIC), was assessed after 3 months. The χ2 and Kruskal-Wallis tests were conducted to analyze the data. The values were considered statistically significant at p ≤ 0.05. RESULTS: A significant difference in the duration of caries removal procedure was noted between the 3 treatment methods based on the median values (e-SDF®: 471 s, CeraBur®: 171 s, BRIX3000®: 1,173 s) (p < 0.001). Post hoc pairwise comparisons indicated significant differences in duration of the procedure between the CeraBur® and BRIX3000® groups, as well as between the e-SDF® and BRIX3000® groups (p < 0.001). The need for local anesthesia varied significantly between the 3 methods (p = 0.021). A significant difference was observed in the incidence of postoperative complications among the 3 methods, with the rate of adverse events equaling 9 (60.0%) in the e-SDF® group and 2 (13.3%) in the remaining groups (p = 0.013). A 3-month follow-up revealed a borderline significant difference in GIC integrity among the 3 methods (p = 0.052). CONCLUSIONS: Caries excavation using BRIX3000® required a longer duration compared with e-SDF® and Ce

BACKGROUND: Managing deep carious lesions in immature permanent molars presents a clinical challenge. Minimally invasive caries removal helps preserve apexogenesis by minimizing tissue loss. This study evaluated the effectiveness of two chemo-mechanical caries removal (CMCR) agents compared to hand excavation alone in young permanent molars. METHODS: A three-arm randomized clinical trial included 108 children (8-10 years) with carious first permanent molars. Participants were assigned to: Group I (ART with Brix 3000), Group II (ART with Papacárie Duo), or Group III (ART with hand excavation). Dentin samples were collected before and after caries removal to assess S. mutans and Lactobacilli counts (CFU/ml). Time for caries removal and pain perception were recorded. Clinical and radiographic outcomes were evaluated at 3, 6, and 12 months. OHRQoL was assessed using CPQ8-10 at baseline and during the follow up. RESULTS: The control group showed significantly shorter caries removal time (5.3 min) than Brix 3000 (11.3 min) and Papacárie Duo (12.1 min) (P < 0.01). However, higher pain scores were reported with hand excavation compared to Brix 3000 (P = 0.003) and Papacárie Duo (P < 0.001). Both within- and between-group comparisons showed significant reductions in S. mutans and Lactobacilli, with greater bacterial reduction in CMCR groups than ART alone (P < 0.001). CMCR groups had significantly higher restoration success rates than the control at 6 and 12 months (P = 0.02), and radiographic success was also greater at 12 months (P < 0.05). CPQ8-10 scores improved post-treatment across all groups (P < 0.001), with a notable difference at 6 months (P = 0.008). CONCLUSIONS: Brix 3000 and Papacárie Duo were more effective than hand excavation in reducing cariogenic bacteria, minimizing pain, and enhancing restoration longevity in immature permanent molars. Both CMCR methods supported favorable clinical, radiographic, and quality-of-life outcomes over one year. TRIAL REGISTRATION: This study was registered in ClinicalTrails.gov (NCT05983900) 09/06/2023, https://clinicaltrials.gov/ct2/show/NCT05983900 . © 2025. The Author(s).

PURPOSE: The concept of Chemomechanical Caries Removal (CMCR) includes the selective removal of caries-infected tissue while preserving caries-affected tissue. However, studies examining its application to children are scarce. The aim was to assess pain perception and time duration of CMCR agents when removing caries in primary molars in a sample of children compared to the conventional method of caries removal using rotary burs. METHODS: A randomized controlled clinical trial with a split-mouth design with a sample of 60 children aged 4-9 years with 120 cavitated occlusal carious primary molars was equally distributed into 2 experiments: BRIX3000® vs. conventional method (Experiment 1) and Carie-Care™ vs. conventional method (Experiment 2). The time duration of caries removal was recorded. Perception of pain during caries excavation was evaluated using the "Wong-Baker FACES® Pain Rating Scale." RESULTS: Caries removal using the conventional method was significantly faster compared to CMCR agents in both experiments (P < 0.001 and P < 0.001). Caries removal using BRIX3000® was significantly faster than Carie-Care™ (P < 0.001). Caries removal with BRIX3000® or Carie-Care™ were reported less painful than the conventional method (P = 0.002 and P = 0.011, respectively). CONCLUSION: The study concluded that although CMCR methods require more time for caries removal, they were reported to be less painful. TRIAL REGISTRATION: The study protocol was registered at www. CLINICALTRIALS: gov under the identifier NCT05427591. © 2025. The Author(s).

BACKGROUND: Traditionally, treating dental caries involves using rotary instruments, which can create noise that may frighten and cause discomfort in children. Recent research into caries management has introduced minimal invasive techniques like the Papacarie, which is a chemomechanical caries removal agent. OBJECTIVES: To determine and compare the average time taken for caries removal and pain perception during caries removal by Papacarie as a chemomechanical caries removal method with the use of mechanical method using rotary instrument on carious primary molars. METHODOLOGY: This randomized controlled clinical study carried out at the dental clinic in Lagos university teaching hospital. A split-mouth design was used and it involved 50 primary molars in 25 healthy children aged 5-9 years, each child having at least two primary molar teeth with occlusal dentine caries. Each tooth was allocated to the intervention using simple balloting method and treated with either Papacarie or conventional method for caries removal. Outcome measured were caries removal time, pain during caries removal and preference. Pain assessment was blinded. The statistical package for social sciences (SPSS) version 25.0 IBM was used for data analysis. The significance level was set at p ≤ 0.05 for all statistical tests at 95% confidence interval. RESULT: Twenty-five children (with 50 primary molars) met the inclusion criteria and were recruited for the study. The children were between ages 5-9 years. Twenty-five primary molars were treated using Papacarie caries removal method while 25 primary molars were treated using conventional rotary method. There was no statistically significant difference in the time of caries removal between the two groups. Pain perception was lower with the Papacarie method compared to the conventional method, which was statistically significant. More participants preferred the Papacarie method. Twenty-five children (with 50 primary molars) met the inclusion criteria and were recruited for the study. The children were between ages 5-9 years. Twenty-five primary molars were treated using Papacarie caries removal method while 25 primary molars were treated using

OBJECTIVE: To evaluate the effect of 10% papain as an enamel deproteinising agent on the shear bond strength (SBS) of three orthodontic adhesives: Transbond XT, resin-modified glass ionomer cement (RMGIC) and Biofix. DESIGN: Single-centre, double-blinded, split-mouth randomised controlled trial. SETTING: Department of Orthodontics and Dentofacial Orthopaedics, Nair Hospital Dental College, Mumbai, India. PARTICIPANTS: A total of 20 participants, requiring bilateral premolar extraction for fixed orthodontic treatment in both the maxillary and mandibular arches, were included in this study. METHODS: In total, 80 premolars from the above-mentioned participants were divided into four groups as follows: group A: Transbond XT deproteinised with 10% papain gel; group B: Biofix deproteinised with 10% papain gel; group C: RMGIC deproteinised with 10% papain gel; and group D: Transbond XT without enamel deproteinisation as a control group-bonded as instructed by the manufacturer. After deproteinisation, brackets were bonded and after a follow-up period of 28 days, the teeth were extracted. The SBS was then measured using the Universal Testing Machine. The force needed to shear the bracket was documented, and bond strengths were subsequently calculated in megapascals (MPa). The obtained results were subjected to statistical analysis and one-way ANOVA was performed to compare the mean SBS between the groups. Subsequently, pairwise comparisons were conducted using Tukey's post hoc test. RESULTS: There was a statistically significant difference in SBS among all groups (P = 0.002). The SBS of TransXT with deproteinisation increased significantly compared with TransXT without deproteinisation (P = 0.03). There was no statistically significant difference between the SBS of TransXT without deproteinisation and RMGIC (P = 0.47) and Biofix (P = 0.39), both with deproteinisation. CONCLUSION: The use of 10% papain for deproteinising enamel improved the SBS of all materials. Deproteinising improved the SBS of RMGIC and Biofix to the level of TransXT without deproteinisation.

In the current odontological era, carious lesions are removed while tooth tissue is preserved. Most of these ideals are met by chemomechanical caries removal (CMCR) methods, which are easy and comfortable to use, differentiate and eliminate infected tissues, minimize pressure, vibration and heat, and are cost-effective. This study examines the efficacy of commercially available CMCR agents, namely Papacarie®, Carie-Care™ and BRIX3000™, and a conventional hand instrumentation method for caries removal in deciduous molars in terms of time consumption, ease of application, and pain perception. For this randomized clinical trial, 120 children aged 4 to 9 years were selected and randomly allocated to four groups of 30 patients each. Time consumption, ease of application, and pain perception were evaluated at three intervals: pre-, during- and post-caries removal, using Wong-Baker FACES (WBF) Pain Rating Scale and the Face, Legs, Activity, Cry, Consolability (FLACC) scale. The results showed that among the compared materials and conventional hand instrumentation technique, Carie-Care™ was statistically found to be the least time-consuming with a p-value of 0.019, have the least pain perception with a p-value of 0.02, and was clinically the best with respect to manipulation and handling. While all three CMCR agents aid in the removal of carious tissue, Carie-Care™ was the most effective based on time consumption, pain perception and simplicity of administration. ©2024 The Author(s). Published by MRE Press.

BACKGROUND: The dentin substrate can be modified by proteolytic agents, which may affect the bonding strength of adhesive systems to the treated dentin surface. Papain, a cysteine protease enzyme with antibacterial and anti-inflammatory properties, can be used for deproteinization of dentin. An alternative deproteinizing enzyme is bromelain. OBJECTIVES: This study aimed to evaluate the impact of deproteinization on the shear bond strength (SBS) of composite resin to deep dentin using different concentrations of bromelain and papain. MATERIAL AND METHODS: Sixty upper premolars were extracted and randomly divided into 5 groups (n = 12 per group). In all groups, the dentin surface was etched with 37% phosphoric acid. Group 1 did not receive any enzyme treatment, group 2 was treated with a 10% papain solution, group 3 was treated with a 15% papain solution, group 4 was treated with a 6% bromelain solution, and group 5 was treated with a 10% bromelain solution. After applying an etch-and-rinse adhesive system, the specimens were restored with composite resin and the SBS was measured. RESULTS: Statistically significant differences were found between groups 2 and 3 (10% papain and 15% papain, p = 0.004), groups 2 and 4 (10% papain and 6% bromelain, p = 0.017), groups 4 and 5 (6% bromelain and 10% bromelain, p = 0.021), and groups 3 and 5 (15% papain and 10% bromelain, p = 0.005). CONCLUSIONS: Deproteinization with papain and bromelain at different concentrations after acid etching did not affect the SBS of composite resin to deep dentin when using an etch-and-rinse adhesive system. However, the group deproteinized with 15% papain demonstrated a higher SBS than the group deproteinized with 10% papain, and the group deproteinized with 6% bromelain showed a higher SBS compared to the group deproteinized with 10% bromelain.

AIM: This research aimed to use an extra-oral 3D scanner for conducting volumetric analysis after caries excavation using caries-detecting dyes and chemomechanical caries removal agents in individuals with occlusal and proximal carious lesions. METHODS: Patients with occlusal (A1, A2, A3) and proximal carious lesions (B1, B2, B3) were treated with the conventional rotary technique, caries detecting dyes (CDD) and chemomechanical caries removal (CMCR) method on 90 teeth (n = 45 for each). Group A1, B1: Excavation was performed using diamond points. Group A2, B2: CDD (Sable Seek™ caries indicator, Ultradent) was applied and left for 10 s, and then the cavity was rinsed and dried. For caries removal, diamond points or excavators were used. Group A3 and B3: BRIX3000 papain gel was applied with a micro-brush for 20 s and was activated for 2 min, and then the carious tissue was removed with a sharp spoon excavator. Post-excavation cavity volume analysis was performed using a 3D scanner. The time required and the verbal pain score (VPS) for pain were scored during excavation. Post-restoration evaluation was performed at 1, 3, and 6 months FDI (Federation Dentaire Internationale) criteria. RESULTS: Comparison of age, time and volume with study groups were made using Independent Sample' t' test and one-way analysis of variance (ANOVA) for two and more than two groups, respectively. Using Cohen's Kappa Statistics, evaluators 1 and 2 agreed on caries removal status aesthetic, functional and biological properties at different follow-ups. The chi-square test revealed that the rotary groups [A1(2.5 ± 0.4 min) B1(4.0 ± 0.4 min)] had significantly less (p = 0.000) mean procedural time than CDD [A2(4.5 ± 0.4 min) B2(5.7 ± 0.4 min)] and CMCR [A3(5.4 ± 0.7 min) B3(6.2 ± 0.6 min)] groups. The CMCR group showed better patient acceptance and less pain during caries excavation than the rotary and CDD groups. CMCR group showed significantly less mean caries excavated volume(p = 0.000). Evaluation of restoration after 1-, 3-, and 6-month intervals was acceptable for all the groups. CONCLUSION: Brix3000 helps effectively remove denatured teeth with less pain or sensitivity. The time requ

The 3-chymotrypsin-like protease (3CLpro), papain-like protease (PLpro), and RNA-dependent RNA polymerase (RdRp) are key enzymes in SARS-CoV-2 replication and serve as critical targets for an antiviral drug. Currently, Paxlovid® and Lagevrio™ specifically target 3CLpro and RdRp, respectively, for COVID-19 treatment. However, no antivirals target for the SARS-CoV-2 PLpro enzyme, essential for viral replication and suppression of the host antiviral immune response. This study identified 9-aminominocycline (9-AMN) as a potent inhibitor of SARS-CoV-2 PLpro. Unlike the parent compound minocycline, 9-AMN inhibits PLpro's proteolytic and deubiquitinase activities by approximately 90%, with IC50 values of 4.15 µM and 4.55 µM, respectively, while showing no effect on the enzymatic activity of 3CLpro or RdRp. Enzyme kinetics reveal that 9-AMN functions as a mixed PLpro inhibitor and binds to its active site, disrupting its function as predicted by computer modeling. Furthermore, 9-AMN demonstrates, efficacy against the Delta and Omicron variants, with EC50 values of 1.04 µM and 2.35 µM, respectively. When combined with EIDD-1931 (an active form of molnupiravir) or nirmatrelvir (PF-332), 9-AMN exhibits synergistic effects, significantly reducing the doses required to inhibit the Omicron variant. In conclusion, 9-AMN inhibits SARS-CoV-2 replication, and PLpro activity, highlighting its potential as a promising candidate for COVID-19 treatment strategies. © 2025. The Author(s).

AIMS: This study aimed to explore the potential of natural anticoagulant compounds as synergistic inhibitors of the main protease (Mpro) and papain-like protease (PLpro) of SARS-CoV-2 and find effective therapies against SARS-CoV-2 by investigating the inhibitory effects of natural anticoagulant compounds on key viral proteases. OBJECTIVE: The objectives of this study were to conduct rigorous virtual screening and molecular docking analyses to evaluate the binding affinities and interactions of selected anticoagulant compounds with Mpro and PLpro, to assess the pharmacokinetic and pharmacodynamic profiles of the compounds to determine their viability for therapeutic use, and to employ molecular dynamics simulations to understand the stability of the identified compounds over time. METHODS: In this study, a curated collection of natural anticoagulant compounds was conducted. Virtual screening and molecular docking analyses were performed to assess binding affinities and interactions with Mpro and PLpro. Furthermore, pharmacokinetic and pharmacodynamic analyses were carried out to evaluate absorption, distribution, metabolism, and excretion profiles. Molecular dynamics simulations were performed to elucidate compound stability. RESULTS: Natural compounds exhibiting significant inhibitory activity against Mpro and PLpro were identified. A dual-target approach was established as a promising strategy for attenuating viral replication and addressing coagulopathic complications associated with SARS-CoV-2 infection. CONCLUSION: The study lays a solid foundation for experimental validation and optimization of identified compounds, potentially leading to the development of precise treatments for SARS-CoV-2.

The COVID-19 pandemic has emerged as the biggest life-threatening disease of this century. Whilst vaccination should provide a long-term solution, this is pitted against the constant threat of mutations in the virus rendering the current vaccines less effective. Consequently, small molecule antiviral agents would be extremely useful to complement the vaccination program. The causative agent of COVID-19 is a novel coronavirus, SARS-CoV-2, which encodes at least nine enzymatic activities that all have drug targeting potential. The papain-like protease (PLpro) contained in the nsp3 protein generates viral non-structural proteins from a polyprotein precursor, and cleaves ubiquitin and ISG protein conjugates. Here we describe the expression and purification of PLpro. We developed a protease assay that was used to screen a custom compound library from which we identified dihydrotanshinone I and Ro 08-2750 as compounds that inhibit PLpro in protease and isopeptidase assays and also inhibit viral replication in cell culture-based assays. © 2021 The Author(s).

Update of ChemRxiv. 2020 Apr 21. doi: 10.26434/chemrxiv.12153615. Effective control of COVID-19 requires antivirals directed against SARS-CoV-2. We assessed 10 hepatitis C virus (HCV) protease-inhibitor drugs as potential SARS-CoV-2 antivirals. There is a striking structural similarity of the substrate binding clefts of SARS-CoV-2 main protease (Mpro) and HCV NS3/4A protease. Virtual docking experiments show that these HCV drugs can potentially bind into the Mpro substrate-binding cleft. We show that seven HCV drugs inhibit both SARS-CoV-2 Mpro protease activity and SARS-CoV-2 virus replication in Vero and/or human cells. However, their Mpro inhibiting activities did not correlate with their antiviral activities. This conundrum is resolved by demonstrating that four HCV protease inhibitor drugs, simeprevir, vaniprevir, paritaprevir, and grazoprevir inhibit the SARS CoV-2 papain-like protease (PLpro). HCV drugs that inhibit PLpro synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, increasing remdesivir's antiviral activity as much as 10-fold, while those that only inhibit Mpro do not synergize with remdesivir.

Disulfiram is a promising repurposed drug that, combining with radiation and chemotherapy, exhibits effective anticancer activities in several preclinical models. The cellular metabolites of disulfiram have been established, however, the intracellular targets of disulfiram remain largely unexplored. We have previously reported that disulfiram suppresses the coronaviral papain-like proteases through attacking their zinc-finger domains, suggesting an inhibitory function potentially on other proteases with similar catalytic structures. Ubiquitin-specific proteases (USPs) share a highly-conserved zinc-finger subdomain that structurally similar to the papain-like proteases and are attractive anticancer targets as upregulated USPs levels are found in a variety of tumors. Here, we report that disulfiram functions as a competitive inhibitor for both USP2 and USP21, two tumor-related deubiquitinases. In addition, we also observed a synergistic inhibition of USP2 and USP21 by disulfiram and 6-Thioguanine (6TG), a clinical drug for acute myeloid leukemia. Kinetic analyses revealed that both drugs exhibited a slow-binding mechanism, moderate inhibitory parameters, and a synergistically inhibitory effect on USP2 and USP21, suggesting the potential combinatory use of these two drugs for USPs-related tumors. Taken together, our study provides biochemical evidence for repurposing disulfiram and 6TG as a combinatory treatment in clinical applications.

SARS-CoV-2 is the pathogen responsible for the COVID-19 pandemic. The SARS-CoV-2 papain-like cysteine protease (PLpro) has been implicated in playing important roles in virus maturation, dysregulation of host inflammation, and antiviral immune responses. The multiple functions of PLpro render it a promising drug target. Therefore, we screened a library of approved drugs and also examined available inhibitors against PLpro. Inhibitor GRL0617 showed a promising in vitro IC50 of 2.1 μM and an effective antiviral inhibition in cell-based assays. The co-crystal structure of SARS-CoV-2 PLproC111S in complex with GRL0617 indicates that GRL0617 is a non-covalent inhibitor and it resides in the ubiquitin-specific proteases (USP) domain of PLpro. NMR data indicate that GRL0617 blocks the binding of ISG15 C-terminus to PLpro. Using truncated ISG15 mutants, we show that the C-terminus of ISG15 plays a dominant role in binding PLpro. Structural analysis reveals that the ISG15 C-terminus binding pocket in PLpro contributes a disproportionately large portion of binding energy, thus this pocket is a hot spot for antiviral drug discovery targeting PLpro.

Alicyclobacillus spp. are spore forming bacteria that are often related to the deterioration of acidic products such as beverages and citrus juices. After the process of industrial pasteurization, the spore produced by the bacteria can germinate and the microorganism can grow, causing sensory abnormalities in the product. Alternative biopreservatives, such as the antimicrobial compounds, are of considerable importance to the food industry. Papain and bromelain are proteolytic enzymes derived frompapaya and pineapple, respectively. These enzymes are widely used in medicine and in the pharmaceutical and food industries, but while some studies have described their antibacterial action, no studies of the Alicyclobacillus spp. exist. The aimof this studywas to analyze the antibacterial effect of papain and bromelain on Alicyclobacillus spp. through 1) determining minimum inhibitory and bactericidal concentration (MIC and MBC); 2) determining the death time curve of the micro-organism in the presence and absence of enzymes; and 3) investigating the enzymatic mechanism on the microorganism. The antibacterial activity of enzymes in combination with nisin was also evaluated. The results showed that for the Alicyclobacillus acidoterrestris strain, the MIC of papain was 0.98 μg/mL and the MBC was 3.91 μg/mL, while theMIC of bromelain was 62.5 μg/mL and the MBCwas 250 μg/mL. The concentration of 4 ×MIC for both the enzymes was sufficient to eliminate 4 logs of the micro-organism after 24 h of incubation. Through the use of enzyme inhibitors specific for cysteine proteases, it was found that the antibacterial activity of papain and bromelain is not related to its proteolytic activity, butmay be related to other activities, such as amidse and esterase. The synergistic activity of the enzymes revealed a fractional inhibitory concentration (FIC) level of 0.16. Combination with nisin revealed an FIC of 0.25 for papain and 0.19 for bromelain, indicating synergism between both compounds. The application of enzymes in reconstituted orange juice contaminated with A. acidoterrestris was found to be effective, as after 48 h of incubation, at three different temperatures, the initial m

Middle East respiratory syndrome coronavirus (MERS-CoV) is a new highly pathogenic human coronaviruses that emerged in Jeddah and Saudi Arabia and has quickly spread to other countries in Middle East, Europe and North Africa since 2012. Up to 17 December 2014, it has infected at least 938 people with a fatality rate of about 36% globally. This has resulted in an urgent need to identify antiviral drugs that are active against MERS-CoV. The papain-like protease (PL(pro)) of MERS-CoV represents an important antiviral target as it is not only essential for viral maturation, but also antagonizes interferon stimulation of the host via its deubiquitination activity. Here, we report the discovery that two SARS-CoV PL(pro) inhibitors, 6-mercaptopurine (6MP) and 6-thioguanine (6TG), as well as the immunosuppressive drug mycophenolic acid, are able to inhibit MERS-CoV PL(pro). Their inhibition mechanisms and mutually binding synergistic effect were also investigated. Our results identify for the first time three inhibitors targeting MERS-CoV PL(pro) and these can now be used as lead compounds for further antiviral drug development.

PURPOSE: The aim of this review is to discuss possible interactions that may occur between warfarin and fruit products. METHODS: A literature search was conducted using the search terms: “warfarin (Coumadin®) and fruit interactions, warfarin and fruit, warfarin and fruit juice, case reports and clinical trials”. RESULTS: A total of 23 citations (15 case reports and 7 controlled clinical trials) were reviewed. The majority of cases involved cranberry products, while pomegranate juice, avocado, grapefruit juice, mango, and papain were also implicated in reports of suspected warfarin-fruit interactions. Cranberry juice was also the most frequently studied fruit product. Other fruit products evaluated with warfarin in controlled clinical trials were cranberry concentrate and grapefruit juice. CONCLUSION: Although a number of case reports have been published that suggest warfarin has the potential to interact with several fruit products, it is difficult to determine their relevance, as scientific evidence is scarce. Until further information is available, clinicians may want to encourage patients to consume cranberry products and grapefruit juice in small to moderate quantities and to inquire about the recent consumption of mangos, pomegranate juice, and avocados when taking a dietary history or when assessing possible causes for international normalized ratio (INR) instability.

Potent and safe inhibitors of norovirus replication are needed for the treatment and prophylaxis of norovirus infections. We here report that the in vitro anti-norovirus activity of the protease inhibitor rupintrivir is extended to murine noroviruses and that rupintrivir clears human cells from their Norwalk replicon after only two passages of antiviral pressure. In addition, we demonstrate that rupintrivir inhibits the human norovirus (genogroup II [GII]) protease and further explain the inhibitory effect of the molecule by means of molecular modeling on the basis of the crystal structure of the Norwalk virus protease. The combination of rupintrivir with the RNA-dependent RNA polymerase inhibitors 2'-C-methylcytidine and favipiravir (T-705) resulted in a merely additive antiviral effect. The fact that rupintrivir is active against noroviruses belonging to genogroup I (Norwalk virus), genogroup V (murine norovirus), and the recombinant 3C-like protease of a GII norovirus suggests that the drug exerts cross-genotypic anti-norovirus activity and will thus most likely be effective against the clinically relevant human norovirus strains. The design of antiviral molecules targeting the norovirus protease could be a valuable approach for the treatment and/or prophylaxis of norovirus infections.

ETHNOPHARMACOLOGICAL RELEVANCE: The rhizome of Dryopteris crassirhizoma Nakai (Dryopteridaceae, RDC), a traditional East Asian herbal medicine, possesses a broad spectrum of medicinal properties, including anti-inflammatory, anticancer, antibacterial, and antiviral activities. AIM OF THE STUDY: This study investigates the 30% ethanolic extract of RDC's antiviral potential against human coronavirus OC43 (HCoV-OC43), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and its variants infections. MATERIALS AND METHODS: A 30% ethanolic extract of RDC or its components, filixic acid ABA (PubChem CID: 15081408) and dryocrassin ABBA (PubChem CID: 3082025) were treated with Human Coronavirus infection (HCoV-OC43, SARS-CoV-2 and its variants). The base peak chromatogram of RDC was evaluated using UPLC-Q/TOF Mass to identify the RDC, and the quantitative analysis of RDC compounds was performed using LC-MS/MS. A cytopathic effect (CPE) reduction assay, Western blot, immunofluorescence staining of viral protein expression, and qRT-PCR were performed to quantify the viral RNA copy numbers and determine the antiviral activity. The time-of-addition assay, the virus attachment, penetration, and virucidal assays, and SARS-CoV-2 Mpro and PLpro activity assay were used to elucidate the mode of action. RESULTS: RDC exhibited dose-dependent inhibition of HCoV-OC43-induced cytopathic effects, reducing viral RNA copy numbers and viral protein levels. Time-of-addition assays indicated that RDC targets the early stages of the HCoV-OC43 life cycle, inhibiting virion attachment and penetration with virucidal activity. Notably, filixic acid ABA and dryocrassin ABBA, constituents of RDC, reduced HCoV-OC43 viral RNA loads. Furthermore, RDC effectively blocked viral entry in pseudotyped lentivirus assays, involving spike proteins of SARS-CoV-2 Delta plus and South Africa variants, as well as control lentiviral particles expressing vesicular stomatitis virus glycoprotein G. Additionally, RDC demonstrated inhibition of SARS-CoV-2 infection and its variants by targeting viral proteases, namely main protease (Mpro) and papain-like protease (PLpro). CONCLUSIONS: These findings underscor

PURPOSE OF REVIEW: Occupational contact urticaria (OCU) is an immediate-type skin reaction triggered by chemicals or proteins encountered in the workplace. It is classified as either nonimmunologic (irritant) or immunologic (IgE-mediated), which differ in pathogenesis, diagnostic approach, and clinical severity. Immunologic OCU may present with generalized urticaria and even anaphylaxis. We conducted a systematic narrative review to provide an updated overview of OCU, integrating findings from a structured literature search (2017-2025) with expert clinical interpretation. This review synthesizes knowledge on causative agents, diagnostic strategies, and management approaches, with a focus on emerging occupational exposures. RECENT FINDINGS: The spectrum of occupational allergens continues to expand, with new reports implicating Cannabis sativa , arthropods (e.g., Anisakis simplex , pine processionary caterpillar), mask materials such as polypropylene, disinfectants (e.g., chloramine-T), antiseptics (e.g., chlorhexidine), cosmetic ingredients (e.g., henna, indigo, and hydrolyzed wheat protein), and enzymes (e.g., alpha-amylase, cellulase, papain, protease, and xylanase). Despite novel exposures, traditional culprits like natural rubber latex, ammonium persulfate, and animal-and plant-derived foods remain prevalent. SUMMARY: Early recognition, diagnostic testing, and prevention are essential to reduce systemic involvement and occupational disability. Strengthening workplace awareness, surveillance programs, and systematic occupational health, safety, and environmental management remains essential to reducing this preventable condition.

INTRODUCTION: Cathepsin K (CTSK) is a lysosomal cysteine protease of the papain superfamily. The enzyme plays a key role in bone homeostasis. Immune cells such as dendritic cells, macrophages, and T cells all express CTSK. It modulates inflammation and immunity through NF-κB, TLR, and the RANKL/RANK/OPG axis. Overexpression or underexpression of CTSK appears in rheumatoid arthritis, periodontitis, tumors, and inflammatory bowel disease. Targeted inhibitors and monoclonal antibodies against CTSK are now emerging therapies. METHODS: Systematic literature search and critical review of experimental and clinical studies examining CTSK expression, genetic modulation, and targeted inhibition in inflammatory and immune-mediated disease models. RESULTS: Elevated CTSK correlates with disease activity and bone destruction; its inhibition reduces inflammatory cytokines, immune-cell infiltration, and extracellular-matrix degradation. Small-molecule inhibitors (odanacatib, MIV-711, ONO-5334) and biologics attenuate pathology in arthritis, periodontitis, and atherosclerosis. DISCUSSION: CTSK is a promising diagnostic biomarker and therapeutic target, yet its promise hinges on inhibitors that act only where needed, sparing other tissues. Next steps must therefore craft more selective allosteric compounds and test ways to confine them to diseased sites.

BACKGROUND: Jellyfish envenomation is common in many coastal regions and varies in severity depending upon the species. Stings cause a variety of symptoms and signs including pain, dermatological reactions, and, in some species, Irukandji syndrome (which may include abdominal/back/chest pain, tachycardia, hypertension, cardiac phenomena, and, rarely, death). Many treatments have been suggested for these symptoms, but their effectiveness is unclear. This is an update of a Cochrane Review last published in 2013. OBJECTIVES: To determine the benefits and harms associated with the use of any intervention, in both adults and children, for the treatment of jellyfish stings, as assessed by randomised and quasi-randomised trials. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and Web of Science up to 27 October 2022. We searched clinical trials registers and the grey literature, and conducted forward-citation searching of relevant articles. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs of any intervention given to treat stings from any species of jellyfish stings. Interventions were compared to another active intervention, placebo, or no treatment. If co-interventions were used, we included the study only if the co-intervention was used in each group. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included nine studies (six RCTs and three quasi-RCTs) involving a total of 574 participants. We found one ongoing study. Participants were either stung accidentally, or were healthy volunteers exposed to stings in a laboratory setting. Type of jellyfish could not be confirmed in beach settings and was determined by investigators using participant and local information. We categorised interventions into comparison groups: hot versus cold applications; topical applications. A third comparison of parenteral administration included no relevant outcome data: a single study (39 participants) evaluated intravenous magnesium sulfate after stings from jellyfish that cause Irukandji syndrome (Carukia). No studies assessed a fourth comparison group of pressure immobilisation banda

Since the appearance of SARS-CoV-2 and the COVID-19 pandemic, the search for new approaches to treat this disease took place in the scientific community. The in silico approach has gained importance at this moment, once the methodologies used in this kind of study allow for the identification of specific protein-ligand interactions, which may serve as a filter step for molecules that can act as specific inhibitors. In addition, it is a low-cost and high-speed technology. Molecular docking has been widely used to find potential viral protein inhibitors for structural and non-structural proteins of the SARS-CoV-2, aiming to block the infection and the virus multiplication. The papain-like protease (PLpro) participates in the proteolytic processing of SARS-CoV-2 and composes one of the main targets studied for pharmacological intervention by in silico methodologies. Based on that, we performed a systematic review about PLpro inhibitors from the perspective of in silico research, including possible therapeutic molecules in relation to this viral protein. The neurological problems triggered by COVID-19 were also briefly discussed, especially relative to the similarities of neuroinflammation present in Alzheimer's disease. In this context, we focused on two molecules, curcumin and glycyrrhizinic acid, given their PLpro inhibitory actions and neuroprotective properties and potential therapeutic effects on COVID-19. © 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Strategies aiming to improve the longevity of resin-dentin adhesive interface developed so far have only been able to retard the problem. Different approaches are thus needed. The objective of this review was to determine whether the use of collagen-depletion strategies after acid-etching procedures may improve the bond strength of resin-based materials to dentin. A systematic review was planned following 2021 PRISMA statement guidelines, with a search strategy performed in five electronic databases: PubMed/Medline, Scopus, EMBASE, SciELO and IADR Abstract Archive (last search: 17/01/2022). Inclusion criteria encompassed studies which evaluated a collagen-depletion strategy in acid-etched human dentin and tensile/shear bond strength tests. Risk of bias assessment was carried out by two reviewers, working independently on an adapted five-domain risk of bias (RoB) checklist for laboratory studies. Results were synthesized qualitatively, as a meta-analysis was not possible due to limited number of studies and their RoB. A total of eight studies were eligible for inclusion in the systematic review after inclusion/exclusion criteria application. Out of these, two evaluated the effect of using NaOCl followed by an antioxidant, and the remaining six evaluated different enzymatic treatments (bromelain, chondroitinase ABC, papain, and trypsin). None of the studies reported a decrease of bond strength when a collagen-depletion strategy was used, in comparison to traditional hybrid layers (control). All enzymatic treatment studies which respected the inclusion criteria improved the bond strength to dentin. Some specific collagen-depletion strategies seem to play a favorable role in improving immediate bond strengths to dentin. Further research with sound methodology is required to consolidate these findings, since limitations in RoB and a low number of studies were found. The assessment of further proteolytic agents and long-term outcomes is also required. © 2022. The Author(s).

BACKGROUND: Chemical-mechanical caries removal (CMCR) products are in constant evolution and were recommended during the COVID-19 pandemic as substitutes for conventional caries removal. AIM: Characterize the worldwide scientific literature about CMCR products, over the years, by means of a critical review. DESIGN: Electronic search was performed on Medline/PubMed, Scopus, Web of Science, Cochrane Library, Lilacs, and Embase up to November 2020. Year, journal, country of authors, and type of study were the data extracted from the retrieved studies. Additional data of the clinical studies and systematic reviews were investigated. RESULTS: 2221 records were identified, 397 selected. 2011-2020 period concentrates higher number of publications (n = 169), in the Journal of Dental Research (n = 51), developed in Brazil (n = 45) and India (n = 44). Most studies were in vitro (n = 211) and clinical trials (n = 101). Carisolv™ (n = 48) and Papacarie Duo Gel™ (n = 33) were the most used products, prescript in isolated usage (n = 101), and compared with drills (n = 77). CMCR were more studied in primary teeth (n = 78), receiving glass ionomer cement (GIC) (n = 51) as restorative material. The most evaluated outcomes were time spent (n = 48) and pain (n = 41). Clinical application of CMCR takes more time than other techniques, but can also reduce patient anxiety, pain, and need for anesthesia. CONCLUSION: In vitro and clinical studies with CMCR products have been increasing, mostly carried out in developing countries, evaluating Carisolv™ and Papacarie Duo Gel™. Clinical studies tend to evaluate the time spent and pain compared to drills for removing caries in primary teeth, posteriorly restored with GIC. CMCR clinical application reduces anxiety, pain, and need for anesthesia, despite increase treatments' time. © 2022. The Author(s), under exclusive licence to European Academy of Paediatric Dentistry.

The novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus) has emerged as a significant threat to public health with startling drawbacks in all sectors globally. This study investigates the practicality of some medicinal plants for SARS-CoV-2 therapy using a systematic review and meta-analysis of their reported SARS-CoV-1 inhibitory potencies. Relevant data were systematically gathered from three databases, viz., Web of Science, PubMed and Scopus. The information obtained included botanical information, extraction method and extracts concentrations, as well as the proposed mechanisms. Fourteen articles describing 30 different plants met our eligibility criteria. Random effects model and subgroup analysis were applied to investigate heterogeneity. According to subgroup analysis, the substantial heterogeneity of the estimated mean based on the IC 50 values reporting the most potent anti-SARS-CoV 3C--like protease (3CLpro) inhibitors (10.07 %, p < 0.0001), was significantly higher compared to the most active anti-SARS-CoV papain-like protease (PLpro) inhibitors (6.12 %, p < 0.0001). More importantly, the literature analysis revealed that fruit extracts of Rheum palmatum L. and the compound cryptotanshinone isolated from the root of Salvia miltiorrhiza (IC 50 = 0.8 ± 0.2 μmol L-1) were excellent candidates for anti--SARS-CoV targeting PLpro. Meanwhile, iguesterin (IC 50 = 2.6 ± 0.6 μmol L-1) isolated from the bark of Tripterygium regelii emerged as the most excellent candidate for anti-SARS--CoV targeting 3CLpro. The present systematic review and meta-analysis provide valuable and comprehensive information about potential medicinal plants for SARS-CoV-2 inhibition. The chemotypes identified herein can be adopted as a starting point for developing new drugs to contain the novel virus. © 2022 Oluwakemi Ebenezer., published by Sciendo.

BACKGROUND/AIM: Bromelain, papain and chymotrypsin are proteolytic enzymes. They can be found in fruits such as pineapple or papaya, but also in the human body, namely in the pancreas. Besides their enzymatic function, they are said to reduce side-effects and even to improve the outcome of cancer therapies. We, therefore, aimed to critically examine and systematically review existing evidence on the role that these enzymes might play in cancer treatment. MATERIALS AND METHODS: In May 2019, a systematic literature search was conducted by using five electronic databases (Embase, Cochrane, PsychInfo, CINAHL and Medline) to find studies concerning the use, effectiveness and potential harm of enzyme therapy on cancer patients. RESULTS: Out of 13,046 search results, 15 studies with 3,008 patients were included in this systematic review. Patients treated with enzymes were diagnosed with various entities of gastrointestinal, gynecologic, head and neck and lung cancer as well as hematological malignancies. The therapy concepts included mainly oral intake of enzymes in addition to conventional therapies. Investigated outcomes were side-effects of anticancer therapy, quality of life, as well as anticancer effects and survival rates. In summary, due to conflicting results and moderate quality of the included studies, the evidence is insufficient to attribute positive effects to enzymes in terms of better tolerability of the various antineoplastic therapies or even improvement in treatment efficacy. In most cases, enzyme therapy was well tolerated; side-effects were mainly gastrointestinal complaints such as diarrhea or meteorism. CONCLUSION: On the basis of existing evidence, there is no clear therapeutic benefit of enzymes neither as supportive therapy nor as part of antineoplastic therapy.

BACKGROUND: COVID-19 caused by SARS-CoV-2 was declared as a global pandemic by the WHO. Famotidine is a histamine-2 (H2) receptor antagonist which blocks the H2 receptors in the parietal cells, decreasing gastric acid secretion. Our review aims to study all the available scientific evidence on famotidine research outcomes systematically to introspect its clinical efficacy and probable mechanisms and clinical efficacy against SARS-CoV-2. METHODOLOGY: An electronic search of PubMed, Scopus and Google Scholar was performed using MeSH terms "SARS CoV-2" OR "COVID-19" AND"FAMOTIDINE". Relevant informationwas extracted from studies reporting the efficacy of famotidine in COVID-19. RESULTS: We found a total of 32 studies, out of which only 14 were relevant and were included in our review.Molecular computational studies showed that famotidine selectively acts on viral replication proteases papain-like protease (PLpro) and 3-chymotrypsin-like protease (3CLpro). Additionally, it acts via inverse-agonism on the H2 receptors present in neutrophils and eosinophils which leads to inhibition of cytokine release. Clinical study findings have pointed toward significant improvements in COVID-19 patient-reported symptoms in non-hospitalized patients and reduction in intubation or death in critically ill patients associated with the usage of famotidine. However,in one of the studies,famotidine has failed to show any significant benefit in reducing mortality due to COVID-19. CONCLUSION: Famotidine has the potential to answer the ongoing global challenge owing to its selective action on viral replication. Additionally, clinical findings in COVID-19 patients support its efficacy to reduce clinical symptoms of COVID-19.We suggest that further optimally powered randomized clinical trials should be carried out to come up with definitive conclusions. Publisher: BACKGROUND: COVID-19 caused by SARS-CoV-2 was declared as a global pandemic by the WHO. Famotidine is a histamine-2 (H2) receptor antagonist which blocks the H2 receptors in the parietal cells, decreasing gastric acid secretion. Our review aims to study all the available scientific evidence on famotidine research outcomes systemat