Current Molecular, Cellular and Genetic Aspects of Peri-Implantitis Disease: A Narrative Review.

(1) Background: Peri-implantitis is a multi-factorial disease with an inflammatory background that occurs in both soft and hard tissues surrounding implants. In recent years, the understanding of the cellular, molecular and genetic background of peri-implantitis has broadened. This study aims to summarize the currently available articles on the subject and highlight the most recent advances over the last 20 years. (2) Methods: For this study, the Embase and PubMed libraries were searched using the keywords: ("peri-implantitis" AND "cytokine" OR "genetics" OR "cellular") and ("peri-implantitis" AND "cytokine" OR "genetics" OR "cellular" AND "risk factors"). The search revealed a total of 3013 articles (992 from PubMed, 2021 from Embase). Following screening of the titles and abstracts and full-text reads, 55 articles were included. (3) Results: In peri-implantitis IL-6, IL-1ß, TNF-α, MMP-8 and their genetic variations appear to be the most important cytokines in relation to not only pathogenesis, but also their potential diagnostic capabilities. Epithelial and inflammatory cells, along with those of the bone lineage, are prime cellular elements found in peri-implantitis. (4) Conclusions: A wide array of cells stand behind peri-implantitis, as well as cytokines and their genetic variations that take part in the process. However, the growing interest in this topic has led to the introduction of specific new diagnostic tools to enable a better understanding of patients' responses to treatment and, in turn, to even enable prediction of the risk of developing peri-implant disease.

Increased oxytocinergic system activity in the cardiac muscle in spontaneously hypertensive SHR rats.

Introduction: The present study aimed to determine whether the presence of cardiac hypertrophy due to arterial hypertension is associated with a change in the activity of the oxytocinergic system in cardiomyocytes. Material and methods: The experiments were performed on male, spontaneously hypertensive rats (SHR, n = 10) and normotensive Wistar-Kyoto rats (WKY, n = 12). Blood samples were collected from both SHR and WKY animals to asses plasma oxytocin (OT) concentration; the rats were sacrificed by decapitation. Samples of the left and right ventricles were harvested for the analysis of the OT and oxytocin receptor (OTR) protein by ELISA, and OT and OTR mRNA expression by RT-PCR. Immunohistopathological studies were performed to confirm the presence of OTR receptors in the cardiac muscle of the ventricles. Results: Plasma OT concentration did not differ between SHR and WKY rats. In the SHR rats, the expression of OT mRNA and the OT protein level was higher in the left and the right ventricle, while OTR mRNA expression was significantly lower in both the left and the right ventricle. However, the level of OTR protein was higher only in the left ventricle of the SHR rats. The presence of OTR receptors was confirmed by immunohistochemical analysis in the muscle of the right and left ventricle. Conclusions: The presence of arterial hypertension is associated with increased activity of the oxytocinergic system in the heart, especially in the area of the left ventricle. These findings support the important role of this system in the maintenance of cardiovascular homeostasis.

COVID-19 in dental care: What do we know?

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is primarily transmitted by airborne droplets and its spread is favored by close human contact, thus the COVID-19 pandemic is the new challenge in dental practice. The oral cavity was considered as a SARS-CoV-2 reservoir, the viruses were detected in the saliva and periodontal pockets of infected persons. Therefore, aside from the most common symptoms, COVID-19 can manifest as lesions in the oral cavity. Due to the high risk of cross-contamination in the dental office, new precautionary measures were implemented in professional dental care to ensure safety for both, dental staff and patients. Given the dynamically changing situation, dental practitioners should follow local guidelines and implement them according to current needs and available resources. The key to success is to reduce the risk of cross-infection with SARS-CoV-2 at no cost to the good oral health of the population.

Myocardial infarction caused by Graves' disease.

Not required for Clinical Vignette.

Polyprenol-Based Lipofecting Agents for In Vivo Delivery of Therapeutic DNA to Treat Hypertensive Rats.

Development of efficient vectors for transfection is one of the major challenges in genetic engineering. Previous research demonstrated that cationic derivatives of polyisoprenoids (PTAI) may serve as carriers of nucleic acids. In the present study, the effectiveness of two PTAI-based formulations (PTAI-6-8 and 10-14) was investigated and compared to the commercial reagents. The purpose of applied gene therapy was to enhance the expression of vascular endothelial growth factor (VEGF-A) in the renal medulla of spontaneously hypertensive rats (SHR) and to test its potential as a novel antihypertensive intervention. In the first part of the study (in vitro), we confirmed that PTAI-based lipoplexes efficiently transfect XC rat sarcoma cells and are stable in 37 °C for 7 days. In the in vivo experiments, we administered selected lipoplexes directly to the kidneys of conscious SHR (via osmotic pumps). There were no blood pressure changes and VEGF-A level in renal medulla was significantly higher only for PTAI-10-14-based formulation. In conclusion, despite the promising results, we were not able to achieve VEGF-A expression level high enough to verify VEGF-A gene therapy usefulness in SHR. However, results of our study give important indications for the future development of PTAI-based DNA carriers and kidney-targeted gene delivery.

Boost of serum resistance and storage stability in cationic polyprenyl-based lipofection by helper lipids compositions.

Lipofection is a widely used molecular biology technique and one of the most promising non-viral gene therapy strategies. However, one of the main drawbacks of using cationic lipids-based lipoplexes in DNA/RNA delivery is serum-associated inhibition of transfection. We have addressed this issue using PTAI (trimethylpolyprenylammonium iodides)-based lipofection model. To overcome serum-sensitivity we used 100 different formulations based on different PTAI, various helper lipids compositions, lipoplex surface modifications with polyethylene glycol (PEG), and precondensation of DNA with poly-L-lysine (PLL). Multicomponent helper lipids compositions boosted serum resistance and largely improved long-term storage of PTAI-based reagents. This was observed, in particular, for PTAI with longer isoprenoid chains. Additionally, our PTAI-based carriers were efficient for DNA and RNA delivery and safe for human red blood cells (RBC). Moreover, a broad array of the modifications used resulted in an important observation - a diverse susceptibility of various cell types to different compositions was noted. Overall, our results show that helper lipids composition mediates efficient serum-resistant DNA/RNA lipofection. Additionally, multicomponent PTAI-based reagents are promising gene delivery carriers both, at the cellular and organismal level.

Diastereoisomerically Pure, (S)-O-1,2-O-isopropyli dene-(5-O-α-d-glucofuranosyl) t-butanesulfinate: Synthesis, Crystal Structure, Absolute Configuration and Reactivity.

The reaction of t-butylmagnesium chlorides with diastereomerically pure (R)-1,2-O-isopropylidene-3,5-O-sulfinyl-α-d-glucofuranose (R)-4 was found to be stopped at the stage of the corresponding, diastereoisomerically pure 1,2-O-isopropylidene-(5-O-α-d-glucofuranosyl) t-butanesulfinate (S)-10 for which the crystal structure and the (S)-absolute configuration was determined by X-ray crystallography. Comparison of the absolute configurations of the starting sulfite (R)-4, and t-butanesulfinate (S)-10 (which crystallizes in the orthorhombic system, space group P212121, with the single compound molecule present in the asymmetric unit), clearly indicates that the reaction of nucleophilic substitution at the stereogenic sulfur atom in the sulfite (R)-4 occurs with the full inversion of configuration via the trigonal bipyramidal sulfurane intermediate 4c in which both the entering and leaving groups are located in apical positions.

Synthesis of ß-lactams via diastereoselective, intramolecular Kinugasa reactions.

Intramolecular Kinugasa reactions on in situ generated carbohydrate-derived alkynylnitrones are described. The effects of the length of chains, their mutual configuration, influence of experimental conditions on product distribution and feasibility of the ß-lactam ring construction were studied. Intramolecular reactions proceed with high stereoselectivity to provide in each case one product only. The cycloadducts from tartaric acid were converted into the corresponding non-racemic 4-acetoxy azetidinones in good yields.

Bypassing the stereoselectivity issue: transformations of Kinugasa adducts from chiral alkynes and non-chiral acyclic nitrones.

An approach to ß-lactams via a reaction between chiral copper acetylides and acyclic nitrones is reported. Electronic circular dichroism (ECD) in combination with NMR spectroscopy was used to determine the absolute configuration of all components of complex mixtures of azetidinones. Stereochemical preferences observed in the studied reactions are discussed and a model of a new reaction pathway supported by DFT conformational analysis is proposed. Subsequent transformations of the synthesized Kinugasa adducts followed by epimerization at the C-3 carbon atom led to trans-substituted azetidinones with improved stereoselectivity, mimicking a variety of important ß-lactam structures. On the other hand, the oxidation of the furyl residue to the carboxylic group followed by oxidative decarboxylation with lead tetraacetate afforded the more thermodynamically stable trans-substituted 4-acetoxy azetidinone. The latter strategy is particularly attractive for the diastereomeric mixture in which isomers with the same configuration at the C-3 carbon atom dominate.

Innovative lipid-based carriers containing cationic derivatives of polyisoprenoid alcohols augment the antihypertensive effectiveness of candesartan in spontaneously hypertensive rats.

Novel lipid-based carriers, composed of cationic derivatives of polyisoprenoid alcohols (amino-prenols, APrens) and 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE), were designed. The carriers, which were previously shown to be nontoxic to living organisms, were now tested if suitable for administration of candesartan, an antihypertensive drug. Spontaneously hypertensive rats (SHR) received injections of candesartan (0.1 mg/kg body weight per day; s.c.) in freshly prepared carriers for two weeks. The rats' arterial pressure was measured by telemetry. Urine and blood collection were performed in metabolic cages. In a separate group of SHR, the pharmacokinetics of the new formulation was evaluated after a single subcutaneous injection. The antihypertensive activity of candesartan administered in DOPE dispersions containing APrens was distinctly greater than that of candesartan dispersions composed of DOPE only or administered in the classic solvent (sodium carbonate). The pharmacokinetic parameters clearly demonstrated that candesartan in APren carriers reached the bloodstream more rapidly and in much greater concentration (almost throughout the whole observation) than the same drug administered in dispersions of DOPE only or in solvent. Serum creatinine (PCr) decreased significantly only in the group receiving candesartan in carriers with APrens (from 0.80 ± 0.04 to 0.66 ± 0.09 mg/dl; p < 0.05), whereas in the other groups PCr remained at the same level after treatment. Moreover, the new derivatives increased the loading capacity of the carriers, which is a valuable feature for any drug delivery system. Taken together, our findings led us to conclude that APrens are potentially valuable components of lipid-based drug carriers.

Effective usage of cationic derivatives of polyprenols as carriers of DNA vaccines against influenza virus.

BACKGROUND: Cationic derivatives of polyprenols (trimethylpolyprenylammonium iodides - PTAI) with variable chain length between 6 and 15 isoprene units prepared from naturally occurring poly-cis-prenols were tested as DNA vaccine carriers in chickens and mice. This study aimed to investigate if PTAI could be used as an efficient carrier of a DNA vaccine. METHODS: Several vaccine mixtures were prepared by combining different proportions of the vaccine plasmid (carrying cDNA encoding a vaccine antigen, hemagglutinin from H5N1 influenza virus) and various compositions of PTAI. The vaccines were delivered by intramuscular injection to either chickens or mice. The presence of specific antibodies in sera collected from the immunized animals was analyzed by enzyme-linked immunosorbent assay (ELISA) and hemagglutination inhibition (HI) test. RESULTS: The mixtures of PTAI with helper lipids, such as DOPE (1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine), DC-cholesterol [{3ß-[N-(N',N'-dimethylaminoethane)-carbamoyl] cholesterol} hydrochloride] or DOPC (1,2-dioleoyl-sn-glycero-3-phosphatidylcholine) induced strong humoral response to the antigen encoded by the DNA vaccine plasmid. CONCLUSION: The animal immunization results confirmed that PTAI compositions, especially mixtures of PTAI with DOPE and DC-cholesterol, do work as effective carriers of DNA vaccines, comparable to the commercially available lipid transfection reagent.

Formal synthesis of Thienamycin.

A formal synthesis of Thienamycin from ethyl (E)-crotonate and a cyclic five-membered nitrone derived from 2-deoxy-d-ribose is described. The synthesis involves 1,3-dipolar cycloaddition, cleavage of the N-O bond in the adduct, and intramolecular N-acylation to afford a bicyclic carbapenam skeleton. Subsequent transformations of the five-membered ring substituents provide the title compound.

Increased sensitivity of prolonged P-wave during exercise stress test in detection of angiographically documented coronary artery disease.

BACKGROUND: A retrospective study was designed to investigate P-wave duration changes in exercise stress test (EST) for the prediction of angiographically documented substantial coronary artery disease (CAD). METHODS: We analyzed 265 cases of patients, who underwent EST and subsequently coronary angiography. Analysis of P-wave duration was performed in leads II, V5 at rest, and in the recovery period. RESULTS: The sensitivity and specificity for the isolated ST-segment depression were only 31% and 76%, respectively. The combination of ST-depression with other exercise-induced clinical and electrocardio-graphic abnormalities (chest pain, ventricular arrhythmia, hypotension, left bundle branch block) was characterized by 41% sensitivity and 69% specificity. The combination of abnormal recovery P-wave duration (≥ 120 ms) with ST-depression and other exercise-induced abnormalities had 83% sensitivity but only 20% specificity. Combined analysis of increased delta P-wave duration, ST-depression and other exercise-induced abnormalities had 69% sensitivity and 42% specificity. Sensitivity and specificity of the increase in delta P-wave duration for left CAD was 69% and 47%, respectively, and for 3-vessel CAD 70% and 50%, respectively. The presence of arterial hypertension negatively influenced the prog-nostic value of P-wave changes in the stress test. CONCLUSIONS: The results of the study show that an addition of P-wave duration changes assessment to ST-depression analysis and other exercise-induced abnormalities increase sensitivity of EST, especially for left CAD and 3-vessel coronary disease. We have also provided evidence for the negative influence of the presence of arterial hypertension on the predictive value of P-wave changes in the stress test. (Cardiol J 2017; 24, 2: 159-166).

Efficient and non-toxic gene delivery by anionic lipoplexes based on polyprenyl ammonium salts and their effects on cell physiology.

BACKGROUND: One of the major challenges limiting the development of gene therapy is an absence of efficient and safe gene carriers. Among the nonviral gene delivery methods, lipofection is considered as one of the most promising. In the present study, a set of cationic polyprenyl derivatives [trimethylpolyprenylammonium iodides (PTAI)] with different lengths of polyprenyl chains (from 7, 8 and 11 to 15 isoprene units) was suggested as a component of efficient DNA vehicles. METHODS: Optimization studies were conducted for PTAI in combination with co-lipid dioleoylphosphatidylethanolamine on DU145 human prostate cancer cells using: size and zeta potential measurements, confocal microscopy, the fluorescein diacetate/ethidium bromide test, cell counting, time-lapse monitoring of cell movement, gap junctional intercellular coupling analysis, antimicrobial activity assay and a red blood cell hemolysis test. RESULTS: The results obtained show that the lipofecting activity of PTAI allows effective transfection of plasmid DNA complexed in negatively-charged lipoplexes of 200-500 nm size into cells without significant side effects on cell physiology (viability, proliferation, morphology, migration and gap junctional intercellular coupling). Moreover, PTAI-based vehicles exhibit a potent bactericidal activity against Staphylococcus aureus and Escherichia coli. The developed anionic lipoplexes are safe towards human red blood cell membranes, which are not disrupted in their presence. CONCLUSIONS: The developed carriers constitute a group of promising lipofecting agents of a new type that can be utilized as effective lipofecting agents in vitro and they are also an encouraging basis for in vivo applications.

1,3-Dipolar cycloaddition of a cyclic nitrone derived from 2-deoxy-D-ribose to α,ß-unsaturated lactones: An entry to carbapenem antibiotics.

1,3-Dipolar cycloadditions of 2-deoxy-D-ribose-derived L-threo five-membered cyclic nitrone to α,ß-unsaturated γ- and δ-lactones were investigated. Cycloadducts obtained from δ-lactones, after NO bond cleavage, opening of the lactone ring, and protection of hydroxyl groups were subjected to ß-lactam ring formation by using Mukaiyama's salt. Cycloadducts from γ-lactones subjected to the same reaction sequence undergo ß-elimination of a water molecule to provide pyrrolidine-substituted unsaturated γ-lactones.

Prenyl Ammonium Salts--New Carriers for Gene Delivery: A B16-F10 Mouse Melanoma Model.

PURPOSE: Prenyl ammonium iodides (Amino-Prenols, APs), semi-synthetic polyprenol derivatives were studied as prospective novel gene transfer agents. METHODS: AP-7, -8, -11 and -15 (aminoprenols composed of 7, 8, 11 or 15 isoprene units, respectively) were examined for their capacity to form complexes with pDNA, for cytotoxicity and ability to transfect genes to cells. RESULTS: All the carriers were able to complex DNA. The highest, comparable to commercial reagents, transfection efficiency was observed for AP-15. Simultaneously, AP-15 exhibited the lowest negative impact on cell viability and proliferation--considerably lower than that of commercial agents. AP-15/DOPE complexes were also efficient to introduce pDNA to cells, without much effect on cell viability. Transfection with AP-15/DOPE complexes influenced the expression of a very few among 44 tested genes involved in cellular lipid metabolism. Furthermore, complexes containing AP-15 and therapeutic plasmid, encoding the TIMP metallopeptidase inhibitor 2 (TIMP2), introduced the TIMP2 gene with high efficiency to B16-F10 melanoma cells but not to B16-F10 melanoma tumors in C57BL/6 mice, as confirmed by TIMP2 protein level determination. CONCLUSION: Obtained results indicate that APs have a potential as non-viral vectors for cell transfection.

Synthesis of Thienamycin methyl ester from 2-deoxy-D-ribose via Kinugasa reaction.

A novel synthesis of thienamycin is described. The crucial step of the synthesis is based on Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade reaction between terminal acetylene derived from D-lactic acid and suitable, partially protected, five-membered cyclic nitrone obtained from 2-deoxy-D-ribose. The reaction was performed in the presence of tetramethylguanidine as a base to provide 5,6-trans substituted carbapenam as the main product. Thus obtained carbapenam 11 with (5R,6S) configuration at the azetidinone ring was subsequently subjected to oxidation/deprotection/oxidation reaction sequence to afford the ß-keto ester 20, which was directly transformed into N,O-protected methyl ester of thienamycin.

Approach to Monobactams and Nocardicins via Diastereoselective Kinugasa Reaction.

A Kinugasa reaction between copper(I) acetylides and cyclic nitrones derived from chiral amino alcohols and glyoxylic acid is reported. The stereochemical preferences observed in this reaction are discussed. The alkyne molecule approaches the nitrone exclusively anti to the large substituent next to the nitrogen atom to provide the cis-substituted ß-lactam ring preferentially. The six-membered oxazinone ring can be opened by reduction with lithium borohydride. Deprotection of the ß-lactam nitrogen atom can be achieved by lithium in liquid ammonia reduction or by CAN oxidation, depending on the substituents attached to the four-membered azetidinone ring. The adducts obtained by the Kinugasa reaction provide an attractive entry to a variety of monocyclic ß-lactam structures related to monobactams and nocardicins.

Glycosyl hydroperoxides: a new class of potential antimalarial agents.

Motivated by the antimalarial properties observed in organic peroxides, an extensive series of glycosyl hydroperoxides was prepared with the aim of identifying new bioactive molecules. Selected compounds were tested against a Plasmodium falciparum culture (chloroquine-susceptible strain D10 and chloroquine-resistant strain W2). Screening results indicated that the factors critical for antimalarial activity were the presence of a hydroperoxide moiety and solubility in water at pH 5.0. Moreover, the ability to inhibit ß-hematin formation in vitro has been evaluated (BHIA Assay).

Effects of liposomes with polyisoprenoids, potential drug carriers, on the cardiovascular and excretory system in rats.

BACKGROUND: The unpredictable side effects of a majority currently used drugs are the substantial issue, in which patients and physicians are forced to deal with. Augmenting the therapeutic efficacy of drugs may prove more fruitful than searching for the new ones. Since recent studies show that new cationic derivatives of polyisoprenoid alcohols (APrens) might exhibit augmenting properties, we intend to use them as a component of liposomal drug carriers. In this study we investigate if these compounds do not per se cause untoward effects on the living organism. METHODS: Male Sprague-Dawley rats received for four weeks daily injections (0.5 ml sc) of liposomes built of dioleoyl phosphatidylethanolamine (DOPE), liposomes built of DOPE and APren-7 (ratio 10:1) or water solvent. Weekly, rats were observed in metabolic cages (24h); blood and urine were sampled for analysis; body weight (BW) and systolic blood pressure (SBP) were determined. After chronic experiment, kidneys and heart were harvested for histological and morphometric analysis. RESULTS: The 4-week BW increments were in the range of 97 ± 4 to 102 ± 4%, intergroup differences were not significant. Microalbuminuria was the lowest in the group receiving liposomes with APren-7 (0.22 ± 0.03 mg/day). Water and food intake, plasma and urine parameters were similar in all groups. CONCLUSIONS: Newly designed liposomes containing APren-7 did not affect functions of the excretory and cardiovascular systems, and renal morphology; therefore we find them suitable as a component of liposomal drug carriers.