МОЛЕКУЛЯРНЫЕ И КЛЕТОЧНЫЕ МЕХАНИЗМЫ РЕМОДЕЛИРОВАНИЯ ПАРОДОНТА ПРИ ТРАВМАТИЧЕСКОЙ ОККЛЮЗИИ. ОБЗОР

Cellular, molecular, and tissue-level reactions to orthodontic force

The islets of Langerhans are highly organized structures that have species-specific, three-dimensional tissue architecture. Islet architecture is critical for proper hormone secretion in response to nutritional stimuli. Islet architecture is disrupted in all types of diabetes mellitus and in cadaveric islets for transplantation during isolation, culture, and perfusion, limiting patient outcomes. Moreover, recapitulating native islet architecture remains a key challenge for in vitro generation of islets from stem cells. In this review, we discuss work that has led to the current understanding of determinants of pancreatic islet architecture, and how this architecture is maintained or disrupted during tissue remodeling in response to normal and pathological metabolic changes. We further discuss both empirical and modeling data that highlight the importance of islet architecture for islet function.

Recent studies suggest that there are multiple regulatory pathways by which chondrocytes in articular cartilage sense and respond to mechanical stimuli, including upstream signaling pathways and mechanisms that may lead to direct changes at the level of transcription, translation, post-translational modifications, and cell-mediated extracellular assembly and degradation of the tissue matrix. This review focuses on the effects of mechanical loading on cartilage and the resulting chondrocyte-mediated biosynthesis, remodeling, degradation, and repair of this tissue. The effects of compression and tissue shear deformation are compared, and approaches to the study of mechanical regulation of gene expression are described. Of particular interest regarding dense connective tissues, recent experiments have shown that mechanotransduction is critically important in vivo in the cell-mediated feedback between physical stimuli, the molecular structure of newly synthesized matrix molecules, and the resulting macroscopic biomechanical properties of the tissue.

Exposure to crystalline silica results in serious adverse health effects, most notably, silicosis. An understanding of the mechanism(s) underlying silica-induced pulmonary toxicity is critical for the intervention and/or prevention of its adverse health effects. Rats were exposed by inhalation to crystalline silica at a concentration of 15 mg/m3, 6 hr/day, 5 days/week for 3, 6 or 12 weeks. Pulmonary toxicity and global gene expression profiles were determined in lungs at the end of each exposure period. Crystalline silica was visible in lungs of rats especially in the 12-week group. Pulmonary toxicity, as evidenced by an increase in lactate dehydrogenase (LDH) activity and albumin content and accumulation of macrophages and neutrophils in the bronchoalveolar lavage (BAL), was seen in animals depending upon silica exposure duration. The most severe histological changes, noted in the 12-week exposure group, consisted of chronic active inflammation, type II pneumocyte hyperplasia, and fibrosis. Microarray analysis of lung gene expression profiles detected significant differential expression of 38, 77, and 99 genes in rats exposed to silica for 3-, 6-, or 12-weeks, respectively, compared to time-matched controls. Among the significantly differentially expressed genes (SDEG), 32 genes were common in all exposure groups. Bioinformatics analysis of the SDEG identified enrichment of functions, networks and canonical pathways related to inflammation, cancer, oxidative stress, fibrosis, and tissue remodeling in response to silica exposure. Collectively, these results provided insights into the molecular mechanisms underlying pulmonary toxicity following sub-chronic inhalation exposure to crystalline silica in rats.

Objectives: Cardiac tissue remodelling in response ischemia/reperfusion is characterized by the interaction of cardiac myocytes (CM) and fibroblasts (cFb). Thereby, activation of Fb leads to different phenotypes, i.e. the alpha-smooth muscle actin (ASMA) positive myofibroblasts (MyoFb) which contribute to interstitial fibrosis and scar formation. For non-activated cFb, a protective effect has been shown for CM injury due to simulated ischemia reperfusion in vitro. Our study was aimed to analyse the influence of activated MyoFb compared to non-activated cFb on the hypoxia induced CM injury and the associated changes in the ECM gene expression profile.

The ratio of free fatty acid (FFA) turnover decreases significantly with the expansion of white adipose tissue. Adipose tissue and dietary saturated fatty acid levels significantly correlate with an increase in fat cell size and number. The G0/G1 switch gene 2 increases lipid content in adipocytes and promotes adipocyte hypertrophy through the restriction of triglyceride (triacylglycerol: TAG) turnover. Hypoxia in obese adipose tissue due to hypertrophic adipocytes results in excess deposition of extracellular matrix (ECM) components. Cluster of differentiation (CD) 44, as the main receptor of the extracellular matrix component regulates cell-cell and cell-matrix interactions including diet-induced insulin resistance. Excess TAGs, sterols, and sterol esters are surrounded by the phospholipid monolayer surface and form lipid droplets (LDs). Once LDs are formed, they grow up because of the excessive amount of intracellular FFA stored and reach a final size. The ratio of FFA turnover/lipolysis decreases significantly with increases in the degree of obesity. Dysfunctional adipose tissue is unable to expand further to store excess dietary lipids, increased fluxes of plasma FFAs lead to ectopic fatty acid deposition and lipotoxicity. Reduced neo-adipogenesis and dysfunctional lipid-overloaded adipocytes are hallmarks of hypertrophic obesity linked to insulin resistance. Obesity-associated adipocyte death exhibits feature of necrosis-like programmed cell death. Adipocyte death is a prerequisite for the transition from hypertrophic to hyperplastic obesity. Increased adipocyte number in obesity has life-long effects on white adipose tissue mass. The positive correlation between the adipose tissue volume and magnetic resonance imaging proton density fat fraction estimation is used for characterization of the obesity phenotype, as well as the risk stratification and selection of appropriate treatment strategies. In obese patients with type 2 diabetes, visceral adipocytes exposed to chronic/intermittent hyperglycemia develop a new microRNAs' (miRNAs') expression pattern. Visceral preadipocytes memorize the effect of hyperglycemia via changes in miRNAs' expression profile and contribute to the progression of diabetic phenotype. Nonsteroidal anti-inflammatory drugs, metformin, and statins can be beneficial in treating the local or systemic consequences of white adipose tissue inflammation. Rapamycin inhibits leptin-induced LD formation. Collectively, in this chapter, the concept of adipose tissue remodeling in response to adipocyte death or adipogenesis, and the complexity of LD interactions with the other cellular organelles are reviewed. Furthermore, clinical perspective of fat cell turnover in obesity is also debated.

Reduced tolerance of steatotic livers to ischemic injury is considered to correlate with impaired microcirculation. The aim of this study was to investigate the impact of heat-shock preconditioning (HSPC) on microcirculatory failure after ischemia/reperfusion (I/R) in steatotic livers by means of intra-vital fluorescence microscopy. Obese Zucker rats were used. In the HS group, rats underwent whole-body hyperthermia followed by 60-min partial liver ischemia. In group IR, rats were exposed only to ischemia. Microcirculation parameters (sinusoidal perfusion rate, sinusoidal diameter, leukocyte-endothelial interaction) were significantly better preserved in the HS group than in the IR group. Liver enzymes, oxygenated glutathione/reduced glutathione (GSSG/GSH) ratio, and electron microscopy showed less damage in the HS group. A marked expression of heat shock protein 72 (HSP72) and heme oxygenase (HO-1) was found only in the livers of group HS. HSPC mitigated the I/R injury of steatotic livers by preventing post-ischemic failure of microcirculation. This beneficial effect was found to be associated with the induction of HSP72 and HO-1.

Reduced tolerance of steatotic livers to ischemic injury is considered to correlate with impaired microcirculation. The aim of this study was to investigate the impact of heat-shock preconditioning (HSPC) on microcirculatory failure after ischemia/reperfusion (I/R) in steatotic livers by means of intra-vital fluorescence microscopy. Obese Zucker rats were used. In the HS group, rats underwent whole-body hyperthermia followed by 60-min partial liver ischemia. In group IR, rats were exposed only to ischemia. Microcirculation parameters (sinusoidal perfusion rate, sinusoidal diameter, leukocyte-endothelial interaction) were significantly better preserved in the HS group than in the IR group. Liver enzymes, oxygenated glutathione/reduced glutathione (GSSG/GSH) ratio, and electron microscopy showed less damage in the HS group. A marked expression of heat shock protein 72 (HSP72) and heme oxygenase (HO-1) was found only in the livers of group HS. HSPC mitigated the I/R injury of steatotic livers by preventing post-ischemic failure of microcirculation. This beneficial effect was found to be associated with the induction of HSP72 and HO-1.

Carbonic anhydrase II (CA II) is involved with the acid-base homeostasis of tissue. This study aims to evaluate the effect of traumatic dental occlusion (TDO) by means of CA II expression in osteoclasts and osteocytes (near the lamina dura and in the centre of alveolar bone septum), in the periodontal ligament (PDL) and in lining cells (periosteum). For this study, 50 male Wistar rats aged seven weeks were divided into 2 groups: Loaded and Unloaded group. The study periods were 2, 5, 7, 14 and 21 days. The Mann-Whitney U test for quantitative, and the Chi-square test for semi-quantitative analyses were used for group comparison, along with Bonferroni’s post-hoc test. Statistically significant differences between the groups were observed in the number of osteoclasts in the lamina dura (days 5, 7 and 21); the alveolar bone septum (days 2 and 7); osteocytes near the lamina dura (days 2, 5, 7 and 14); and in the centre of the alveolar bone septum (days 2, 5, 7 and 14). There were also differences between-group in CA II expression in the lining cells on days 7 and 14. TDO increases CA II expression in osteoclasts, osteocytes, the PDL and lining cells of the periosteum. Clinical Relevance: Traumatic dental occlusion stimulates higher cells activity of the alveolar bone at short (lamina dura) and long (centre of alveolar bone and periosteum) distances.

Although the issue of the occlusal load influence on the occurrence of pathological phenomena in the body has been discussed for decades, it is still a subject of debate. Pathogenic occlusion is defined as excessive occlusal forces (premature contacts and interference) that can cause injuries to the dentition, including teeth and periodontal tissues. Changes in occlusal dimensions, if not properly performed or treated, can lead to dysfunctions of the dentition, such as joint clicking, difficulty in chewing, occlusal discomfort, muscle fatigue, and pain.
 Aim: to determine the morphological changes of periodontium in rats of different age groups in the supraocclusal relationship of individual teeth in the age aspect.
 Materials and methods of the study. The study was conducted on 60 white laboratory rats aged 4 to 22 months and weighing 90 to 330 g. The rats were divided into control (30 animals) and experimental (30 animals) groups. Each group was divided into 3 subgroups (10 animals each) depending on the age of the rats: young, mature and senile. Young animals included rats aged 3 4 months with a weight of 90 100 g; mature animals aged 6-8 months with a weight of 150 170 g; senile rats 20 22 months and weighing 200 220 g. In the experimental group, the state of supraocclusion was modeled by increasing the height of the lower right second molars by placing 1 mm high filling. For the placement of the filling, 37% orthophosphorus etching gel for enamel and dentin (Latus, Ukraine), microapplicators (Latus, Ukraine), the fifth generation Prime&Bond NT adhesive system (Dentsply Sirona, Germany), the universal microhybrid light-curing composite material Latelux (Latus, Ukraine) and the photopolymerizer LED.D (WOODPECKER, China) were used according to the manufacturer's instructions. The experimental animals were withdrawn from the experiment on the 15th day by decapitation under general anesthesia with sodium thiopental. The lower jaws were skeletonized, and dental blocks were cut out in the area of the molars. For histological examination, the dental blocks were fixed in a 10% solution of neutral formalin for two days, dehydrated in alcohols of increasing concentration and embedded in paraffin. Then, sections were made from the obtained preparations on a Shandon Finesse 325 rotary microtome with a section thickness of 4-6 μm. The histological sections were fixed on degreased slides and dried. Van Gieson staining was performed. The width of the periodontal gap was determined using the ZEISS ZEN 3.7 program by Carl Zeiss Microscopy.
 Results of the study. Histometric analysis has showed significant morphological changes in the experimental group of all age categories. In young rats, the fibrinoid edema phenomena of the periodontal ligament collagen fibers were observed. In mature rats, there was a picture of mucoid edema of collagen fibers of the periodontal ligament. In senile rats, fibrinoid necrosis of collagen fibers of the periodontal ligament were discovered, an inflammatory infiltrate, macrophages and neutrophils, with a predominance of neutrophilic inflammatory microenvironment, and initial hyaline tissue changes were found. In all age groups, there was cement resorption on the lateral surfaces of the tooth root, lacunar resorption of alveolar bone tissue and the presence of a large number of osteoclasts. In senile rats, hypercementosis was determined in the apical part of the root. In the control group of all age categories, neither resorption nor disorganization of connective tissue, nor hypercementosis was detected.
 Conclusions. The study shows that traumatic occlusion leads to resorption of root and alveolar cementum in all age groups. In young rats, traumatic occlusion causes fibrinoid edema of collagen fibers of the periodontal ligament. In mature rats, traumatic occlusion causes mucoid edema of collagen fibers of the periodontal ligament. In senile rats, traumatic occlusion causes fibrinoid necrosis of collagen fibers of the periodontal ligament, initial hyaline tissue changes and hypercementosis.

Some aspects of the biochemical dynamics in the periodontal ligament and alveolar bone resulting from traumatic occlusion

Critical limb ischemia (CLI) is characterized by the impairment of microcirculation, necrosis and inflammation of the muscular tissue. Although the role of glycans in mediating inflammation has been reported, changes in the glycosylation following muscle ischemia remains poorly understood.Here, a murine CLI model was used to show the increase of high mannose, α-(2, 6)-sialic acid and the decrease of hybrid and bisected N-glycans as glycosylation associated with the ischemic environment. Using this model, the efficacy of an elastin-like recombinamers (ELR) hydrogel was assessed. The hydrogel modulates key angiogenic signaling pathways, resulting in capillary formation, and ECM remodeling. Arterioles formation, reduction of fibrosis and anti-inflammatory macrophage polarization wa also induced by the hydrogel administration. Modulation of glycosylation was observed, suggesting, in particular, a role for mannosylation and sialylation in the mediation of tissue repair. Our study elucidates the angiogenic potential of the ELR hydrogel for CLI applications and identifies glycosylation alterations as potential new therapeutic targets.

SummaryPeriodontitis is a chronic inflammatory disease causing alveolar bone loss and tooth damage. Traumatic occlusion (TO) exacerbates its progression, although the process is mechanistically unclear. This study investigated the role of the mechanosensitive ion channel PIEZO1 in TO-aggravated periodontal destruction. In a rat model combining periodontitis and TO, PIEZO1 expression decreased, with increased inflammation and impaired osteogenesis. Yoda1 treatment alleviated periodontal inflammation and bone loss, demonstrating its therapeutic potential. In vitro, mechanical stress and lipopolysaccharide (LPS) synergistically downregulated PIEZO1 in human periodontal ligament fibroblasts (hPDLFs), reducing osteogenic potential and elevating pro-inflammatory responses. Transcriptomics identified mitogen-activated protein kinase (MAPK) pathway inhibition as a key downstream effect. Yoda1-mediated activation restored Extracellular Signal-regulated Kinase (ERK), Jun N-terminal Kinase (JNK), and p38 phosphorylation; promoted osteogenesis; and suppressed inflammatory cytokines. Overall, TO exacerbates periodontitis by suppressing PIEZO1-MAPK signaling, and PIEZO1 activation may protect periodontal tissues from mechanical and inflammatory damage.

Tooth avulsion occurs when a tooth is completely displaced from its natural position due to an impact, causing significant damage to surrounding tissues, including the cementum, periodontal ligament, alveolar bone, gingiva, and dental pulp. Accidental tooth loss poses a significant challenge to public health, negatively impacting oral health-related quality of life. In this context, the objective of this study is to examine the primary impacts and evaluate the influence of tooth avulsion on the quality of life of children, seeking to understand the long-term consequences of this condition. This work is a narrative literature review. According to the literature analysis, tooth avulsion is a type of dentoalveolar trauma that involves the complete displacement of one or more teeth from their socket. In most cases, the injury affects a single tooth, although multiple avulsions can occur in some situations. Tooth avulsion in childhood represents a premature loss that can generate various complications for the child. Among the main problems associated, the following stand out: deficiency in mastication, alterations in phonation, modifications in bone and gingival structure, and psychosocial problems. Thus, we conclude that tooth avulsion in children represents not only a clinical challenge but also a profound impact on the quality of life of those affected. The consequences of this injury, which go far beyond the loss of a tooth, include functional and aesthetic compromises, as well as significant damage to the child's mental and emotional health.

BackgroundBecause of the low regeneration efficiency and unclear underlying molecular mechanism, tooth regeneration applications are limited. In this study, we explored the influence of residual periodontal ligament on the dentin regeneration potential of dental pulp stem cells (DPSCs) in the jaw.MethodsTo establish a tooth regeneration model, the incisors of New Zealand white rabbits were extracted while preserving residual periodontal ligament, followed by the implantation of DPSCs. After 3 months, micro-computed tomography (micro-CT), stereomicroscopy and scanning electron microscopy (SEM) were used to observe the volume, morphology and microstructure of regenerated tissue. Histological staining and immunostaining analyses were used to observe the morphological characteristics and expression of the dentin-specific proteins DMP1 and DSPP. To explore the mechanism, DPSCs and periodontal ligament stem cells (PDLSCs) were cocultured in vitro, and RNA was collected from the DPSCs for RNA-seq and bioinformatic analysis.ResultsThe results of micro-CT and stereomicroscopy showed that the number of sites with regeneration and the volume of regenerated tissue in the DPSCs/PDL group (6/8, 1.07 ± 0.93 cm3) were larger than those in the DPSCs group (3/8, 0.23 ± 0.41 cm3). The results of SEM showed that the regenerated dentin-like tissue in the DPSCs and DPSCs/PDL groups contained dentin tubules. Haematoxylin and eosin staining and immunohistochemical staining indicated that compared with the DPSCs group, the DPSCs/PDL group showed more regular regenerated tissue and higher expression levels of the dentin-specific proteins DMP1 and DSPP (DMP1: P = 0.02, DSPP: P = 0.01). RNA-seq showed that the coculture of DPSCs with PDLSCs resulted in the DPSCs differentially expressing 427 mRNAs (285 upregulated and 142 downregulated), 41 lncRNAs (26 upregulated and 15 downregulated), 411 circRNAs (224 upregulated and 187 downregulated), and 19 miRNAs (13 upregulated and 5 downregulated). Bioinformatic analysis revealed related Gene Ontology function and signalling pathways, including extracellular matrix (ECM), tumour necrosis factor (TNF) signalling and chemokine signalling pathways.ConclusionsResidual periodontal ligament in the extraction socket promotes the dentin regeneration potential of DPSCs in the jaw. RNA-seq and bioinformatic analysis revealed that ECM, TNF signalling and chemokine signalling pathways may represent the key factors and signalling pathways.