Abstract

Osteoporosis is a systemic bone disease characterized by reduced bone mass and deterioration of the microstructure of bone tissue, leading to an increased risk of fragility fractures and affecting human health worldwide. Food-derived peptides are widely used in functional foods due to their low toxicity, ease of digestion and absorption, and potential to improve osteoporosis. This review summarized and discussed methods of diagnosing osteoporosis, treatment approaches, specific peptides as alternatives to conventional drugs, and the laboratory preparation and identification methods of peptides. It was found that peptides interacting with RGD (arginine-glycine-aspartic acid)-binding active sites in integrin could alleviate osteoporosis, analyzed the interaction sites between these osteogenic peptides and integrin, and further discussed their effects on improving osteoporosis. These may provide new insights for rapid screening of osteogenic peptides, and provide a theoretical basis for their application in bone materials and functional foods.

Osteoporosis

As the global population ages, the prevalence of diseases associated with aging, such as diabetes, arthritis, and dementia, also increases ( Li et al., 2021 , Lopes et al., 2022 ). Among these, the increasing incidence of chronic diseases such as osteoporosis have caused a significant societal burden ( Su et al., 2020 ). Osteoporosis affects more than 200 million people worldwide ( Shen et al., 2022 ). By 2030, the number of hip fractures among males are estimated to increase by 51.8% globally, and females are at even higher risk ( Gasparik et al., 2023 ). The increasing incidence of osteoporosis may contribute to a higher risk of fractures and reduced life expectancy, necessitating investigations on the prevention and treatment of this condition.

In the human body, normal bone metabolism involves persistent bone tissue remodeling through osteoblast-dependent bone formation and osteoclast-dependent bone resorption. Enhanced bone resorption leads to reduced bone density, a primary factor in the development of osteoporosis ( Malluche, Davenport, Lima, & Monier-Faugere, 2022 ). Osteoporosis is characterized by reduced bone density, deteriorating bone microstructure, and aggravated bone fragility, which increase the risk of fracture. These changes in bone structure are closely linked to the activities of osteoblasts and osteoclasts: osteoblasts secrete non-collagen proteins to regulate the mineralization of bone matrix, while osteoclasts are responsible for bone resorption ( Kittivanichkul, Watanabe, Nagaoka, & Malaivijitnond, 2016 ). Osteocytes, the most abundant cells in mature bone ( Fig. 1 ), interact with osteoblasts and osteoclasts to influence bone formation and resorption and are closely related to osteoporosis.

Perspectives

The value of food protein digests and bioactive peptides as functional foods in the future cannot be estimated. A healthy diet should contain osteogenic peptides that have been investigated through preclinical research and clinical trials. Prediction of osteogenic peptides directly from enzymatic hydrolysis products has significantly reduced the cost of osteogenic peptides compared to multi-step purification, isolation, screening and identification. Moreover, advanced and powerful technologies, such as mass spectrometry, protein purification, bioinformatics, crystallography, micro-computed tomography, and biofilm interference, are widely utilized to study molecular structure and provide a theoretical basis for understanding the relationship between structure and activity at the molecular level. In this review, the evaluation methods and treatment methods of osteoporosis are reviewed, and it is found that osteopoietic peptides from food sources are a potential source to replace drugs with side effects for osteoporosis treatment. Peptides can improve osteoporosis by interacting with RGD binding sites within integrins, which may be used in future computer simulations to rapidly predict and screen new methods of osteogenic peptides. Taken together, these not only improve the safety of osteoporosis treatment but also reduce the cost of screening osteogenic peptides. This review aims to encourage studies on the structure-activity relationships between osteogenic peptides and integrins that regulate cell adhesion, promoting osteoblast and inhibiting osteoclast proliferation and differentiation. Osteogenic peptides also have the potential for application in the development of bioadhesives for bone materials. Therefore, research ideas for predicting and screening bone-forming active peptides have been summarized, these ideas may lead to the development of bone materials, active drugs that promote bone formation and functional foods.

Abstract

Nowadays, it is an established concept that the capability to reach a specialised cell identity via differentiation, as in the case of multi- and pluripotent stem cells, is not only determined by biochemical factors, but that also physical aspects of the microenvironment play a key role; interpreted by the cell through a force-based signalling pathway called mechanotransduction. However, the intricate ties between the elements involved in mechanotransduction, such as the extracellular matrix, the glycocalyx, the cell membrane, Integrin adhesion complexes, Cadherin-mediated cell/cell adhesion, the cytoskeleton, and the nucleus, are still far from being understood in detail. Here we report what is currently known about these elements in general and their specific interplay in the context of multi- and pluripotent stem cells. We furthermore merge this overview to a more comprehensive picture, that aims to cover the whole mechanotransductive pathway from the cell/microenvironment interface to the regulation of the chromatin structure in the nucleus. Ultimately, with this review we outline the current picture of the interplay between mechanotransductive cues and epigenetic regulation and how these processes might contribute to stem cell dynamics and fate.

Introduction

One of the basic principles enabling multicellular life is the differentiation of stem cells (SCs), into specialised cells with a defined identity, shape, and function ( McBeath et al., 2004 ) ( Tewary et al., 2018 ). SCs are defined as cells that are clonogenic, which defines their capability of both, self-renewing and retaining multilineage differentiation potency. In vertebrates, the Zygote represents the earliest stem cell (totipotent) in ontogeny, from which originate the pluripotent stem cells (PSCs) of the inner cell mass of the blastocyst ( Dean et al., 2003 , Smith, 2017 ). Soon thereafter, PSCs continue to expand during embryo development becoming progressively committed in their cell fate and acquiring a more restricted potency ( Dean et al., 2003 , Osorno et al., 2012 , Smith, 2017 ). Even at the end of embryogenesis, when the organism is fully formed, and its organs are composed of functionally mature cells, some SCs are still present. These cells, which possess a more limited differentiating potential (multipotent), in turn, give rise to a progeny of precursor cells and, finally, to functionally mature cells. Some examples are represented by the hematopoietic SCs in the bone marrow, the intestinal SCs in the gut’s crypts, the epithelial SCs in the epidermis or the mesenchymal stem cells (MSCs) which play an important role in the maintenance and regeneration of bones and cartilage ( Barker, 2014 , Evans et al., 2013 , Guan et al., 2012 , Tewary et al., 2018 , Watt, 2002 , Weissman, 2000 ).

The inherent high level of plasticity characterising SCs is at the base of their capability to respond precisely to appropriate stimuli with differentiative behaviour. Understanding this essential principle of multicellular life; i.e., the regulation of cell identity and fate, is one of the most important fields of research in modern cell biology, primarily due to its impact on the development of new therapeutic approaches in regenerative medicine. Such knowledge can directly benefit stem cell bioengineering by leveraging the SC plasticity and control over SC behaviour for the application in tissue engineering, patient-specific disease modelling and cell therapies ( Tewary et al., 2018 ).

Conclusions

In recent years there has been a fascinating expansion of our knowledge about the interplay between mechanotransductive signalling and chromatin regulation, and how this impacts on multi- and pluripotent stem cell dynamics, which we try to highlight in this review.

However, what shapes the life of a cell and its identity, from the outside (biophysical and structural cues of the cellular microenvironment) and from the inside (nuclear and chromatin organisation) and how it is connected (mechanotransduction and epigenetics) are highly relevant biological issues that are yet far from being understood in detail. Starting from the stem cell/microenvironment interface, a much more detailed understanding of the nanoscale events in this interface is necessary to unravel 1) what the SC perceives of the biophysical nature and the 3D adhesion site configuration and 2) how the immanent nanoscale information is interpreted and converted, through force-based actions, into a remodelling at the level of the IACs, cell/cell adhesions, cytoskeleton and nucleus.

Abstract

Liver fibrosis is an intrahepatic chronic damage repair response caused by various reasons such as alcoholic liver, fatty liver, viral hepatitis, autoimmune diseases, etc., and is closely related to the progression of liver disease. Currently, the mechanisms of liver fibrosis and its treatment are hot research topics in the field of liver disease remedy. Mesenchymal stem cells (MSCs) are a class of adult stem cells with self-renewal and multidirectional differentiation potential, which can ameliorate fibrosis through hepatic-directed differentiation, paracrine effects, and immunomodulation. However, the low inner-liver colonization rate, low survival rate, and short duration of intervention after stem cell transplantation have limited their wide clinical application. With the intensive research on liver fibrosis worldwide, it has been found that MSCs and MSCs-derived exosomes combined with drugs have shown better intervention efficiency than utilization of MSCs alone in many animal models of liver fibrosis. In this paper, we review the interventional effects and mechanisms of mesenchymal stem cells and their exosomes combined with drugs to alleviate hepatic fibrosis in vivo in animal models in recent years, which will provide new ideas to improve the efficacy of mesenchymal stem cells and their exosomes in treating hepatic fibrosis in the clinic.

Introduction

The liver is mainly composed of hepatocytes, hepatic stellate cells (HSCs), and liver sinusoidal endothelial cells (LSECs) that perform a comprehensive range of hepatic functions, such as detoxification, bile acid synthesis, and participation in various metabolic processes. However, a variety of stimuli, such as alcohol, drugs, inflammation, or cholestasis, often cause damage to hepatocytes resulting in abnormal liver function and a series of pathophysiologic changes [1] . Liver fibrosis is a common intermediate pathological process of various chronic liver diseases, which is mainly manifested by diffuse excessive deposition of extracellular matrix, leading to abnormal changes in liver tissue structure and affecting the normal physiological functions of liver severely [2] . Clinically, if liver fibrosis is not effectively reversed or curbed, it will progress to irreversible cirrhosis, hepatocellular carcinoma, and other end-stage liver diseases, eventually, leading to the death of patients [3] . Therefore, finding effective therapeutic strategies to ameliorate liver fibrosis in patients is of great importance in preventing the development of end-stage liver diseases.

In the clinical setting, liver transplantation is mostly used for the treatment of end-stage liver diseases, but liver transplantation cannot be widely used due to the defects of extremely rare donors, high cost, rejection, etc [4] . Currently, mesenchymal stem cells for the treatment of liver disease have become a hot spot in the field of biomedicine. As the intermediate pathological process of end-stage liver disease, mesenchymal stem cells can effectively ameliorate hepatic fibrosis through hepatogenic differentiation, immunomodulation, paracrine effects, and other mechanisms [5] . However, it has been reported that MSCs transplanted in the body may have some disadvantages such as low inner-liver colonization and short duration of intervention, which affect their therapeutic efficacy [6] . Nowadays, an increasing number of researchers have demonstrated in animal models of liver fibrosis that the combination of MSCs with drugs can boost the therapeutic effect of MSCs in the treatment of liver fibrosis by promoting the homing of MSCs, differentiating them into functional hepatocyte-like cells, improving the microenvironment, inhibiting the activation of HSCs, and modulating the signaling pathway, and so on. In addition, MSCs-derived extracellular vesicles with the advantages of higher penetrability and lower carcinogenicity also effectively ameliorate liver fibrosis with ultimate safety. What’s more, nanoscale intracellular vesicles can also be used as carriers of natural drugs for drug delivery. This provides new ideas to solve the poor efficiency of MSCs in the treatment of liver fibrosis in the clinic.

Discussion and outlook

Liver fibrosis, as an intermediate pathological process from chronic liver disease to cirrhosis and hepatocellular carcinoma, has become a research hotspot for the treatment of liver diseases due to its reversible properties. However, there is no very effective means to treat liver fibrosis in clinical practice. MSCs, as a kind of pluripotent stem cells, have no ethical issues and wide sources compared with liver transplantation and hepatocyte transplantation, which have attracted much attention in animal experiments and clinical studies of cell transplantation for the treatment of liver fibrosis. Unfortunately, MSCs confront with the challenges such as in vivo microenvironment inadaptation and attenuation of inflammatory response ability after isolation and culture in vitro [45] , which ultimately leads to a low colonization rate and short duration of intervention after transplantation of MSCs into the liver [6] . Therefore, it has not been widely used in clinical practice.

Abstract

Oral cavity stem cells (OCSCs) have been the focus of intense scientific efforts due to their accessibility and stem cell properties. The present work aims to compare the different characteristics of 6 types of dental stem cells derived from the oral cavity: dental pulp stem cells (DPSC), stem cells from human exfoliated deciduous teeth (SHED), periodontal ligament stem cells (PDLSC), stem cells from the apical papilla (SCAP), bone marrow mesenchymal stem cells (BMSC), and gingival mesenchymal stem cells (GMSC). Using immunofluorescence and real-time polymerase chain reaction techniques, we analysed the cells for stem cell, differentiation, adhesion, and extracellular matrix markers; the ability to proliferate in vitro; and multilineage differentiation potential. Markers such as vimentin, CD44, alkaline phosphatase, CD146, CD271, CD49f, Oct 3/4, Sox 9, FGF7, nestin, and BMP4 showed significant differences in expression levels, highlighting the heterogeneity and unique characteristics of each cell type. At the same time, we confirmed that all cell types successfully differentiated into osteogenic, chondrogenic, or adipose lineages, with different readiness. In conclusion, our study reveals the distinct properties and potential applications of various dental-derived stem cells. These findings contribute to a deeper understanding of OCSCs and their significance in future clinical applications.

Introduction

Bone marrow mesenchymal stem cells (BMSCs) exhibit high proliferation ability and multilineage differentiation potential. They were the first mesenchymal stem cells (MSCs) to be described, isolated from adults’ bone marrow aspirate.1 They have been extensively researched in human and animal model systems using in vivo and in vitro cell cultures. Further, they have bridged the divide and are integrated into various trials for clinical applications, with mixed success.2,3 BMSCs are not easily accessible, and an invasive procedure is required. Therefore, further research in the field, aiming at identifying alternative stem cell sources, has led to the discovery of oral cavity stem cells (OCSCs).

Currently, several different types of OCSCs are well known, including dental pulp stem cells (DPSC), stem cells from human exfoliated deciduous teeth (SHED), periodontal ligament stem cells (PDLSC), stem cells from the apical papilla (SCAP), dental follicle stem cells (DFSC), and gingival mesenchymal stem cells (GMSC).

Conclusions

This analysis of oral cavity–derived stem cells has exposed distinct and specific expression patterns of surface markers, ECM components, ECM remodelling enzymes, collagen genes, integrins, and differentiation potential. These findings may provide insights into the functional properties of these cell populations. Оur study aims to uncover the nuanced characteristics specific to each distinct cell type. Through experimentation and analysis, we anticipate to not only understand their individual functionalities but also gain deeper insights into their collective behaviour. Understanding both their shared characteristics and distinct attributes is an important step in using their regenerative potential in various tissue repair and regeneration contexts, thereby advancing the field of regenerative medicine and tissue engineering. By contributing meaningfully to the advancement of knowledge in regenerative medicine and tissue engineering, we aspire to pave the way for transformative breakthroughs in health care.

Abstract

Background
Evidence on the association between single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) and depressive symptoms is inconclusive.

Objectives
The primary aim of the study was to investigate the association between SNPs in the VDR gene and depressive symptoms.

Methods
In a sample of older adults from the Longitudinal Ageing Study Amsterdam (n = 922), depressive symptoms were assessed using the Centre for Epidemiological Studies Depression scale (CES-D scale) at baseline and after 3, 6, and 10 y of follow-up. Blood samples for SNP and serum 25-hydroxyvitamin D3 (25(OH)D3) determination were obtained at baseline. The association between 13 SNPs in the VDR gene and the course of depressive symptoms were evaluated using linear mixed models. The interaction between SNPs and serum 25(OH)D3 in relation to depressive symptoms was evaluated using multiple linear regression.

Results
No SNPs were associated with the course of depressive symptoms. Significant interactions between serum 25(OH)D3 and SNPs in the VDR gene were found. Stratified analysis revealed that within the GG genotype strata, 10 nmol/L higher serum 25(OH)D3 was associated with 0.27 (95% CI: −0.50, −0.04) and 0.23 (95% CI: −0.48, 0.02) lower scores on the CES-D scale for Cdx-2 and 1b-G-886A, respectively. This association was not found in persons having the GA or AA genotype.

Conclusions
No SNPs is associated with the course of depressive symptoms. Stratified analysis shows that the effect of serum 25(OH)D3 concentrations on depressive symptoms is different among genotypes of Cdx-2 and 1b-G-886A. Future research should elucidate on the function of Cdx-2 and 1b-G-886A to describe their effect.

Introduction

Depressive symptoms follow a U-shaped relationship with age, increasing again after the age of 60–65 y [1]. This is, however, not solely due to aging and varies widely between people [2]. A higher medical burden [3], aging-related anxiety [4], and nonhealth-related events [5] have been associated with depressive symptoms in older adults. The prevalence of depressive symptoms in older adults is estimated at 17% [6], but they are often overlooked [7] due to the overlap with symptoms, among others [6,8]. The burden will continue to rise due to the aging population and increasing life expectancy [9], thereby increasing years lived with disease [10] and societal costs [11].

Different factors (e.g., biological, social, and psychological) play a role in the onset and course of depressive symptoms [[12], [13], [14], [15]]. Vitamin D – a modifiable risk factor of which the status decreases with age [16] – has been associated with the course of depressive symptoms. In a previous study of the Longitudinal Ageing Study Amsterdam (LASA), an association between low vitamin D status and an increase in depressive symptoms among women was observed [17]. Two recent meta-analyses found a similar association in both men and women [18,19]. Genetic factors, such as single nucleotide polymorphisms (SNPs) in vitamin D-related genes may influence the response to, and therefore the requirement of, vitamin D [20]. The vitamin D receptor (VDR) gene encodes the VDR, the transporter of active vitamin D (1,25(OH)2D), and thereby influences the availability of 1,25(OH)2D [21].

Results

The study sample consisted of 922 participants who were on average 75.6 (SD 6.6) y old, were 51% women, and had a median CES-D score of 13.6 (IQR: 11.6–15.6). The prevalence of depressive symptoms [40] and antidepressant use at baseline was 24% and 2.5%, respectively. Mean serum 25(OH)D3 concentration was 46.6 nmol/L (SD 17.7), mean BMI was 26.6 kg/m2 (SD 5.2), and median physical activity in minutes per week was 128.6 (IQR: 67.7–189.7). The basic characteristics are summarized in Table 1 [35,36,40]. Compared with nonresponders, participants in the study sample were older and more often women, never smokers, moderate-to-excessive alcohol users, and more often had 2 or more comorbidities (all P < 0.05; Supplemental Table 2). The minor allele frequency was smallest for 282 W (n = 63/919; 3%), and no SNPs departed from Hardy–Weinberg equilibrium (Supplemental Table 1).

Abstract

Background
Evidence on the association between single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) and depressive symptoms is inconclusive.

Objectives
The primary aim of the study was to investigate the association between SNPs in the VDR gene and depressive symptoms.

Methods
In a sample of older adults from the Longitudinal Ageing Study Amsterdam (n = 922), depressive symptoms were assessed using the Centre for Epidemiological Studies Depression scale (CES-D scale) at baseline and after 3, 6, and 10 y of follow-up. Blood samples for SNP and serum 25-hydroxyvitamin D3 (25(OH)D3) determination were obtained at baseline. The association between 13 SNPs in the VDR gene and the course of depressive symptoms were evaluated using linear mixed models. The interaction between SNPs and serum 25(OH)D3 in relation to depressive symptoms was evaluated using multiple linear regression.

Results
No SNPs were associated with the course of depressive symptoms. Significant interactions between serum 25(OH)D3 and SNPs in the VDR gene were found. Stratified analysis revealed that within the GG genotype strata, 10 nmol/L higher serum 25(OH)D3 was associated with 0.27 (95% CI: −0.50, −0.04) and 0.23 (95% CI: −0.48, 0.02) lower scores on the CES-D scale for Cdx-2 and 1b-G-886A, respectively. This association was not found in persons having the GA or AA genotype.

Conclusions
No SNPs is associated with the course of depressive symptoms. Stratified analysis shows that the effect of serum 25(OH)D3 concentrations on depressive symptoms is different among genotypes of Cdx-2 and 1b-G-886A. Future research should elucidate on the function of Cdx-2 and 1b-G-886A to describe their effect.

Introduction

Depressive symptoms follow a U-shaped relationship with age, increasing again after the age of 60–65 y [1]. This is, however, not solely due to aging and varies widely between people [2]. A higher medical burden [3], aging-related anxiety [4], and nonhealth-related events [5] have been associated with depressive symptoms in older adults. The prevalence of depressive symptoms in older adults is estimated at 17% [6], but they are often overlooked [7] due to the overlap with symptoms, among others [6,8]. The burden will continue to rise due to the aging population and increasing life expectancy [9], thereby increasing years lived with disease [10] and societal costs [11].

Different factors (e.g., biological, social, and psychological) play a role in the onset and course of depressive symptoms [[12], [13], [14], [15]]. Vitamin D – a modifiable risk factor of which the status decreases with age [16] – has been associated with the course of depressive symptoms. In a previous study of the Longitudinal Ageing Study Amsterdam (LASA), an association between low vitamin D status and an increase in depressive symptoms among women was observed [17]. Two recent meta-analyses found a similar association in both men and women [18,19]. Genetic factors, such as single nucleotide polymorphisms (SNPs) in vitamin D-related genes may influence the response to, and therefore the requirement of, vitamin D [20]. The vitamin D receptor (VDR) gene encodes the VDR, the transporter of active vitamin D (1,25(OH)2D), and thereby influences the availability of 1,25(OH)2D [21].

Results

The study sample consisted of 922 participants who were on average 75.6 (SD 6.6) y old, were 51% women, and had a median CES-D score of 13.6 (IQR: 11.6–15.6). The prevalence of depressive symptoms [40] and antidepressant use at baseline was 24% and 2.5%, respectively. Mean serum 25(OH)D3 concentration was 46.6 nmol/L (SD 17.7), mean BMI was 26.6 kg/m2 (SD 5.2), and median physical activity in minutes per week was 128.6 (IQR: 67.7–189.7). The basic characteristics are summarized in Table 1 [35,36,40]. Compared with nonresponders, participants in the study sample were older and more often women, never smokers, moderate-to-excessive alcohol users, and more often had 2 or more comorbidities (all P < 0.05; Supplemental Table 2). The minor allele frequency was smallest for 282 W (n = 63/919; 3%), and no SNPs departed from Hardy–Weinberg equilibrium (Supplemental Table 1).

Abstract

Objective
To describe the use of nutritional supplements and blood status (hemogram, lipidogram, hepatic function, inflammatory markers, minerals, and homocysteine) in a sample of Brazilian T21 children with private health support before their first consultation with a T21 expert.

Method
This descriptive cross-sectional study enrolled 102 participants. Brazilian families with a T21 member under 18 years old were contacted and those that consented answered a survey regarding socio-demographics and the use of nutritional supplements and shared the blood tests that their T21 members have collected for the first consultation with a T21 expert.

Results
Frequencies and percentages were used to describe the variables. The most used supplements included vitamins (A, C and D), minerals (zinc and iron), omega-3, and antioxidants (curcumin). Hypothyroidism was observed in 56.9% of the participants. Hemogram alterations (increased hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin and red cell distribution width, leukopenia, and lymphocytopenia), dyslipidemia, altered hepatic and inflammatory blood markers were frequently found.

Conclusions
Nutritional supplements (mainly vitamins, minerals, omega-3 and antioxidants) are frequently used by Brazilian T21 children independently of professional counseling and/or supervision and should be a question to be raised during the clinical anamnesis since some of them may impact medical conduct. Moreover, many blood tests are altered in this population and clinicians should be aware of them in order to warrant an appropriate screening and the implementation of risk management measures as soon as possible and improve the general health of these persons.

Introduction

Down syndrome or trisomy 21 (T21) is the most common genetic disorder with a prevalence ranging from 1:600 to 1:800 live births in Brazil.1 The decreased life expectancy is attributed to associated risk factors but it has greatly increased with improved health care in the past decades. Despite this, many Brazilian families report that primary care clinicians usually do not follow the basic recommendations regarding health assistance for persons with T21 published by the Brazilian Ministry of Health.1 To avoid inappropriate health monitoring, many families that have resources consult with one of the few specialized clinicians with knowledge in T21, and those who do not, seek information on social networks.

In the last 10 years, social networks have become popular for caregivers to exchange information. On the one hand, these networks increase awareness about educational, health, and social issues related to the T21 population. On the other hand, the exchange of information on medication, nutritional supplements, and dietetic interventions may lead to decision-making without professional counseling and monitoring, bringing risks to the health of these persons.

Results

After the invitation, 189 families demonstrated interest to participate in the study and were contacted privately. Of those, 109 signed the informed consent. However, 7 families were excluded because they did not answer the survey (n = 1) or did not submit the blood exams (n = 6). The results reported represent 102 participants from 13 out of 26 Brazilian states.

Participants aged from 3 months to 16 years and data are presented in the Tables by age category, i.e., infants (≤ 24 months, n = 47), children (from 25 months to ≤12 years, n = 50), and teenagers (>12 years, n = 5).

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease in the world. It is classified as familial and sporadic. The dominant familial or autosomal presentation represents 1–5% of the total number of cases. It is categorized as early onset (EOAD; <65 years of age) and presents genetic mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), or the Amyloid precursor protein (APP). Sporadic AD represents 95% of the cases and is categorized as late-onset (LOAD), occurring in patients older than 65 years of age. Several risk factors have been identified in sporadic AD; aging is the main one. Nonetheless, multiple genes have been associated with the different neuropathological events involved in LOAD, such as the pathological processing of Amyloid beta (Aβ) peptide and Tau protein, as well as synaptic and mitochondrial dysfunctions, neurovascular alterations, oxidative stress, and neuroinflammation, among others. Interestingly, using genome-wide association study (GWAS) technology, many polymorphisms associated with LOAD have been identified. This review aims to analyze the new genetic findings that are closely related to the pathophysiology of AD. Likewise, it analyzes the multiple mutations identified to date through GWAS that are associated with a high or low risk of developing this neurodegeneration. Understanding genetic variability will allow for the identification of early biomarkers and opportune therapeutic targets for AD.

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disease and represents the most common form of dementia (60–80% of all cases of dementia) [1]. At present, an estimated 50 million people worldwide suffer from some form of dementia; however, as a result of the increase in life expectancy rates, it is expected that by 2050, 139 million people worldwide will suffer from some type of dementia [2,3], which will cause major socioeconomic and health system impacts [4].

AD is characterized by chronic and acquired memory impairment and cognitive deficits in domains, such as language, spatio-temporal orientation, and executive capacity, as well as behavior alterations, all of which lead to progressive loss of personal autonomy [5]. Histopathologically, AD is characterized by two pathognomonic hallmarks (Figure 1) [6]: (1) the intracellular deposition of abnormally phosphorylated Tau protein that promotes the formation of neurofibrillary tangles (NFTs) in the cerebral cortex and subcortical gray matter (Figure 1a); and (2) extracellular aggregates of Amyloid-beta peptide (Aβ) fibrils in the form of neuritic plaques (NPs; Figure 1b). In this context, it has been postulated that endogenous “damage signals”, such as Aβ oligomers, could cause the activation of microglial cells with the consequent release of proinflammatory cytokines, which would trigger signaling cascades in neurons causing hyperphosphorylation and the aggregation of Tau protein. This protein is released when neurons die, triggering microglial cell activation and, therefore, becomes a cyclic pathological process that culminates in neurodegeneration [7,8]. Therefore, both NPs and NFTs are involved in several neuronal processes and ultimately trigger neuronal death [9,10], synaptic alteration, oxidative stress, mitochondrial disturbance, neuroinflammation, alterations in the permeability of the blood–brain barrier (BBB), and neu

Impact of GWAS on Understanding Alzheimer’s Disease

rom 2005 to the present, multiple genetic studies have tracked most of the genes that conform to the human genome. These genetic studies are known as Genome-wide Association Studies (GWAS) and their objective is to associate certain genes with multiple pathologies or disorders [145,146]. Until 2007, only mutations in the APOE-ε4 allele were reliably associated with increased susceptibility to LOAD. Nonetheless, to date, multiple analyses have been performed with GWAS technology, demonstrating many possible genes associated with LOAD (Table 2). Targeted genetic approaches and next-generation sequencing studies have also identified several low-frequency genes that are associated with a relatively high risk of developing AD, therefore providing insight into the pathogenesis [5]. GWAS have associated more than 40 risk alleles with AD, identifying variants that trigger neurodegeneration, such as lipid metabolism, inflammation, innate immunity, Aβ production and clearance, and endosomal vesicle recycling (as shown in Table 1 and Figure 2) [147,148]. In particular, GWAS have also allowed us to identify those genes related to the development of both EOAD and LOAD [14]

Abstract

     DNA storage is a new digital data storage technology based on specific encoding and decoding methods between 0 and 1 binary codes of digital data and A-T-C-G quaternary codes of DNAs, which and is expected to develop into a major data storage form in the future due to its advantages (such as high data density, long storage time, low energy consumption, convenience for carrying, concealed transportation and multiple encryptions). In this review, we mainly summarize the recent research advances of four main encoding and decoding methods of DNA storage technology: direct mapping method between 0 and 1 binary and A-T-C-G quaternary codes in early-stage, fountain code for higher logical storage density, inner and outer codes for random access DNA storage data, and CRISPR mediated in vivo DNA storage method. The first three encoding/decoding methods belong to in vitro DNA storage, representing the mainstream research and application in DNA storage. Their advantages and disadvantages are also reviewed: direct mapping method is easy and efficient, but has high error rate and low logical density; fountain code can achieve higher storage density without random access; inner and outer code has error-correction design to realize random access at the expense of logic density. This review provides important references and improved understanding of DNA storage methods. Development of efficient and accurate DNA storage encoding and decoding methods will play a very important and even decisive role in the transition of DNA storage from the laboratory to practical application, which may fundamentally change the information industry in the future.

Introduction

     DNA storage technology is a new data storage technology through DNA storage medium, which can achieve digital data storage (text, image, audio, video, etc.) by encoding and decoding for the synthesized DNAs with specific sequences based on certain encoding/decoding methods. Specially, according to certain encoding methods/rules of DNA storage, the 0–1 binary codes encoding for various digital data (text, image, audio, video, etc.) can be converted to corresponding DNA quaternary codes (i.e., combinations of A, T, C, and G), and the corresponding DNAs were then synthesized to store the digital data information into the DNAs with specific sequences. Conversely, based on corresponding decoding methods/rules, the stored DNAs can be sequenced to obtain DNA quaternary codes, further restoring to the digital data with 0–1 binary codes. Here the encoding and decoding methods follow the same “codebook”, and the encoding is the reverse process of the decoding (Fig. 1).

Conclusion

     This paper reviews the research advances of encoding and decoding methods in the field of DNA storage, covering several primary encoding and decoding methods (Table 1): direct mapping between 0–1 binary digital data and A-T-C-G quaternary DNA storage data in the early stages (Church, Blawat, Goldman and Bornholt labs), fountain code (Erlich & Zielinski and Anavy labs), inner and outer codes for random access DNA storage data (Grass and Organick labs), and CRISPR mediated in vivo DNA storage technology (developed by Church et al. 2012).

     Each encoding and decoding method has its advantages and disadvantages. Here, the direct mapping method is easy and efficient but has a high error rate and low logical density. Fountain code made a breakthrough for logical density, reaching up to 80% of the upper limit of theoretical estimation of DNA storage, but it could not achieve random access. Grass’s inner and outer code has an error-correction design (at the chain and data block levels) to realize random access at the expense of logic density. In all, the above three encoding/decoding methods belong to in vitro DNA storage, with the advantage of high-throughput storage and lower cost. CRISPR mediated DNA storage technology belongs to in vivo DNA storage, with the advantage of long-term stable storage and cheaper/random amplification of DNA storage data copies, but it is nowadays in the early exploration stage only for a small amount of data storage due to some insurmountable technical bottlenecks (such as biochemical restrictions in vivo).

1- Introduction

2- Breast cancer

3- Drug resistance

4- miRNA biogenesis

5- miR-21 in BC

6- Expression of miR-21 in cancer tissues and cells

7- Role of miR-21 as a mediator in drug resistance in BC

8- Upstream pathway of miR-21

9- Potential targets of miR-21

10- Conclusion and future perspectives

References

Abstract

Breast cancer (BC) is the most common cancer among women that is responsible for the most of the cancer-related death in worldwide. Drug resistance is remaining as a significant clinical obstacle to treat BC patients effectively. Therefore, to help overcome this problem, it is necessary to understand the mechanisms of drug resistance. microRNAs classify as highly conserved non-coding RNAs (~22 nucleotides) and interact with mRNAs-coding genes for direct post-transcriptional repression. It has been reported that miR-21 is overexpressed and also acts as oncomiR in many human malignancies by targeting of several tumor suppressor genes–associated with apoptosis, proliferation and metastasis. Specifically, it has been reported that miR-21 is responsible for the drug resistance and its overexpression is related to the development of Multi Drug Resistance (MDR) in breast cancer. In this review, we discussed about the role of miR-21 on the drug resistance of breast cancer.

Introduction

Breast cancer (BC) is responsible for the death of approximately 500,000 women per year in the world. Also, more than one million new case of BC is diagnosed across the world per year. The occurrence of BC accounts for 7-8% of the entire number of malignant tumors. Chemotherapy is known as a principal strategy for cancer treatment; however, its application is limited due to drug resistance. Resistance to chemotherapeutics is mainly divided into two extensive categories: (i) intrinsic and (ii) acquired. Intrinsic resistance shows the presence of resistance-mediating factors in the tumor before starting of treatment process that makes chemotherapy ineffective. Acquired drug resistance, however, will be developed during of the treatment [1,2]. Drug resistance brings serious clinical obstacles to the prosperous treatment of BC patients. To overcome these problems, a well understanding of the drug resistance mechanisms is definitely required. The molecular mechanism of chemotherapeutic resistance in BC cells is completely complicated, and comprises multiple processes, including epigenetic changes, gene mutation, gene amplification and microRNA expression. miRNAs are short non-coding RNAs (~22 nucleotides) that could be found in all eukaryotic cells. They have a significant role in the progression of cancer by binding to the 3′ untranslated region (UTR) of the target genes, leading to the target mRNA degradation and inhibition of translation.

1- Introduction

2- Materials and methods

3- Results

4- Discussion

References

Abstract

Introduction: Long non-coding RNAs (lncRNAs) are RNA molecules that structurally resemble mRNA but do not encode proteins. Studies have been associated this class of non-coding RNA with the development of several disease, among them the different types of leukemia. However, the results are contradictory. Thus, we performed a systematic review of the literature available in order to better understand the involvement of lncRNAs in the development of leukemia. Materials and Methods: Pubmed and Embase databases were used to identify all studies that evaluated the expression of one or more lncRNA between human samples (peripheral blood, bone marrow) with leukemia (cases) and without leukemia (controls). Results: A total of 3675 articles were found in the databases, and after exclusion of articles that did not meet the eligibility criteria, 86 articles were included in this systematic review. In the 86 included studies, 3927 lncRNAs were differentially expressed between cases and controls. Among these, 110 lncRNAs were reported as being altered in samples from at least 2 studies and only 16 of them in ≥ 3 studies, which were selected for further evaluation. Of these, 12 lncRNAs were consistently dysregulated between cases and controls (CCAT1, CCDC26, CRNDE, HOTAIR, KCNQ5IT1, LINC00265, MALAT1, PVT1, SNHG5,TUG1: increased in cases, MEG3 and NEAT1: decreased in cases) in human samples of patients with some type of leukemia. Conclusion: Our data demonstrate that 12 lncRNAs are dysregulated in leukemia.

Introduction

Leukemia is a type of cancer that affects the blood and bone marrow and is characterized by the uncontrolled production and accumulation of blood cells (1). According to American Cancer Society (2), cancer the second leading cause of deaths among children, adolescents and young adults younger than 20 years, and leukemia is the main type of cancer that affect children. In addition, 381,774 people are living with or in remission from leukemia in the US (2). Radiation exposure, viral infections, ethnicity, gender and genetic mutations are some of the risk factors of leukemia (1). However, more studies are necessary to better understand the development and the pathogenesis of the different types of leukemia. In this context, epigenetic factors, such as non-coding RNAs (ncRNA), have been associated with leukemia development. NcRNAs are a group of regulatory RNAs that are not translated into protein (3). NcRNAs longer than 200 nucleotides are classified as long non-coding RNAs (lncRNAs). LncRNAs are located in nucleus, where they can act as molecular scaffolds, help in alternative splicing or modify chromatin structures. In addition, there are some lncRNAs that have functions in cytoplasm, such as modulating translation, promoting or inhibiting mRNA degradation, and acting as miRNAs sponges (4).

1- Introduction

2- Materials and methods

3- Results

4- Discussion

5- Conclusions

References

Abstract

Body mass index (BMI) has a complex relationship with Alzheimer’s disease (AD); in midlife, high BMI is associated with increased risk for AD, whereas the relationship in late-life is still unclear. To clarify the relationship between late-life BMI and risk for AD, this study examined the extent to which genetic predisposition for AD moderates BMI and AD-related biomarker associations. Participants included 126 cognitively normal older adults at baseline from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Genetic risk for AD was assessed via polygenic hazard score. AD-related biomarkers assessed were medial temporal lobe volume and cerebrospinal fluid (CSF) biomarkers. Hierarchical linear regressions were implemented to examine the effects of BMI and polygenic hazard score on AD-related biomarkers. Results showed that BMI moderated the relationship between genetic risk for AD and medial temporal lobe volume, such that individuals with high BMI and high genetic risk for AD showed lower volume in the entorhinal cortex and hippocampus. In sex-stratified analyses, these results remained significant only in females. Finally, BMI and genetic risk for AD were independently associated with CSF biomarkers of AD. These results provide evidence that high BMI is associated with lower volume in AD-vulnerable brain regions in individuals at genetic risk for AD, particularly females. The genetic pathways of AD may be exacerbated by high BMI. Environmental and genetic risk factors rarely occur in isolation, which underscores the importance of looking at their synergistic effects, as they provide insight into early risk factors for AD that prevention methods could target.

Introduction

Alzheimer’s disease (AD), the most common form of dementia, is a global health concern that places an epic burden on families, caregivers, healthcare systems, and the economy. An estimated 5.6 million Americans currently live with AD, and this number is expected to increase rapidly as the number of individuals over the age of 65 increases (Hebert et al., 2013). Brain changes, including atrophy and accumulation of β-amyloid peptide (Aβ) and tau, begin years before noticeable clinical and cognitive symptoms develop (Braak and Braak, 1991; Jack et al., 2013; Villemagne et al., 2013), making it imperative to investigate early risk factors that prevention methods could target to delay or prevent progression to AD. One variable that may play a role in development of AD is obesity. Obesity is a serious and growing health concern that impacts 38.9% of U.S. adults (Hales et al., 2018), and is associated with numerous deleterious health conditions, including diabetes and cardiovascular disease, as well as impaired quality of life (Dixon, 2010). One measure of obesity, body mass index (BMI), has a complex relationship with AD.

1- A brief history of CRISPR

2- CRISPR/Cas9: biology, functionality, and applications

3- Therapeutic targets for ex vivo cell-based CRISPR/Cas9 genome editing

4- CRISPR therapy in clinical trials

5- Challenges and opportunities

References

Abstract

The recently developed CRISPR/Cas9 technology has revolutionized the genome engineering field. Since 2016, increasing number of studies regarding CRISPR therapeutics have entered clinical trials, most of which are focusing on the ex vivo genome editing. In this review, we highlight the ex vivo cell-based CRISPR/Cas9 genome editing for therapeutic applications. In these studies, CRISPR/Cas9 tools were used to edit cells in vitro and the successfully edited cells were considered as therapeutics, which can be introduced into patients to treat diseases. Considering a large number of previous reviews have been focused on the CRISPR/Cas9 delivery methods and materials, this review provides a different perspective, by mainly introducing the targeted conditions and design strategies for ex vivo CRISPR/Cas9 therapeutics. Brief descriptions of the history, functionality, and applications of CRISPR/Cas9 systems will be introduced first, followed by the design strategies and most significant results from previous research that used ex vivo CRISPR/Cas9 genome editing for the treatment of conditions or diseases. The last part of this review includes general information about the status of CRISPR/Cas9 therapeutics in clinical trials. We also discuss some of the challenges as well as the opportunities in this research area.

A brief history of CRISPR

The term CRISPR, or the clustered regularly interspaced palindromic repeats, was first used by Jansen et al., in 2002 to describe a novel family of repetitive DNA sequences presented in the genomes of prokaryotes [1]. These unusual repeated sequences were first detected in 1987 by Nakata et al. in Escherichia coli [2], and then recognized to be widespread in archaea and bacteria by Mojica et al., in 2000 [3]. After Jansen et al. identified the CRISPR-associated (Cas) genes in 2002 [1], Mojica et al. [4], Vergnaud et al. [5], and Bolotin et al. [6] revealed the exrtachromosomal and phage-associated origins of the spacers that separate the individual direct repeats, in 2005. Speculations about CRISPR arrays as immune memory and defense mechanism against virus envisions were then proposed [6,7], while the first experimental evidence for CRISPR/Cas system based adaptive immunity was reported by Horvath et al., in 2007 [8]. Following the series discoveries on the basic function and mechanism of CRISPR systems [9–12], in 2010 Moineau et al. demonstrated the Cas9 enzyme (formerly named Cas5, COG3513, Csn1 or Csx12), which is guided by spacer sequences, cleaves target DNA [13]. In 2012, Doudna, Charpentier et al. [14], and Siksnys et al. [15] proved that Streptococcus pyogenes and Streptococcus thermophiles Cas9 can be guided by CRSIPR RNAs (crRNAs) to cleave target DNA in vitro, through forming a double-strand break (DSB). In 2013, Zhang et al. [16], Church et al. [17], and Doudna et al. [18] independently demonstrated the applications of engineered CRISPR/Cas9 systems for genome editing in mammalian cells. This represented a giant leap forward in the genome engineering field and triggered a tremendous number of studies regarding the use of the CRISPR/Cas9 platform for eukaryotic gene editing in a wide range of species, including flies [19,20], zebrafish [21–24], frogs [25], mice [26–28], rats [26,29], pigs [30], and monkeys [31,32].