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•New steroidal lactones with modifications in positions C5 and C6 were synthesized.•Compounds were tested on six tumor cell lines for their cytotoxic properties.•Compounds were ...evaluated for affinity to the ligand binding domains of ERα/β or AR.•The most active compounds were studied for their apoptosis-induction potential.•Molecular docking predicts binding of polyhydroxy compound to EGFR tyrosine kinase.
A series of 5,6-modified steroidal d-homo lactones, comprising of halogenated and/or oxygenated derivatives, was synthesized and evaluated for potential anticancer properties. Preparation of many of these compounds involved investigating alternative synthetic pathways. In silico ADME testing was performed for both novel and some previously synthesized compounds. Calculated physicochemical properties were in accordance with the Lipinski, Veber, Egan, Ghose and Muegge criteria, suggesting the potential of these molecules as orally active agents. Cytotoxicity of the synthesized steroid derivatives was tested on six tumor and one normal human cell line. None of the investigated derivatives was toxic to non-cancerous MRC-5 control cells. Most of the compounds showed significant cytotoxicity against the treated cancer cell lines. Most notably, the 3β,5α,6β-trihydroxy derivative exhibited strong cytotoxicity against multiple cell lines (MCF-7, MDA-MB-231 and HT-29), with the highest effect observed for lung adenocarcinoma (A549) cells, for which this steroid was more cytotoxic than all of the three commercial chemotherapeutic agents used as reference compounds. Molecular docking suggests the 3β,5α,6β-trihydroxy derivative could bind the EGFR tyrosine kinase domain with high affinity, providing a potential mechanism for its cytotoxicity via inhibition of EGFR signaling. The most active compounds were further studied for their potential to induce apoptosis by the double-staining fluorescence method; where the 5α,6β-dibromide, 5α,6β-dichloride and 3β,5α,6β-triol induced apoptotic changes in all three treated cell lines: MDA-MB-231, HT-29 and A549. To predict interactions with nuclear steroidal receptors, affinity for the ligand binding domains of ERα, ERβ and AR was measured using a yeast-based fluorescence assay. The 5β,6β-epoxide, dibromide and 5α-hydroxy-3,6-dioxo derivatives showed affinity for ERα, while the 5α-fluoro-6β-hydroxy and 3β-acetoxy-5α,6β-dihydroxy derivatives were identified as ERβ ligands. None of the tested compounds showed affinity for AR. Structure-activity relationships of selected compounds were also examined.
This article provides an overview of how sleep and circadian rhythm disturbances mutually influence the occurrence of dental caries and how it is possible to reduce the risk of circadian rhythm ...disturbances, sleep, and associated adverse effects. Dental caries is a global problem worldwide that contributes to sociological limitations. Numerous factors influence the occurrence of dental caries, from socioeconomic factors to cariogenic bacteria, dietary habits, and oral hygiene. However, sleep disorders and circadian rhythm disturbances represent a new approach in the fight against the increasing prevalence of dental caries worldwide. Bacteria in the oral cavity and the oral microbiome are mainly responsible for the development of caries, and saliva plays an important role in their regulation. The circadian rhythm regulates numerous physiological functions, including sleep and saliva production. Disturbances in sleep and circadian rhythms affect saliva production, which impacts the development of dental caries, as saliva is necessary for regulating and maintaining oral health, especially for controlling oral infections. A person's preference for a particular time of day depends on the circadian rhythm called chronotype. Individuals with an evening chronotype have a less healthy lifestyle that can lead to a higher caries risk than individuals with a morning chronotype. Because circadian rhythms are critical to maintaining sleep homeostasis and oral health, sleep disturbances can disrupt circadian rhythms and lead to a vicious cycle.
Radioactivity is a process in which the nuclei of unstable atoms spontaneously decay, producing other nuclei and releasing energy in the form of ionizing radiation in the form of alpha (α) and beta ...(β) particles as well as the emission of gamma (γ) electromagnetic waves. People may be exposed to radiation in various forms, as casualties of nuclear accidents, workers in power plants, or while working and using different radiation sources in medicine and health care. Acute radiation syndrome (ARS) occurs in subjects exposed to a very high dose of radiation in a very short period of time. Each form of radiation has a unique pathophysiological effect. Unfortunately, higher organisms-human beings-in the course of evolution have not acquired receptors for the direct "capture" of radiation energy, which is transferred at the level of DNA, cells, tissues, and organs. Radiation in biological systems depends on the amount of absorbed energy and its spatial distribution, particularly depending on the linear energy transfer (LET). Photon radiation with low LET leads to homogeneous energy deposition in the entire tissue volume. On the other hand, radiation with a high LET produces a fast Bragg peak, which generates a low input dose, whereby the penetration depth into the tissue increases with the radiation energy. The consequences are mutations, apoptosis, the development of cancer, and cell death. The most sensitive cells are those that divide intensively-bone marrow cells, digestive tract cells, reproductive cells, and skin cells. The health care system and the public should raise awareness of the consequences of ionizing radiation. Therefore, our aim is to identify the consequences of ARS taking into account radiation damage to the respiratory system, nervous system, hematopoietic system, gastrointestinal tract, and skin.
Abstract
A 6-year-old boy was referred to a hematologist due to excessive mucocutaneous bleeding. Diagnostic assessment for von Willebrand disease (VWD) was indicated and included both coagulation ...and genetic testing. Laboratory testing revealed proportionally decreased von Willebrand factor (VWF) glycoprotein Ib-binding activity (23.6%) compared to VWF antigen (24.7%), similarly decreased VWF collagen-binding activity (24.2%), and normally distributed VWF multimers, with decreased intensity of all fractions. Diagnosis of type 1 VWD was established. Genetic analysis by means of next-generation sequencing (NGS) of VWF and coagulation factor VIII genes did not identify any causative mutations. Additionally, multiplex ligation-dependent probe amplification (MLPA) of VWF gene exons revealed a heterozygous deletion of exons 1 to 6, which is reported in type 1 VWD for the first time. Application of MLPA was crucial for revealing the genetic basis of type 1 VWD in this case, which would have remained undetected if only NGS was used.
This study reevaluated von Willebrand disease (vWD) diagnosis in a Croatian paediatric cohort by combining bleeding scores (BS), phenotypic laboratory testing, and next-generation sequencing (NGS).
A ...total of 25 children (11 males and 14 females, median age 10 years, from 2 to 17) previously diagnosed with vWD were included. BS were calculated using an online bleeding assessment tool. Phenotypic laboratory analyses included platelet count, platelet function analyser closure times, prothrombin time, activated partial thromboplastin time, von Willebrand factor antigen (vWF:Ag), vWF gain-of-function mutant glycoprotein Ib binding activity (vWF:GPIbM), vWF collagen binding activity (vWF:CBA), factor VIII activity (FVIII:C) and multimeric analysis. Next-generation sequencing covered regions of both vWF and FVIII genes and was performed on MiSeq (Illumina, San Diego, USA).
Disease-associated variants identified in 15 patients comprised 11 distinct heterozygous vWF gene variants in 13 patients and one novel FVIII gene variant (p.Glu2085Lys) in two male siblings. Four vWF variants were novel (p.Gln499Pro, p.Asp1277Tyr, p.Asp1277His, p.Lys1491Glu). Three patients without distinctive variants had vWF:GPIbM between 30 and 50%. Patients with identified vWF gene variants had statistically significant lower values of vWF:GPIbM (P = 0.002), vWF:Ag (P = 0.007), vWF:CBA (P < 0.001) and FVIII:C (P = 0.002), compared to those without. Correlations between BS and phenotypic laboratory test results were not statistically significant for either of the tests.
The applied diagnostic approach confirmed the diagnosis of vWD in 13 patients and mild haemophilia A in two. Limited utility of BS in the paediatric population was evidenced.
Atopic dermatitis is the most common chronic inflammatory skin disease. It is often the first indicator of allergic diseases, and a certain percentage of patients are affected by allergic rhinitis ...and/or asthma as a consequence. The study aimed to investigate the link between atopic dermatitis and comorbidity in family medicine. In the specialist family medicine practice Osijek, a retrospective study was conducted in the period from January 1, 2016 to July 1, 2017 on the percentage of patients with atopic dermatitis in the total number of patients, and their comorbid diseases. The data source was the E-chart. The results showed that 195 (10.53%) out of 2056 patients had atopic dermatitis, 80 (41%) patients had atopic dermatitis and allergic rhinitis, 34 (17.4%) asthma, 132 (67.7%) infections, 59 (30.3%) gastrointestinal disturbances, and 68 (34.3%) had mental disorders. Patients up to 18 years old were more likely to have infections, and adult patients were exposed to chronic stress. The most commonly used drug was loratadine (60.5%), while mometasone was the most commonly administered topical drug (40%). The result of this research showed the steps of the ˝atopic march˝. Atopic dermatitis is followed by changes in the skin and its progression to other organ systems in most of the patients.
is a commensal fungal species that commonly colonizes the human body, but it is also a pervasive opportunistic pathogen in patients with malignant diseases. A growing body of evidence suggests that ...this fungus is not only coincidental in oncology patients, but may also play an active role in the development of cancer. More specifically, several studies have investigated the potential association between
and various types of cancer, including oral, esophageal, and colorectal cancer, with a possible role of this species in skin cancer as well. The proposed mechanisms include the production of carcinogenic metabolites, modulation of the immune response, changes in cell morphology, microbiome alterations, biofilm production, the activation of oncogenic signaling pathways, and the induction of chronic inflammation. These mechanisms may act together or independently to promote cancer development. Although more research is needed to fully grasp the potential role of
in carcinogenesis, the available evidence suggests that this species may be an active contributor and underscores the importance of considering the impact of the human microbiome on cancer pathogenesis. In this narrative review, we aimed to summarize the current state of evidence and offer some insights into proposed mechanisms.
The epidemiology of bacterial pathogens causing bloodstream infections (BSIs) in pediatric hematology/oncology patients is changing and resistance to antimicrobial agents is globally spread. We ...retrospectively assessed demographic, clinical, and microbiologic data of BSIs during a 5-year period at a pediatric hematology/oncology unit from January 1, 2017, to December 31, 2021, at the University Hospital Centre Zagreb, Zagreb, Croatia. In 66 pediatric patients with malignancies, 93 BSI episodes were registered and 97 bacterial isolates were cultured. The Gram-positive versus Gram-negative ratio was 67 (69.1%) versus 30 (30.9%). Coagulase-negative staphylococci (48; 49.6%) were the most frequent isolates, followed by Enterobacterales (17; 17.5%) and Staphylococcus aureus (6; 6.2%). Multidrug resistance isolates included extended spectrum β-lactamase producers (n=3). Resistance rates to piperacillin/tazobactam, cefepime, and meropenem in Gram-negative isolates were 15.4%, 14.3%, and 0.0%, respectively. Gram-positive bacteria are the most common cause of BSI in our patients. Resistance rates to piperacillin/tazobactam and cefepime in Gram-negative isolates make meropenem a better choice for empirical antimicrobial treatment. As national and hospital data may differ, the surveillance of pathogen distribution and antimicrobial susceptibility in pediatric hematology/oncology wards is necessary to adjust empirical treatment accordingly.
From Bacteriophage to Antibiotics and Back Talapko, Jasminka; Škrlec, Ivana; Alebić, Tamara ...
Collegium antropologicum,
2018, Letnik:
42, Številka:
2
Journal Article, Book Review
Recenzirano
Odprti dostop
Life is a phenomenon, and evolution has given it countless forms and possibilities of survival and formation. Today, almost all relationship mechanisms between humans who are at the top of the ...evolutionary ladder, and microorganisms which are at its bottom are known. Preserving health or life is not just an instinctive response to threat anymore; rather it is a deliberate action and use of knowledge. During major epidemics and wars which create great suffering, experiences of the man-disease (cause) relationships were examined, so we can note the use of bacteriophages in Poland and Russia before and during the Second World War, while almost at the same time antibiotic therapy was introduced. Since bacteriophages “tracked” the evolution of bacteria, the mechanism of their action lies in the prokaryotic cell, and it is not dangerous for the eukaryotic cell of human parenchyma. It is, therefore, necessary only to reuse these experiences nowadays when we are convinced that bacteria have an inexhaustible genetic and phenotypic resistance mechanism of their own. Antibiotics continue to represent the foundation of health preservation, but now they work together with specific viruses – bacteriophages that we can produce and apply in the context of multi-resistance, as well as for the preparation of new pharmacological preparations. This new approach promises knowledge and possibilities for a new antibiotic-bacteriophage model.
Candida albicans is a commensal fungal species that commonly colonizes the human body, but it is also a pervasive opportunistic pathogen in patients with malignant diseases. A growing body of ...evidence suggests that this fungus is not only coincidental in oncology patients, but may also play an active role in the development of cancer. More specifically, several studies have investigated the potential association between C. albicans and various types of cancer, including oral, esophageal, and colorectal cancer, with a possible role of this species in skin cancer as well. The proposed mechanisms include the production of carcinogenic metabolites, modulation of the immune response, changes in cell morphology, microbiome alterations, biofilm production, the activation of oncogenic signaling pathways, and the induction of chronic inflammation. These mechanisms may act together or independently to promote cancer development. Although more research is needed to fully grasp the potential role of C. albicans in carcinogenesis, the available evidence suggests that this species may be an active contributor and underscores the importance of considering the impact of the human microbiome on cancer pathogenesis. In this narrative review, we aimed to summarize the current state of evidence and offer some insights into proposed mechanisms.
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