Synergistic Antifungal Interactions between Antibiotic Amphotericin B and Selected 1,3,4-thiadiazole Derivatives, Determined by Microbiological, Cytochemical, and Molecular Spectroscopic Studies.

In recent years, drug-resistant and multidrug-resistant fungal strains have been more frequently isolated in clinical practice. This phenomenon is responsible for difficulties in the treatment of infections. Therefore, the development of new antifungal drugs is an extremely important challenge. Combinations of selected 1,3,4-thiadiazole derivatives with amphotericin B showing strong synergic antifungal interactions are promising candidates for such formulas. In the study, microbiological, cytochemical, and molecular spectroscopy methods were used to investigate the antifungal synergy mechanisms associated with the aforementioned combinations. The present results indicate that two derivatives, i.e., C1 and NTBD, demonstrate strong synergistic interactions with AmB against some Candida species. The ATR-FTIR analysis showed that yeasts treated with the C1 + AmB and NTBD + AmB compositions, compared with those treated with single compounds, exhibited more pronounced abnormalities in the biomolecular content, suggesting that the main mechanism of the synergistic antifungal activity of the compounds is related to a disturbance in cell wall integrity. The analysis of the electron absorption and fluorescence spectra revealed that the biophysical mechanism underlying the observed synergy is associated with disaggregation of AmB molecules induced by the 1,3,4-thiadiazole derivatives. Such observations suggest the possibility of the successful application of thiadiazole derivatives combined with AmB in the therapy of fungal infections.

Serum concentration of interleukin 6 is related to inflammation and dyslipidemia in patients with psoriasis.

INTRODUCTION: Patients with psoriasis and psoriatic arthritis (PsA) have metabolic disturbances, which may be due to chronic inflammation. AIM: Because interleukin-6 (IL-6) regulates both metabolic and inflammatory processes, we evaluated IL-6 as a potential marker of inflammation and metabolic disturbances in psoriasis. MATERIAL AND METHODS: This study involved 93 patients with psoriasis, including 31 patients with concurrent PsA. We investigated whether serum markers of lipid metabolism and inflammation, including IL-6, were related to each other and to disease activity. RESULTS: We found that concurrent PsA was associated with higher serum concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and IL-6. In patients with psoriasis alone, the IL-6 serum concentration correlated positively with the concentrations of TC and LDL-c and with erythrocyte sedimentation rates (ESRs). Moreover, IL-6 concentrations tended to correlate positively with the percentage of the body area affected by psoriatic lesions. Among all patients, those with normal blood lipids had lower ESRs and IL-6 concentrations than patients with abnormal blood lipids. A logistic regression model showed that PsA, Psoriasis Area Severity Index (PASI), and ESR were significant predictors of the serum IL-6 concentration. CONCLUSIONS: Interleukin-6 may be an indicator of inflammatory activity in psoriasis. Moreover, IL-6 may be related to lipid abnormalities in patients with this disease.

The effect of statins on psoriasis severity: a meta-analysis of randomized clinical trials.

INTRODUCTION: Statins may reduce the severity of psoriasis, but the available evidence is unclear. We conducted a meta-analysis of randomized controlled studies (RCTs) that investigated the effect of statins on psoriasis severity assessed with the Psoriasis Area and Severity Index (PASI). MATERIAL AND METHODS: Two investigators searched independently the following databases: Medline, EMBASE, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov from inception to February 2019. Additionally, reference lists from all available articles were searched manually. We included only RCTs carried out among adult (≥ 16 years) patients with psoriasis who received oral statins for ≥ 8 weeks and had psoriasis severity assessed with the PASI at baseline and at the end of follow-up. We used random effects meta-analysis to calculate the mean difference (D) in PASI change between patients who received either a statin or a comparator. RESULTS: Of 279 records identified, there were 5 eligible RCTs, with a total of 223 patients, including 128 patients who received a statin (atorvastatin or simvastatin). The improvement in psoriasis severity (PASI) was significantly greater in patients who received statins than in those who received comparators (D = 2.76, 95% CI: 0.49-5.04, p = 0.017). In subgroup analyses, the improvement in PASI values was significant for simvastatin (D = 3.70, 95% CI: 2.52-4.89, p < 0.001) but not for atorvastatin (D = 2.30, 95% CI: -1.28-5.88, p = 0.210). CONCLUSIONS: Oral statins may improve psoriasis, particularly in patients with severe disease. This observation should be verified in long-term, well-designed studies that will enable analyses adjusted for clinical variables.

Antifungal effects of a 1,3,4-thiadiazole derivative determined by cytochemical and vibrational spectroscopic studies.

Compounds belonging to the group of 5-substituted 4-(1,3,4-thiadiazol-2-yl) benzene-1,3-diols exhibit a broad spectrum of biological activity, including antibacterial, antifungal, and anticancer properties. The mechanism of the antifungal activity of compounds from this group has not been described to date. Among the large group of 5-substituted 4-(1,3,4-thiadiazol-2-yl) benzene-1,3-diol derivatives, the compound 4-(5-methyl-1,3,4-thiadiazole-2-yl) benzene-1,3-diol, abbreviated as C1, was revealed to be one of the most active agents against pathogenic fungi, simultaneously with the lowest toxicity to human cells. The C1 compound is a potent antifungal agent against different Candida species, including isolates resistant to azoles, and molds, with MIC100 values ranging from 8 to 96 µg/ml. The antifungal activity of the C1 compound involves disruption of the cell wall biogenesis, as evidenced by the inability of cells treated with C1 to maintain their characteristic cell shape, increase in size, form giant cells and flocculate. C1-treated cells were also unable to withstand internal turgor pressure causing protoplast material to leak out, exhibited reduced osmotic resistance and formed buds that were not covered with chitin. Disturbances in the chitin septum in the neck region of budding cells was observed, as well as an uneven distribution of chitin and ß(1→3) glucan, and increased sensitivity to substances interacting with wall polymerization. The ATR-FTIR spectral shifts in cell walls extracted from C. albicans cells treated with the C1 compound suggested weakened interactions between the molecules of ß(1→3) glucans and ß(1→6) glucans, which may be the cause of impaired cell wall integrity. Significant spectral changes in the C1-treated cells were also observed in bands characteristic for chitin. The C1 compound did not affect the ergosterol content in Candida cells. Given the low cytotoxicity of the C1 compound to normal human dermal fibroblasts (NHDF), it is possible to use this compound as a therapeutic agent in the treatment of surface and gastrointestinal tract mycoses.

Synergistic antifungal interactions of amphotericin B with 4-(5-methyl-1,3,4-thiadiazole-2-yl) benzene-1,3-diol.

Amphotericin B (AmB) is a very potent antifungal drug with very rare resistance among clinical isolates. Treatment with the AmB formulations available currently is associated with severe side effects. A promising strategy to minimize the toxicity of AmB is reducing its dose by combination therapy with other antifungals, showing synergistic interactions. Therefore, substances that display synergistic interactions with AmB are still being searched for. Screening tests carried out on several dozen of synthetic 1,3,4-thiadiazole derivatives allowed selection of a compound called 4-(5-methyl-1,3,4-thiadiazole-2-yl) benzene-1,3-diol (abbreviated as C1), which shows strong synergistic interaction with AmB and low toxicity towards human cells. The aim of the present study was to investigate the type of in vitro antifungal interactions of the C1 compound with AmB against fungal clinical isolates differing in susceptibility. The results presented in the present paper indicate that the C1 derivative shows strong synergistic interaction with AmB, which allows the use of a dozen to several dozen times lower AmB concentration necessary for 100% inhibition of the growth of pathogenic fungi in vitro. Synergistic interactions were noted for all tested strains, including strains with reduced sensitivity to AmB and azole-resistant isolates. These observations give hope for the possibility of application of the AmB - C1 combinatory therapy in the treatment of fungal infections.

Serum concentrations of interleukin 18 and 25-hydroxyvitamin D3 correlate with depression severity in men with psoriasis.

OBJECTIVE: Psoriasis and depression may have common mechanisms, such as systemic inflammation, dysfunction of the hypothalamic-pituitary-adrenal axis, and vitamin D3 deficiency. Among men with psoriasis, this study examined whether depression severity was associated with serum concentrations of different metabolic and inflammatory markers. METHODS: The study included 85 men with psoriasis (mean age ± standard deviation [SD], 47 ± 14 years) and 65 men without psoriasis (mean age ± SD, 44 ± 13 years). In both groups, we measured the body mass index; blood pressure; and serum concentrations of lipids, uric acid, lipase, interleukins 6 and 18, cortisol, and 25-hydroxyvitamin D3. All participants completed the Beck Depression Inventory. Other variables analyzed included psoriasis duration, the Psoriasis Area Severity Index, and the percentage of body surface area affected by psoriatic lesions. RESULTS: Compared with controls, patients with psoriasis had significantly greater depression severity, higher body mass indices, and higher serum concentrations of total cholesterol and interleukins 6 and 18; moreover, they had significantly lower serum 25-hydroxyvitamin D3 concentrations. In patients with psoriasis, depression severity correlated positively with psoriasis duration, the Psoriasis Area Severity Index, the percentage of body surface area affected by psoriatic lesions, and interleukin-18 concentration. In patients with psoriasis, depression severity correlated negatively with 25-hydroxyvitamin D3 concentration, but it did not correlate significantly with the serum concentrations of interleukin 6 and cortisol. CONCLUSIONS: High concentrations of interleukin 18 and low concentrations of 25-hydroxyvitamin D3 may be associated with depression severity in men with psoriasis. Thus, further studies should examine whether effective anti-inflammatory treatments or vitamin D3 supplementation can improve depression outcomes in these patients.

Correction to: Digestive system in psoriasis: an update.

In the original publication, the data labels are incorrect in Fig. 3. The corrected Fig. 3 is given here.

Digestive system in psoriasis: an update.

Psoriasis is a chronic inflammatory immune-mediated disorder associated and often coexisting with many other immune-related clinical conditions including those affecting the gastrointestinal tract. Data obtained from the reviewed literature suggest an association between psoriasis and pathologies of the oral cavity, both psoriasis-specific lesions, as well as non-specific, such as geographic tongue or fissured tongue. These findings show the importance of thorough examination of oral mucosa in psoriatic patients. Inflammatory bowel diseases (IBD) are also linked with psoriasis. Crohn's disease and ulcerative colitis share a common genetic background, inflammatory pathways and have an evident iatrogenic anti-TNF treatment link, necessitating dermatological or gastroenterological care in patients with IBD or psoriasis, respectively, as well as treatment adjusted to manifestations. The presence of celiac disease-specific antibodies in psoriatic patients and their correlation with the severity of the disease show the association between these disorders. The linking pathogenesis comprises vitamin D deficiency, immune pathway, genetic background and increase in the intestinal permeability, which suggests a potential benefit from gluten-free diet among psoriatic patients. The link between psoriasis and non-alcoholic fatty liver disease implies screening patients for components of metabolic syndrome and lifestyle changes necessity. Some studies indicate increased prevalence of cancer in patients with psoriasis, probably due to negative influence of skin lesion impact on lifestyle rather than the role of psoriasis in carcinogenesis. However, there are no sufficient data to exclude such an oncogenic hit, which is yet to be confirmed. Therefore, all psoriasis-associated comorbidities establish the importance of a multidisciplinary approach in the treatment of these patients.

Depressiveness, measured with Beck Depression Inventory, in patients with psoriasis.

BACKGROUND: The aim of this study was to identify demographic and clinical factors predisposing to depressiveness during the course of psoriasis. METHOD: The study included 239 patients with psoriasis (15-76 years, 31.8% of women) and 123 healthy controls (17-74 years, 32.5% of women). Dependent variable in the analysis was Beck Depression Inventory (BDI) score. Explanatory variables included: age, sex, marital status, education, occupational activity, body mass index (BMI), systolic and diastolic blood pressure, history of smoking, average number of smoked cigarettes, skin lesions visible to others, comorbidities, including arterial hypertension and arthritis, number of previous hospitalizations and family history of psoriasis. RESULTS: Psoriatics showed higher BDI scores than the controls, and significantly more often presented with depressiveness. Depressiveness correlated with psoriasis, older age, female sex, lack of higher education, occupational inactivity, higher BMI, visible skin lesions, comorbidities, including arterial hypertension and arthritis, greater number of previous hospitalizations and lack of family history of psoriasis. Multivariate analysis showed than independent predictors of any grade depressiveness were psoriasis (OR=2.26, 95%CI: 1.11-4.60, p=0.024), older age (OR=1.03, 95%CI: 1.01-1.05, p=0.005) and female sex (OR=2.73, 95%CI: 1.45-5.12, p=0.002). LIMITATIONS: Cross-sectional, non-prospective analysis. Selection bias. CONCLUSIONS: Patients with psoriasis, irrespective of its severity and related complications, are at increased risk of depressiveness. The risk of secondary depressiveness is particularly high in psoriatic women and older persons (or individuals diagnosed with psoriasis at younger age). Individuals from this group should be monitored for potential depressive symptoms.