Potential of ferroptosis and ferritinophagy in migraine pathogenesis.

Objective: To assess the potential of ferroptosis and ferritinophagy in migraine pathogenesis. Background: Ferroptosis and ferritinophagy are related to increased cellular iron concentration and have been associated with the pathogenesis of several neurological disorders, but their potential in migraine pathogenesis has not been explored. Increased iron deposits in some deep brain areas, mainly periaqueductal gray (PAG), are reported in migraine and they have been associated with the disease severity and chronification as well as poor response to antimigraine drugs. Results: Iron deposits may interfere with antinociceptive signaling in the neuronal network in the brain areas affected by migraine, but their mechanistic role is unclear. Independently of the location, increased iron concentration may be related to ferroptosis and ferritinophagy in the cell. Therefore, both phenomena may be related to increased iron deposits in migraine. It is unclear whether these deposits are the reason, consequence, or just a correlate of migraine. Still, due to migraine-related elevated levels of iron, which is a prerequisite of ferroptosis and ferritinophagy, the potential of both phenomena in migraine should be explored. If the iron deposits matter in migraine pathogenesis, they should be mechanically linked with the clinical picture of the disease. As iron is an exogenous essential trace element, it is provided to the human body solely with diet or supplements. Therefore, exploring the role of iron in migraine pathogenesis may help to determine the potential role of iron-rich/poor dietary products as migraine triggers or relievers. Conclusion: Ferroptosis and ferritinophagy may be related to migraine pathogenesis through iron deposits in the deep areas of the brain.

Urine 5-Hydroxyindoleacetic Acid Negatively Correlates with Migraine Occurrence and Characteristics in the Interictal Phase of Episodic Migraine.

Although migraine belongs to the main causes of disability worldwide, the mechanisms of its pathogenesis are poorly known. As migraine diagnosis is based on the subjective assessment of symptoms, there is a need to establish objective auxiliary markers to support clinical diagnosis. Tryptophan (TRP) metabolism has been associated with the pathogenesis of neurological and psychiatric disorders. In the present work, we investigated an association between migraine and the urine concentration of TRP and its metabolites 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QA) in 21 low-frequency episodic migraine patients and 32 controls. We chose the interictal phase as the episodic migraine patients were recruited from the outpatient clinic and had monthly migraine days as low as 1-2 in many cases. Migraine patients displayed lower urinary levels of 5-HIAA (p < 0.01) and KYNA (p < 0.05), but KYN and QA were enhanced, as compared with the controls (p < 0.05 and 0.001, respectively). Consequently, the patients were characterized by different values of the 5-HIAA/TRP, KYN/TRP, KYNA/KYN, and KYNA/QA ratios (p < 0.001 for all). Furthermore, urinary concentration of 5-HIAA was negatively correlated with Migraine Disability Assessment score and monthly migraine and monthly headache days. There was a negative correlation between Patient Health Questionnaire 9 scores assessing depression. In conclusion, the urinary 5-HIAA level may be further explored to assess its suitability as an easy-to-determine marker of migraine.

PGC-1α regulates the interplay between oxidative stress, senescence and autophagy in the ageing retina important in age-related macular degeneration.

We previously showed that mice with knockout in the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) gene encoding the PGC-1α protein, and nuclear factor erythroid 2 like 2 (NFE2L2) gene, exhibited some features of the age-related macular degeneration (AMD) phenotype. To further explore the mechanism behind the involvement of PGC-1α in AMD pathogenesis we used young (3-month) and old (12-month) mice with knockout in the PPARGC1A gene and age-matched wild-type (WT) animals. An immunohistochemical analysis showed age-dependent different expression of markers of oxidative stress defence, senescence and autophagy in the retinal pigment epithelium of KO animals as compared with their WT counterparts. Multivariate inference testing showed that senescence and autophagy proteins had the greatest impact on the discrimination between KO and WT 3-month animals, but proteins of antioxidant defence also contributed to that discrimination. A bioinformatic analysis showed that PGC-1α might coordinate the interplay between genes encoding proteins involved in antioxidant defence, senescence and autophagy in the ageing retina. These data support importance of PGC-1α in AMD pathogenesis and confirm the utility of mice with PGC-1α knockout as an animal model to study AMD pathogenesis.

A New Generation of Gene Therapies as the Future of Wet AMD Treatment.

Age-related macular degeneration (AMD) is an eye disease and the most common cause of vision loss in the Western World. In its advanced stage, AMD occurs in two clinically distinguished forms, dry and wet, but only wet AMD is treatable. However, the treatment based on repeated injections with vascular endothelial growth factor A (VEGFA) antagonists may at best stop the disease progression and prevent or delay vision loss but without an improvement of visual dysfunction. Moreover, it is a serious mental and financial burden for patients and may be linked with some complications. The recent first success of intravitreal gene therapy with ADVM-022, which transformed retinal cells to continuous production of aflibercept, a VEGF antagonist, after a single injection, has opened a revolutionary perspective in wet AMD treatment. Promising results obtained so far in other ongoing clinical trials support this perspective. In this narrative/hypothesis review, we present basic information on wet AMD pathogenesis and treatment, the concept of gene therapy in retinal diseases, update evidence on completed and ongoing clinical trials with gene therapy for wet AMD, and perspectives on the progress to the clinic of "one and done" therapy for wet AMD to replace a lifetime of injections. Gene editing targeting the VEGFA gene is also presented as another gene therapy strategy to improve wet AMD management.

The Ketogenic Diet in the Prevention of Migraines in the Elderly.

Migraines display atypical age dependence, as the peak of their prevalence occurs between the ages of 20-40 years. With age, headache attacks occur less frequently and are characterized by a lower amplitude. However, both diagnosis and therapy of migraines in the elderly are challenging due to multiple comorbidities and polypharmacy. Dietary components and eating habits are migraine triggers; therefore, nutrition is a main target in migraine prevention. Several kinds of diets were proposed to prevent migraines, but none are commonly accepted due to inconsistent results obtained in different studies. The ketogenic diet is featured by very low-carbohydrate and high-fat contents. It may replace glucose with ketone bodies as the primary source of energy production. The ketogenic diet and the actions of ketone bodies are considered beneficial in several aspects of health, including migraine prevention, but studies on the ketogenic diet in migraines are not standardized and poorly evidenced. Apart from papers claiming beneficial effects of the ketogenic diet in migraines, several studies have reported that increased levels of ketone bodies may be associated with all-cause and incident heart failure mortality in older adults and are supported by research on mice showing that the ketogenic diets and diet supplementation with a human ketone body precursor may cause life span shortening. Therefore, despite reports showing a beneficial effect of the ketogenic diet in migraines, such a diet requires further studies, including clinical trials, to verify whether it should be recommended in older adults with migraines.

Autophagy may protect the brain against prolonged consequences of headache attacks: A narrative/hypothesis review.

OBJECTIVE: To assess the potential of autophagy in migraine pathogenesis. BACKGROUND: The interplay between neurons and microglial cells is important in migraine pathogenesis. Migraine-related effects, such as cortical spreading depolarization and release of calcitonin gene-related peptide, may initiate adenosine triphosphate (ATP)-mediating pro-nociceptive signaling in the meninges causing headaches. Such signaling may be induced by the interaction of ATP with purinergic receptor P2X 7 (P2X7R) on microglial cells leading to a Ca2+ -mediated pH increase in lysosomes and release of autolysosome-like vehicles from microglial cells indicating autophagy impairment. METHODS: A search in PubMed was conducted with the use of the terms "migraine," "autophagy," "microglia," and "degradation" in different combinations. RESULTS: Impaired autophagy in microglia may activate secretory autophagy and release of specific proteins, including brain-derived neurotrophic factor (BDNF), which can be also released through the pores induced by P2X7R activation in microglial cells. BDNF may be likewise released from microglial cells upon ATP- and Ca2+ -mediated activation of another purinergic receptor, P2X4R. BDNF released from microglia might induce autophagy in neurons to clear cellular debris produced by oxidative stress, which is induced in the brain as the response to migraine-related energy deficit. Therefore, migraine-related signaling may impair degradative autophagy, stimulate secretory autophagy in microglia, and degradative autophagy in neurons. These effects are mediated by purinergic receptors P2X4R and P2X7R, BDNF, ATP, and Ca2+ . CONCLUSION: Different effects of migraine-related events on degradative autophagy in microglia and neurons may prevent prolonged changes in the brain related to headache attacks.

Epigallocatechin-3-Gallate, an Active Green Tea Component to Support Anti-VEGFA Therapy in Wet Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a largely incurable disease and an emerging problem in aging societies. It occurs in two forms, dry and wet (exudative, neovascular), which may cause legal blindness and sight loss. Currently, there is not any effective treatment for dry AMD. Meanwhile, repeated intravitreal injections with antibodies effective against vascular endothelial growth factor A (VEGFA) slow down wet AMD progression but are not free from complications. (-)-Epigallocatechin-3-gallate (EGCG) is an active compound of green tea, which exerts many beneficial effects in the retinal pigment epithelium and the neural retina. It has been reported to downregulate the VEGFA gene by suppressing its activators. The inhibition of mitogen-activated protein kinases 1 and 3 (MAPK1 and MAPK3) may lie behind the antiangiogenic action of EGCG mediated by VEGFA. EGCG exerts protective effects against UV-induced damage to retinal cells and improves dysfunctional autophagy. EGCG may also interact with the mechanistic target rapamycin (MTOR) and unc-51-like autophagy activating kinase (ULK1) to modulate the interplay between autophagy and apoptosis. Several other studies report beneficial effects of EGCG on the retina that may be related to wet AMD. Therefore, controlled clinical trials are needed to verify whether diet supplementation with EGCG or green tea consumption may improve the results of anti-VEGFA therapy in wet AMD.

Epigenetic Connections of the TRPA1 Ion Channel in Pain Transmission and Neurogenic Inflammation - a Therapeutic Perspective in Migraine?

Persistent reprogramming of epigenetic pattern leads to changes in gene expression observed in many neurological disorders. Transient receptor potential cation channel subfamily A member 1 (TRPA1), a member of the TRP channels superfamily, is activated by many migraine triggers and expressed in trigeminal neurons and brain regions that are important in migraine pathogenesis. TRP channels change noxious stimuli into pain signals with the involvement of epigenetic regulation. The expression of the TRPA1 encoding gene, TRPA1, is modulated in pain-related syndromes by epigenetic alterations, including DNA methylation, histone modifications, and effects of non-coding RNAs: micro RNAs (miRNAs), long non-coding RNAs, and circular RNAs. TRPA1 may change epigenetic profile of many pain-related genes as it may modify enzymes responsible for epigenetic modifications and expression of non-coding RNAs. TRPA1 may induce the release of calcitonin gene related peptide (CGRP), from trigeminal neurons and dural tissue. Therefore, epigenetic regulation of TRPA1 may play a role in efficacy and safety of anti-migraine therapies targeting TRP channels and CGRP. TRPA1 is also involved in neurogenic inflammation, important in migraine pathogenesis. The fundamental role of TRPA1 in inflammatory pain transmission may be epigenetically regulated. In conclusion, epigenetic connections of TRPA1 may play a role in efficacy and safety of anti-migraine therapy targeting TRP channels or CGRP and they should be further explored for efficient and safe antimigraine treatment. This narrative/perspective review presents information on the structure and functions of TRPA1 as well as role of its epigenetic connections in pain transmission and potential in migraine therapy.

Different Aspects of Aging in Migraine.

Migraine is a common neurological disease displaying an unusual dependence on age. For most patients, the peak intensity of migraine headaches occurs in 20s and lasts until 40s, but then headache attacks become less intense, occur less frequently and the disease is more responsive to therapy. This relationship is valid in both females and males, although the prevalence of migraine in the former is 2-4 times greater than the latter. Recent concepts present migraine not only as a pathological event, but rather as a part of evolutionary adaptive response to protect organism against consequences of stress-induced brain energy deficit. However, these concepts do not fully explain that unusual dependence of migraine prevalence on age. Many aspects of aging, both molecular/cellular and social/cognitive, are interwound in migraine pathogenesis, but they neither explain why only some persons are affected by migraine, nor suggest any causal relationship. In this narrative/hypothesis review we present information on associations of migraine with chronological aging, brain aging, cellular senescence, stem cell exhaustion as well as social, cognitive, epigenetic, and metabolic aging. We also underline the role of oxidative stress in these associations. We hypothesize that migraine affects only individuals who have inborn, genetic/epigenetic, or acquired (traumas, shocks or complexes) migraine predispositions. These predispositions weakly depend on age and affected individuals are more prone to migraine triggers than others. Although the triggers can be related to many aspects of aging, social aging may play a particularly important role as the prevalence of its associated stress has a similar age-dependence as the prevalence of migraine. Moreover, social aging was shown to be associated with oxidative stress, important in many aspects of aging. In perspective, molecular mechanisms underlying social aging should be further explored and related to migraine with a closer association with migraine predisposition and difference in prevalence by sex.

Oral Glucosamine in the Treatment of Temporomandibular Joint Osteoarthritis: A Systematic Review.

Temporomandibular disorders (TMDs) occur frequently within the general population and are the most common non-dental cause of orofacial pain. Temporomandibular joint osteoarthritis (TMJ OA) is a degenerative joint disease (DJD). There have been several different methods of treatment of TMJ OA listed, including pharmacotherapy among others. Due to its anti-aging, antioxidative, bacteriostatic, anti-inflammatory, immuno-stimulating, pro-anabolic and anti-catabolic properties, oral glucosamine seems to be a potentially very effective agent in the treatment of TMJ OA. The aim of this review was to critically assess the efficacy of oral glucosamine in the treatment of TMJ OA on the basis of the literature. PubMed and Scopus databases were analyzed with the keywords: (temporomandibular joints) AND ((disorders) OR (osteoarthritis)) AND (treatment) AND (glucosamine). After the screening of 50 results, eight studies have been included in this review. Oral glucosamine is one of the symptomatic slow-acting drugs for osteoarthritis. There is not enough scientific evidence to unambiguously confirm the clinical effectiveness of glucosamine supplements in the treatment of TMJ OA on the basis of the literature. The most important aspect affecting the clinical efficacy of oral glucosamine in the treatment of TMJ OA was the total administration time. Administration of oral glucosamine for a longer period of time, i.e., 3 months, led to a significant reduction in TMJ pain and a significant increase in maximum mouth opening. It also resulted in long-term anti-inflammatory effects within the TMJs. Further long-term, randomized, double-blind studies, with a unified methodology, ought to be performed to draw the general recommendations for the use of oral glucosamine in the treatment of TMJ OA.

Vitamin D3 Metabolism and Its Role in Temporomandibular Joint Osteoarthritis and Autoimmune Thyroid Diseases.

The aim of this review was to present the metabolism of vitamin D3, as well as to discuss the role of vitamin D3 in bone metabolism, temporomandibular joint osteoarthritis (TMJ OA), and autoimmune thyroid diseases (AITD) on the basis of the literature. Vitamin D3 plays a significant role in human health, as it affects the calcium-phosphate balance and regulates the bone metabolism. Calcitriol impresses the pleiotropic effect on human biology and metabolism. Its modulative function upon the immune system is based on the reduction of Th1 cell activity and increased immunotolerance. Vitamin D3 deficiency may lead to an imbalance in the relationship between Th1/Th17 and Th2, Th17/Th reg, and is considered by some authors as one of the possible backgrounds of autoimmune thyroid diseases (AITD), e.g., Hashimoto's thyroiditis or Graves' disease. Moreover, vitamin D3, through its direct and indirect influence on bones and joints, may also play an important role in the development and progression of degenerative joint diseases, including temporomandibular joint osteoarthritis. Further randomized, double blind studies are needed to unequivocally confirm the relationship between vitamin D3 and abovementioned diseases and to answer the question concerning whether vitamin D3 supplementation may be used in the prevention and/or treatment of either AITD or OA diseases.

DNA Damage and Repair in Migraine: Oxidative Stress and Beyond.

Energy generation in the brain to ameliorate energy deficit in migraine leads to oxidative stress as it is associated with reactive oxygen species (ROS) that may damage DNA and show a pronociceptive action in meninges mediated by transient receptor potential cation channel subfamily A member 1 (TRPA1). Recent studies show high levels of single-strand breaks (SSBs) at specific sites in the genome of postmitotic neurons and point at SSB repair (SSBR) as an important element of homeostasis of the central nervous system. DNA topoisomerase 1 (TOP1) is stabilized in the DNA damage-inducing state by neuronal stimulation, including cortical spreading depression. Impairment in poly (ADP-ribose) polymerase 1 (PARP-1) and X-ray repair cross complementing 1 (XRCC1), key SSBR proteins, may be linked with migraine by transient receptor potential melastatin 2 (TRPM2). TRPM2 may also mediate the involvement of migraine-related neuroinflammation with PARP-1 activated by oxidative stress-related SSBs. In conclusion, aberrant activity of SSBR evoked by compromised PARP-1 and XRCC1 may contribute to pathological phenomena in the migraine brain. Such aberrant SSBR results in the lack of repair or misrepair of SSBs induced by ROS or resulting from impaired TOP1. Therefore, components of SSBR may be considered a prospective druggable target in migraine.

Interplay between aging and other factors of the pathogenesis of age-related macular degeneration.

Age-related macular degeneration (AMD) is a complex eye disease with the retina as the target tissue and aging as per definition the most serious risk factor. However, the retina contains over 60 kinds of cells that form different structures, including the neuroretina and retinal pigment epithelium (RPE) which can age at different rates. Other established or putative AMD risk factors can differentially affect the neuroretina and RPE and can differently interplay with aging of these structures. The occurrence of ß-amyloid plaques and increased levels of cholesterol in AMD retinas suggest that AMD may be a syndrome of accelerated brain aging. Therefore, the question about the real meaning of age in AMD is justified. In this review we present and update information on how aging may interplay with some aspects of AMD pathogenesis, such as oxidative stress, amyloid beta formation, circadian rhythm, metabolic aging and cellular senescence. Also, we show how this interplay can be specific for photoreceptors, microglia cells and RPE cells as well as in Bruch's membrane and the choroid. Therefore, the process of aging may differentially affect different retinal structures. As an accurate quantification of biological aging is important for risk stratification and early intervention for age-related diseases, the determination how photoreceptors, microglial and RPE cells age in AMD may be helpful for a precise diagnosis and treatment of this largely untreatable disease.

Position of the Hyoid Bone and Dimension of Nasopharynx and Oropharynx after Occlusal Splint Therapy and Physiotherapy in Patients Diagnosed with Temporomandibular Disorders.

Background: The aim of the study was to assess the position of the hyoid bone, as well as the width of the nasopharynx and oropharynx after occlusal splint therapy combined with physiotherapy in patients diagnosed with temporomandibular disorders (TMD). Methods: This was a clinical trial study. The study group consisted of 40 patients diagnosed with TMD, who were qualified for the treatment combining physiotherapy and occlusal splint therapy. Hyoid bone position as well as the width of the nasopharynx and oropharynx were assessed in lateral cephalograms taken before and after the end of the treatment. There were 15 generally healthy participants included into the control group, who had taken lateral cephalograms twice within the period of 1 to 2 years and did not receive any occlusal treatment in the meantime. Results: The position of the hyoid bone was significantly lowered and the dimension of the lower part of the oropharynx was significantly decreased after the end of the long-term occlusal splint therapy combined with physiotherapy in patients diagnosed with TMD. Conclusions: Long-term occlusal splint therapy combined with physiotherapy affected the position of the hyoid bone and the dimension of the lower part of the oropharynx.

Epigenetic Connection of the Calcitonin Gene-Related Peptide and Its Potential in Migraine.

The calcitonin gene-related peptide (CGRP) is implicated in the pathogenesis of several pain-related syndromes, including migraine. Targeting CGRP and its receptor by their antagonists and antibodies was a breakthrough in migraine therapy, but the need to improve efficacy and limit the side effects of these drugs justify further studies on the regulation of CGRP in migraine. The expression of the CGRP encoding gene, CALCA, is modulated by epigenetic modifications, including the DNA methylation, histone modification, and effects of micro RNAs (miRNAs), circular RNAs, and long-coding RNAs (lncRNAs). On the other hand, CGRP can change the epigenetic profile of neuronal and glial cells. The promoter of the CALCA gene has two CpG islands that may be specifically methylated in migraine patients. DNA methylation and lncRNAs were shown to play a role in the cell-specific alternative splicing of the CALCA primary transcript. CGRP may be involved in changes in neural cytoarchitecture that are controlled by histone deacetylase 6 (HDAC6) and can be related to migraine. Inhibition of HDAC6 results in reduced cortical-spreading depression and a blockade of the CGRP receptor. CGRP levels are associated with the expression of several miRNAs in plasma, making them useful peripheral markers of migraine. The fundamental role of CGRP in inflammatory pain transmission may be epigenetically regulated. In conclusion, epigenetic connections of CGRP should be further explored for efficient and safe antimigraine therapy.

Craniovertebral and Craniomandibular Changes in Patients with Temporomandibular Joint Disorders after Physiotherapy Combined with Occlusal Splint Therapy: A Prospective Case Control Study.

Background and Objectives: The aim of the study was to assess the craniovertebral and craniomandibular changes in patients diagnosed with temporomandibular joint disorders (TMD) after physiotherapy combined with occlusal splint therapy. Materials and Methods: There were forty patients (32 females, 80%), diagnosed with TMD, included into the study group. After the initial series of physiotherapy, patients received maxillary occlusal splints to be worn day and night. Participants continued physiotherapy simultaneously with occlusal splint therapy for 6 months. Lateral cephalograms taken in natural head position before and after the end of the therapy were used for measurements. The control group consisted of 15 healthy participants (12 females, 80%), who had taken lateral cephalograms twice, and did not receive any type of occlusal treatment nor physiotherapy in the meantime. Results: Occlusal splint therapy and physiotherapy combined together significantly affected: the vertical position of the mandible (significant increase, p < 0.0001), the sagittal position of mandible (significant decrease, p = 0.0065), as well as the width of the functional space between C1 and C2 (significant decrease, p = 0.0042). Moreover, the cervical lordosis was restored after the end of the treatment (p < 0.0001). Conclusions: Cooperation of physiotherapists with dental practitioners is necessary in the treatment of patients with TMD, including temporomandibular joint osteoarthritis.

Vitamin D May Protect against Breast Cancer through the Regulation of Long Noncoding RNAs by VDR Signaling.

Dietary vitamin D3 has attracted wide interest as a natural compound for breast cancer prevention and therapy, supported by in vitro and animal studies. The exact mechanism of such action of vitamin D3 is unknown and may include several independent or partly dependent pathways. The active metabolite of vitamin D3, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D, calcitriol), binds to the vitamin D receptor (VDR) and induces its translocation to the nucleus, where it transactivates a myriad of genes. Vitamin D3 is involved in the maintenance of a normal epigenetic profile whose disturbance may contribute to breast cancer. In general, the protective effect of vitamin D3 against breast cancer is underlined by inhibition of proliferation and migration, stimulation of differentiation and apoptosis, and inhibition of epithelial/mesenchymal transition in breast cells. Vitamin D3 may also inhibit the transformation of normal mammary progenitors into breast cancer stem cells that initiate and sustain the growth of breast tumors. As long noncoding RNAs (lncRNAs) play an important role in breast cancer pathogenesis, and the specific mechanisms underlying this role are poorly understood, we provided several arguments that vitamin D3/VDR may induce protective effects in breast cancer through modulation of lncRNAs that are important for breast cancer pathogenesis. The main lncRNAs candidates to mediate the protective effect of vitamin D3 in breast cancer are lncBCAS1-4_1, AFAP1 antisense RNA 1 (AFAP1-AS1), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), long intergenic non-protein-coding RNA 511 (LINC00511), LINC00346, small nucleolar RNA host gene 6 (SNHG6), and SNHG16, but there is a rationale to explore several other lncRNAs.

Do the Mandibular Condyles Change Their Positions within Glenoid Fossae after Occlusal Splint Therapy Combined with Physiotherapy in Patients Diagnosed with Temporomandibular Joint Disorders? A Prospective Case Control Study.

The research question was: do the mandibular condyles change their position within glenoid fossae after treatment combining occlusal splint therapy and physiotherapy in patients diagnosed with temporomandibular disorders (TMD)? Forty patients with TMD were included into the study. They underwent initial physiotherapy, and a six-month treatment of occlusal splint therapy with physiotherapy. Cone-beam computed tomography images of temporomandibular joints (TMJs) were taken before and after the treatment. The control group consisted of 15 asymptomatic patients, who did not receive any type of occlusal treatment. The changes in the dimension of anterior, superior, posterior, and medial joint spaces after the end of the treatment in patients with TMD were statistically insignificant. The average value of condylar ratio was significantly higher after the end of the treatment (p = 0.025). The changes in the condylar sagittal position were statistically insignificant. Occlusal splint therapy with physiotherapy did not change significantly the dimension of joint spaces, nor placed the mandibular condyles into the centric relation. Treatment of patients with TMD should not aim at gnathological concept of placing the mandibular condyles into centric relation, because centric relation appears not to be mandatory to achieve successful results of treatment in patients with TMD.

General Characteristics, Biomedical and Dental Application, and Usage of Chitosan in the Treatment of Temporomandibular Joint Disorders: A Narrative Review.

The aim of this narrative review was to present research investigating chitosan, including its general characteristics, properties, and medical and dental applications, and finally to present the current state of knowledge regarding the efficacy of chitosan in the treatment of temporomandibular disorders (TMDs) based on the literature. The PICO approach was used for the literature search strategy. The PubMed database was analyzed with the following keywords: ("chitosan"[MeSH Terms] OR "chitosan"[All Fields] OR "chitosans"[All Fields] OR "chitosan s"[All Fields] OR "chitosane"[All Fields]) AND ("temporomandibular joint"[MeSH Terms] OR ("tem-poromandibular"[All Fields] AND "joint"[All Fields]) OR "temporomandibular joint"[All Fields] OR ("temporomandibular"[All Fields] AND "joints"[All Fields]) OR "temporo-mandibular joints"[All Fields]). After screening 8 results, 5 studies were included in this review. Chitosan presents many biological properties and therefore it can be widely used in several branches of medicine and dentistry. Chitosan promotes wound healing, helps to control bleeding, and is used in wound dressings, such as sutures and artificial skin. Apart from its antibacterial property, chitosan has many other properties, such as antifungal, mucoadhesive, anti-inflammatory, analgesic, antioxidant, antihyperglycemic, and antitumoral properties. Further clinical studies assessing the efficacy of chitosan in the treatment of TMD are required. According to only one clinical study, chitosan was effective in the treatment of TMD; however, better clinical results were obtained with platelet-rich plasma.

RIF1 Links Replication Timing with Fork Reactivation and DNA Double-Strand Break Repair.

Replication timing (RT) is a cellular program to coordinate initiation of DNA replication in all origins within the genome. RIF1 (replication timing regulatory factor 1) is a master regulator of RT in human cells. This role of RIF1 is associated with binding G4-quadruplexes and changes in 3D chromatin that may suppress origin activation over a long distance. Many effects of RIF1 in fork reactivation and DNA double-strand (DSB) repair (DSBR) are underlined by its interaction with TP53BP1 (tumor protein p53 binding protein). In G1, RIF1 acts antagonistically to BRCA1 (BRCA1 DNA repair associated), suppressing end resection and homologous recombination repair (HRR) and promoting non-homologous end joining (NHEJ), contributing to DSBR pathway choice. RIF1 is an important element of intra-S-checkpoints to recover damaged replication fork with the involvement of HRR. High-resolution microscopic studies show that RIF1 cooperates with TP53BP1 to preserve 3D structure and epigenetic markers of genomic loci disrupted by DSBs. Apart from TP53BP1, RIF1 interact with many other proteins, including proteins involved in DNA damage response, cell cycle regulation, and chromatin remodeling. As impaired RT, DSBR and fork reactivation are associated with genomic instability, a hallmark of malignant transformation, RIF1 has a diagnostic, prognostic, and therapeutic potential in cancer. Further studies may reveal other aspects of common regulation of RT, DSBR, and fork reactivation by RIF1.