Novel Perspectives of TSLP and RXR Signaling in Corticosteroid-Resistant Asthma: Updates on TSLP Blockers.

Previous studies described that asthma patients who received corticosteroid therapy have been constrained by the corticosteroid resistance subsequently fostered to severe refractory asthma. In this review, we discussed the implications of TSLP, RXR, the role of STAT5-activating cytokines, and IL-33/NH-cell signaling pathways, and recent clinical evidence on TSLP blockers in steroid-resistant asthma. We have searched several public databases such as Pubmed, Scopus, and Relemed and obtained information pertinent to the TSLP, RXR, TSLP blockers, the STAT5-activating cytokines, and IL-33. We discussed the multiple cell signaling mechanisms underlying steroid resistance. Blocking the TSLP and other key signaling molecules like STAT5 can retrieve the sensitivity of natural helper-cells to corticosteroids. RXR derivatives treatment can modulate the activity of TSLP, which further modulates steroid resistance in severe asthmatic patients and in patients with refractory asthma. We discussed the steroid-resistance mediated by the Th2 cells and Th2-driven eosinophilia upon corticosteroid intake. Thus, this review will be beneficial for clinicians and molecular biologists to explore the inflammatory pathways associated with refractory asthma conditions and develop novel therapies against corticosteroid-resistant asthma.

Single nucleotide polymorphism rs527236194 of the cytochrome B gene (MT-CYB) is associated with alterations in sperm parameters.

BACKGROUND: The mitochondrial genome is substantially susceptible to mutations and has high polymorphism due to structural features, location, and lack of recombinant variability, as its inheritance is strictly maternal. All of these events can be accompanied by the accumulation of mitochondrial single nucleotide polymorphisms (mtSNPs) in the sperm. The aim of this research was to analyze the influence of mutations in the MT-CYB gene on sperm quality. METHODS AND RESULTS: We conducted a case‒control study to identify mutations in the mitochondrial cytochrome B (MT-CYB) gene in men with asthenoteratozoospermia (89 cases) and oligoasthenoteratozoospermia (65 cases). The comparison group consisted of 164 fertile men. Somatic cell lysis followed by mtDNA extraction was conducted to analyze three mtDNA polymorphisms, rs28357373 (T15629C (Leu295=), rs527236194 (T15784C (p.Pro346=), rs2853506 (A15218G, p.Thr158Ala). Detection and genotyping of polymorphic loci in the MT-CYB gene was performed using the TaqMan allelic discrimination assay. To verify mutations in the MT-CYB gene, automated Sanger DNA sequencing was used. We found that rs527236194 was associated with asthenoteratozoospermia. rs28357373 in the MT-CYB gene did not show any polymorphism in the analyzed groups, which indicates a rare frequency of the TT genotype in our region. Rs28357373 and rs2853506 are not associated with male sperm abnormalities in the Volga-Ural region. CONCLUSION: The association of the rs527236194 polymorphic variant with sperm parameter alterations suggests its role in the pathophysiology of male infertility and requires further investigation in larger samples.

Recent Investigations on Neurotransmitters' Role in Acute White Matter Injury of Perinatal Glia and Pharmacotherapies-Glia Dynamics in Stem Cell Therapy.

Periventricular leukomalacia (PVL) and cerebral palsy are two neurological disease conditions developed from the premyelinated white matter ischemic injury (WMI). The significant pathophysiology of these diseases is accompanied by the cognitive deficits due to the loss of function of glial cells and axons. White matter makes up 50% of the brain volume consisting of myelinated and non-myelinated axons, glia, blood vessels, optic nerves, and corpus callosum. Studies over the years have delineated the susceptibility of white matter towards ischemic injury especially during pregnancy (prenatal, perinatal) or immediately after child birth (postnatal). Impairment in membrane depolarization of neurons and glial cells by ischemia-invoked excitotoxicity is mediated through the overactivation of NMDA receptors or non-NMDA receptors by excessive glutamate influx, calcium, or ROS overload and has been some of the well-studied molecular mechanisms conducive to the injury of white matter. Expression of glutamate receptors (GluR) and transporters (GLT1, EACC1, and GST) has significant influence in glial and axonal-mediated injury of premyelinated white matter during PVL and cerebral palsy. Predominantly, the central premyelinated axons express extensive levels of functional NMDA GluR receptors to confer ischemic injury to premyelinated white matter which in turn invoke defects in neural plasticity. Several underlying molecular mechanisms are yet to be unraveled to delineate the complete pathophysiology of these prenatal neurological diseases for developing the novel therapeutic modalities to mitigate pathophysiology and premature mortality of newborn babies. In this review, we have substantially discussed the above multiple pathophysiological aspects of white matter injury along with glial dynamics, and the pharmacotherapies including recent insights into the application of MSCs as therapeutic modality in treating white matter injury.

Mitochondrial mutations and mitoepigenetics: Focus on regulation of oxidative stress-induced responses in breast cancers.

Epigenetic regulation of mitochondrial DNA (mtDNA) is an emerging and fast-developing field of research. Compared to regulation of nucler DNA, mechanisms of mtDNA epigenetic regulation (mitoepigenetics) remain less investigated. However, mitochondrial signaling directs various vital intracellular processes including aerobic respiration, apoptosis, cell proliferation and survival, nucleic acid synthesis, and oxidative stress. The later process and associated mismanagement of reactive oxygen species (ROS) cascade were associated with cancer progression. It has been demonstrated that cancer cells contain ROS/oxidative stress-mediated defects in mtDNA repair system and mitochondrial nucleoid protection. Furthermore, mtDNA is vulnerable to damage caused by somatic mutations, resulting in the dysfunction of the mitochondrial respiratory chain and energy production, which fosters further generation of ROS and promotes oncogenicity. Mitochondrial proteins are encoded by the collective mitochondrial genome that comprises both nuclear and mitochondrial genomes coupled by crosstalk. Recent reports determined the defects in the collective mitochondrial genome that are conducive to breast cancer initiation and progression. Mutational damage to mtDNA, as well as its overproliferation and deletions, were reported to alter the nuclear epigenetic landscape. Unbalanced mitoepigenetics and adverse regulation of oxidative phosphorylation (OXPHOS) can efficiently facilitate cancer cell survival. Accordingly, several mitochondria-targeting therapeutic agents (biguanides, OXPHOS inhibitors, vitamin-E analogues, and antibiotic bedaquiline) were suggested for future clinical trials in breast cancer patients. However, crosstalk mechanisms between altered mitoepigenetics and cancer-associated mtDNA mutations remain largely unclear. Hence, mtDNA mutations and epigenetic modifications could be considered as potential molecular markers for early diagnosis and targeted therapy of breast cancer. This review discusses the role of mitoepigenetic regulation in cancer cells and potential employment of mtDNA modifications as novel anti-cancer targets.

The level of secondary messengers and the redox state of NAD+/NADH are associated with sperm quality in infertility.

In order to explore the interrelation of Calcium, cAMP, and redox state of pyridine nucleotides in seminal plasma and ejaculate quality in cases of idiopathic infertility we conducted an evaluation of 170 infertile males and 46 fertile males aged 20-43 years. Sperm analysis was undertaken according to WHO protocol. The content of Calcium in the seminal plasma was detected using optical emission spectrometry, cAMP levels were determined via enzymatic immunoassay. The redox state of pyridine nucleotides was evaluated from the ratio of pyruvate to lactate, determined via enzymatic method. Our results show a decrease in Calcium, cAMP, pyruvate and the oxidation-reduction potential of pyridine nucleotides in the seminal plasma of infertile males with pathospermia. This corresponds to anaerobic inversion of oxidative conversions and metabolism inadaptation. Such processes are often seen in inflammatory and autoimmune conditions. cAMP levels reliably correlated with the number of progressively mobile sperm cells, but not with the number of their pathological forms. A positive correlation between the concentration of cAMP and calcium was discovered as well. Pathospermia was characterized by the positive relation between the value of the NAD+/NADH coefficient and the spermatozoa concentration that was not present in fertile donors. Our study shows distinct changes in the concentration of secondary messengers and redox state of pyridine nucleotides in the seminal fluid that can act as molecular predictors for the development of idiopathic infertility.

The mystery of claustral neural circuits and recent updates on its role in neurodegenerative pathology.

INTRODUCTION: The claustrum is a structure involved in formation of several cortical and subcortical neural microcircuits which may be involved in such functions as conscious sensations and rewarding behavior. The claustrum is regarded as a multi-modal information processing network. Pathology of the claustrum is seen in certain neurological disorders. To date, there are not enough comprehensive studies that contain accurate information regarding involvement of the claustrum in development of neurological disorders. OBJECTIVE: Our review aims to provide an update on claustrum anatomy, ontogenesis, cytoarchitecture, neural networks and their functional relation to the incidence of neurological diseases. MATERIALS AND METHODS: A literature review was conducted using the Google Scholar, PubMed, NCBI MedLine, and eLibrary databases. RESULTS: Despite new methods that have made it possible to study the claustrum at the molecular, genetic and epigenetic levels, its functions and connectivity are still poorly understood. The anatomical location, relatively uniform cytoarchitecture, and vast network of connections suggest a divergent role of the claustrum in integration and processing of input information and formation of coherent perceptions. Several studies have shown changes in the appearance, structure and volume of the claustrum in neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), autism, schizophrenia, and depressive disorders. Taking into account the structure, ontogenesis, and functions of the claustrum, this literature review offers insight into understanding the crucial role of this structure in brain function and behavior.

Health Science Community Will Miss This Bright and Uniting Star: In Memory of Professor Gjumrakch Aliev, M.D, Ph.D.

It is with deep sadness that we offer our memorial on the unexpected demise of our dear colleague, Professor Gjumrakch Aliev [...].

In Vivo Antidepressant Efficacy of 3-Substituted Thietane-1,1-dioxide Derivative - A Preliminary Study for Novel Anti-Depression Therapy in Neurological Disorders.

BACKGROUND: Psychosocial stress-induced depressive behavior is linked to the etiology of several neurological diseases viz., PTSD, and neurodegenerative disease like Alzheimer's Disease (AD). The repeated bouts of social stress defeat can be induced using Resident-Intruder- Paradigm (RIP) and Chronic Mild Social Stress (CMSS) animal models to assess the stress-induced depressive behavioral patterns. OBJECTIVES: The aim of this study to examine the anti-depressive efficacy of 3-methoxythietane- 1,1-dioxide (N-14) in RIP models of behavioral alterations. METHODS: In this study, we have used Sprague-Dawley rats in Resident-Intruder-Paradigm (RIP), where intruders interacted with residents Day 0 to Day +5 for 10 minutes to invoke CMSS in intruders and became defeated/submissive rats due to the depressive-like behavioral alterations in social activity, explorations, grooming, defense, aggressive behavior, social interaction, freeze, rearing etc., with residents. Control intact animals are included in group I, group II received N-14 alone; group III received CMSS, and group IV received cotreatment of N14 with CMSS. N-14 (2 mg/kg) was administered intraperitoneally from Day 0 to Day +5 to intact animals and intruder animals under conditions of CMSS. RESULTS: Several behavioral tests viz., forced swim test, open field test, and elevated-plus maze test were used to examine the above behavioral dynamic parameters. The dynamic interaction between Residents and Intruders during the study showed substantial alterations in exploratory activity, aggressiveness, defensive behavior, body weight, and thymus mass in stressed animals. N-14 cotreatment has mitigated sociability, exploratory activity, aggressiveness increased social adaptability and defensive behavior. An extensive rise in active forms of defense and submission latency indicates that N-14 has induced antidepressant activity with a psycho-sedative component of action. CONCLUSION: Serendipitously, we observed the ameliorative capability of N-14 cotreatment to mitigate depressive-behavioral symptoms in intruders.

Withdrawal Notice: Applying Peer Mentoring to Improve Learning Human Anatomy

The article has been withdrawn at the request of the co-authors due to the death of the corresponding author (Dr. Aliev). Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused. The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policies-main.php BENTHAM SCIENCE DISCLAIMER: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

Paneth cells: Maintaining dynamic microbiome-host homeostasis, protecting against inflammation and cancer.

The human intestines are constantly under the influence of numerous pathological factors: enteropathogenic microorganisms, food antigens, physico-chemical stress associated with digestion and bacterial metabolism, therefore it must be provided with a system of protection against adverse impact. Recent studies have shown that Paneth cells play a crucial role in maintaining homeostasis of the small intestines. Paneth cells perform many vital functions aimed at maintaining a homeostatic balance between normal microbiota, infectious pathogens and the human body, regulate the qualitative composition and number of intestinal microorganisms, prevent the introduction of potentially pathogenic species, and protect stem cells from damage. Paneth cells take part in adaptive and protective-inflammatory reactions. Paneth cells maintain dynamic balance between microbial populations, and the macroorganism, preventing the development of intestinal infections and cancer. They play a crucial role in gastrointestinal homeostasis and may be key factors in the etiopathological progression of intestinal diseases.

Novel MicroRNA Binding Site SNPs and the Risk of Clear Cell Renal Cell Carcinoma (ccRCC): A Case-Control Study.

BACKGROUND: Renal cell carcinoma represents 3% of all adult malignancies. MicroRNAs exhibit specific functions in various biological processes through their interaction with cellular mRNA involved in apoptosis and cell cycle control. Recent studies have reported the potential association of single-nucleotide polymorphisms (SNPs) in miRNA-binding sites of VHL-HIF1α pathway genes with renal cancer development and progression. OBJECTIVE: The objective of this study is to investigate SNPs invoking an alteration in the nature of interaction with miRNA binding sites of VHL-HIF1α pathway genes. PATIENTS & METHODS: Total 450 cases of histologically and clinically verified ccRCC and 490 controls were included in our study. Genotyping was performed using a TaqMan PCR allelic discrimination method. Kaplan-Meier method of statistical analysis was implemented to analyze the overall patient survival rate. RESULTS: Polymorphism rs10491534 in TSC1 gene was significantly associated with risk of developing advanced ccRCC. Allele G of rs1642742 in VHL gene was significantly prevalent in ccRCC compared with control group aged 55 and older (OR = 1.5566; CI [1.1532-2.1019]). Results from the dominant model combining individuals with AG or AA genotype showed that the A allele bearers of CDCP1 rs6773576 exhibited higher risk of death compared to GG carriers (HR 3.93, 95% CI 1.76-17.21, log-rank P = 0.0033). CONCLUSION: The present study delineated the association of miRNA binding site variants in VHL-HIF1α pathway genes with the ccRCC risk, which may affect clinical outcome.

Can miRNAs Be Considered as Diagnostic and Therapeutic Molecules in Ischemic Stroke Pathogenesis?-Current Status.

Ischemic stroke is one of the leading causes of death worldwide. Clinical manifestations of stroke are long-lasting and causing economic burden on the patients and society. Current therapeutic modalities to treat ischemic stroke (IS) are unsatisfactory due to the intricate pathophysiology and poor functional recovery of brain cellular compartment. MicroRNAs (miRNA) are endogenously expressed small non-coding RNA molecules, which can act as translation inhibitors and play a pivotal role in the pathophysiology associated with IS. Moreover, miRNAs may be used as potential diagnostic and therapeutic tools in clinical practice; yet, the complete role of miRNAs is enigmatic during IS. In this review, we explored the role of miRNAs in the regulation of stroke risk factors viz., arterial hypertension, metabolic disorders, and atherosclerosis. Furthermore, the role of miRNAs were reviewed during IS pathogenesis accompanied by excitotoxicity, oxidative stress, inflammation, apoptosis, angiogenesis, neurogenesis, and Alzheimer's disease. The functional role of miRNAs is a double-edged sword effect in cerebral ischemia as they could modulate pathological mechanisms associated with risk factors of IS. miRNAs pertaining to IS pathogenesis could be potential biomarkers for stroke; they could help researchers to identify a particular stroke type and enable medical professionals to evaluate the severity of brain injury. Thus, ascertaining the role of miRNAs may be useful in deciphering their diagnostic role consequently it is plausible to envisage a suitable therapeutic modality against IS.

The role of microglia in the development of neurodegeneration.

Microglia-mediated central nervous system (CNS) inflammation is one of the key features of various neurodegenerative diseases, including Parkinson's and Alzheimer's diseases. In the last few years, a number of studies have investigated the link between neurodegenerative diseases and CNS glial cells, in particular microglia. Microglial cells are the main resident immune cells and comprise approximately 10-15% of all CNS cells. Microglia at rest regulates CNS homeostasis via phagocytic activity, by removing pathogens and cell detritus. "Resting" microglia cells transform into an activated form and produce inflammatory mediators, thus protecting neurons and providing defense against invading pathogens. Excessive inflammation leads to neuronal damage and neurodegenerative diseases. Various microglial reactions at different stages of the disease can open up new directions for treatment interventions and modification of the inflammatory activity. This review focuses on the potential role of microglia and the dynamic M1/M2 phenotype changes that are critically linked to certain neurodegenerative diseases.

MicroRNA-200 family expression analysis in metastatic clear cell renal cell carcinoma patients.

The aim of this study is to analyse the of expression levels of microRNA-200 family members in patients with metastatic clear cell renal cell carcinoma (ccRCC). Analysis of microRNA expression was performed on 23 paired DNA samples extracted from kidney tumour tissue and the surrounding normal renal parenchyma. MicroRna-200c was found to have significantly lower expression (in kidney tumour tissue compared to normal renal parenchyma. No other microRna-200 family members showed statistically significant differences in expression levels between tumour and normal kidney tissue. Recent data suggest that the role of microRNA-200c in tumour pathogenesis is rather contradictory, and the underlying mechanisms by which microRNA-200c affects the carcinogenic potential of malignant cells remains unclear and requires further investigation at the molecular level.