scholarly journals Tissue Specific Age Dependence of the Cell Receptors Involved in the SARS-CoV-2 Infection

2021 ◽  
Author(s):  
Christian V Forst ◽  
Lu Zeng ◽  
Qian Wang ◽  
Xianxiao Zhou ◽  
Sezen Vatansever ◽  
...  
Keyword(s):  
Transcriptional Response ◽  
Cytokine Signaling ◽  
Young Population ◽  
Age Dependence ◽  
Old Patients ◽  
Tissue Specific ◽  
Cell Receptors ◽  
Gene Regulatory ◽  
Regulatory Organization ◽  
The Brain

The coronavirus disease 2019 (COVID-19) pandemic has affected tens of millions of individuals and caused hundreds of thousands of deaths worldwide. Due to its rapid surge, there is a shortage of information on viral behavior and host response after SARS-CoV-2 infection. Here we present a comprehensive, multiscale network analysis of the transcriptional response to the virus. We particularly focus on key-regulators, cell-receptors, and host-processes that are hijacked by the virus for its advantage. ACE2-controlled processes involve a key-regulator CD300e (a TYROBP receptor) and the activation of IL-2 pro-inflammatory cytokine signaling. We further investigate the age-dependency of such receptors and identify the adipose and the brain as potentially contributing tissues for the disease's severity in old patients. In contrast, several other tissues in the young population are more susceptible to SARS-CoV-2 infection. In summary, this present study provides novel insights into the gene regulatory organization during the SARS-CoV-2 infection and the tissue-specific age dependence of the cell receptors involved in COVID-19.

scholarly journals Shared Blood Transcriptomic Signatures between Alzheimer’s Disease and Diabetes Mellitus

Biomedicines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 34
Author(s):  
Taesic Lee ◽  
Hyunju Lee
Keyword(s):  
Diabetes Mellitus ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Interactions ◽  
Expression Patterns ◽  
Protein Protein Interactions ◽  
Hub Genes ◽  
Gene Modules ◽  
Gene Regulatory ◽  
The Brain

Alzheimer’s disease (AD) and diabetes mellitus (DM) are known to have a shared molecular mechanism. We aimed to identify shared blood transcriptomic signatures between AD and DM. Blood expression datasets for each disease were combined and a co-expression network was used to construct modules consisting of genes with similar expression patterns. For each module, a gene regulatory network based on gene expression and protein-protein interactions was established to identify hub genes. We selected one module, where COPS4, PSMA6, GTF2B, GTF2F2, and SSB were identified as dysregulated transcription factors that were common between AD and DM. These five genes were also differentially co-expressed in disease-related tissues, such as the brain in AD and the pancreas in DM. Our study identified gene modules that were dysregulated in both AD and DM blood samples, which may contribute to reveal common pathophysiology between two diseases.

scholarly journals Tissue-specific distribution of cross-linked somatostatin receptor proteins in the rat

1992 ◽  
Vol 282 (2) ◽  
pp. 339-344 ◽  
Author(s):  
C B Srikant ◽  
K K Murthy ◽  
Y C Patel
Keyword(s):  
Exocrine Pancreas ◽  
Receptor Protein ◽  
Cross Linking ◽  
Molecular Heterogeneity ◽  
Dependent Manner ◽  
Tissue Specific ◽  
Receptor Proteins ◽  
Specific Distribution ◽  
A Minor ◽  
The Brain

Pharmacological studies have suggested that the somatostatin (SS) receptor is heterogeneous and exhibits SS-14-and SS-28-selective subtypes. Whether such subtypes arise from molecular heterogeneity of the receptor protein has not been definitively established. Previous reports characterizing the molecular properties of the SS receptor by the cross-linking approach have yielded divergent size estimates ranging from 27 kDa to 200 kDa. In order to resolve this discrepancy, as well as to determine whether SS-14 and SS-28 interact with specific receptor proteins, we have cross-linked radioiodinated derivatives of [125I-Tyr11]SS-14 (T*-SS-14) and [Leu8,D-Trp22,125I-Tyr25]SS-28 (LTT*-SS-28) to membrane SS receptors in rat brain, pituitary, exocrine pancreas and adrenal cortex using a number of chemical and photoaffinity cross-linking agents. The labelled cross-linked receptor proteins were analysed by SDS/PAGE under reducing conditions followed by autoradiography. Our findings indicate that the pattern of specifically labelled cross-linked SS receptor proteins is sensitive to the concentration of chemical cross-linking agents such as disuccinimidyl suberate and dithiobis-(succinimidyl propionate). Labelled high-molecular-mass complexes of cross-linked receptor-ligand proteins were observed only when high concentrations of these cross-linkers were employed. Using optimized low concentrations of cross-linkers, however, two major labelled bands of 58 +/- 3 kDa and 27 +/- 2 kDa were detected. These two bands were identified as specifically labelled SS receptor proteins subsequent to cross-linking with a number of photoaffinity cross-linking agents as well. We demonstrate here that the 58 kDa protein is the major SS receptor protein in the rat pituitary, adrenal and exocrine pancreas, whereas the 27 kDa moiety represents the principal form in the brain. Additionally, the presence of a minor specifically labelled band of 32 kDa was detected uniquely in the brain, and a minor labelled protein of 42 kDa was observed in the pancreas. The labelling pattern obtained with LTT*-SS-28 was identical to that observed with T*-SS-14. Labelling of the 27 kDa band by either ligand was inhibited by SS-14 and SS-28 in a dose-dependent manner. Densitometric quantification showed that SS-14 exhibited greater than 2-fold greater potency than SS-28 for inhibiting the labelling of the 27 kDa species. These findings emphasize the need for careful interpretation of cross-linking data obtained for SS receptors, and provide evidence for molecular heterogeneity and for a tissue-specific distribution of the two principal SS receptor proteins.

scholarly journals Synaptic and epidermal accumulations of human acetylcholinesterase are encoded by alternative 3'-terminal exons.

1995 ◽  
Vol 15 (6) ◽  
pp. 2993-3002 ◽  
Author(s):  
S Seidman ◽  
M Sternfeld ◽  
R Ben Aziz-Aloya ◽  
R Timberg ◽  
D Kaufer-Nachum ◽  
...  
Keyword(s):  
Neuromuscular Junctions ◽  
Gene Transcript ◽  
Dna Encoding ◽  
Tissue Specific ◽  
Evolutionarily Conserved ◽  
Low Salt ◽  
Catalytically Active ◽  
Specific Accumulation ◽  
The Brain ◽  
Muscle Ache

Tissue-specific heterogeneity among mammalian acetylcholinesterases (AChE) has been associated with 3' alternative splicing of the primary AChE gene transcript. We have previously demonstrated that human AChE DNA encoding the brain and muscle AChE form and bearing the 3' exon E6 (ACHE-E6) induces accumulation of catalytically active AChE in myotomes and neuromuscular junctions (NMJs) of 2- and 3-day-old Xenopus embryos. Here, we explore the possibility that the 3'-terminal exons of two alternative human AChE cDNA constructs include evolutionarily conserved tissue-recognizable elements. To this end, DNAs encoding alternative human AChE mRNAs were microinjected into cleaving embryos of Xenopus laevis. In contrast to the myotomal expression demonstrated by ACHE-E6, DNA carrying intron 14 and alternative exon E5 (ACHE-I4/E5) promoted punctuated staining of epidermal cells and secretion of AChE into the external medium. Moreover, ACHE-E6-injected embryos displayed enhanced NMJ development, whereas ACHE-I4/E5-derived enzyme was conspicuously absent from muscles and NMJs and its expression in embryos had no apparent effect on NMJ development. In addition, cell-associated AChE from embryos injected with ACHE-I4/E5 DNA was biochemically distinct from that encoded by the muscle-expressible ACHE-E6, displaying higher electrophoretic mobility and greater solubility in low-salt buffer. These findings suggest that alternative 3'-terminal exons dictate tissue-specific accumulation and a particular biological role(s) of AChE, associate the 3' exon E6 with NMJ development, and indicate the existence of a putative secretory AChE form derived from the alternative I4/E5 AChE mRNA.

PREVALENCE AND FEATURES OF GERIATRIC SYNDROMES TREATMENT IN OLD PATIENTS (CLINICAL AND EPIDEMIOLOGICAL STUDY)

2020 ◽  
pp. 331-338
Author(s):  
Е. Д. Голованова ◽  
Н. Е. Титова ◽  
Т. Е. Афанасенкова ◽  
И. А. Аргунова ◽  
Т. Н. Янковая ◽  
...  
Keyword(s):  
Geriatric Patients ◽  
Age Groups ◽  
Older Age ◽  
Age Dependence ◽  
Old Patients ◽  
Increased Risk ◽  
Planning Treatment ◽  
Risk Of Falls ◽  
Gender Characteristics ◽  
Outpatient Practice

Изучали распространенность хронических неинфекционных заболеваний (ХНИЗ) у пациентов пожилого и старческого возраста во взаимосвязи с синдромом старческой астении, распространенность саркопении в зависимости от гендерных особенностей и частоту встречаемости синдрома падений у пациентов старших возрастных групп с саркопенией. Анализировали особенности медикаментозной терапии в амбулаторной практике. Использовали метод комплексной гериатрической оценки у 528 пациентов, разделенных на три возрастные группы (65-74 года, 75-84 года, 85 лет и старше). Оказалось, что в структуре ХНИЗ у пациентов гериатрического профиля преобладают артериальная гипертензия, ИБС, а также их осложнения - ХСН и фибрилляция предсердий, частота встречаемости которых имеет выраженную возрастную зависимость и увеличивается у больных со старческой астенией. Для пациентов старших возрастных групп обоего пола характерно увеличение частоты встречаемости саркопении и связанного с ней повышенного риска синдрома падений, что необходимо учитывать при планировании лечебно-реабилитационных мер как в стационаре, так и при оказании первичной медикосоциальной помощи. We studied the prevalence of chronic non-communicable diseases (CND) in elderly and senile patients in conjunction with the syndrome of senile asthenia, the prevalence of sarcopenia depending on gender characteristics and the frequency of occurrence of the falls syndrome in patients with sarcopenia of older age groups. The features of drug therapy in outpatient practice were analyzed. The method of complex geriatric assessment was used in 528 patients divided into 3 age groups (65-74 years, 75-84 years, 85 years or more). It turned out that in the structure of CND in geriatric patients dominated: arterial hypertension, coronary heart disease, and their complications - chronic heart failure and atrial fi brillation their incidence has a pronounced age dependence and increases in patients with senile asthenia. Patients of older age groups of both sexes are characterized by an increase in the incidence of sarcopenia and the associated increased risk of falls syndrome, which must be taken into account when planning treatment and rehabilitation measures both in the hospital and when providing primary medical and social care.

scholarly journals CD40 up-regulation on dendritic cells correlates with Th17/Treg imbalance in chronic periodontitis in young population

2020 ◽  
Vol 26 (6) ◽  
pp. 482-489
Author(s):  
Xin Su ◽  
Jiahui Zhang ◽  
Xue Qin
Keyword(s):  
Dendritic Cells ◽  
Chronic Periodontitis ◽  
Th17 Cell ◽  
Young Patients ◽  
Serum Levels ◽  
Cd40 Ligand ◽  
Young Population ◽  
Soluble Cd40 Ligand ◽  
Old Patients

We aimed to discover the influence of age on the development of chronic periodontitis and illustrate the molecular mechanism in this process. Blood samples were collected from 63 chronic periodontitis patients and 30 healthy controls. Th17 cell/Foxp3+ regulatory T cell (Treg) ratio and expression of costimulatory molecules in dendritic cells (DCs) were analyzed by flow cytometry. The serum levels of soluble CD40 ligand (CD40L) and IL-17 were examined by ELISA. In young chronic periodontitis patients, the Th17/Treg ratio was significantly higher than that in old patients. CD40 on DCs and serum levels of CD40L and IL-17 were all higher in young chronic periodontitis patients. Mature DCs with high CD40 expression level elevated the Th17/Treg ratio in vitro. During the pathogenesis of chronic periodontitis, young patients had higher Th17/Treg ratio than old patients and this phenomenon was in line with the differential expression levels of CD40 in DCs.

scholarly journals P13.06 Transcriptome-wide Mendelian randomization study to identify brain-specific causal genes influencing glioma

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii63-iii63
Author(s):  
J W Robinson ◽  
J Zheng ◽  
S Tscavachidis ◽  
A E Howell ◽  
C L Relton ◽  
...  
Keyword(s):  
Gene Expression ◽  
Whole Blood ◽  
Malignant Gliomas ◽  
Cerebellar Hemisphere ◽  
Standard Deviation Increase ◽  
Tissue Specific ◽  
Human Transcriptome ◽  
Causal Genes ◽  
Glioma Risk ◽  
The Brain

Abstract BACKGROUND The drug treatment regimen for glioma has remained relatively static since the introduction of temozolomide, although new drugs and drug combinations are being trialled. The human transcriptome can provide promising insights into causal genes as potential drug interventions for glioma treatment and may guide drug discovery methods. MATERIAL AND METHODS We apply two sample Mendelian randomisation and colocalisation to explore the influence of genetically-predicted gene expression across 12 tissue types located in the brain (4,554 genes from GTEx) and whole blood (16,112 genes from eQTLGen) on glioma risk (5,739 cases, 5,501 controls from a meta-analysis of GICC and MDA glioma GWAS). We used the MR-Base R package to conduct these analyses. RESULTS We identify 9 genes whose genetically-predicted expression was strongly associated with glioma risk. Of these genes, 7/9 are shown to have tissue-specific expression while the other two genes showed an association with glioma across multiple brain tissues and whole blood. For example, JAK1, involved in the well-known JAK-STAT pathway, is found in the frontal cortex (OR=1.49 for glioma per standard deviation increase in gene expression; 95% CI: 1.28 to 1.73; P=1.79 × 10−7), the cerebellar hemisphere (OR=1.32; 95% CI: 1.19 to 1.47; P=2.64 × 10−7), the cerebellum (OR=1.27; 95% CI: 1.16 to 1.39; P=2.64 × 10−7) and the cortex (OR=1.38; 95% CI: 1.22 to 1.57; P=2.64 × 10−7). This pathway has been highlighted in previous research as a potential intervention target for glioma therapies. We found that 5/9 of the genes from the MR analysis are expressed in the cerebellum. However malignant cerebellar glioma is a rare tumour (~3% of all malignant gliomas). This suggests that tumourigenesis elsewhere in the brain may be affected by other tissue-specific genes, specifically in the cerebellum, though this will require further research to elucidate. We further triangulate the MR findings with evidence from the OpenTargets platform to strengthen the putative causal associations. OpenTargets aims to “generate evidence on the validity of therapeutic targets based on genome-scale experiments and analysis”. For example, JAK1 receives an overall OpenTargets score of 0.89 out of 1, with most of the evidence for this JAK1-glioma association coming from affected pathways data. CONCLUSION This study has combined genetic epidemiological approaches to the analysis of the human transcriptome on glioma incidence. We provide evidence that these genes may inform putative drug targets for tertiary treatment of glioma. Future research specifically towards this aim will be required to fully elucidate intervention targets.

scholarly journals Immune-to-brain signaling and central prostaglandin E2 synthesis in fasted rats with altered lipopolysaccharide-induced fever

2008 ◽  
Vol 295 (1) ◽  
pp. R133-R143 ◽  
Author(s):  
Wataru Inoue ◽  
Gokce Somay ◽  
Stephen Poole ◽  
Giamal N. Luheshi
Keyword(s):  
Inflammatory Responses ◽  
Mammalian Species ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Plasma Cytokines ◽  
Thermoregulatory Function ◽  
Underlying Mechanisms ◽  
Fever Response ◽  
The Brain ◽  
Fasted Rats

Acute starvation attenuates the fever response to pathogens in several mammalian species. The underlying mechanisms responsible for this effect are not fully understood but may involve a compromised immune and/or thermoregulatory function, both of which are prerequisites for fever generation. In the present study, we addressed whether the impaired innate immune response contributes to the reported attenuation of the fever response in fasted rats during LPS-induced inflammation. Animals fasted for 48 h exhibited a significant and progressive hypothermia prior to drug treatment. An intraperitoneal injection of LPS (100 μg/kg) resulted in a significantly attenuated fever in the fasted animals compared with the fed counterparts. This attenuation was accompanied by the diminution in the concentration of some [TNF and IL-1 receptor antagonist (RA)] but not all (IL-1β and IL-6) of the plasma cytokines normally elevated in association with the fever response. Nevertheless, fasting had no effect on the LPS-induced inflammatory responses at the level of the brain, as assessed by mRNA expressions of inhibitory factor(I)-κB, suppressor of cytokine signaling (SOCS3), IL-1β, cyclooxygenase (COX)-2, and microsomal PGE synthase (mPGES)-1 in the hypothalamus, as well as by PGE2 elevations in the cerebrospinal fluid. In contrast, fasting significantly attenuated the fever response to central PGE2 injection. These results show that fasting does not alter the febrigenic signaling from the periphery to the brain important for central PGE2 synthesis but does affect thermoregulatory mechanisms downstream of and/or independent of central PGE2 action.

scholarly journals Nanoparticle-Based Technology Approaches to the Management of Neurological Disorders

2020 ◽  
Vol 21 (17) ◽  
pp. 6070 ◽  
Author(s):  
Tao Ming Sim ◽  
Dinesh Tarini ◽  
S. Thameem Dheen ◽  
Boon Huat Bay ◽  
Dinesh Kumar Srinivasan
Keyword(s):  
Neurological Disorders ◽  
Pathological Condition ◽  
Cerebrovascular Diseases ◽  
Drug Bioavailability ◽  
Tissue Specific ◽  
The Central Nervous System ◽  
Cns Drugs ◽  
Treatment And Diagnosis ◽  
The Brain ◽  
Target Side

Neurological disorders are the most devastating and challenging diseases associated with the central nervous system (CNS). The blood-brain barrier (BBB) maintains homeostasis of the brain and contributes towards the maintenance of a very delicate microenvironment, impairing the transport of many therapeutics into the CNS and making the management of common neurological disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), cerebrovascular diseases (CVDs) and traumatic brain injury (TBI), exceptionally complicated. Nanoparticle (NP) technology offers a platform for the design of tissue-specific drug carrying systems owing to its versatile and modifiable nature. The prospect of being able to design NPs capable of successfully crossing the BBB, and maintaining a high drug bioavailability in neural parenchyma, has spurred much interest in the field of nanomedicine. NPs, which also come in an array of forms including polymeric NPs, solid lipid nanoparticles (SLNs), quantum dots and liposomes, have the flexibility of being conjugated with various macromolecules, such as surfactants to confer the physical or chemical property desired. These nanodelivery strategies represent potential novel and minimally invasive approaches to the treatment and diagnosis of these neurological disorders. Most of the strategies revolve around the ability of the NPs to cross the BBB via various influx mechanisms, such as adsorptive-mediated transcytosis (AMT) and receptor-mediated transcytosis (RMT), targeting specific biomarkers or lesions unique to that pathological condition, thereby ensuring high tissue-specific targeting and minimizing off-target side effects. In this article, insights into common neurological disorders and challenges of delivering CNS drugs due to the presence of BBB is provided, before an in-depth review of nanoparticle-based theranostic strategies.

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