AmyloGraph: a comprehensive database of amyloid-amyloid interactions.

Information about the impact of interactions between amyloid proteins on their fibrillization propensity is scattered among many experimental articles and presented in unstructured form. We manually curated information located in almost 200 publications (selected out of 562 initially considered), obtaining details of 883 experimentally studied interactions between 46 amyloid proteins or peptides. We also proposed a novel standardized terminology for the description of amyloid-amyloid interactions, which is included in our database, covering all currently known types of such a cross-talk, including inhibition of fibrillization, cross-seeding and other phenomena. The new approach allows for more specific studies on amyloids and their interactions, by providing very well-defined data. AmyloGraph, an online database presenting information on amyloid-amyloid interactions, is available at (http://AmyloGraph.com/). Its functionalities are also accessible as the R package (https://github.com/KotulskaLab/AmyloGraph). AmyloGraph is the only publicly available repository for experimentally determined amyloid-amyloid interactions.

New Oxazolo[5,4-d]pyrimidines as Potential Anticancer Agents: Their Design, Synthesis, and In Vitro Biological Activity Research.

Cancer is a large group of diseases in which the rapid proliferation of abnormal cells generally leads to metastasis to surrounding tissues or more distant ones through the lymphatic and blood vessels, making it the second leading cause of death worldwide. The main challenge in designing a modern anticancer therapy is to develop selective compounds that exploit specific molecular targets. In this work, novel oxazolo[5,4-d]pyrimidine derivatives were designed, synthesized, and evaluated in vitro for their cytotoxic activity against a panel of four human cancer cell lines (lung carcinoma: A549, breast adenocarcinoma: MCF7, metastatic colon adenocarcinoma: LoVo, primary colon adenocarcinoma: HT29), along with their P-glycoprotein-inhibitory ability and pro-apoptotic activity. These oxazolo[5,4-d]pyrimidine derivatives, which are structurally similar to nucleic purine bases in general, are characterized by the presence of a pharmacologically favorable isoxazole substituent at position 2 and aliphatic amino chains at position 7 of the condensed heterocyclic system. In silico analysis of the obtained compounds identified their potent inhibitory activity towards human vascular endothelial growth factor receptor-2 (VEGFR-2). Molecular docking was performed to assess the binding mode of new derivatives to the VEGFR-2 active site. Then, their physicochemical, pharmacokinetic, and pharmacological properties (i.e., ADME-administration, distribution, metabolism, and excretion) were also predicted to assess their druglikeness. In particular, compound 3g (with a 3-(N,N-dimethylamino)propyl substituent) was found to be the most potent against the HT29 cell line, with a 50% cytotoxic concentration (CC50) of 58.4 µM, exceeding the activity of fluorouracil (CC50 = 381.2 µM) and equaling the activity of cisplatin (CC50 = 47.2 µM), while being less toxic to healthy human cells (such as normal human dermal fibroblasts (NHDFs)) than these reference drugs. The results suggest that compound 3g is a potentially promising candidate for the treatment of primary colorectal cancer.

Investigation of the Properties of Linen Fibers and Dressings.

In antiquity, flax was used as a dressing for healing wounds. Currently, work is underway on the genetic modification of flax fibers to improve their properties. Genetic modifications have resulted in an increased content of antioxidants and more favorable mechanical properties. The works published so far have presented independent tests of fibers and dressings after appropriate technological treatments in cell cultures. This study aimed to compare the properties of the fibers and the dressing produced in cell cultures-hamster fibroblasts-V79. The research material was traditional NIKE fibers; genetically modified M, B, and MB fibers; and linen dressings obtained from these fibers. The extract from 48-h incubation of 40 mg of fiber in the culture medium, which was desolved into 10, 20, and 30 mg, was administered to the cell culture. On the other hand, a linen dressing was placed on cells with an area of 0.5 cm2, 1 cm2, 1.5 cm2, and 2 cm2. Cells with fiber or dressing were incubated for 48 h, and then, biological tests were performed, including cell viability (in propidium iodide staining), cell proliferation (in the SRB assay), evaluation of the intracellular free radical level (in the DCF-DA assay), genotoxicity (in the comet assay), assessment of the apoptotic and necrotic cells (in staining anexin-V and iodide propidium), the course of the cell cycle, and the scratch test. The correlation between apoptosis and genotoxicity and the levels of free radicals and genotoxicity were determined for the tested linen fibers and fabrics. The tests presented that the fibers are characterized by the ability to eliminate damaged cells in the elimination phase. However, the obtained fabrics gain different properties during the technological processing of the fibers into linen dressings. Linen fabrics have better regenerative properties for cells than fibers. The linseed dressing made of MB fiber has the most favorable regenerative properties.

The Role of the Microbiota-Gut-Brain Axis in the Development of Alzheimer's Disease.

Along with the increase in life expectancy in the populations of developed and developing countries resulting from better access and improved health care, the number of patients with dementia, including Alzheimer's disease (AD), is growing. The disease was first diagnosed and described at the beginning of the 20th century. However, to this day, there is no effective causal therapy, and symptomatic treatment often improves patients' quality of life only for a short time. The current pharmacological therapies are based mainly on the oldest hypotheses of the disease-cholinergic (drugs affecting the cholinergic system are available), the hypothesis of amyloid-ß aggregation (an anti-amyloid drug was conditionally approved by the FDA in 2020), and one drug is an N-methyl-D-aspartate receptor (NMDAR) antagonist (memantine). Hypotheses about AD pathogenesis focus on the nervous system and the brain. As research progresses, it has become known that AD can be caused by diseases that have been experienced over the course of a lifetime, which could also affect other organs. In this review, we focus on the potential association of AD with the digestive system, primarily the gut microbiota. The role of diet quality in preventing and alleviating Alzheimer's disease is also discussed. The problem of neuroinflammation, which may be the result of microbiota disorders, is also described. An important aspect of the work is the chapter on the treatment strategies for changing the microbiota, potentially protecting against the disease and alleviating its course in the initial stages.

Sanguinarine-Chelerythrine Fraction of Coptis chinensis Exerts Anti-inflammatory Activity in Carrageenan Paw Oedema Test in Rats and Reveals Reduced Gastrotoxicity.

Inflammatory diseases are a common therapeutic problem and nonsteroidal anti-inflammatory drugs are not deprived of side effects, of which ulcerogenic activity is one of the most frequent. The aim of the study was to evaluate the anti-inflammatory activity of the sanguinarine-chelerythrine (SC) fraction of Coptis chinensis and its influence on the integrity of gastric mucosa. The study was conducted on sixty male rats randomly divided into six experimental groups: two control groups (a negative control group CON and a positive control group CAR); three groups receiving an investigational fraction of C. chinensis (1, 5, 10 mg/kg i.g.) named SC1, SC5, and SC10, respectively; and a group receiving indomethacin (IND) (10 mg/kg i.g.) as a reference drug. In all animals, the carrageenan-induced paw oedema was measured; PGE2 release, TNFα production, and MMP-9 concentration in inflamed tissue were determined. Additionally, the macroscopic and microscopic damage of gastric mucosa was evaluated. Administration of SC dose-dependently inhibited the second phase of carrageenan rat paw oedema and PGE2 release, decreased the production of TNFα, and reduced the concentration of MMP-9, and the efficacy of the highest dose was comparable to the effect of IND. Contrary to IND, no gastrotoxic activity of SC was detected. The investigated sanguinarine-chelerythrine fraction of C. chinensis seems to be a promising candidate for further research on new anti-inflammatory and analgesic drugs characterized with a safer gastric profile compared to existing NSAIDs.

The Technological Process of Obtaining New Linen Dressings Did Not Cause the Loss of Their Wound-Healing Properties.

BACKGROUND: Linen dressings were invented a few years ago but are still being worked on. METHODS: The obtained fabrics from the traditional variety of flax (Nike), two transgenic types of flax (M50 and B14) and the combination of these two flax fibers (M50 + B14) were tested in direct contact in cell cultures. Cell viability tests were performed, and the proliferation potential of cells on Balb3T3 and NHEK cell lines was checked using the Sulforhodamine-B (SRB) test. Moreover, the effect of new linen fabrics on apoptosis of THP-1 cells, as well as on the cell cycle of NHEK, HMCEV and THP-1, cells after 24 h of incubation was assessed. RESULTS: All tested linen fabrics did not raise the number of necrotic cells. The tested fabrics caused a statistically significant decrease in the total protein content in skin cancer (except for 0.5 cm of Nike-type fabrics). The smallest cells in the apoptotic phase were in cultures treated with M50 fiber on an area of 0.5 cm. After 48 h of incubation of HEMVEC, NHEK and THP-1 cells with the tested fabrics, the growth of S-phase cells was noticed in all cases. At the same time, the greatest increase was observed with the use of B14 fabric. Necrosis is not statistically significant. CONCLUSIONS: All the obtained flax fibers in the form of flax dressings did not lose their wound-healing properties under the influence of the technological process. New dressings made of genetically modified flax are a chance to increase the effectiveness of treatment of difficult healing wounds.

Preclinical Study of Immunological Isoxazole Derivatives as a Potential Support for Melanoma Chemotherapy.

(1) Background: Melanoma is an aggressive neoplasm derived from melanocyte precursors with a high metastatic potential. Responses to chemotherapy and immunotherapy for melanoma remain weak, underlining the urgent need to develop new therapeutic strategies for the treatment of melanoma. (2) Methods: The viability of NHDF and A375 cell cultures after the administration of the tested isoxazole derivatives was assessed after 24-h and 48-h incubation periods with the test compounds in the MTT test. ROS and NO scavenging analyses, a glycoprotein-P activity analysis, a migration assay, a test of apoptosis, and a multiple-criteria decision analysis were also performed. (3) Results: All compounds that were tested resulted in a slower migration of melanoma neoplastic cells. The mechanism of the antitumor activity of the tested compounds was confirmed-i.e., the pro-apoptotic activity of the compounds in A375 cell cultures. Compound O7K qualified for further research. (4) Conclusions: All the tested compounds inhibited the formation of melanoma metastases and demonstrated the ability to reduce the risk of developing drug resistance in the tumor. The MCDA results showed that O7K showed the strongest antitumor activity.

Patients' Habits and the Role of Pharmacists and Telemedicine as Elements of a Modern Health Care System during the COVID-19 Pandemic.

Aims/Introduction: The Polish government introduced the epidemic on 20 March 2020, after The World Health Organization (WHO) announced the new coronavirus disease (COVID-19) in January 2020. Patients' access to specialist clinics and family medicine clinics was limited. In this situation, pharmacists were likely the first option for patient's health information. On 18 March 2020, the National Health Fund issued modifications that increased the accessibility to primary health care such as telemedicine. The development of e-health in Poland during the COVID-19 pandemic included the implementation of electronic medical records (EDM), telemedicine development, e-prescription, and e-referrals implementation. We investigated this emergency's effect on patients' health habits, access to healthcare, and attitude to vaccination. MATERIALS AND METHODS: An anonymous study in the form of an electronic and paper questionnaire was conducted in March 2021 among 926 pharmacies patients in Poland. The content of the questionnaire included access to medical care, performing preventive examinations, implementation of e-prescriptions, patient satisfaction with telepathing, pharmaceutical care, and COVID-19 vaccination. RESULTS: During the COVID-19 pandemic, 456 (49.2%) patients experienced worse access to a doctor. On the other hand, 483 (52.2%) patients did not perform preventive examinations during the COVID-19 pandemic. Almost half of the patients (45.4% (n = 420)) were not satisfied with the teleconsultation visit to the doctor. A total of 90% (n = 833) of the respondents do not need help in making an appointment with a doctor and buying medications prescribed by a doctor in the form of an e-prescription. In the absence of access to medical consultation, 38.2% (n = 354) of respondents choose the Internet as a source of medical advice. However, in the absence of contact with a doctor, 229 persons (24.7%) who took part in the survey consulted a pharmacist. In addition, 239 persons (25.8%) used pharmacist advice more often during the COVID-19 pandemic than before its outbreak on 12 March 2020. Moreover, 457 (49.4%) respondents are satisfied with the advice provided by pharmacists, and even 439 patients of pharmacies (47.4%) expect an increase in the scope of pharmaceutical care in the future, including medical advice provided by pharmacists. Most of the respondents, 45.6% (n = 422), want to be vaccinated in a hospital or clinic, but at the same time, for a slightly smaller number of people, 44.6% (n = 413), it has no meaning where they are will be vaccinated against COVID-19. CONCLUSIONS: Telemedicine is appreciated by patients but also has some limitations. The COVID-19 pandemic is the chance for telemedicine to transform from implementations to a routine healthcare system structure. However, some patients still need face-to-face contact with the doctor or pharmacist. Pharmacists are essential contributors to public health and play an essential role during the COVID-19 pandemic. Integration of pharmaceutical care with public health care and strong growth in the professional group of pharmacists may have optimized patient care.

Long-Term Administration of Abacavir and Etravirine Impairs Semen Quality and Alters Redox System and Bone Metabolism in Growing Male Wistar Rats.

Highly active antiretroviral therapy (HAART) is used in HIV-infected patients. Alongside the prolongation of patients' life, adverse side effects associated with long-term therapy are becoming an increasing problem. Therefore, optimizing of HAART is extremely important. The study is aimed at evaluating the toxicity of abacavir and etravirine in monotherapy on the reproductive system, liver, kidneys, and bones in young, sexually mature, male rats. Thirty-six 8-week-old male Wistar rats randomized into three 12-animal groups received either normal saline (control), abacavir 60 mg/kg (AB group), or etravirine 40 mg/kg (ET group) once daily for 16 weeks. Semen morphology, oxide-redox state parameters (MDA, SOD, catalase, GPx, glutathione, GSH/GSSG ratio) in tissue homogenates (testes, liver, kidneys), and serum samples were studied. In bones, microcomputed tomography and a four-point bending test were performed. Total sperm count, sperm concentration, motility, and sperm morphology did not differ significantly in AB or ET groups compared to the control. In the flow cytometry of semen, an increased percentage of cells with denatured DNA was noticed for both tested drugs. However, no significant changes of oxide-redox state in testicular homogenates were found, except of increased SOD activity in the AB-receiving group. Additionally, ET significantly altered catalase and GPx in the liver and SOD activity in kidneys. Abacavir decreased catalase in the liver and GSH levels in kidneys. AB caused significant changes to bone microarchitecture (bone volume fraction, trabecular number, connectivity density, total porosity) and increased Young's modulus. Etravirine had a greater impact on macrometric parameters of bones (tibial index, mid-tibial diameter, femur length). After 4 weeks in the ET group, a lower 1,25-dihydroxyvitamin D3 serum concentration was found. The results showed that abacavir and etravirine disturb oxidative stress. An increase in the percentage of sperms with chromatin damage suggests decreased fertility in rats receiving the studied drugs. Both drugs affected bone formation in growing rats. Additionally, etravirine disturbed vitamin D metabolism.

The Incidence and Severity of Post-Vaccination Reactions after Vaccination against COVID-19.

The pandemic of COVID-19 might be limited by vaccination. Society should be vaccinated to prevent the spread of coronavirus disease 2019 (COVID-19) and to protect persons who are at high risk for complications. In Poland, the National Vaccination Program has been introduced, which is a strategy for planning activities to ensure safe and effective vaccinations among Polish citizens. It includes not only the purchase of an appropriate number of vaccines, their distribution but also monitoring of the course and effectiveness of vaccination and the safety of Poles. The national COVID-19 immunization program has been divided into four stages. Stage 0 covers the healthcare workers to be vaccinated first, as they are most at risk of being infected with the coronavirus. The study aims to prove the thesis that GIS statistical data on the incidence of COVID-19 post-vaccination reactions should be verified, as patients do not report their occurrence through the procedure indicated by GIS. In March 2021, an anonymous questionnaire survey was conducted using an electronic questionnaire among persons belonging to group zero of the National Vaccination Program. The survey consisted of 19 short questions concerning, inter alia, getting COVID-19, post-vaccination reactions after receiving the first and second doses of the COVID-19 vaccine, and motivation to proceed with vaccination. A total of 1678 complete responses were received. It has been shown that only a small number of post-vaccination reactions are reported to the Sanitary Inspection, which makes GIS statistics on the incidence of post-vaccination reactions in COVID-19 unreliable. In addition, having earlier suffered from COVID-19 had an impact on the occurrence of more severe side effects after the first dose of the COVID-19 vaccine.

The N'-Substituted Derivatives of 5-Chloro-3-Methylisothiazole-4-Carboxylic Acid Hydrazide with Antiproliferative Activity.

Thanks to the progress in oncology, pharmacological treatment of cancer is gaining in importance and in the near future anti-cancer chemotherapeutics are expected to be the main method of treatment for cancer diseases. What is more, the search for new anti-cancer compounds with the desired application properties is constantly underway. As a result of designed syntheses, we obtained some new N'-substituted 5-chloro-3-methylisothiazole-4-carboxylic acid hydrazide derivatives with anticancer activity. The structure of new compounds was determined by mass spectrometry (MS), elemental analysis, proton nuclear magnetic resonance spectroscopy (1H-NMR), carbon nuclear magnetic resonance spectroscopy (13C-NMR), 1H-13C NMR correlations and infrared spectroscopy (IR). Moreover, the structures of the compounds were confirmed by crystallographic examination. The antiproliferative MTT tests for 11 prepared compounds was conducted towards human biphenotypic B cell myelomonocytic leukemia MV4-11. SRB test was used to examine their potential anticancer activity towards human colon adenocarcinoma cell lines sensitive LoVo, resistant to doxorubicin LoVo/DX, breast adenocarcinoma MCF-7 and normal non-tumorigenic epithelial cell line derived from mammary gland MCF-10A. The most active compound was 5-chloro-3-methyl-N'-[(1E,2E)-(3-phenyloprop-2-en-1-ylidene]isothiazole-4-carbohydrazide, which showed the highest antiproliferative activity against all tested cell lines.

The 5-hydrazino-3-methylisothiazole-4-carboxylic acid, its new 5-substituted derivatives and their antiproliferative activity.

Currently, the basic method of treatment of colon cancer is surgery. The range of anticancer drugs used in the treatment of colorectal cancer is small and is based mainly on systemic combination chemotherapy. As a result of the designed syntheses, we received new isothiazole derivatives with anticancer activity. The synthesized 5-hydrazino-3-methylisothiazole-4-carboxylic acid has never been obtained before. It is also a substrate for the synthesis of its innovative derivatives, i.e. compounds that are Schiff bases. The identification of the structure of new compounds was carried out using mass spectrometry (MS), proton nuclear magnetic resonance spectroscopy (1H NMR), carbon nuclear magnetic resonance spectroscopy (13C NMR) and infrared spectroscopy (IR). Potential antitumor activity was confirmed in antiproliferative MTT and SRB tests. The selected, most biologically active substances were characterized by high selectivity towards leukemia and colon cancer cell lines. They caused high inhibition of proliferation of human biphenotypic B cell myelomonocytic leukemia MV4-11 (13 compounds), human colon adenocarcinoma cell lines sensitive LoVo (8 compounds) and resistant to doxorubicin LoVo/DX (12 compounds). However, in the conducted studies, their activity against breast adenocarcinoma MCF-7 and normal non-tumorigenic epithelial cell line derived from mammary gland MCF-10A was substantially lower. The result of this work is claimed Polish patent application.

Effectiveness of screening for atrial fibrillation and its determinants. A meta-analysis.

BACKGROUND: Many atrial fibrillation patients eligible for oral anticoagulants are unaware of the presence of AF, and improved detection is necessary to facilitate thromboprophylaxis against stroke. OBJECTIVE: To assess the effectiveness of screening for AF compared to no screening and to compare efficacy outcomes of different screening strategies. MATERIALS AND METHODS: Cochrane Central Register of Controlled Trials, EMBASE and MEDLINE from Jan 1, 2000 -Dec 31, 2015 were searched. Studies employing systematic or opportunistic screening and using ECG or pulse palpation in populations age ≥40 years were included. Data describing study and patient characteristics and number of patients with new AF were extracted. The outcome was the incidence of previously undiagnosed AF. RESULTS: We identified 25 unique (3 RCTs and 22 observational) studies (n = 88 786) from 14 countries. The incidence of newly detected AF due to screening was 1.5% (95% CI 1.1 to 1.8%). Systematic screening was more effective than opportunistic: 1.8% (95% CI 1.4 to 2.3%) vs. 1.1% (95% CI 0.6 to 1.6%), p<0.05, GP-led screening than community based: 1.9% (95% CI 1.4 to 2.4%) vs. 1.1% (95% CI 0.7 to 1.6%), p<0.05, and repeated heart rhythm measurements than isolated assessments of rhythm: 2.1% (95% CI 1.5-2.8) vs. 1.2% (95% CI 0.8-1.6), p<0.05. Only heart rhythm measurement frequency had statistical significance in a multivariate meta-regression model (p<0.05). CONCLUSIONS: Active screening for AF, whether systematic or opportunistic, is effective beginning from 40 years of age. The organisation of screening process may be more important than technical solutions used for heart rhythm assessment.

Genetic polymorphism of ABCB1 gene (C3435T) in patients with inflammatory bowel diseases. Is there any gender dependency?

BACKGROUND: In recent years, an increasing incidence of inflammatory bowel disease (IBD) has been reported, mainly as Crohn's disease (CD) and ulcerative colitis (UC). The individual susceptibility, the disease's course and response to the applied therapy is likely due to genetic factors such as ABCB1 gene mutations, exemplified by C3435T polymorphism. The aim of the study was to evaluate the distribution of C3435T polymorphism regarding the gender in IBD patients and control subjects from Lower Silesia region and its possible association with IBD susceptibility. METHODS: The research was conducted in groups of 61 IBD patients and 101 healthy subjects from the Lower Silesia region. Polymorphism of C3435T was determined using PCR-RFLP method. RESULTS: Frequency distributions of C3435T genotype and of 3435T or 3435C gene alleles of IBD, CD or UC patients were compared to control group; each treated as a whole or split further by gender. The statistically significant correlation was discovered between gender and C3435T genotype both for IBD and CD patients, with 3435CT heterozygote prevailing in IBD and CD males. Odds ratio calculations revealed statistically significant difference for the 3435CT genotype between control and: IBD group considered as a whole; IBD males; CD males; and for 3435TT variant between control and IBD males. Conclusions. The 3435CT genotype could be a risk factor for IBD and CD in men. The 3435TT genotype in males seems to be associated with the lower chance of IBD presence.