Retinoid X Receptor: Cellular and Biochemical Roles of Nuclear Receptor with a Focus on Neuropathological Involvement

Retinoid X receptors (RXRs) present a subgroup of the nuclear receptor superfamily with particularly high evolutionary conservation of ligand binding domain. The receptor exists in α, β, and γ isotypes that form homo-/heterodimeric complexes with other permissive and non-permissive receptors. While research has identified the biochemical roles of several nuclear receptor family members, the roles of RXRs in various neurological disorders remain relatively under-investigated. RXR acts as ligand-regulated transcription factor, modulating the expression of genes that plays a critical role in mediating several developmental, metabolic, and biochemical processes. Cumulative evidence indicates that abnormal RXR signalling affects neuronal stress and neuroinflammatory networks in several neuropathological conditions. Protective effects of targeting RXRs through pharmacological ligands have been established in various cell and animal models of neuronal injury including Alzheimer disease, Parkinson disease, glaucoma, multiple sclerosis, and stroke. This review summarises the existing knowledge about the roles of RXR, its interacting partners, and ligands in CNS disorders. Future research will determine the importance of structural and functional heterogeneity amongst various RXR isotypes as well as elucidate functional links between RXR homo- or heterodimers and specific physiological conditions to increase drug targeting efficiency in pathological conditions.

Review on Strategies and Technologies for Exosome Isolation and Purification

Exosomes, a nano-sized subtype of extracellular vesicles secreted from almost all living cells, are capable of transferring cell-specific constituents of the source cell to the recipient cell. Cumulative evidence has revealed exosomes play an irreplaceable role in prognostic, diagnostic, and even therapeutic aspects. A method that can efficiently provide intact and pure exosomes samples is the first step to both exosome-based liquid biopsies and therapeutics. Unfortunately, common exosomal separation techniques suffer from operation complexity, time consumption, large sample volumes and low purity, posing significant challenges for exosomal downstream analysis. Efficient, simple, and affordable methods to isolate exosomes are crucial to carrying out relevant researches. In the last decade, emerging technologies, especially microfluidic chips, have proposed superior strategies for exosome isolation and exhibited fascinating performances. While many excellent reviews have overviewed various methods, a compressive review including updated/improved methods for exosomal isolation is indispensable. Herein, we first overview exosomal properties, biogenesis, contents, and functions. Then, we briefly outline the conventional technologies and discuss the challenges of clinical applications of these technologies. Finally, we review emerging exosomal isolation strategies and large-scale GMP production of engineered exosomes to open up future perspectives of next-generation Exo-devices for cancer diagnosis and treatment.

The Emerging Role of PIWI-Interacting RNAs (piRNAs) in Gastrointestinal Cancers: An Updated Perspective

Gastrointestinal (GI) cancers produce ~3.4 million related deaths worldwide, comprising 35% of all cancer-related deaths. The high mortality among GI cancers is due to late diagnosis, the presence of metastasis and drug resistance development. Additionally, current clinical markers do not adequately guide patient management, thereby new and more reliable biomarkers and therapeutic targets are still needed for these diseases. RNA-seq technology has allowed the discovery of new types of RNA transcripts including PIWI-interacting RNAs (piRNAs), which have particular characteristics that enable these molecules to act via diverse molecular mechanisms for regulating gene expression. Cumulative evidence has described the potential role of piRNAs in the development of several tumor types as a likely explanation for certain genomic abnormalities and signaling pathways’ deregulations observed in cancer. In addition, these piRNAs might be also proposed as promising diagnostic or prognostic biomarkers or as potential therapeutic targets in malignancies. This review describes important topics about piRNAs including their molecular characteristics, biosynthesis processes, gene expression silencing mechanisms, and the manner in which these transcripts have been studied in samples and cell lines of GI cancers to elucidate their implications in these diseases. Moreover, this article discusses the potential clinical usefulness of piRNAs as biomarkers and therapeutic targets in GI cancers.

Human Anelloviruses: Prevalence and Clinical Significance During Pregnancy

Although the bacterial microbiota of various compartments (e.g. vagina, amniotic fluid, and placenta) have been studied in pregnancy, there has been far less emphasis on normal and pathological viral communities. Cumulative evidence shows the presence of a number of apathogenic viruses in various tissues of healthy people, including pregnant individuals. What role, if any, these viruses play in human physiology is unknown. Anelloviruses (family Anelloviridae) are circular, single-stranded DNA viruses commonly detected with high prevalence in vertebrate hosts, including primates. Humans are nearly always colonized with at least 1 of 3 anellovirus subtypes, namely Alphatorquevirus (torque teno virus, TTV), Betatorquevirus (torque teno midi virus, TTMDV), and Gammatorquevirus (torque teno mini virus, TTMV). In healthy pregnant people, the prototype anellovirus, TTV, has been found in maternal and (variably) fetal blood, amniotic fluid, cervical and vaginal secretions, breast milk, and saliva. Nonetheless, the relevance of human anelloviruses in pregnancy and labor is unclear. There is evidence suggesting a link between anellovirus colonization and preterm birth. In this review, we discuss what is known about this family of commensal viruses in health and disease, and specifically the roles they might play during pregnancy and in the timing of delivery.

Regulated cell death: discovery, features and implications for neurodegenerative diseases

Regulated cell death (RCD) is a ubiquitous process in living organisms that is essential for tissue homeostasis or to restore biological balance under stress. Over the decades, various forms of RCD have been reported and are increasingly being found to involve in human pathologies and clinical outcomes. We focus on five high-profile forms of RCD, including apoptosis, pyroptosis, autophagy-dependent cell death, necroptosis and ferroptosis. Cumulative evidence supports that not only they have different features and various pathways, but also there are extensive cross-talks between modes of cell death. As the understanding of RCD pathway in evolution, development, physiology and disease continues to improve. Here we review an updated classification of RCD on the discovery and features of processes. The prominent focus will be placed on key mechanisms of RCD and its critical role in neurodegenerative disease. Graphical Abstract

HigB1 Toxin in Mycobacterium tuberculosis Is Upregulated During Stress and Required to Establish Infection in Guinea Pigs

The extraordinary expansion of Toxin Antitoxin (TA) modules in the genome of Mycobacterium tuberculosis has received significant attention over the last few decades. The cumulative evidence suggests that TA systems are activated in response to stress conditions and are essential for M. tuberculosis pathogenesis. In M. tuberculosis, Rv1955-Rv1956-Rv1957 constitutes the only tripartite TAC (Toxin Antitoxin Chaperone) module. In this locus, Rv1955 (HigB1) encodes for the toxin and Rv1956 (HigA1) encodes for antitoxin. Rv1957 encodes for a SecB-like chaperone that regulates HigBA1 toxin antitoxin system by preventing HigA1 degradation. Here, we have investigated the physiological role of HigB1 toxin in stress adaptation and pathogenesis of Mycobacterium tuberculosis. qPCR studies revealed that higBA1 is upregulated in nutrient limiting conditions and upon exposure to levofloxacin. We also show that the promoter activity of higBA1 locus in M. tuberculosis is (p)ppGpp dependent. We observed that HigB1 locus is non-essential for M. tuberculosis growth under different stress conditions in vitro. However, guinea pigs infected with higB1 deletion strain exhibited significantly reduced bacterial loads and pathological damage in comparison to the animals infected with the parental strain. Transcriptome analysis suggested that deletion of higB1 reduced the expression of genes involved in virulence, detoxification and adaptation. The present study describes the role of higB1 toxin in M. tuberculosis physiology and highlights the importance of higBA1 locus during infection in host tissues.

Downregulation of NEDD4L by EGFR Signaling Promotes the Development of Lung Adenocarcinoma

Cumulative evidence indicates that the abnormal regulation of the NEDD4 family of E3-ubiquitin ligases participates in the tumorigenesis and development of cancer. However, their role in lung adenocarcinoma (LUAD) remains unclear. This study comprehensively analyzed the NEDD4 family in LUAD data sets from public databases and found only NEDD4L was associated with the overall survival of LUAD patients. Gene set enrichment analysis (GSEA) indicated that NEDD4L might be involved in the regulation of mTORC1 pathway. Both cytological and clinical assays showed that NEDD4L inhibited the activity of the mTOR signaling pathway. In vivo and in vitro experiments showed that NEDD4L could significantly inhibit the proliferation of LUAD cells. In addition, this study also found that the expression of NEDD4L was regulated by EGFR signaling. These findings firstly revealed that NEDD4L mediates an interplay between EGFR and mTOR pathways in LUAD, and suggest that NEDD4L held great potential as a novel biomarker and therapeutic target for LUAD.

The Impact of Antepartum Depression and Postpartum Depression on Exclusive Breastfeeding: A Systematic Review and Meta-Analysis

The aim of this study was to systematically review the impact of antepartum depression on exclusive breastfeeding. A total of 15 studies were included in the review and 12 studies were used for the meta-analysis. The mean values of antepartum depression indicated that women who breastfed exclusively between 3 and 6 months had less antepartum depression symptoms (Mean Difference = −0.55, 95% CI = −0.76 to −0.35). The analysis also showed that the existence of antepartum depression was negatively related to continuing exclusive breastfeeding for longer than 3 months postpartum as well as for 8 weeks postpartum (OR = 0.48, 95% CI = 0.26–0.88 and OR = 0.83, 95% CI = 0.75–0.91, respectively). The cumulative evidence is conclusive that antepartum depressive symptoms are negatively associated with exclusive breastfeeding, particularly between 3 and 6 months postpartum. This review supports the necessity of screening and follow-up for depression throughout the perinatal period to promote exclusive breastfeeding for 6 months.

Urgent considerations and assessment of acute dizziness

The quality of symptoms assessment of patients with acute dizziness adds much to the diagnostic value in the affected patients within the emergency department. Many previous review articles have concentrated on addressing and assessing these approaches in the emergency department, however, there is increasing evidence regarding these concerns that are not adequately reviewed and comprehended. Emergency physicians should be aware of the recent advances in the field because of the critical role they represent in these settings. In the present literature review, we aim to formulate evidence regarding the urgent considerations that should be considered when assessing acute dizziness. The initial step would be to conduct a differential diagnosis to adequately evaluate the underlying etiology and help plan for adequate interventions. Caring for the serious causes is also critical to reduce the potential harm that might result from a misdiagnosis of these conditions and enhance patient outcomes. Our cumulative evidence also shows that conducting a thorough adequate examination is the ideal approach to a proper diagnosis, as reports indicate that imaging modalities and other neurological tests are not favorable in these situations. Providing adequate training episodes about the neurological and physical examination should be a priority to the emergency physicians as they are located within the first line to which patients with acute dizziness is present.The quality of symptoms assessment of patients with acute dizziness adds much to the diagnostic value in the affected patients within the emergency department. Many previous review articles have concentrated on addressing and assessing these approaches in the emergency department, however, there is increasing evidence regarding these concerns that are not adequately reviewed and comprehended. Emergency physicians should be aware of the recent advances in the field because of the critical role they represent in these settings. In the present literature review, we aim to formulate evidence regarding the urgent considerations that should be considered when assessing acute dizziness. The initial step would be to conduct a differential diagnosis to adequately evaluate the underlying etiology and help plan for adequate interventions. Caring for the serious causes is also critical to reduce the potential harm that might result from a misdiagnosis of these conditions and enhance patient outcomes. Our cumulative evidence also shows that conducting a thorough adequate examination is the ideal approach to a proper diagnosis, as reports indicate that imaging modalities and other neurological tests are not favorable in these situations. Providing adequate training episodes about the neurological and physical examination should be a priority to the emergency physicians as they are located within the first line to which patients with acute dizziness is present.

Cumulative evidence for association of rhinitis and depression

Background Several primary studies evaluated the association between rhinitis and the incidence of depression and yielded inconsistent results. We conducted a meta-analysis of studies evaluating the association between rhinitis and depression. Methods We searched the EMBASE, PubMed and Cochrane Library databases for studies published in English before April 1, 2019. The studies were included if they reported any type of rhinitis in relation to depression. Two authors independently extracted the data. The odds ratios (ORs) were pooled using a random-effects model. Stratified analyses were conducted to evaluate the association. Results Among the 3472 initially identified studies, we included 14 studies involving a total of 19.36 ± 1.1 million participants according to predefined inclusion criteria. The associations between rhinitis (R), allergic rhinitis (AR), and nonallergic rhinitis (NAR) and depression were significant with ORs of 1.86 (95% CI 1.32 to 2.62, p < 0.05), 1.54 (95% CI 1.24 to 1.90, p < 0.05), and 2.15 (95% CI 1.49 to 3.09, p < 0.05), respectively. The results were consistent and statistically significant in all subgroup analyses. Conclusions Rhinitis was associated with an increased risk of depression. Further prospective studies involving large sample sizes are required to confirm the results by considering more confounders and clarify the mechanisms.