The Role of TNF-α and Anti-TNF-α Agents during Preconception,Pregnancy, and Breastfeeding

Tumor necrosis factor-alpha (TNF-α) is a multifunctional Th1 cytokine and one of the most important inflammatory cytokines. In pregnancy, TNF-α influences hormone synthesis, placental architecture, and embryonic development. It was also shown that increased levels of TNF-α are associated with pregnancy loss and preeclampsia. Increased TNF-α levels in complicated pregnancy draw attention to trophoblast biology, especially migratory activity, syncytialisation, and endocrine function. Additionally, elevated TNF-α levels may affect the maternal-fetal relationship by altering the secretory profile of placental immunomodulatory factors, which in turn affects maternal immune cells. There is growing evidence that metabolic/pro-inflammatory cytokines can program early placental functions and growth in the first trimester of pregnancy. Furthermore, early pregnancy placenta has a direct impact on fetal development and maternal immune system diseases that release inflammatory (e.g., TNF-α) and immunomodulatory factors, such as chronic inflammatory rheumatic, gastroenterological, or dermatological diseases, and may result in an abnormal release of cytokines and chemokines in syncytiotrophoblasts. Pregnancy poses a challenge in the treatment of chronic disease in patients who plan to have children. The activity of the disease, the impact of pregnancy on the course of the disease, and the safety of pharmacotherapy, including anti-rheumatic agents, in pregnancy should be considered.     

Recent Advances in Preclinical Research Using PAMAM Dendrimers for Cancer Gene Therapy

Carriers of genetic material are divided into vectors of viral and non-viral origin. Viral carriers are already successfully used in experimental gene therapies, but despite advantages such as their high transfection efficiency and the wide knowledge of their practical potential, the remaining disadvantages, namely, their low capacity and complex manufacturing process, based on biological systems, are major limitations prior to their broad implementation in the clinical setting. The application of non-viral carriers in gene therapy is one of the available approaches. Poly(amidoamine) (PAMAM) dendrimers are repetitively branched, three-dimensional molecules, made of amide and amine subunits, possessing unique physiochemical properties. Surface and internal modifications improve their physicochemical properties, enabling the increase in cellular specificity and transfection efficiency and a reduction in cytotoxicity toward healthy cells. During the last 10 years of research on PAMAM dendrimers, three modification strategies have commonly been used: (1) surface modification with functional groups; (2) hybrid vector formation; (3) creation of supramolecular self-assemblies. This review describes and summarizes recent studies exploring the development of PAMAM dendrimers in anticancer gene therapies, evaluating the advantages and disadvantages of the modification approaches and the nanomedicine regulatory issues preventing their translation into the clinical setting, and highlighting important areas for further development and possible steps that seem promising in terms of development of PAMAM as a carrier of genetic material.     

Gouda Cheese with Modified Content of β-Casein as a Source of Peptides with ACE- and DPP-IV-Inhibiting Bioactivity: A Study Based on In Silico and In Vitro Protocol

In silico and in vitro methods were used to analyze ACE- and DPP-IV-inhibiting potential of Gouda cheese with a modified content of β-casein. Firstly, the BIOPEP-UWM database was used to predict the presence of ACE and DPP-IV inhibitors in casein sequences. Then, the following Gouda cheeses were produced: with decreased, increased, and normative content of β-casein after 1 and 60 days of ripening each (six variants in total). Finally, determination of the ACE/DPP-IV-inhibitory activity and the identification of peptides in respective Gouda-derived water-soluble extracts were carried out. The identification analyses were supported with in silico calculations, i.e., heatmaps and quantitative parameters. All Gouda variants exhibited comparable ACE inhibition, whereas DPP-IV inhibition was more diversified among the samples. The samples derived from Gouda with the increased content of β-casein (both stages of ripening) had the highest DPP-IV-inhibiting potency compared to the same samples measured for ACE inhibition. Regardless of the results concerning ACE and DPP-IV inhibition among the cheese samples, the heatmap showed that the latter bioactivity was predominant in all Gouda variants, presumably because it was based on the qualitative approach (i.e., peptide presence in the sample). Our heatmap did not include the bioactivity of a single peptide as well as its quantity in the sample. In turn, the quantitative parameters showed that the best sources of ACE/DPP-IV inhibitors were all Gouda-derived extracts obtained after 60 days of the ripening. Although our protocol was efficient in showing some regularities among Gouda cheese variants, in vivo studies are recommended for more extensive investigations of this subject.     

Combinations of Piperine with Hydroxypropyl-β-Cyclodextrin as a Multifunctional System

Piperine is an alkaloid that has extensive pharmacological activity and impacts other active substances bioavailability due to inhibition of CYP450 enzymes, stimulation of amino acid transporters and P-glycoprotein inhibition. Low solubility and the associated low bioavailability of piperine limit its potential. The combination of piperine with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) causes a significant increase in its solubility and, consequently, an increase in permeability through gastrointestinal tract membranes and the blood–brain barrier. X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR) were used to characterize interactions between piperine and HP-β-CD. The observed physicochemical changes should be combined with the process of piperine and CD system formation. Importantly, with an increase in solubility and permeability of piperine as a result of interaction with CD, it was proven to maintain its biological activity concerning the antioxidant potential (2,2-diphenyl-1-picryl-hydrazyl-hydrate assay), inhibition of enzymes essential for the inflammatory process and for neurodegenerative changes (hyaluronidase, acetylcholinesterase, butyrylcholinesterase).     

Radiation- and Photo-Induced Oxidation Pathways of Methionine in Model Peptide Backbone under Anoxic Conditions

Within the reactive oxygen species (ROS) generated by cellular metabolisms, hydroxyl radicals (HO^•) play an important role, being the most aggressive towards biomolecules. The reactions of HO^• with methionine residues (Met) in peptides and proteins have been intensively studied, but some fundamental aspects remain unsolved. In the present study we examined the biomimetic model made of Ac-Met-OMe, as the simplest model peptide backbone, and of HO^• generated by ionizing radiation in aqueous solutions under anoxic conditions. We performed the identification and quantification of transient species by pulse radiolysis and of final products by LC-MS and high-resolution MS/MS after γ-radiolysis. By parallel photochemical experiments, using 3-carboxybenzophenone (CB) triplet with the model peptide, we compared the outcomes in terms of short-lived intermediates and stable product identification. The result is a detailed mechanistic scheme of Met oxidation by HO^•, and by CB triplets allowed for assigning transient species to the pathways of products formation.     

Nephrotoxicity as a Complication of Chemotherapy and Immunotherapy in the Treatment of Colorectal Cancer,Melanoma and Non-Small Cell Lung Cancer

Acute kidney injury is a common complication of many medical procedures, including those used in cancer treatment. Both chemotherapy and immunotherapy may result in deterioration of kidney function, which may lead to an increase in mortality among patients with cancer. Antineoplastic agents can affect any element of the nephron, leading to the appearance of clinical symptoms such as proteinuria, hypertension, electrolyte disorders, glomerulonephritis, acute and chronic interstitial nephritis and acute kidney injury. The medical literature describing renal complications occurring during chemotherapeutic and immunotherapeutic treatment in neoplasms, such as colorectal cancer, non-small cell lung cancer and melanoma, was analysed. The immune system plays an important role in controlling the development of neoplasms and fighting them. Oncological treatment algorithms include immunotherapy as monotherapy, combined with chemotherapy or chemotherapy as monotherapy. In the treatment of the above-mentioned neoplasms immunotherapeutics are used, such as checkpoint inhibitors (CPI) (i.e., ipilimumab, pembrolizumab, nivolumab, atezolizumab), vascular endothelial growth factor (VEGF) inhibitors (i.e., bevacizumab, ramucirumab) and a variety of chemotherapeutic agents (irinotecan, capecitabine, oxaliplatin, gefitinib, erlotinib, gemcitabine, cisplatin, paclitaxel, carboplatin, doclitaxel, vinorelbine, topotecan, etoposide). In our article, we focused on the number and type of renal complications as well as on the time of their manifestation when using specific treatment regimens. Our analysis also includes case reports. We discussed treatment of immunological complications and adjustments of the dose of chemotherapeutic agents depending on the creatinine clearance. Analysing the data from the literature, when two immunotherapeutic agents are used together, the number of recorded renal complications increases. Bevacizumab and ramucirumab are the cause of the largest number of renal complications among the immunotherapeutic agents described above. Cisplatin is the best-described substance with the greatest nephrotoxic potential among the chemotherapeutic agents. Crucial for renal complications are also cancer stage, previous chemotherapy and other risk factors of AKI such as age, comorbidities and medications used. Due to the described complications during oncological treatment, including kidney damage, it seems necessary to elaborate standards of cooperation between oncologists and nephrologists both during and after treatment of a patient with cancer. Therefore, it is necessary to conduct further research and develop algorithms for management of a cancer patient, especially during such an intensive progress in oncology.     

Current Diagnosis and Treatment Options for Cutaneous Adnexal Neoplasms with Follicular Differentiation

Neoplasms derived from follicular tissue are extremely rare. Clinically, they are reported as non-symptomatic, slow-growing nodules. These lesions are mainly benign, but the malignant type can occur. Mainly middle-aged people (50–60 years of age) are affected. These carcinomas are mainly localized on the head and neck or torso. They can be locally aggressive and infiltrate surrounding tissue and metastasize to regional lymph nodes. In the minority of cases, distant metastases are diagnosed. Quick and relevant diagnosis is the basis of a treatment for all types of tumors. The patient’s life expectancy depends on multiple prognostic factors, including the primary tumor size and its mitotic count. Patients should be referred to a specialized skin cancer center to receive optimal multidisciplinary treatment. This article tries to summarize all the information that is currently available about pathogenesis, diagnosis, and treatment methods of follicular tumors.     

Antimicrobial Activity of 1,3,4-Oxadiazole Derivatives

The worldwide development of antimicrobial resistance forces scientists to search for new compounds to which microbes would be sensitive. Many new structures contain the 1,3,4-oxadiazole ring, which have shown various antimicrobial activity, e.g., antibacterial, antitubercular, antifungal, antiprotozoal and antiviral. In many publications, the activity of new compounds exceeds the activity of already known antibiotics and other antimicrobial agents, so their potential as new drugs is very promising. The review of active antimicrobial 1,3,4-oxadiazole derivatives is based on the literature from 2015 to 2021.     

Interaction of Cationic Carbosilane Dendrimers and Their siRNA Complexes with MCF-7 Cells

The application of siRNA in gene therapy is mainly limited because of the problems with its transport into cells. Utilization of cationic dendrimers as siRNA carriers seems to be a promising solution in overcoming these issues, due to their positive charge and ability to penetrate cell membranes. The following two types of carbosilane dendrimers were examined: CBD-1 and CBD-2. Dendrimers were complexed with pro-apoptotic siRNA (Mcl-1 and Bcl-2) and the complexes were characterized by measuring their zeta potential, circular dichroism and fluorescence of ethidium bromide associated with dendrimers. CBD-2/siRNA complexes were also examined by agarose gel electrophoresis. Both dendrimers form complexes with siRNA. Moreover, the cellular uptake and influence on the cell viability of the dendrimers and dendriplexes were evaluated using microscopic methods and XTT assay on MCF-7 cells. Microscopy showed that both dendrimers can transport siRNA into cells; however, a cytotoxicity assay showed differences in the toxicity of these dendrimers.     

UVB Radiation and Selected Tryptophan-Derived AhR Ligands—Potential Biological Interactions in Melanoma Cells

Excessive UV exposure is considered the major environmental factor in melanoma progression. Human skin is constantly exposed to selected tryptophan-derived aryl hydrocarbon receptor (AhR) ligands, including kynurenine (KYN) and kynurenic acid (KYNA), as they are endogenously produced and present in various tissues and body fluids. Importantly, recent studies confirmed the biological activity of KYN and KYNA toward melanoma cells in vitro. Thus, in this study, the potential biological interactions between UVB and tryptophan metabolites KYN and KYNA were studied in melanoma A375, SK-MEL-3, and RPMI-7951 cells. It was shown that UVB enhanced the antiproliferative activity of KYN and KYNA in melanoma cells. Importantly, selected tryptophan-derived AhR ligands did not affect the invasiveness of A375 and RPMI-7951 cells; however, the stimulatory effect was observed in SK-MEL-3 cells exposed to UVB. Thus, the effect of tryptophan metabolites on metabolic activity, cell cycle regulation, and cell death in SK-MEL-3 cells exposed to UVB was assessed. In conclusion, taking into account that both UVB radiation and tryptophan-derived AhR ligands may have a crucial effect on skin cancer formation and progression, these results may have a significant impact, revealing the potential biological interactions in melanoma cells in vitro.