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Nucleoside reverse transcriptase inhibitors (NRTIs) are mainstay therapeutics for HIV that block retrovirus replication. Alu (an endogenous retroelement that also requires reverse transcriptase for its life cycle)–derived RNAs activate P2X7 and the NLRP3 inflammasome to cause cell death of the retinal pigment epithelium in geographic atrophy, a type of age-related macular degeneration. We found that NRTIs inhibit P2X7-mediated NLRP3 inflammasome activation independent of reverse transcriptase inhibition. Multiple approved and clinically relevant NRTIs prevented caspase-1 activation, the effector of the NLRP3 inflammasome, induced by Alu RNA. NRTIs were efficacious in mouse models of geographic atrophy, choroidal neovascularization, graft-versus-host disease, and sterile liver inflammation. Our findings suggest that NRTIs are ripe for drug repurposing in P2X7-driven diseases.

ObjectivesTo determine whether the process of ubiquitination and/or activity of the 26S proteasome are involved in the induction of osteoarthritis (OA).MethodsBovine cartilage resorption assays, chondrocyte cell-line SW1353 and primary human articular chondrocytes were used with the general proteasome inhibitor MG132 or vehicle to identify a role of the ubiquitin–proteasome system (UPS) in cartilage destruction and matrix metalloproteinase-13 (MMP13) expression. In vivo, MG132 or vehicle, were delivered subcutaneously to mice following destabilisation of the medial meniscus (DMM)-induced OA. Subsequently, DMM was induced in Lys-to-Arg (K48R and K63R) mutant ubiquitin (Ub) transgenic mice. Cytokine signalling in SW1353s was monitored by immunoblotting and novel ubiquitinated substrates identified using Tandem Ubiquitin Binding Entities purification followed by mass spectrometry. The ubiquitination of TRAFD1 was assessed via immunoprecipitation and immunoblotting and its role in cytokine signal-transduction determined using RNA interference and real-time RT-PCR for MMP13 and interleukin-6 (IL6).ResultsSupplementation with the proteasome inhibitor MG132 protected cartilage from cytokine-mediated resorption and degradation in vivo in mice following DMM-induced OA. Using transgenic animals only K48R-mutated Ub partially protected against OA compared to wild-type or wild-type Ub transgenic mice, and this was only evident on the medial femoral condyle. After confirming ubiquitination was vital for NF-κB signalling and MMP13 expression, a screen for novel ubiquitinated substrates involved in cytokine-signalling identified TRAFD1; the depletion of which reduced inflammatory mediator-induced MMP13 and IL6 expression.ConclusionsOur data for the first time identifies a role for ubiquitination and the proteasome in the induction of OA via regulation of inflammatory mediator-induced MMP13 expression. These data open avenues of research to determine whether the proteasome, or K48-linked ubiquitination, are potential therapeutic targets in OA.

Embryo implantation is a key moment in pregnancy. Abnormal production of pro- and anti-inflammatory cytokines, their receptors and other immune factors may result in embryo implantation failure and pregnancy loss. The aim of this study was to determine the profile of selected pro- and anti-inflammatory factors in the blood plasma of patients undergoing in vitro fertilization (IVF) and control women who achieved pregnancy after natural conception. The examined patients were administered steroid prednisone. We present results concern the plasma levels of IFN-ɣ, BDNF, LIF, VEGF-A, sTNFR1 and IL-10. We found that IVF patients receiving steroids differed significantly from patients who were not administered such treatment in terms of IFN-γ and IL-10 levels. Moreover, IVF patients differed in secretion of all tested factors with the fertile controls. Our results indicated that women who secrete at least 1409 pg/ml of sTNFR1 have a chance to become pregnant naturally and give birth to a child, while patients after IVF must achieve a concentration of 962.3 pg/ml sTNFR1 in blood plasma for successful pregnancy. In addition, IVF patients secreting VEGF-A above 43.28 pg/ml have a greater risk of miscarriage or a failed transfer in comparison to women secreting below this value. In conclusion, fertile women present a different profile of pro- and anti-inflammatory cytokines, and growth factors compared to patients with recurrent implantation failure (RIF).

Background Although pregnancy is a physiological process it causes hormonal changes that can also affect the oral cavity. Pregnancy increases the risk of gum disease inflammation and tooth caries which could affect the health of the developing baby. Proper oral health is crucial both for mother and her babies and is related with mothers’ awareness of this connection. The aim of this study was the self-assessment of women’s both oral health and oral health literacy as well as mothers’ awareness of the connection of oral health and pregnancy. Material and methods In the study anonymous questionnaire was prepared and provided to be filled in by 200 mothers at the age from 19 to 44 y.o. who gave birth in the gynecological clinic. The questionnaire included demographic, and concerning the areas of oral health before and during pregnancy and after the childbirth questions. Results Only 20% of the investigated women underwent the oral examination before the pregnancy and the next 38.5% underwent it intentionally when the pregnancy had been confirmed. As much as 24% of women pointed out lack of awareness of the importance of proper oral hygiene during pregnancy. 41.5% of investigated women declared complaints during the pregnancy concerning teeth or gums and 30.5% underwent dental treatment; 68%, brushed their teeth properly—twice a day; 32% of women observed deterioration of oral health state during the pregnancy. The knowledge of the importance of oral health during pregnancy presented by the majority of mothers was relatively proper, which was strongly connected with higher education status and living in big cities. A significant correlation between higher birth weight and more frequent daily tooth brushing was observed. Both higher frequency of problems concerning the oral cavity and dental treatment during pregnancy were significantly related to the younger age of mothers. Conclusions The knowledge of women concerning of oral health on the management of pregnancy and development of fetus is still insufficient. Gynecologists should inquire pregnant women if they have done dental examination, and provide wider education about importance of oral health in pregnancy.

Endometriosis is a disease in which endometriotic tissue occurs outside the uterus. Its pathogenesis is still unknown. The most widespread hypothesis claims that ectopic endometrium appears as a result of retrograde menstruation and its insufficient elimination by immunocytes. Some reports have shown expression of non-classical HLA-G molecules on ectopic endometrium. HLA-G is recognized by KIR2DL4, LILRB1 and LILRB2 receptors on natural killer (NK) and other cells. These receptors are polymorphic, which may affect their activity. In this study we investigated whether HLA-G, KIR2DL4, LILRB1 and LILRB2 polymorphisms may influence susceptibility to endometriosis and disease progression. We used polymerase chain reaction (PCR), PCR-restriction fragment length polymorphism (PCR-RFLP) and allelic discrimination methods with TaqMan SNP Genotyping Assays for typing of 276 patients with endometriosis and 314 healthy fertile women. The HLA-G rs1632947:GG genotype was associated with protection against the disease and its severe stages; HLA-G rs1233334:CT protected against progression; LILRB1 rs41308748:AA and LILRB2 rs383369:AG predisposed to the disease and its progression. No effect of KIR2DL4 polymorphism was observed. These results support the role of polymorphisms of HLA-G and its receptors LILRB1 and LILRB2 in susceptibility to endometriosis and its progression.

OBJECTIVES:The aim of this study was to determine whether the environmental exposure to pyrethroids affects semen quality and the level of reproductive hormones in men. METHODS:The study population consisted of 334 men who attended the infertility clinic for diagnostic purposes and who had normal semen concentration of 15 to 300 mln/mL. Participants were interviewed and provided a semen sample. The pyrethroids metabolites—3-phenoxybenzoic acid (3PBA), cis-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (CDCCA), trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (TDCCA), and cis-2,2-dibromovinyl-2,2-dimethylcyclopropane-1-carboxylic acid (DBCA) were analyzed in the urine using a validated gas chromatography ion-trap mass spectrometry method. RESULTS:Urinary pyrethroids metabolites levels were significantly associated with an increase in the percentage of sperm with abnormal morphology and decrease in sperm concentration, the level of testosterone, and computer-aided semen analysis parameters. CONCLUSIONS:Environmental pyrethroids exposure may affect semen quality and the level of reproductive hormones.

Background The COVID-19 pandemic has spread very rapidly around the world. Various regional and national lockdowns were imposed to control the spread. Meanwhile, vaccine development and population vaccination were the next steps for pandemic control. Workers in the dental field, both dentists and dental assistants, however, were close to the sources of aerosol generated during dental procedures and thus were the group of workers the most exposed to COVID-19 infection. The aim of our study was to monitor the immune response before and after the vaccine in a high-risk population, composed by dental professionals. Methods A clinical prospective study was carried out among dental professionals at the Academic Dental Polyclinic, Wroclaw Medical University (Wrocław, Lower Silesia region, Poland). Blood samples were collected at an interval of one year – March/April 2020, before the vaccination against COVID-19, and April 2021, after the vaccination. The analysis was performed on serum with four different methods: qualitative, semi-quantitative, and quantitative IgG count for SARS-CoV-2, and SARS-CoV-2 neutralizing antibodies. Results A total of 42 healthy adult volunteers participated in the study. The results showed a statistically significant difference (p < 0.05) in antibody levels before and after vaccination (1st and 2nd measurement) for each test method. The tests that were used affected the results and the test that showed the strongest relationship with the result was the Qualitative test. Conclusions Dental professionals are the adult working population most at risk for COVID-19. Monitoring SARS-CoV-2-status-related seropositivity can provide useful information occupational risk factors for dental professionals.

“Marta Kot” was not included as an author in the original publication [...]

Here we report a new Raman probe for cellular studies on lipids detection and distribution. It is (3S, 3'S)-astaxanthin (AXT), a natural xanthophyll of hydrophobic properties and high solubility in lipids. It contains a chromophore group, a long polyene chain of eleven conjugated C=C bonds including two in the terminal rings, absorbing light in the visible range that coincides with the excitation of lasers commonly used in Raman spectroscopy for studying of biological samples. Depending on the laser, resonance (excitation in the visible range) or pre-resonance (the near infrared range) Raman spectrum of astaxanthin is dominated by bands at ca. 1008, 1158, and 1520 cm−1 that now can be also a marker of lipids distribution in the cells. We showed that AXT accumulates in lipidic structures of endothelial cells in time-dependent manner that provides possibility to visualize e.g. endoplasmic reticulum, as well as nuclear envelope. As a non-toxic reporter, it has a potential in the future studies on e.g. nucleus membranes damage in live cells in a very short measuring time.

The growing number of female reproductive system disorders creates a need for novel treatment methods. Tissue engineering brings hope for patients, which enables damaged tissue reconstruction. For this purpose, epithelial cells are cultured on three-dimensional scaffolds. One of the most promising materials is chitosan, which is known for its biocompatibility and biodegradability. The aim of the following study was to verify the potential of chitosan-based biomaterials for pelvic organ prolapse regeneration. The scaffolds were obtained under microwave-assisted conditions in crosslinking reactions, using dicarboxylic acids and aminoacid as crosslinkers, including l-glutamic acid, adipic acid, malonic acid, and levulinic acid. The products were characterized over their physicochemical and biological properties. FT–IR analysis confirmed formation of amide bonds. The scaffolds had a highly porous structure, which was confirmed by SEM analysis. Their porosity was above 90%. The biomaterials had excellent swelling abilities and very good antioxidant properties. The cytotoxicity study was performed on vaginal epithelial VK2/E6E7 and human colon cancer HCT116 cell lines. The results showed that after certain modifications, the proposed scaffolds could be used in pelvic organ prolapse (POP) treatment.