Non-weight-bearing exercise attenuates papain-induced knee osteoarthritis in rats via the TLR4/MyD88/NF-κB signaling pathway.

BACKGROUND AND AIM: Knee osteoarthritis (KOA) is characterized by joint wear and degeneration. Unfortunately, the medical community currently lacks effective treatment options for this disease. Suspension exercise therapy is considered an effective form of non-weight-bearing exercise for treating KOA. However, its mechanism of intervention in KOA is unclear. Therefore, this study aimed to evaluate the protective effects of non-weight-bearing exercise on rats with KOA and attempted to explore the underlying mechanisms. METHODS: In this study, a papain-induced KOA model was constructed, and the pathological changes in cartilage tissue were observed by hematoxylin and eosin (H&E) staining and scored according to the Mankin scoring principle. The serum levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α (TNF-α) were detected by enzyme-linked immunosorbent assay. Reverse transcription-quantitative polymerase chain reaction and Western blotting were used to detect the expression of mRNA and proteins in the TLR4/MyD88/NF-κB signaling pathway. RESULTS: H&E staining and Mankin score data confirmed that non-weight-bearing exercise significantly improved articular cartilage degradation compared with that in the model group. Further, we observed that non-weight-bearing exercise differentially reduced serum levels of IL-1ß, IL-6, and TNF-α. Mechanistically, non-weight-bearing exercise downregulated gene and protein expression of TLR4, MyD88, and NF-κB in cartilage tissue. CONCLUSION: Non-weight-bearing exercise resulted in the progression of KOA by modulating the TLR4/MyD88/NF-κB signaling pathway and decreasing the levels of the inflammatory cytokines IL-1ß, IL-6, and TNF-α to slow down the degeneration of articular cartilage.

Mouse Abdominal Aortic Aneurysm Model Induced by Periarterial Incubation of Papain.

For decades, numerous experimental animal models have been developed to examine the pathophysiologic mechanisms and potential treatments for abdominal aortic aneurysms (AAAs) in diverse species with varying chemical or surgical approaches. This study aimed to create an AAA mouse model by the periarterial incubation with papain, which can mimic human AAA with advantages such as simplicity, convenience, and high efficiency. Eighty C57BL/6J male mice were randomly assigned to 1 of the 4 groups: papain (1.0 or 2.0 mg), porcine pancreatic elastase, and phosphate-buffered solution. The aortic segment was wrapped for 20 minutes, and the diameter was measured using ultrasound preoperatively and postoperative days 7 and 14. Then, the mice were killed for histomorphometric and immunohistochemical analyses. According to ultrasound measurements and histomorphometric analyses, on postoperative day 7, 65% of mice in the 1.0-mg papain group and 60% of mice in the 2.0-mg papain group developed AAA. In both papain groups, 100% of mice developed AAA, and 65% of mice in the porcine pancreatic elastase group developed AAA on postoperative day 14. Furthermore, hematoxylin/eosin, elastin van Gieson, and Masson staining of tissues from the papain group revealed thickened media and intimal hyperplasia, collagen sediments, and elastin destruction, indicating that AAA histochemical alteration was similar to that of humans. In addition, the immunohistochemical analysis was conducted to detect infiltrated inflammatory cells, such as macrophages and leukocytes, in the aortic wall and hyperplasic adventitia. The expression of matrix metalloproteinase 2 and 9 was significantly upregulated in papain and human AAA tissues. Periarterial incubation with 1.0 mg of papain for 20 minutes can successfully create an experimental AAA model in mice for 14 days, which can be used to explore the mechanism and treatment of human AAA.

Development and clinical application of hydrogel formulations containing papain and urea for wound healing

Abstract Hydrogels are used for wound treatment, as they may contain one or more active components and protect the wound bed. Papain is one of the active substances that have been used with this purpose, alongside urea. In this paper, carboxypolymethylene hydrogels containing papain (2% and 10% concentrations) and urea (5% concentration) were produced. Physical-chemical stability was performed at 0, 7, 15 and 30 days at 2-8ºC, 25ºC and 40ºC, as well as the rheological aspects and proteolytic activity of papain by gel electrophoresis. Clinical efficacy of the formulations in patients with lower limb ulcers was also evaluated in a prospective, single-center, randomized, double-blind and comparative clinical trial. The results showed 7-day stability for the formulations under 25ºC, in addition to approximately 100% and 15% of protein activity for 10% and 2% papain hydrogel, respectively. The rheological profile was non-Newtonian for the 10% papain hydrogel tested. There were no significant differences regarding the mean time for healing of the lesions, although 10% papain presented a better approach to be used in all types of tissue present in the wound bed.

Wogonoside attenuates the articular cartilage injury and the infiltration of Th1/Th2-type cytokines in papain-induced osteoarthritis in rat model via inhibiting the NF-κB and ERK1/2 activation.

OBJECTS: Osteoarthritis is the most common joint disease and a major cause of functional limitation and pain in adults. This study aims to investigate the effect of wogonoside (WOG) on the progression of knee osteoarthritis (KOA) in model rats. MATERIALS AND METHODS: Rats KOA models were established and treated with different doses of WOG (10 mg/kg, 20 mg/kg and 30 mg/kg). The degree of cartilage injury was detected by Mankin scores via HE/Alcian blue staining. The levels of IFN-γ and IL-4 in peripheral blood and synovial fluid and the Th1/Th2 ratio were detected by flow cytometry. The model mice were injected with NF-κB p65 or ERK1/2 inhibitors or activators to further investigate the effect of WOG on KOA. RESULTS: WOG significantly improved cartilage tissue damage and reduced the Mankins score. WOG down-regulated the level of IFN-γ while up-regulated the expression of IL-4, which maintained the balance of Th1/Th2 cells. Further studies showed that the expression of NF-κB p65, phosphorylated p65, cytoplasmic ERK1/2 and nuclear ERK1/2 were all inhibited by WOG. The results of reverse verification experiments showed that the activator of NF-κB p65 and ERK1/2 weakened the protective effect of WOG on KOA, and the inhibitor of NF-κB p65ERK1/2 enhanced the protective effect of WOG on KOA. CONCLUSIONS: WOG inhibited the activation of NF-κB and ERK1/2 to alleviate the articular cartilage injury and Th1/th2 cytokine infiltration in KOA rats.

Total dose defines the incidence of percutaneous IgE/IgG1 mediated immediate-type hypersensitivity caused by papain.

Assessment of human health risk requires an understanding of antigen dose metrics associated with toxicity. Whereas assessment of the human health risk for delayed-type hypersensitivity is understood, the metrics remain unclear for percutaneous immediate-type hypersensitivity (ITH) mediated by IgE/IgG1. In this work, we aimed to investigate the dose metric for percutaneous ITH mediated by IgE/IgG1 responses. Papain, which causes ITH via percutaneous sensitization in humans, was used to sensitize guinea pigs and mice. The total dose per animal or dose per unit area was adjusted to understand the drivers of sensitization. Passive cutaneous anaphylaxis (PCA) and enzyme-linked immunosorbent assay (ELISA) for papain-specific IgG1 enabled quantification of the response in guinea pigs. In mice, the number of antigen-bearing B cells in the draining lymph nodes (DLN) was calculated using flow cytometry papain-specific IgG1 and IgE levels were quantified by ELISA. PCA positive test rates and the amounts of antigen-specific antibody corresponded with total dose per animal, not dose per unit area. Furthermore, the number of B cells taking up antigen within DLN also correlated with total dose. These findings indicate that the total antigen dose is the important metric for percutaneous IgE/IgG1-mediated ITH.

Topical delivery of 3,5,4'-trimethoxy-trans-stilbene-loaded microemulsion-based hydrogel for the treatment of osteoarthritis in a rabbit model.

The aim of this study was to develop a microemulsion-based hydrogel (MBH) formulation of 3,5,4'-trimethoxy-trans-stilbene (BTM) as topical delivery system for the treatment of osteoarthritis (OA). The pseudo-ternary phase diagrams were constructed to optimize the microemulsion (ME) formulation. The ME formulation containing 18.8% Cremopher EL35 (surfactant), 9.4% Transcutol HP (co-surfactant), 3.1% LABRAFIL M 1944 CS (oil), and 68.7% water was selected. The obtained BTM-loaded ME (BTM-ME) had a spherical morphology (17.5 ± 1.4 nm), with polydispersity index (PDI) value of 0.068 ± 0.016 and zeta potential of - 11.8 ± 0.5 mV, and was converted into BTM-loaded MBH (BTM-MBH) using Carbopol 940. Ex vivo skin permeation study showed that both ME and MBH formulations significantly enhanced the amount of BTM permeated. The cumulative amount of BTM permeated after 12 h (Q12) for ME, and MBH formulations were 3.25- and 1.96-fold higher than that for emulsion gel (EG). Pharmacokinetic study showed that the AUC of BTM suspension (oral) was three times higher than that of BTM-MBH (topical). Topical delivery of BTM-MBH demonstrated remarkable anti-OA effect in a rabbit model of OA induced by papain, with decreased levels of pro-inflammatory cytokines. The developed MBH formulation might be a promising strategy for topical delivery of BTM for treatment of OA.

Contributions of Interleukin-33 and TSLP in a papain-soaked contact lens-induced mouse conjunctival inflammation model.

INTRODUCTION: Pathological changes of severe chronic allergic conjunctivitis are driven not only via acquired immunity but also via innate immunity. Type 2 immune response-initiating cytokines may play some roles as innate immunity-dependent components of the ocular surface inflammation. To investigate the involvement of type 2 immune response-initiating cytokines in innate immunity-dependent, papain-induced conjunctival inflammation model using IL-25-, IL-33-, and TSLP receptor (TSLPR)-knockout (KO) mice with reference to basophils and ILC2. METHODS: Papain-soaked contact lenses (papain-CLs) were installed in the conjunctival sacs of C57BL/6-IL-25 KO, IL-33 KO, TSLPR KO, Rag2 KO, Bas-TRECK, and wild-type mice and their eyes were sampled at day 5. The eosinophil and basophil infiltration in papain-CL model was evaluated histologically and cytokine expression was examined. To clarify the roles of basophils and ILC2, basophil/ILC2-depletion experiments were carried out. RESULTS: Papain-induced conjunctival inflammation exhibited eosinophil infiltration and upregulation of Th2 cytokine expression. Reduction of eosinophil and basophil infiltration and attenuated Th2 cytokine expression were observed in the papain-CL model using IL-33 KO and TSLPR KO mice. Depletion of basophils or ILC2s in the conjunctivae of the papain-CL model reduced eosinophil infiltration. CONCLUSIONS: Innate immunity-driven type 2 immune responses of the ocular surface are dependent on IL-33, TSLP, basophils, and ILC2. These components may be possible therapeutic targets for refractory allergic keratoconjunctivitis.

Early detection of rheumatoid arthritis in rats and humans with 99mTc-3PRGD2 scintigraphy: imaging synovial neoangiogenesis.

OBJECTIVES: To validate 99mTc-labeled arginylglycylaspartic acid (99mTc-3PRGD2) scintigraphy as a means to image synovial neoangiogenesis in joints afflicted by rheumatoid arthritis and to investigate its potential in the early detection and management of rheumatoid arthritis. METHODS: Rheumatoid arthritis and osteoarthritis were generated in Sprague Dawley rats by type II collagen immunization and papain injection, respectively. Rats were imaged with 99mTc-3PRGD2 and 99mTc- methyl diphosphonate (99mTc MDP). X-ray images were also obtained and assessed by a radiologist. Immunohistochemistry of αvß3 and CD31confirmed the onset of synovial neoangiogenesis. The effect of bevacizumab on rheumatoid arthritis was followed with 99mTc-3PRGD2 scintigraphy. A patient with rheumatoid arthritis and a healthy volunteer were scanned with 99mTc-3PRGD2. RESULTS: Two weeks after immunization, a significant increase in 99mTc-3PRGD2 was observed in the joints of the rheumatoid arthritis model though uptake in osteoarthritis model and untreated controls was low. 99mTc-MDP whole body scans failed to distinguish early rheumatoid arthritis joints from healthy controls. The expression of αvß3 and CD31was significantly higher in the joints of rheumatoid arthritis rats compared to normal controls. In serial 99mTc-3PRGD2 scintigraphy studies, 99mTc-3PRGD2 uptake increased in parallel with disease progression. Bevacizumab anti-angiogenetic therapy both improved the symptoms of the rheumatoid arthritis rats and significantly decreased 99mTc-3PRGD2 uptake. Significantly higher 99mTc-3PRGD2 accumulation was also observed in rheumatoid arthritis joints in the patient. CONCLUSIONS: Our findings indicate that 99mTc-3PRGD2 scintigraphy could detect early rheumatoid arthritis by imaging the associated synovial neoangiogenesis, and may be useful in disease management.

Papain and its inhibitor E-64 reduce camelid semen viscosity without impairing sperm function and improve post-thaw motility rates.

In camelids, the development of assisted reproductive technologies is impaired by the viscous nature of the semen. The protease papain has shown promise in reducing viscosity, although its effect on sperm integrity is unknown. The present study determined the optimal papain concentration and exposure time to reduce seminal plasma viscosity and investigated the effect of papain and its inhibitor E-64 on sperm function and cryopreservation in alpacas. Papain (0.1mg mL-1, 20min, 37°C) eliminated alpaca semen viscosity while maintaining sperm motility, viability, acrosome integrity and DNA integrity. Furthermore E-64 (10 µM at 37°C for 5min after 20min papain) inhibited the papain without impairing sperm function. Cryopreserved, papain-treated alpaca spermatozoa exhibited higher total motility rates after chilling and 0 and 1h after thawing compared with control (untreated) samples. Papain treatment, followed by inhibition of papain with E-64, is effective in reducing alpaca seminal plasma viscosity without impairing sperm integrity and improves post-thaw motility rates of cryopreserved alpaca spermatozoa. The use of the combination of papain and E-64 to eliminate the viscous component of camelid semen may aid the development of assisted reproductive technologies in camelids.

Isolated and combined effects of photobiomodulation therapy, topical nonsteroidal anti-inflammatory drugs, and physical activity in the treatment of osteoarthritis induced by papain.

Osteoarthritis (OA) is a chronic inflammatory disease and is characterized as a degenerative process. This study aimed to evaluate and compare the effects of a topical nonsteroidal anti-inflammatory drug (NSAID), physical activity, and photobiomodulation therapy (PBMT) applied alone and/or in combination between them in an experimental model of knee OA. OA was induced by injection of papain in the knees of rats. After 21 days, the animals started to be treated with the above treatment. Histological analysis shows that the experimental model of OA induction causes morphological changes consistent with the disease, and among treatments, the PBMT is the most effective for reducing these changes. Moreover, the results demonstrate that PBMT and NSAID reduce the total number of cells in the inflammatory infiltrate (p<0.05) and PBMT was the most effective for reducing the activity of myeloperoxidase (p<0.05). Finally, we observed that both NSAID and PBMT were effective for reducing the gene expression of MMP-3 (p<0.05), but in relation to the gene expression of MMP-13, PBMT was the most effective treatment (p<0.05). The results of this study indicate that PBMT is the most effective therapy in stopping disease progression, and improving inflammatory conditions observed in OA.

Effects of Balsamodendron mukul Gum Resin Extract on Articular Cartilage in Papain-induced Osteoarthritis.

Context • Osteoarthritis (OA) is one of the most prevalent chronic diseases of the musculoskeleton, causing functional disability among older adults. Management of OA includes conventional pharmacological treatments consisting primarily of nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, physiotherapy, and surgical procedures. The medications are not ideal therapeutic agents; NSAIDs in particular can cause serious side effects. Objective • The study was conducted to investigate the effects of Balsamodendron mukul (BDM) gum resin extract on cartilage damage and microstructural changes in the subchondral bone of rats with papain-induced, osteoarthritic knee joints. Design • The authors designed a parallel randomized, controlled study to examine the effects of 3 concentrations of BDM on OA in a murine model. Setting • The present study was undertaken at the research laboratory, Faculty of Biological Engineering, Shobhit University (Modipuram, Meerut, India). Intervention • OA was induced by intra-articular injections of 0.2 mL of 4% papain solution and 0.1 mL of 0.03 M cysteine through the patellar ligament using a 26-gauge, 1.27-cm needle. The rats in the sham group received same volume of isotonic sodium chloride solution. The rats were divided into 6 groups : (1) control group-fresh rats, with ages and genders similar to those of the other groups but with no induction of OA and no treatments; (2) sham group-rats receiving a sham induction of OA using an intra-articular injection of saline of the same volume as the papain given to all OA rats but no treatments; (3) OA group-rats induced with OA but receiving no treatments; (4) OA + BDM (10%) group-rats induced with OA that received a 10% dose of BDM; (5) OA + BDM (20%) group-rats induced with OA that received a 20% dose of BDM; and (6) OA + BDM (40%) group-rats induced with OA that received a 40% dose of BDM. Rats in the treatment groups were fed their respective doses of BDM extract for 30 d. Outcome Measures • The articular cartilages from the knee joints and epiphyseal bones of the femur and tibia were extracted from the right- and left-side limbs to perform the biochemical, microarchitectural, and histological analyses. Results • The total protein and collagen content of the articular cartilage of the knees were significantly higher in all treated groups when compared with the OA group of rats. The histological analysis revealed a thicker cartilage and a higher trabecular density of the subchondral bone (epiphyseal bone) in BDM-treated rats. Conclusions • The oral dose of BDM gum resin extract was shown to relieve OA pain, regenerate the cartilaginous matrix, and increase the subchondral bone components. On the basis of the findings, the research team suggests that the BDM gum resin extract may be used for therapeutic interventions for reversal of OA and reduction in its related inflammatory pain.

Comparison of the chondroprotective effect of a novel hydrogel compound and traditional hyaluronate on rat cartilage in a papain-induced osteoarthritis model.

PURPOSE: The aim of this experimental study is to evaluate the efficacy of a novel intraarticular drug in a papain induced osteoarthritis (OA) rat model and compare with the traditional hyaluronat (HA) visco supplementation. METHODS: An early stage OA model was induced by the intra-articular injection of papain enzyme in the right knee joints of 44 Sprague-Dawley rats. Eleven rats (eleven right knees: papain group, 11 left knees: control group) were chosen randomly 28 days after the last injection and sacrificed for verifying OA. The remaining rats (n = 33) were randomly divided into 3 groups. Group 1 was injected 0,2 mL of sterile saline solution (0,9%), group 2 was injected 0,2 mL HA and the group 3 was injected 0,2 mL of HA-CSNAG (hyaluronat, chondritin sulfate, N-acetyl-d-glucosamine) combination in the right knees. Injections were performed on the 35th, the 42nd and the 49th days consecutively. Two weeks after the last injection, all groups were sacrificed to evaluate the severity of OA according to Mankin system. RESULTS: Early stage of OA was verified regarding total Mankin scores (p < 0.05). There was statistically significant difference between Group 1 and Group 2 (p < 0.05), between Group 1 and Group 3 (p < 0.05) on the 63th day regarding total Mankin scores. Group 3 showed statistically significant improvement in terms of proteoglycan content of matrix when compared to Group 2 (p < 0,05). CONCLUSION: HA-CS-NAG compound in hydrogel form is more chondroprotective to rats' cartilage when compared to HA during the early stages of OA.

Papain-induced occupational rhinoconjunctivitis and asthma - A case report.

This report presents a case of occupational asthma, rhinitis and conjunctivitis to papain in a 50-year-old herbs and spices packer, with documented increased eosinophilia in induced sputum and in the nasal lavage fluids after a specific inhalation challenge test (SICT) and specific nasal challenge test (SNCT) with this enzyme. Immunoglobulin E-mediated (IgE) sensitization to papain was confirmed by positive results of a skin prick test with specific solution. Specific inhalation and nasal challenge tests demonstrated a direct and significant link between the exposure to this protease and the allergic response from the respiratory system. Additionally, the SNCT induced a severe reaction of the conjunctivae and a significant increase in the count of eosinophils in tears, despite the lack of direct contact of the allergen with the conjunctiva.

Efeitos da papaína intramamária em vacas com mastite subclínica sobre a contagem de células somáticas e sólidos totais / Effects of intramammary papain in cows with subclinical mastitis on somatic cell count and total solids / Efectos de la papaína intramamaria en vacas con mastitis subclínica en recuento de células somáticas y sólidos totales

A mastite é a principal enfermidade que acomete o gado leiteiro. De todas as formas, a mastite subclínica é a que causa maiores perdas, na redução da produção, na diminuição da qualidade do leite e pelos altos custos de tratamento e descarte precoce de vacas. Altas contagens de células somáticas e baixo teor de sólidos totais no leite geralmente estão associados à mastite. Dessa forma, o objetivo deste estudo foi avaliar os efeitos de um creme de papaína a 2%, associado ou não ao cloridrato de ceftiofur (125mg) por via intramamária sobre a contagem de células somáticas e sólidos totais. O estudo foi realizado em 23 quartos mamários com mastite subclínica, detectadas pelo exame do CMT (California Mastitis Test) e da CCS (contagem de células somáticas), divididas em 4 grupos (1 ­ cloridrato de ceftiofur 125 mg; 2- cloridrato de ceftiofur 125mg + papaína 2%; 3- papaína 2%; 4- controle). As análises foram feitas com base no CMT, na CCS e de sólidos totais (ST) antes e após o tratamento. Os quartos mamários que foram tratados com papaína 2% tiveram alterações no leite, com catarro, grumos e coágulo com intensificação do quadro inflamatório. Não houve diferença significativa ao teste T entre as amostras antes e após o tratamento em nenhum dos grupos para as variáveis estudadas.(AU)

Mastitis is the main disease affecting dairy cattle. From all forms, subclinical mastitis is the one that causes the greater losses, with reduced production, decreased milk quality and by high treatment costs and early disposal of cows. High somatic cell counts and low total solids in milk are usually associated with mastitis. Thus, the aim of this study was to assess the effects of a intrammamarily 2% papain cream associated or not with ceftiofur hydrochloride (125mg) on somatic cell count and total solids. The study was performed on 23 breasts with subclinical mastitis, detected through CMT (California Mastitis Test) and SCC (somatic cell count), divided into 4 groups (1 - 125 mg ceftiofur hydrochloride, 2 - ceftiofur hydrochloride 125mg + 2% papain, 3 - 2% papain, 4 - control). The analyzes were based on CMT, SCC and total solids (TS) before and after treatment. The breasts that were treated with 2% papain presented changes in milk, with phlegm, lumps and clot with intensification of the inflammation. There were no significant differences between the T-test samples before and after treatment in either group for the studied variables.(AU)

La mastitis es la principal enfermedad que afecta el ganado lechero. La mastitis subclínica es la que causa grandes pérdidas en la reducción de la producción, disminución de la calidad de la leche, los altos costos de tratamiento y desecho precoz de vacas. Los altos recuentos de células somáticas y bajo contenido de sólidos totales en la leche están generalmente asociados con mastitis. Por lo tanto, el objetivo de este estudio fue evaluar los efectos de un 2% de papaína crema, con o sin el clorhidrato de ceftiofur (125 mg) por vía intramamaria en el recuento de células somáticas y sólidos totales. El estudio se realizó en 23 cuartos mamarios con mastitis subclínica, detectadas mediante el examen de la CMT (Prueba de Mastitis de California) y CCS (recuento de células somáticas), dividido en 4 grupos (1 - ceftiofur clorhidrato 125 mg; 2- clorhidrato de ceftiofur 125 mg + papaína 2%; 3- papaína 2%; 4 - control). Los análisis se basaron en CMT, en CCS y sólidos totales (ST), antes y después del tratamiento. Las glándulas mamarias que fueron tratadas con papaína 2% tuvieron cambios en la leche, con flema, grañones y coágulos con intensificación de inflamación. No hubo diferencia significativa por la prueba T, entre las muestras antes y después del tratamiento, en ninguno de los grupos para las variables estudiadas.(AU)

Spred1, a Suppressor of the Ras-ERK Pathway, Negatively Regulates Expansion and Function of Group 2 Innate Lymphoid Cells.

Cytokines from group 2 innate lymphoid cells (ILC2s) have been implicated in acute allergic responses, such as papain-induced lung inflammation. However, the means of homeostatic regulation of ILC2s have not been established. In this study, we demonstrated that Spred1, a negative regulator of the Ras-ERK pathway, plays an important role in the proliferation and apoptosis of ILC2s and in cytokine secretion from ILC2s. Intranasal administration of papain stimulated IL-5 and IL-13 production in the lung, which was enhanced when Spred1 was deleted. In vitro, Spred1(-/-) ILC2s proliferated faster than wild type ILC2s did and produced higher levels of cytokines in response to IL-33. On the contrary, a MEK inhibitor suppressed ILC2 proliferation and cytokine production. Spred1 deficiency resulted in stabilization of GATA3, which has been shown to play essential roles in the maintenance and cytokine production of ILC2. These data suggest that Spred1 negatively regulates ILC2 development and functions through the suppression of the Ras-ERK pathway.

Treatment of mild to moderate acne with a fixed combination of hydroxypinacolone retinoate, retinol glycospheres and papain glycospheres.

AIM: A fixed combination of 0.1% hydroxypinacolone retinoate (synthetic esther of 9-cis-retinoic acid), 1% retinol in glycospheres and 2% papain in glycospheres in aqueous gel has been recently introduced into the Italian market in order to reduce the incidence and severity of irritant contact dermatitis caused by topical retinoids, without compromising their efficacy. Primary objectives of this sponsor-free, pilot, open, multicenter study were to evaluate the efficacy and tolerability of this gel in patients with comedonal-papular, mild to moderate acne of the face. METHODS: Ninety-eight Caucasian patients (28 males and 70 females), with an age ranging from 15 to 40 years, were treated with the gel once daily for 12 weeks. Acne severity and treatment efficacy were evaluated by means of the Global Acne Grading System (GAGS) and lesions count. RESULTS: Ninety-four patients were considered evaluable. A 41% mean reduction in the GAGS score was observed; a 40.8% mean reduction of total lesions was recorded; 15.3% of patients experienced mild to moderate local side effects (dryness, peeling, erythema, burning). No patients stopped the treatment because of these side effects. CONCLUSION: This study, based on a high number of evaluable patients, demonstrates that this fixed combination is an effective and safe option for the treatment of comedonal-papular, mild to moderate acne of the face. A controlled clinical study is necessary to confirm these data.

Tougu Xiaotong capsule inhibits the tidemark replication and cartilage degradation of papain-induced osteoarthritis by the regulation of chondrocyte autophagy.

The tidemark is located between calcified and non-calcified cartilage matrices. Tidemark replication plays an important role in the pathogenesis of osteoarthrosis (OA). Autophagy, or cellular self-digestion, is an essential cellular homeostasis mechanism that was found to be deficient in osteoarthritic cartilage. This study evaluated the effects of Tougu Xiaotong capsule (TXC) on the tidemark replication and cartilage degradation, and also investigated LC3 I/II, which executes autophagy, the potential role of ULK1, an inducer of autophagy, and Beclin1, a regulator of autophagy, in the development of a papain-induced OA in rat knee joints. Using a papain-injected knee rat model, standard histological methods were used to validate our model as well as treatment with TXC or glucosamine (GlcN). After 12 weeks of treatment, the changes of cartilage structure were observed by digital radiography (DR), optical microscopy, scanning electron microscopy and transmission electron microscopy, and the LC3 I/II, ULK1 and Beclin1 levels were measured by western blotting. Cartilage degradation was evaluated by the Mankin score on paraffin-embedded sections stained with Safranin O-fast green. TXC was found to improve the arrangement of subchondral bone collagen fibers and calcium phosphate crystals, inhibit the tidemark replication and delay the cartilage degradation in the papain-induced OA. Our results also showed that LC3 I/II, ULK1 and Beclin1 levels in both the TXC+OA and GlcN+OA groups were significantly increased compared to those in the OA group. The results indicate that TXC could inhibit the tidemark replication and cartilage degradation by the regulation of chondrocyte autophagy.

Chondroprotective and anti-inflammatory effects of sesamin.

Osteoarthritis (OA) is a major disability of elderly people. Sesamin is the main compound in Sesamun indicum Linn., and it has an anti-inflammatory effect by specifically inhibiting Δ5-desaturase in polyunsaturated fatty acid biosynthesis. The chondroprotective effects of sesamin were thus studied in a porcine cartilage explant induced with interleukin-1beta (IL-1ß) and in a papain-induced osteoarthritis rat model. With the porcine cartilage explant, IL-1ß induced release of sulfated-glycosaminoglycan (s-GAG) and hydroxyproline release, and this induction was significantly inhibited by sesamin. This ability to inhibit these processes might be due to its ability to decrease expression of MMP-1, -3 and -13, which can degrade both PGs and type II collagen, both at the mRNA and protein levels. Interestingly, activation of MMP-3 might also be inhibited by sesamin. Moreover, in human articular chondrocytes (HACs), some pathways of IL-1ß signal transduction were inhibited by sesamin: p38 and JNK. In the papain-induced OA rat model, sesamin treatment reversed the following pathological changes in OA cartilage: reduced disorganization of chondrocytes in cartilage, increased cartilage thickness, and decreased type II collagen and PGs loss. Sesamin alone might increase formation of type II collagen and PGs in the cartilage tissue of control rats. These results demonstrate that sesamin efficiently suppressed the pathological processes in an OA model. Thus, sesamin could be a potential therapeutic strategy for treatment of OA.

[Effects of proteolytic enzyme therapy with Wobe Mugos against chemotherapy-induced toxicity in breast cancer patients - results of a pilot study]. / Proteolytische enzymtherapie mit wobe mugos gegen chemotherapie-bedingte toxizitäten bei brustkrebs-patientinnen - ergebnisse einer pilotstudie.

BACKGROUND: Wobe Mugos(®) is an enzyme preparation containing the proteases trypsin and papain from the pancreatic calf and commonly used in complementary medicine. From non-randomized studies, its multiple favorable effects including the reduction of adverse events from radiotherapy and chemotherapy in oncology patients have been reported. METHODS: Patients with invasive breast cancer receiving adjuvant or palliative chemotherapy between 2005 and 2006 and who were scheduled for at least two further cycles of this specific chemotherapy were included in this pilot study. A specific toxicity of at least grade 2 using the NCI common toxicity criteria which occurred during the preceeding cycle and was relevant to the patient was recorded. This specific toxicity, e.g. grade 2 emesis, was again evaluated after two analogously administered further chemotherapy cycles in which Wobe Mugos(®) had been coadministered. The hypothesis was that specific toxicites of individual patients will be reduced by this enzyme therapy. The majority of the 57 consecutive patients received palliative chemotherapy. Peroral enzyme therapy was coadministered with two uncracked coated tablets three times daily on all days of a chemotherapy cycle except on the day of chemotherapy administration. RESULTS: Tolerability was good. Positive and neutral effects on toxicity parameters were observed in 11 and 42 patients, respectively, and a negative influence in 4 women. CONCLUSION: We observed only a marginal influence of Wobe Mugos(®) in patients with breast cancer who had experienced at least a grade 2 toxicity in the preceding cycle and who received two further identical cycles of this chemotherapy in conjunction with the enzyme preparation. Randomized studies on homogenous patient populations are necessary.