Mechanisms Of Certain Diseases Research Articles

Targeting the chemerin/CMKLR1 axis by small molecule antagonist α-NETA mitigates endometriosis progression.

Endometriosis is a common gynecological disease, characterized by the presence of endometrial-like lesions outside the uterus. This debilitating disease causes chronic pelvic pain and infertility with limited therapeutics. Chemerin is a secretory protein that acts on CMKLR1 (Chemokine-Like Receptor 1) to execute functions vital for immunity, adiposity, and metabolism. Abnormal chemerin/CMKLR1 axis underlies the pathological mechanisms of certain diseases including cancer and inflammatory diseases, but its role in endometriosis remains unknown. Herein, our results showed that chemerin and CMKLR1 are up-regulated in endometriotic lesions by analyzing the human endometriosis database and murine model. Knockdown of chemerin or CMKLR1 by shRNA led to mesenchymal-epithelial transition (MET) along with compromised viability, migration, and invasion of hEM15A cells. Most importantly, 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA), a small molecule antagonist for CMKLR1, was evidenced to exhibit profound anti-endometriosis effects (anti-growth, anti-mesenchymal features, anti-angiogenesis, and anti-inflammation) in vitro and in vivo. Mechanistically, α-NETA exhibited a dual inhibition effect on PI3K/Akt and MAPK/ERK signaling pathways in hEM15A cells and murine endometriotic grafts. This study highlights that the chemerin/CMKLR1 signaling axis is critical for endometriosis progression, and targeting this axis by α-NETA may provide new options for therapeutic intervention.

Cell and Tissue Imaging by TOF-SIMS and MALDI-TOF: An Overview for Biological and Pharmaceutical Analysis.

The potential of mass spectrometry imaging (MSI) has been demonstrated in cell and tissue research since 1970. MSI can reveal the spatial distribution of a wide range of atomic and molecular ions detected from biological sample surfaces, it is a powerful and valuable technique used to monitor and detect diverse chemical and biological compounds, such as drugs, lipids, proteins, and DNA. MSI techniques, notably matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) and time of flight secondary ion mass spectrometry (TOF-SIMS), witnessed a dramatic upsurge in studying and investigating biological samples especially, cells and tissue sections. This advancement is attributed to the submicron lateral resolution, the high sensitivity, the good precision, and the accurate chemical specificity, which make these techniques suitable for decoding and understanding complex mechanisms of certain diseases, as well as monitoring the spatial distribution of specific elements, and compounds. While the application of both techniques for the analysis of cells and tissues is thoroughly discussed, a briefing of MALDI-TOF and TOF-SIMS basis and the adequate sampling before analysis are briefly covered. The importance of MALDI-TOF and TOF-SIMS as diagnostic tools and robust analytical techniques in the medicinal, pharmaceutical, and toxicology fields is highlighted through representative published studies.

Specific two-photon fluorescent probe for cysteine detection in vivo

Cysteine (Cys), an essential amino acid, plays several crucial functions in numerous biological processes. Notably, the detection of Cys is critical to disease diagnosis. Fluorescent probes that can quickly detect Cys will help to study the mechanism of certain diseases. Herein, a new fluorescent probe, ANP, which is based on 6-acetyl-N-methyl-2-naphthyl amine, has been developed for Cys detection over Hcy and GSH in vivo. The addition of thiol on α,β-unsaturated ketone promotes 87-fold fluorescence turn-on response with a 65 nM limit of detection. The high two-photon efficiency of the probe ANP (cross-section = 22.3) makes it a suitable probe for evaluating Cys in living cells without background fluorescence interference. Its application was extended to monitor the Cys distribution in live cells and tissues.

RWRNET: A Gene Regulatory Network Inference Algorithm Using Random Walk With Restart.

Inferring gene regulatory networks from expression data is essential in identifying complex regulatory relationships among genes and revealing the mechanism of certain diseases. Various computation methods have been developed for inferring gene regulatory networks. However, these methods focus on the local topology of the network rather than on the global topology. From network optimisation standpoint, emphasising the global topology of the network also reduces redundant regulatory relationships. In this study, we propose a novel network inference algorithm using Random Walk with Restart (RWRNET) that combines local and global topology relationships. The method first captures the local topology through three elements of random walk and then combines the local topology with the global topology by Random Walk with Restart. The Markov Blanket discovery algorithm is then used to deal with isolated genes. The proposed method is compared with several state-of-the-art methods on the basis of six benchmark datasets. Experimental results demonstrated the effectiveness of the proposed method.

A fluorescent turn-on probe for highly selective detection of cysteine and its bioimaging applications in living cells and tissues

Due to the abnormal concentration of cysteine (Cys) related to various diseases, it is of great significance in disease diagnosis to monitoring Cys under pathophysiological conditions. Fluorescence probe capable of fast detecting Cys would be beneficial to the study of mechanisms of certain diseases. In this paper, we designed and synthesized a novel fluorescent probe LC-Cys, which employed the acrylate group and α, β-unsaturated ketone as the two response groups. It could swiftly respond to Cys within 10 min, and exhibit satisfactory sensitivity and excellent selectivity to Cys. Furthermore, probe LC-Cys can be conveniently used to detect cysteine in living HepG2 cells and tissues with low cytotoxicity, indicating it would have great promise for biological applications.

Advances in Regenerative Medicine: From Stem Cells to Organoids

Stem cells have moved from lab to bedside, and many initial studies showed promising results. Therefore big companies are entering the business. However, most initial studies did not used controls to make sure of the efficacy of stem cells. Many phase-1 studies showed safety of stem cell therapies, when precaution measures were adapted. However, efficacy needs to be proven by randomized controlled trials (RCT) to exclude placebo effects. Recently, various RCTs for various conditions have been done with various contradictory results. Therefore, a meta-analysis is very useful to know whether a stem cell therapy really work for a certain condition. As various centres used various type of stem cells, various dose, and route of application, as well as different outcome measures with various results for one certain condition, sometimes it is difficult to conduct a meta-analysis when there is high heterogeneity, which is like pooling “apples” with “oranges” and “avocado” that will lead to a misleading conclusion. In many cases, where the studies are highly heterogeneous, and the heterogeneity can’t be identified, then a descriptive systematic review is the best solution to take a conclusion which protocol is the best and valuable to be standardized. Formerly it was believed that stem cells that are given to patients work by differentiating into the needed cells, and thus replacing damaged cell. However, recent evidence showed that only a few stem cells homed to the desired area, while a large amount went to various areas that were remote from the damaged area. Even though they were trapped in remote areas, the stem cells still exerted beneficial effects by remote signalling and secretion of various beneficial factors. Therefore, there are attempts to produce stem cell secretomes/metabolites to replace the stem cells, as metabolites are easier to handle and transported compared to the cells themselves. In addition, various studies worked on substitute tissue/organs “ex vivo” to be transplanted to replace a damaged organ. There are various means to produce a tissue/an organ/organoid “ex vivo” (tissue engineering) by using various stem cells, scaffold, and soluble factors, in various vessels from static vessel to bioreactors, and “on chips”. Though these attempts are in the initial stage, but some translational animal studies have been done. A more usual use of these “ex vivo” developed tissues/organs/organoids is for drug testing, such as toxicity testing, and for studying the mechanism of certain diseases that is directed toward the development of a cure of the diseases. In conclusion, many stem cell therapies have entered RCTs, but no standardized and approved protocol has been established, while organoids are usually used for drug testing and studying the mechanism of certain diseases.

Novel NIR fluorescent probe with dual models for sensitively and selectively monitoring and imaging Cys in living cells and mice

Cys plays paramount roles in human physiologies and pathologies. Abnormal levels of Cys are linked to a variety of diseases. Near-infrared fluorescence probe capable of detecting intracellular Cys in vivo would be beneficial to the study of mechanisms of certain diseases. Herein, we reported a rational and novel dual-site fluorescence probe JC-2 responded to Cys, which enjoyed different modes of fluorescence signals towards different concentration ranges of Cys. The probe was cell- membrane-permeable and could selectively detect Cys over other species. The potential biological utility of JC-2 was based on the fluorescence imaging of Cys in living cells and animals. The combined results elucidated the promising application of JC-2 in pathological analysis for diseases related to Cys.

MicroRNAs in the intracellular space, regulation of organelle specific pathways in health and disease.

MicroRNAs (miRNA) are small (~22 nucleotide] non-coding RNA molecules originally characterised as nonsense or junk DNA. Emerging research suggests that these molecules have diverse regulatory roles in an array of molecular, cellular and physiological processes. MiRNAs are versatile and highly stable molecules, therefore, they are able to exist as intracellular or extracellular miRNAs. The purpose of this paper is to review the function and role of miRNAs in the intracellular space with specific focus on the interactions between miRNAs and organelles such as the mitochondria and the rough endoplasmic reticulum. Understanding the role of miRNAs in the intracellular space may be vital in understanding the mechanism of certain diseases.

MetFlexo: An Automated Simulation of Realistic H1-NMR Spectra

The development of the ‘omics’ technologies such as transcriptomics, proteomics and metabolomics has made it possible to realize some of the goals of systems biology, where biological systems are interrogated at different levels of biochemical activity (such as gene expression, protein activity and/or metabolite concentration). Metabolomics deals with the metabolome that represents the complete set of small-molecule metabolites. Even though metabolomics can be thought of as a relatively young method, it is nevertheless a rapidly growing one that has the potential to reveal the molecular mechanism of certain diseases. H1 nuclear magnetic resonance (NMR) spectroscopy is commonly used in the metabolic profiling of biofluids as it has the potential to detect all proton-containing metabolites. Metabolites in biofluids are in dynamic equilibrium with those in cells and tissues, so their metabolic profile reflects changes in the state of an organism due to disease or environmental effects. ResultsMetFlexo is as an easy-to-use C package that allows the simulation of datasets of 1H-NMR spectra in order to test data analysis techniques, hypotheses and experimental designs. The idea is based on transforming statistical parameters of metabolites (shifts, couplings, concentrations and magnetic field) to an NMR spectrum using chemical-physics theory. Our method helps in the deconvolution of NMR spectra and in a better determination of metabolite concentrations, as these concentrations are key in detecting diseases and abnormalities. Unlike others, this program generates NMR spectrum of biofluids with no limit on magnetic field or pH. Thus, our approach is able to produce complex NMR profiles with flexible conditions. It is also simple to implement in C, requires small storage, is easy to compute and uses an independent platform. It will be available in R and MATLAB soon. The algorithm is freely available upon request to the corresponding author.

On the Inseparability of Mental and Physical Health in Aged Persons: Lessons From Depression and Medical Comorbidity

Recent research findings demonstrate that general medical and mental health are inseparable in older individuals. The medical consequences of depression can be summarized with the unifying hypothesis that depression interacts with medical or neurological illness to modify the course of disease and to amplify its associated effects. The medical causes of depression can be divided into specific mechanisms of certain diseases or medications and general mechanisms that may integrate effects of a number of the common chronic disorders of late life. The authors discuss two general hypotheses: One suggests that depression may be associated with subclinical cerebrovascular disease in older patients with cerebrovascular risk factors; the other suggests that depression occurring in association with various conditions may be related to cytokine-mediated "sickness behavior." The research literature makes a compelling case for the need to address psychiatric-medical comorbidity in late life as a central issue in public policy and the design of health care systems.

Dermatology in Internal Medicine

In this text Dr Shuster chose sparingly from a plethora of material, that which was of interest to him. The result is a book modest only in size and price. Those who have heard Dr Shuster or have read his interesting articles should enjoy this text as much as I did. His dynamism, unabashed enthusiasm, and fearless speculation bring alive the essence of pathogenetic mechanisms of certain diseases of the skin. The first chapter consists of an introduction to cutaneous anatomy, relating structure to function. In the second chapter, diseased skin is discussed in a general way, making some strong points against the notion that most cutaneous disorders are psychogenic. Shuster also believes many skin diseases have no systemic cause. I am not as certain as he appears to be about the independence of the skin from other organs. Evidence has begun to incriminate inadequate cellular immunity in even such

Diagnostic Procedures In Immunodermatology

Most immunologic diseases are caused by the derailment of the humoral or cellular pathways of the immunologic defense system. This derailment results from numerous factors such as the inability of the patient to remove the pathogen; the consumption, defect, or deficiency in any component of these pathways, and the overproduction of any of the components. To diagnose these immunologic disorders one has to detect the pathogen and the reactions caused by it and to determine the cause of its nonclearance. The immunofluorescence techniques has been invaluable in detecting both the antigen that causes the disease and the reactions initiated by the antigen, such as the production of antibodies and the activation of the complement system. The immunoperoxidase technique has also been used for these purposes in certain instances. For detecting the circulating immune complexes which occur as intermediates in the chain of reactions initiated by the antigen, various physiochemical and biologic techniques have been used. However, none of these tests seems to be totally reliable for determining whether circulating immune complexes are present. The consumption of complement was detected by hemolytic estimations and radial immunodiffusion or rocket electrphoresis. These techniques were also useful in detecting the hereditary deficiencies in immunoglobulins and components of classical and alternative pathways of complement activation. Since these techniques cannot be used to estimate IgE, the radioallergosorbent test was used to measure such levels in the atopic patients. Cellular hypersensitivity was detected with skin tests together with methods which assess the ability of lymphocytes to produce mediators in response to antigen. Many of these mediator assays, however, are not suitable for this purpose. A satisfactory substitute appears to be to determine the factor in antigen-stimulated, lymphocyte culture supernatants which activates macrophages to take up radiolabeled colloidal gold or radiolabeled glucosamine. In contact allergic dermatitis, an increase in the IgD-bearing lymphocytes and granulocytes has also been correlated with cellular hypersensitivity. Lymphocytes and polymorphonuclear leukocytes coated with antibodies mainly directed against nuclear antigens of the basal layer cells of the noninvolved epidermis have invariably been encountered in psoriasis. The use of these findings for diagnostic purposes and for understanding the mechanisms of certain diseases is being explored.