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Neuroscience and Biobehavioral Reviews Jul 2019Environmental stressors, such as childhood maltreatment, have been recognized to contribute to the development of depression. Growing evidence suggests that epigenetic...
Environmental stressors, such as childhood maltreatment, have been recognized to contribute to the development of depression. Growing evidence suggests that epigenetic changes are a key mechanism by which stressors interact with the genome leading to stable changes in DNA structure, gene expression, and behaviour. The current review aimed to evaluate the relationship between stress-associated epigenetic changes and depression. Human studies were identified via systematic searching of PubMed/Medline from inception to February 2018. Seventeen articles were identified. Stress-associated epigenetic changes in the following genes were correlated with depression: NRC31, SLCA4, BDNF, FKBP5, SKA2, OXTR, LINGO3, POU3F1 and ITGB1. Epigenetic changes in glucocorticoid signaling (e.g., NR3C1, FKBP5), serotonergic signaling (e.g. SLC6A4), and neurotrophin (e.g., BDNF) genes appear to be the most promising therapeutic targets for future research. However, continued research is warranted due to inconsistent findings regarding the directionality of epigenetic modification. Future studies should also aim to control for the use of psychotropic agents due to their widespread use in depressed populations and established effects on DNA methylation.
Topics: Adult; Adverse Childhood Experiences; Child; Child Abuse; Depression; Depressive Disorder, Major; Epigenesis, Genetic; Humans; Stress, Psychological
PubMed: 31005627
DOI: 10.1016/j.neubiorev.2019.04.010 -
Signal Transduction and Targeted Therapy Mar 2023The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. The p53 protein is a transcription... (Review)
Review
The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. The p53 protein is a transcription factor that can activate the expression of multiple target genes and plays critical roles in regulating cell cycle, apoptosis, and genomic stability, and is widely regarded as the "guardian of the genome". Accumulating evidence has shown that p53 also regulates cell metabolism, ferroptosis, tumor microenvironment, autophagy and so on, all of which contribute to tumor suppression. Mutations in TP53 not only impair its tumor suppressor function, but also confer oncogenic properties to p53 mutants. Since p53 is mutated and inactivated in most malignant tumors, it has been a very attractive target for developing new anti-cancer drugs. However, until recently, p53 was considered an "undruggable" target and little progress has been made with p53-targeted therapies. Here, we provide a systematic review of the diverse molecular mechanisms of the p53 signaling pathway and how TP53 mutations impact tumor progression. We also discuss key structural features of the p53 protein and its inactivation by oncogenic mutations. In addition, we review the efforts that have been made in p53-targeted therapies, and discuss the challenges that have been encountered in clinical development.
Topics: Humans; Tumor Suppressor Protein p53; Apoptosis; Autophagy; Cell Cycle; Ferroptosis
PubMed: 36859359
DOI: 10.1038/s41392-023-01347-1 -
World Neurosurgery Jan 2022Lumbar disc degeneration is one of the leading causes of chronic low back pain. The degenerative cascade is often initiated by an imbalance between catabolic and...
Lumbar disc degeneration is one of the leading causes of chronic low back pain. The degenerative cascade is often initiated by an imbalance between catabolic and anabolic processes in the intervertebral discs. As a consequence of extracellular matrix degradation, neoinnervation and neovascularization take place. Ultimately, this degenerative process results in disc bulging and loss of nucleus pulposus and water content and subsequent loss of disc height. Most patients respond to conservative management and surgical interventions well initially, yet a significant number of patients continue to suffer from chronic low back pain. Because of the high prevalence of long-term discogenic pain, regenerative biological therapies, including gene therapies, growth factors, cellular-based injections, and tissue-engineered constructs, have attracted significant attention in light of their potential to directly address the degenerative process. Understanding the pathophysiology of degenerative disc disease is important in both refining existing technologies and developing innovative techniques to reverse the degenerative processes in the discs. In this review, we aimed to cover the underlying pathophysiology of degenerative disc disease as well as its associated risk factors and give a comprehensive summary about the developmental, structural, radiological, and biomechanical properties of human intervertebral discs.
Topics: Humans; Intervertebral Disc Degeneration; Low Back Pain; Lumbar Vertebrae; Stress, Mechanical
PubMed: 34929784
DOI: 10.1016/j.wneu.2021.09.066 -
International Journal of Molecular... May 2022Currently, myofascial pain has become one of the main problems in healthcare systems. Research into its causes and the structures related to it may help to improve its... (Review)
Review
Currently, myofascial pain has become one of the main problems in healthcare systems. Research into its causes and the structures related to it may help to improve its management. Until some years ago, all the studies were focused on muscle alterations, as trigger points, but recently, fasciae are starting to be considered a new, possible source of pain. This systematic review has been conducted for the purpose of analyze the current evidence of the muscular/deep fasciae innervation from a histological and/or immunohistochemical point of view. A literature search published between 2000 and 2021 was made in PubMed and Google Scholar. Search terms included a combination of fascia, innervation, immunohistochemical, and different immunohistochemical markers. Of the 23 total studies included in the review, five studies were performed in rats, four in mice, two in horses, ten in humans, and two in both humans and rats. There were a great variety of immunohistochemical markers used to detect the innervation of the fasciae; the most used were Protein Gene Marker 9.5 (used in twelve studies), Calcitonin Gene-Related Peptide (ten studies), S100 (ten studies), substance P (seven studies), and tyrosine hydroxylase (six studies). Various areas have been studied, with the thoracolumbar fascia being the most observed. Besides, the papers highlighted diversity in the density and type of innervation in the various fasciae, going from free nerve endings to Pacini and Ruffini corpuscles. Finally, it has been observed that the innervation is increased in the pathological fasciae. From this review, it is evident that fasciae are well innerved, their innervation have a particular distribution and precise localization and is composed especially by proprioceptors and nociceptors, the latter being more numerous in pathological situations. This could contribute to a better comprehension and management of pain.
Topics: Animals; Fascia; Horses; Mechanoreceptors; Mice; Musculoskeletal Physiological Phenomena; Pain; Rats; Sensory Receptor Cells
PubMed: 35628484
DOI: 10.3390/ijms23105674 -
Orphanet Journal of Rare Diseases Feb 2019Congenital myasthenic syndromes (CMSs) are a genotypically and phenotypically heterogeneous group of neuromuscular disorders, which have in common an impaired...
OBJECTIVES
Congenital myasthenic syndromes (CMSs) are a genotypically and phenotypically heterogeneous group of neuromuscular disorders, which have in common an impaired neuromuscular transmission. Since the field of CMSs is steadily expanding, the present review aimed at summarizing and discussing current knowledge and recent advances concerning the etiology, clinical presentation, diagnosis, and treatment of CMSs.
METHODS
Systematic literature review.
RESULTS
Currently, mutations in 32 genes are made responsible for autosomal dominant or autosomal recessive CMSs. These mutations concern 8 presynaptic, 4 synaptic, 15 post-synaptic, and 5 glycosilation proteins. These proteins function as ion-channels, enzymes, or structural, signalling, sensor, or transporter proteins. The most common causative genes are CHAT, COLQ, RAPSN, CHRNE, DOK7, and GFPT1. Phenotypically, these mutations manifest as abnormal fatigability or permanent or fluctuating weakness of extra-ocular, facial, bulbar, axial, respiratory, or limb muscles, hypotonia, or developmental delay. Cognitive disability, dysmorphism, neuropathy, or epilepsy are rare. Low- or high-frequency repetitive nerve stimulation may show an abnormal increment or decrement, and SF-EMG an increased jitter or blockings. Most CMSs respond favourably to acetylcholine-esterase inhibitors, 3,4-diamino-pyridine, salbutamol, albuterol, ephedrine, fluoxetine, or atracurium.
CONCLUSIONS
CMSs are an increasingly recognised group of genetically transmitted defects, which usually respond favorably to drugs enhancing the neuromuscular transmission. CMSs need to be differentiated from neuromuscular disorders due to muscle or nerve dysfunction.
Topics: Cholinesterase Inhibitors; Humans; Mutation; Myasthenic Syndromes, Congenital; Neuromuscular Agents; Proteins
PubMed: 30808424
DOI: 10.1186/s13023-019-1025-5 -
Journal of Clinical Periodontology Mar 2017The oral microbiome is diverse and exists as multispecies microbial communities on oral surfaces in structurally and functionally organized biofilms. (Review)
Review
BACKGROUND
The oral microbiome is diverse and exists as multispecies microbial communities on oral surfaces in structurally and functionally organized biofilms.
AIM
To describe the network of microbial interactions (both synergistic and antagonistic) occurring within these biofilms and assess their role in oral health and dental disease.
METHODS
PubMed database was searched for studies on microbial ecological interactions in dental biofilms. The search results did not lend themselves to systematic review and have been summarized in a narrative review instead.
RESULTS
Five hundred and forty-seven original research articles and 212 reviews were identified. The majority (86%) of research articles addressed bacterial-bacterial interactions, while inter-kingdom microbial interactions were the least studied. The interactions included physical and nutritional synergistic associations, antagonism, cell-to-cell communication and gene transfer.
CONCLUSIONS
Oral microbial communities display emergent properties that cannot be inferred from studies of single species. Individual organisms grow in environments they would not tolerate in pure culture. The networks of multiple synergistic and antagonistic interactions generate microbial inter-dependencies and give biofilms a resilience to minor environmental perturbations, and this contributes to oral health. If key environmental pressures exceed thresholds associated with health, then the competitiveness among oral microorganisms is altered and dysbiosis can occur, increasing the risk of dental disease.
Topics: Biofilms; Humans; Microbial Interactions; Microbiota; Mouth Diseases; Oral Health; Tooth
PubMed: 28266111
DOI: 10.1111/jcpe.12679 -
Cureus May 2022Resorbable collagen has been utilized to treat wounds, close graft, and tooth extraction sites, and enhance recovery. Collagen-based membranes are also used as barriers... (Review)
Review
Resorbable collagen has been utilized to treat wounds, close graft, and tooth extraction sites, and enhance recovery. Collagen-based membranes are also used as barriers in periodontal and implant therapy to limit epithelial migration and allow cells with the regenerative capacity to fill the problem area. This systematic review was carried out to analyze the studies focusing on collagen structure, synthesis, and its applications. A detailed and extensive search was performed with the help of the keywords "collagen structure", "collagen synthesis" and "collagen applications". There was extensive literature search in reliable and authentic databases like PubMed, Scopus, Web of Sciences, Ovidsp, and Cochrane library to obtain papers focusing on collagen structure, synthesis, and applications. During the systematic review, data were obtained concerning the following parameters. Type of study, nature of aim of the study, size of the sample in the study, gender and age of the subjects included in the study, prevalence of skin diseases where collagen was used for treatment, dose of collagen used, form in which collagen was used, the origin of collagen used, analysis of different variables, structure, and synthesis of collagen. Twenty-two studies were included in this systematic review. The studies discussed the structure, synthesis, and applications of collagen in treatment. In studies focusing on the application of collagen supplements, most of the study subjects were females (68.3%). The study subjects included both healthy and unhealthy subjects. The study subjects were divided into two categories. One category was the intervention group, while another group was the placebo group. Collagen was administered in hydrolysate form (90%) in some studies, bovine form (2.3%), and porcine form (3.4%) in other studies. Collagen supplementation was found to provide better results in both healthy and unhealthy effects in improving the health of skin, cornea, bone, periodontium, face, etc. It can be concluded that collagen is an integral part of the body. The application of collagen supplements can be pretty effective in maintaining the proper health of several important structures of the body like skin, face, cornea, nails, periodontium, etc. Thus, a detailed study of the molecular structure of collagen and genes associated with each type of collagen is essential for further research and treatment of collagen-associated disorders.
PubMed: 35702467
DOI: 10.7759/cureus.24856 -
Journal of Cosmetic Dermatology Dec 2022Bakuchiol (BAK), a meroterpene phenol abundant in the plant Psoralea corylifolia, is an emerging cosmeceutical agent with promising anti-aging, anti-inflammatory, and... (Review)
Review
BACKGROUND
Bakuchiol (BAK), a meroterpene phenol abundant in the plant Psoralea corylifolia, is an emerging cosmeceutical agent with promising anti-aging, anti-inflammatory, and antibacterial properties. The trend for "clean" skincare products and search for anti-aging retinoid alternatives have poised BAK as a "must-have" ingredient in skincare.
AIMS
Our aim was to review the data for the applications of BAK in dermatology.
METHODS
This is a systematic review of PubMed.
RESULTS
Thirty articles matched our search terms ["Bakuchiol" and "Dermatology"] or ["Bakuchiol" and "Skin"] of which one did not meet inclusion criteria, 16 were pre-clinical studies, seven clinical studies, three commentaries, two narrative reviews, and one report on adverse events. BAK has been mostly studied for its effects on photoaging, acne, and post-inflammatory hyperpigmentation (PIH), showing beneficial results comparable to those achieved by topical retinoids. While having no structural resemblance to retinoids, BAK can function as a retinol analog, through retinol-like regulation of gene expression. In in vivo studies, BAK was used alone or in combination with other products resulting in a significant reduction in photodamage, hyperpigmentation, wrinkle scores, and acne severity. Additionally, in vitro studies hinted at its anti-cancer properties by inhibiting epidermal growth factor induced neoplastic cell transformation. Also, demonstrated potential applications in psoriasis by normalizing keratinocyte activity and in pigmentary disorders through inhibition of melanogenesis. There was one adverse event case reported of contact dermatitis in the literature.
CONCLUSIONS
Bakuchiol is a retinol alternative with anti-aging, antibacterial, and anti-inflammatory properties. Additional studies are warranted to better understand its applications in dermatology.
Topics: Humans; Vitamin A; Retinoids; Phenols; Acne Vulgaris; Anti-Bacterial Agents
PubMed: 36176207
DOI: 10.1111/jocd.15420 -
Pharmacological Reviews Oct 2020RNA-based therapies, including RNA molecules as drugs and RNA-targeted small molecules, offer unique opportunities to expand the range of therapeutic targets. Various...
RNA-based therapies, including RNA molecules as drugs and RNA-targeted small molecules, offer unique opportunities to expand the range of therapeutic targets. Various forms of RNAs may be used to selectively act on proteins, transcripts, and genes that cannot be targeted by conventional small molecules or proteins. Although development of RNA drugs faces unparalleled challenges, many strategies have been developed to improve RNA metabolic stability and intracellular delivery. A number of RNA drugs have been approved for medical use, including aptamers (e.g., pegaptanib) that mechanistically act on protein target and small interfering RNAs (e.g., patisiran and givosiran) and antisense oligonucleotides (e.g., inotersen and golodirsen) that directly interfere with RNA targets. Furthermore, guide RNAs are essential components of novel gene editing modalities, and mRNA therapeutics are under development for protein replacement therapy or vaccination, including those against unprecedented severe acute respiratory syndrome coronavirus pandemic. Moreover, functional RNAs or RNA motifs are highly structured to form binding pockets or clefts that are accessible by small molecules. Many natural, semisynthetic, or synthetic antibiotics (e.g., aminoglycosides, tetracyclines, macrolides, oxazolidinones, and phenicols) can directly bind to ribosomal RNAs to achieve the inhibition of bacterial infections. Therefore, there is growing interest in developing RNA-targeted small-molecule drugs amenable to oral administration, and some (e.g., risdiplam and branaplam) have entered clinical trials. Here, we review the pharmacology of novel RNA drugs and RNA-targeted small-molecule medications, with a focus on recent progresses and strategies. Challenges in the development of novel druggable RNA entities and identification of viable RNA targets and selective small-molecule binders are discussed. SIGNIFICANCE STATEMENT: With the understanding of RNA functions and critical roles in diseases, as well as the development of RNA-related technologies, there is growing interest in developing novel RNA-based therapeutics. This comprehensive review presents pharmacology of both RNA drugs and RNA-targeted small-molecule medications, focusing on novel mechanisms of action, the most recent progress, and existing challenges.
Topics: Aptamers, Nucleotide; Betacoronavirus; COVID-19; Chemistry Techniques, Analytical; Clustered Regularly Interspaced Short Palindromic Repeats; Coronavirus Infections; Drug Delivery Systems; Drug Development; Drug Discovery; Humans; MicroRNAs; Oligonucleotides, Antisense; Pandemics; Pneumonia, Viral; RNA; RNA, Antisense; RNA, Messenger; RNA, Ribosomal; RNA, Small Interfering; RNA, Viral; Ribonucleases; Riboswitch; SARS-CoV-2
PubMed: 32929000
DOI: 10.1124/pr.120.019554 -
Frontiers in Psychiatry 2021Clinical studies suggest the therapeutic potential of psychedelics, including ayahuasca, DMT, psilocybin, and LSD, in stress-related disorders. These substances induce...
Clinical studies suggest the therapeutic potential of psychedelics, including ayahuasca, DMT, psilocybin, and LSD, in stress-related disorders. These substances induce cognitive, antidepressant, anxiolytic, and antiaddictive effects suggested to arise from biological changes similar to conventional antidepressants or the rapid-acting substance ketamine. The proposed route is by inducing brain neuroplasticity. This review attempts to summarize the evidence that psychedelics induce neuroplasticity by focusing on psychedelics' cellular and molecular neuroplasticity effects after single and repeated administration. When behavioral parameters are encountered in the selected studies, the biological pathways will be linked to the behavioral effects. Additionally, knowledge gaps in the underlying biology of clinical outcomes of psychedelics are highlighted. The literature searched yielded 344 results. Title and abstract screening reduced the sample to 35; eight were included from other sources, and full-text screening resulted in the final selection of 16 preclinical and four clinical studies. Studies ( = 20) show that a single administration of a psychedelic produces rapid changes in plasticity mechanisms on a molecular, neuronal, synaptic, and dendritic level. The expression of plasticity-related genes and proteins, including Brain-Derived Neurotrophic Factor (BDNF), is changed after a single administration of psychedelics, resulting in changed neuroplasticity. The latter included more dendritic complexity, which outlasted the acute effects of the psychedelic. Repeated administration of a psychedelic directly stimulated neurogenesis and increased BDNF mRNA levels up to a month after treatment. Findings from the current review demonstrate that psychedelics induce molecular and cellular adaptations related to neuroplasticity and suggest those run parallel to the clinical effects of psychedelics, potentially underlying them. Future (pre)clinical research might focus on deciphering the specific cellular mechanism activated by different psychedelics and related to long-term clinical and biological effects to increase our understanding of the therapeutic potential of these compounds.
PubMed: 34566723
DOI: 10.3389/fpsyt.2021.724606