scholarly journals The new external drug for the treatment of psoriasis based on inhibition of serine proteases

2021 ◽  
Vol 97 (3) ◽  
pp. 47-55
Author(s):  
Alexander S. Zhukov ◽  
Evgeny R. Zharun ◽  
Vladislav R. Khairutdinov ◽  
Alexey V. Samtsov ◽  
Mihail Yu. Krasavin ◽  
...  

Background: Psoriasis is a chronic inflammatory immune-mediated disease characterized by an increased rate of keratinocyte division. The results of recent studies have made it possible to establish that the cytokines of the IL-36 family occupy a significant place in the initiation and regulation of the inflammatory process in psoriasis. IL-36 is in an inactive form and proteolytic processing is required for its activation in the skin, which is possible with the participation of neutrophilic serine proteases. Localization of these enzymes in the upper layers of the epidermis suggests the clinical efficacy of a topical targeted drug that inhibits serine proteases, sivelestat. On the basis of this active substance, we have created a drug in an external dosage form and conducted an experimental study of its effectiveness on a laboratory model of psoriasis. Aims: to evaluate the therapeutic efficacy of sivelestat in a laboratory model of imiquimod-induced psoriasis. Materials and methods: In the experiment, 40 inbred BALB/c mice were used, which were randomized into 4 groups of 10 each. An imiquimod-induced model of psoriasis was used. Mice of group No. I - without therapy (control), No. II - ointment (vaseline) containing 1% sivelestat, No. III - cream (lanolin + olive oil + water in equal proportions) containing 1% sivelestat, No. IV - betamethasone cream dipropionate 0.05%. Clinical assessment of skin rashes was performed using the PASI-modified method (mPASI), as well as histological and immunohistochemical examination of the skin. Results: When evaluating clinical manifestations, it was found that the total mPASI index when using sivelestat cream decreased by 50%, and sivelestat ointment - by 36%. The histological examination showed that the thickness of the epidermis in the groups where the therapy was applied was 2.4-3.6 times less than in the control group. An immunohistochemical study of the skin found that after treatment with sivelestat, the number of CD3 + cells in the skin was 1.8-2.2 times less, and the level of proliferative activity (Ki-67 + cells) was 2.3-2.9 times less. lower than in the group without therapy Conclusions: On a laboratory model of imiquimod-induced psoriasis, it was found that a serine protease inhibitor (sivelestat) has a therapeutic efficacy comparable to a strong topical glucocorticosteroid drug (betamethasone dipropionate 0.05%). A pronounced resolution of the elements of the skin rash, a reduction in the thickness of the epidermis, a decrease in skin infiltration with T-lymphocytes and a normalization of the rate of cell division of the epidermis and dermis are shown. Suppression of the activity of IL-36-mediated inflammation in the skin by means of topical inhibitors of serine proteases is a promising new direction in the treatment of patients with psoriasis.

Author(s):  
Iskander I. Zaidullin ◽  
Denis O. Karimov ◽  
Lilija K. Karimova ◽  
Milyausha F. Kabirova ◽  
Rasima R. Galimova ◽  
...  

The susceptibility to the development and progression of inflammatory periodontal diseases, which depends on genetic and external factors (smoking, stress, oral hygiene), varies widely. In the development of these diseases, an important role is played not only by the presence of periodontal pathogenic microorganisms, but also by the presence of congenital or acquired immunodeficiency, immunoregulatory defects. The immune system plays a key role in the physiological and pathological processes of periodontal tissues. In this regard, IL17, produced by CD4+ Th cells, which has both Pro-inflammatory and protective activity, is of particular interest in the pathogenesis of periodontitis. The aim of study was to identify the relationship between polymorphic loci of the IL-17A (rs2275913) and MMP-1 (rs1799750) genes and clinical manifestations of chronic periodontitis in petrochemical workers. Dental examination was performed in 92 ethylene oxide production workers with chronic periodontitis and 74 patients with chronic periodontitis who did not come into contact with chemical factors (control group). Genotyping of polymorphisms rs2275913 of the IL17A gene and rs1799750 of the MMP1 gene was performed by allele-specific real-time polymerase chain reaction (PCR). Hygienic assessment of the degree of air pollution of the working area with harmful substances was carried out by gas chromatography according to the guidelines for the determination of harmful substances in the air № 5098-89, № 3119-84. When comparing the results of studies of both groups, there were no statistically significant differences in the frequency distributions of allelic variants and genotypes of the IL-17A and MMP-1 genes. The AA/AG genotypes of the IL-17A gene were associated with an increased risk of severe disease compared to the GG genotype in workers in the main group (OR=6.1; 95% CI 1.33-28.5; p=0.021) and in the control group (OR=7.26; 95% CI 1.34-39.25; p=0.016). Carriers of the A allele in the control group increased the risk of severe chronic periodontitis by 2.4 times compared to carriers of the G allele (OR=2.41; 95% CI 1.19-4.87; p=0.014). During the dental examination of employees of the ethylene oxide plant, the clinical course of periodontal diseases was more severe in comparison with the control group, and the number of patients with severe periodontitis was twice as high. It was found that the AA/AG genotypes of the IL-17A gene and the carrier of the A allele are associated with increased susceptibility to the development of severe chronic periodontitis. The association between the MMP-1 gene polymorphism and the risk of severe forms of chronic periodontitis has not been established. A risk factor for the development of inflammatory periodontal diseases in employees of the petrochemical complex is a complex of harmful production factors.


Nephron ◽  
2021 ◽  
pp. 1-13
Author(s):  
Minfang Zhang ◽  
Wenyan Zhou ◽  
Shaojun Liu ◽  
Liyin Zhang ◽  
Zhaohui Ni ◽  
...  

Introduction: IgA-dominant infection-related glomerulonephritis (IgA-IRGN) is a unique form of IRGN, which needs to be distinguished from IgA nephropathy (IgAN), due to overlapping clinical and pathological features. The key factor in the pathogenesis of IgAN is galactose-deficient IgA1 (Gd-IgA1). However, the mechanism of glomerular IgA deposition in patients with IgA-IRGN is unclear. Therefore, we evaluated whether Gd-IgA1 could be a useful biomarker to distinguish between these 2 diseases. Methods: A case-control study was conducted to analyze the clinical and pathological characteristics of 12 patients with IgA-IRGN. The intensity and distribution of glomerular Gd-IgA1 (KM55) staining in renal biopsies were assessed. The control group consisted of 15 patients diagnosed with IgAN and an additional 17 patients with glomerulopathy involving IgA deposition. Results: The main clinical manifestations of patients with IgA-IRGN were nephrotic-range proteinuria, hematuria, acute renal injury, and hypocomplementemia. Active lesions were the leading pathological feature, while focal segmental sclerosis was rare. Half of the patients exhibited hump-shaped subepithelial deposits. Glomerular KM55 staining was negative in 7 patients, trace in 4 patients, and 2+ in 1 patient. The median intensity of KM55 staining in IgA-IRGN patients was 0 (range 0∼2+), which was significantly lower than that of primary IgAN patients (median 2+, range 1+∼3+). The receiver operating characteristic analysis demonstrated that the optimal cutoff level to identify these 2 diseases was 0.5+. Conclusions: Glomerular KM55 staining intensity might be helpful to distinguish IgA-IRGN from primary IgAN. Weak or negative staining may favor IgA-IRGN. In addition, integrated analysis including clinical data, pathological findings, and prognostic information would further improve the differential diagnosis.


2021 ◽  
pp. jim-2021-001788
Author(s):  
Xiumei Liu ◽  
Xueming Wang ◽  
Xiaoling Zhang ◽  
Ai hua Cao

Tic disorders (TD) are childhood-onset neurological disorders. Immune system dysregulation has been postulated to play a role in TD, and its mechanisms likely involve dysfunctional neural-immune cross-talk, which ultimately leads to altered maturation of the brain pathways that control different TD clinical manifestations and behavioral and emotional damages. Clinical studies have demonstrated an association between TD and allergies and overactive immune responses at a systemic level. In this study, the Yale Global Tic Severity Scale was taken as a global measure of tic severity. Compared with the control group, the group of children with TD plus allergic diseases displayed significantly increased Yale total scores (p<0.05), which suggests that children with TD plus allergic diseases have heavier tic symptoms. Both motor and vocal tic scores are higher in the group of children with TD plus allergy compared with the control group. We counted immune cell subpopulations using FACS. T lymphocyte subset comparison of CD3, CD4, CD8, and CD4:CD8 expression ratios revealed that the level of CD3, CD4, and CD4:CD8 in children with TD plus allergic diseases was significantly lower than those of children with TD without allergic diseases. These differences were statistically significant (p<0.05) and suggest that children with TD plus allergic diseases have imbalanced T lymphocyte subsets. We concluded that allergy increased the severity of TD through an imbalance in cellular immunity. Studies need to be done to show whether treatment of allergic symptoms leads to a decrease in TD manifestations.


Medicina ◽  
2021 ◽  
Vol 57 (6) ◽  
pp. 607
Author(s):  
Rudolfs Janis Viksne ◽  
Gunta Sumeraga ◽  
Mara Pilmane

Background and Objectives: Chronic rhinosinusitis (CRS) is a condition that affects as much as 10.9% of the population and, along with presence of nasal polyps, is associated with significant morbidity and decreased quality of life. Studies on molecular pathways that have been activated in nasal polyp tissue are mainly based on cytokine concentration detection. Therefore, our aim is to investigate the complex appearance, relative distribution and interlinks of IL-1, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12 and Ki 67 in chronic rhinosinusitis with nasal polyps (CRSwNP) affected human nasal mucosa. Materials and Methods: Samples of nasal polyps were obtained from 12 patients with previously diagnosed CRSwNP and no prior surgery. Control group consisted of samples from 17 otherwise healthy individuals with isolated nasal septum deviation. Tissues were stained for IL-1, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12 and Ki67 immunohistochemically. Non-parametric statistic, Mann–Whitney U test and Spearman’s rank correlation coefficient were used. Results: All factors, except connective tissue cytokine IL-10 and proliferation marker Ki-67, had increased presence in connective tissue and decreased presence in epithelium of nasal polyps when compared to controls. Very strong and strong positive correlations between factors were observed. Conclusions: Decreased appearance of IL-1α, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12 positive structures in the nasal epithelium with selective increase of IL-1α and IL-12 in nasal subepithelial connective tissue characterize the cytokine endotype with dysfunctional epithelial barrier and local stimulation of immune response in the connective tissue in case of chronic rhinosinusitis with polyps. Decrease of IL-6 in both—epithelium and connective tissue with strong correlation between it and IL-7 and IL-10 in connective tissue suggests significant stimulation of this regulatory cytokine and, possibly, the important role in pathogenesis of the development in nasal polyps. Correlations between Ki67 and cytokines indicate possible involvement of IL-4, IL-7 and IL-12 in regulation of cellular proliferation.


2011 ◽  
Vol 4 (6) ◽  
pp. 338-343 ◽  
Author(s):  
Elias Armenis ◽  
Nikolaos Pefanis ◽  
Georgios Tsiganos ◽  
Panagiotis Karagounis ◽  
Panagiotis Baltopoulos

Sports activities cause increased loads in elite athletes’ joints. Current scientific knowledge highlights the importance of applied mechanical loads on the physiology and pathophysiology of the articular cartilage. Thus, it is possible that sporting activity has a role in the development of osteoarthritis (OA), a painful and damaging joint disease. The aim of the present study was to investigate and record osteoarthritic alterations in the ankle and foot complex in former Greek soccer players and also compare them with those in the general population. The study sample consisted of 170 male, former elite soccer players, aged between 42 and 55 years (mean = 49.8 years, standard deviation [SD] = 7.4). A control group of 132 men, aged between 42 and 55 years (mean, 50.7 years, SD = 9.9), with no regular athletic activity were examined. The development of osteoarthritic alterations was recorded through a questionnaire and clinical and radiological examination. Radiographic analysis of the images in former athletes group showed not only more signs of cartilage degeneration in comparison with the control group (P < .05) but also similar clinical manifestations (pain and impaired mobility; P > .05). Osteophyte formation is a frequent disease among former soccer players—with variations on radiographic images—but it does not appear in their clinical picture. However, it is likely that both spurs and subchondral sclerosis (main findings) are preclinical manifestations of OA. Levels of Evidence: Prognostic, Level II


2002 ◽  
Vol 76 (10) ◽  
pp. 5184-5197 ◽  
Author(s):  
Judit Jané-Valbuena ◽  
Laura A. Breun ◽  
Leslie A. Schiff ◽  
Max L. Nibert

ABSTRACT Entry of mammalian reovirus virions into target cells requires proteolytic processing of surface protein σ3. In the virion, σ3 mostly covers the membrane-penetration protein μ1, appearing to keep it in an inactive form and to prevent it from interacting with the cellular membrane until the proper time in infection. The molecular mechanism by which σ3 maintains μ1 in this inactive state and the structural changes that accompany σ3 processing and μ1 activation, however, are not well understood. In this study we characterized the early steps in σ3 processing and determined their effects on μ1 function and particle infectivity. We identified two regions of high protease sensitivity, “hypersensitive” regions located at residues 208 to 214 and 238 to 244, within which all proteases tested selectively cleaved σ3 as an early step in processing. Further processing of σ3 was required for infection, consistent with the fact that the fragments resulting from these early cleavages remained bound to the particles. Reovirus type 1 Lang (T1L), type 3 Dearing (T3D), and T1L × T3D reassortant virions differed in the sites of early σ3 cleavage, with T1L σ3 being cleaved mainly at residues 238 to 244 and T3D σ3 being cleaved mainly at residues 208 to 214. These virions also differed in the rates at which the early cleavages occurred, with cleavage of T1L σ3 occurring faster than cleavage of T3D σ3. Analyses using chimeric and site-directed mutants of recombinant σ3 identified carboxy-proximal residues 344, 347, and 353 as the primary determinants of these strain differences. The spatial relationships between these more carboxy-proximal residues and the hypersensitive regions were discerned from the σ3 crystal structure. The results indicate that proteolytic processing of σ3 during reovirus disassembly is a multistep pathway with a number of molecular determinants.


2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 47.2-47
Author(s):  
C. Gioia ◽  
B. Lucchino ◽  
C. Iannuccelli ◽  
G. Dolcini ◽  
M. DI Franco

Background:Fibromyalgia (FM) is a common rheumatic disease characterized by chronic widespread pain, sleep and mood disorders. A higher prevalence of FM in women compared with men is well known, although the specific differences in clinical manifestations related to gender are still poorly defined. Brain-Derived Neurotrophic Factor (BDNF) is an endogenous growth factor that gained attention for its potential as biomarker of several diseases, including FM and depression.Objectives:The aims of this study were to investigate gender-related difference among males and females affected by FM in clinical manifestations, depressive features and BDNF serum level, evaluating also the diagnostic potential of the latter.Methods:We consecutively enrolled adult patients affected by FM (ACR 2016) referring to our out-patient clinic. Each subject underwent clinical and answered to questionnaires for the severity of FM symptoms (Revised Fibromyalgia Impact Questionnaire, R-FIQ) and depressive symptoms (Beck Depression Inventory-II, BDI-II). We collected blood samples from a subgroup of patients of both sexes, matched for age, for BDNF serum level dosage through ELISA. BDNF levels were assessed also in a control group, matched for sex and age.Results:The cohort was composed by 201 FM patients (172 F, 29 M), mean age 49.13. Females showed higher values of R-FIQ total score (p=0,0005) as well the specific items of the R-FIQ for pain (p=0,013), fatigue (p=0,014), memory problems (p=0,007), tenderness to touch (p<0,0001), balance problems (p<0,0001) and sensitivity to environmental stimuli (p=0,012) when compared with males (fig. 1). There was no difference in BDI-II between males and females, but notably male patients reported a significantly higher frequency of coexisting depressive disorder (p=0,038) (fig. 2). Serum BDNF levels were evaluated in 40 FM patients and 40 healthy controls (HC) (F:M 1:1). BDNF levels were significantly lower in FM patients compared with HC (p<0,0001). Among FM patients, BDNF levels were lower in males compared with females (p<0,0001) (fig.3). BDNF did not correlate with any clinical and clinimetric parameter. BDNF showed a good diagnostic performance (AUC=0,89, CI95%=0,82-0,9630, p<0,0001) (fig. 4). At a cut-off value <6,47 ng/dl, BDNF showed a specificity of 75% and a sensibility of 92,31%,(CI 95%=79,68-97.35) for FM identification (LR=3,692).Conclusion:FM clinical manifestations are strongly dependant from gender. While females present a more severe disease and a higher burden of symptoms, mood disorders tend to be a major characteristic of males with FM. Reduced BDNF serum levels have been reported as typical of depressive disorders. Our findings of lower BDNF levels in male FM patients compared to females support this hypothesis. BDNF have potential as biomarker of the disease and should be validated in larger cohorts.References:[1]Sarzi-Puttini et al. Nature Reviews 2020[2]Colucci-D’Amato et al. Int J Molecular Sciences 2020[3]Nugraha et al. Rheumatol Int 2012[4]Schmitt et al. Ann Med 2016[5]Melchior et al. Neuroscience 2016[6]Stefani et al. Neuroscience Letters 2012Disclosure of Interests:None declared


2020 ◽  
pp. 8-14
Author(s):  
R. M. Mallaeva ◽  
A. N. Makhinko ◽  
M. B. Uzdenov

The purpose of the study is to improve rehabilitation treatment of patients with chronic pancreatitis (CP) at inpatient stage by strengthening pharmacological potential of drug therapy due to inclusion of therapeutic physical factors (TPF) in therapeutic programs. Materials and methods. 159 patients with acute CP were observed. By simple randomization, 4 groups were formed: the control group (MG, 39 people) received standard drug therapy; 1st comparison group (GC1; 38 people) additionally received TPF; GC2 (40 people) in addition to treatment in GC1 had drinking mineral water «Slavyanovskaya»; in main group (42 people) in addition to the treatment in GC2 got preformed peloidotherapy on the cervical-collar zone. All the patients underwent the evaluation of clinical score and quality of life before and after medical rehabilitation. Results. In MG, clinical symptomatology leveling was by 78,2% (p<0,01), in GC1 — by 71,5% (p<0,01), GC2 — by 62,3% (p<0,01), CG — by 57,2% (p<0,01) on average immediately after the treatment, which was in a clear correlation with indicators of quality of life. In the long term (in 6 and 12 months), the advantage of combination therapy was noted with the same validity, the preservation of the achieved positive result was mostly noted in the MG: after 6 months the improvement in physical health compared to the initial values was noted by 34,4% (p<0,01), after 12 months — by 24,0% (p<0,05); mental — by 32,3% (p<0,01) and 22,5% (p<0,05), respectively. In both comparison groups, positive dynamics was 10–12% lower, and in the control group, after 6 months, there was only a tendency to improve quality of life indicators. Conclusion. The inclusion of TPF in the programs of the inpatient stage of medical rehabilitation of patients with chronic pancreatitis by strengthening the pharmacological potential of drug therapy contributes to the leveling of clinical manifestations (abdominal pain, dyspepsia and diarrhea), the result of which is an improvement in the quality of life of this category of patients.


2021 ◽  
Vol 26 (2) ◽  
pp. 163-169
Author(s):  
V. A. Gordeeva ◽  
I. V. Kulik ◽  
E. A. Khromova ◽  
A. L. Rubezhov ◽  
M. V. Gordeeva

Relevance. The paper demonstrates the need to implement modern diagnostic techniques for diagnosis of precancerous and cancerous lesions at early or preclinical stages. Additional diagnostic methods are necessary, e.g. tissue autofluorescence, which allows revealing insidious pathological risk zones, particularly precancerous and cancerous lesions, to evaluate the condition of the oral tissues in patients with chronic oral mucosa disorders, especially caused by trauma. Purpose – to assess trauma-specific effectiveness of autofluorescence spectroscopy (AFS) in risk group patients with chronic trauma of the oral mucosa to reveal early malignization signs.Materials and methods. 25 subjects were selected for the study and divided into 2 groups: main group – 20 patients with different manifestations of chronic oral mucosa trauma; control group – 5 subjects without visible clinical manifestations and without oral trauma factors. Autofluorescence spectroscopy was performed in both groups using AFS-400 stomatoscope.Results. The received data demonstrated that the change in autofluorescence doesn’t allow drawing final conclusions on the presence or absence of chronic oral trauma malignization signs.Conclusion. AFS-400 stomatoscope may be effective in differentiating between healthy and damaged tissues, but there is no solid evidence that the change in fluorescence shade can help differentiate between various types of damaged tissues. Autofluorescence spectroscopy should be considered as an additional method for examination of patients with chronic oral mucosa trauma to reveal early malignization signs.


2018 ◽  
pp. 79-86
Author(s):  
A.A. Sukhanova ◽  
◽  
M.Yu. Yegorov ◽  

The objective: to increase the effectiveness of treatment of patients with benign and borderline epithelial ovarian tumors (EOT) after conservative operations performed based on the definition of a high risk group for recurrence and malignancy according to the molecular expression profile of the markers p53, Ki-67, estrogen receptors (ER), CD34 and E-cadherin and inclusion in the complex anti-relapse therapy of the immunomodulating drug Glutoxim. Materials and methods. A clinical examination of 60 patients of reproductive age with EOT was performed, which were treated with organ-sparing surgical treatment (main group). Of these 60 patients, 30 women (subgroup I) were diagnosed with benign EOT (BEOT), the remaining 30 women (subgroup II) were diagnosed with borderline EOT (BoEOT) Ia and Ib stages in FIGO. In removed tumors after routine histopathological examination, the molecular profile was determined by immunohistochemically determining the protein regulator of apoptosis p53, proliferation index (PI) by Ki-67 expression, estrogen receptors — ER, microvessel density by CD34 expression and E-cadherin intercellular adhesion protein. Based on the molecular profile determination data, the removed tumor was ranked as high or low risk of recurrence and malignancy. Patients from the high-risk group for relapse and malignancy according to the molecular profile data included the immunomodulating drug Glutoxim in the complex anti-relapse therapy - intramuscularly 10 mg daily for 2 weeks with a course repeated every six months for 3 years. The control group consisted of 64 patients with BEOT and BoEOT, who underwent conservative surgical treatment without further anti-relapse treatment. Results. During the molecular profile study, it was found that high risk of recurrence and malignancy had EOT with p53 expression (LI ≥15%), high proliferative activity of cells with Ki-67 expression (PI ≥10%), low estrogen reception (LI ER < 49.5%), high density of microvessels on the expression of CD34 (IM ≥40 mv /mm2), low level of intercellular adhesion on the expression of E-cadherin (LI <59%). Molecular profile characterizing a high risk of recurrence and malignancy, in most cases was inherent in BoEOT. The purpose of a comprehensive anti-relapse treatment with the inclusion of the immunomodulatory drug Glutoxim (intramuscularly daily at 10 mg for 2 weeks) after performing of sparing conservative surgical treatment with a repetition of the course every six months in patients at high risk of relapse and malignancy according to molecular profile data has reduced the relapse of EOT to 6.7% in patients of the main group compared with 20.3% in the control group during three years of follow-up observation of patients. The difference is statistically significant (p <0.05). Conclusion. In order to prevent cases of recurrence and malignancy in patients with EOT at high risk of relapse and malignancy according to molecular profile data after a sparing surgical treatment that preserves their reproductive function, it is recommended that Glutoxim is administered in complex anti-relapse therapy at 10 mg intramuscularly per every day for 2 weeks with a repetition of the course every six months for 3 years. Key words: benign epithelial ovarian tumors, borderline epithelial ovarian tumors, high risks of recurrence and malignancy, anti-relapse therapy, reproductive function, Glutoxim.


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