Secretome Profiling and Computational Biology of Human Leiomyoma Samples Unravel Molecular Signatures with Potential for Diagnostic and Therapeutic Interventions

2021 ◽  
Author(s):  
Tahreem Sahar ◽  
Aruna Nigam ◽  
Shadab Anjum ◽  
Nimisha Gupta ◽  
Saima Wajid
Keyword(s):  
Computational Biology ◽  
Therapeutic Interventions ◽  
Molecular Signatures ◽  
Secretome Profiling

scholarly journals Computational Biology and Machine Learning Approaches to Understand Mechanistic Microbiome-Host Interactions

2021 ◽  
Vol 12 ◽  
Author(s):  
Padhmanand Sudhakar ◽  
Kathleen Machiels ◽  
Bram Verstockt ◽  
Tamas Korcsmaros ◽  
Séverine Vermeire
Keyword(s):  
Machine Learning ◽  
Computational Biology ◽  
Molecular Mechanisms ◽  
Community Level ◽  
Therapeutic Interventions ◽  
Host Responses ◽  
Learning Approaches ◽  
Host Interactions ◽  
Bowel Diseases ◽  
Biological Interpretation

The microbiome, by virtue of its interactions with the host, is implicated in various host functions including its influence on nutrition and homeostasis. Many chronic diseases such as diabetes, cancer, inflammatory bowel diseases are characterized by a disruption of microbial communities in at least one biological niche/organ system. Various molecular mechanisms between microbial and host components such as proteins, RNAs, metabolites have recently been identified, thus filling many gaps in our understanding of how the microbiome modulates host processes. Concurrently, high-throughput technologies have enabled the profiling of heterogeneous datasets capturing community level changes in the microbiome as well as the host responses. However, due to limitations in parallel sampling and analytical procedures, big gaps still exist in terms of how the microbiome mechanistically influences host functions at a system and community level. In the past decade, computational biology and machine learning methodologies have been developed with the aim of filling the existing gaps. Due to the agnostic nature of the tools, they have been applied in diverse disease contexts to analyze and infer the interactions between the microbiome and host molecular components. Some of these approaches allow the identification and analysis of affected downstream host processes. Most of the tools statistically or mechanistically integrate different types of -omic and meta -omic datasets followed by functional/biological interpretation. In this review, we provide an overview of the landscape of computational approaches for investigating mechanistic interactions between individual microbes/microbiome and the host and the opportunities for basic and clinical research. These could include but are not limited to the development of activity- and mechanism-based biomarkers, uncovering mechanisms for therapeutic interventions and generating integrated signatures to stratify patients.

scholarly journals Exosomes are the Driving Force in Preparing the Soil for the Metastatic Seeds: Lessons from the Prostate Cancer

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 564 ◽  
Author(s):  
Saber H. Saber ◽  
Hamdy E. A. Ali ◽  
Rofaida Gaballa ◽  
Mohamed Gaballah ◽  
Hamed I. Ali ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Membrane Vesicles ◽  
Cell Types ◽  
Bioactive Molecules ◽  
Therapeutic Interventions ◽  
Target Cells ◽  
Molecular Signatures ◽  
Cellular Processes

Exosomes are nano-membrane vesicles that various cell types secrete during physiological and pathophysiological conditions. By shuttling bioactive molecules such as nucleic acids, proteins, and lipids to target cells, exosomes serve as key regulators for multiple cellular processes, including cancer metastasis. Recently, microvesicles have emerged as a challenge in the treatment of prostate cancer (PCa), encountered either when the number of vesicles increases or when the vesicles move into circulation, potentially with an ability to induce drug resistance, angiogenesis, and metastasis. Notably, the exosomal cargo can induce the desmoplastic response of PCa-associated cells in a tumor microenvironment (TME) to promote PCa metastasis. However, the crosstalk between PCa-derived exosomes and the TME remains only partially understood. In this review, we provide new insights into the metabolic and molecular signatures of PCa-associated exosomes in reprogramming the TME, and the subsequent promotion of aggressive phenotypes of PCa cells. Elucidating the molecular mechanisms of TME reprogramming by exosomes draws more practical and universal conclusions for the development of new therapeutic interventions when considering TME in the treatment of PCa patients.

Designing TIMP (tissue inhibitor of metalloproteinases) variants that are selective metalloproteinase inhibitors

2003 ◽  
Vol 70 ◽  
pp. 201-212 ◽  
Author(s):  
Hideaki Nagase ◽  
Keith Brew
Keyword(s):  
Three Dimensional ◽  
Therapeutic Interventions ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Structural Basis ◽  
Structural Elements ◽  
Ridge Structure ◽  
Extracellular Matrix Components ◽  
Metalloproteinase Inhibitors ◽  
The Matrix ◽  
A Disintegrin And Metalloproteinase

The tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of the matrix metalloproteinases (MMPs), enzymes that play central roles in the degradation of extracellular matrix components. The balance between MMPs and TIMPs is important in the maintenance of tissues, and its disruption affects tissue homoeostasis. Four related TIMPs (TIMP-1 to TIMP-4) can each form a complex with MMPs in a 1:1 stoichiometry with high affinity, but their inhibitory activities towards different MMPs are not particularly selective. The three-dimensional structures of TIMP-MMP complexes reveal that TIMPs have an extended ridge structure that slots into the active site of MMPs. Mutation of three separate residues in the ridge, at positions 2, 4 and 68 in the amino acid sequence of the N-terminal inhibitory domain of TIMP-1 (N-TIMP-1), separately and in combination has produced N-TIMP-1 variants with higher binding affinity and specificity for individual MMPs. TIMP-3 is unique in that it inhibits not only MMPs, but also several ADAM (a disintegrin and metalloproteinase) and ADAMTS (ADAM with thrombospondin motifs) metalloproteinases. Inhibition of the latter groups of metalloproteinases, as exemplified with ADAMTS-4 (aggrecanase 1), requires additional structural elements in TIMP-3 that have not yet been identified. Knowledge of the structural basis of the inhibitory action of TIMPs will facilitate the design of selective TIMP variants for investigating the biological roles of specific MMPs and for developing therapeutic interventions for MMP-associated diseases.

Inflammageing in the cardiovascular system: mechanisms, emerging targets, and novel therapeutic strategies

2020 ◽  
Vol 134 (17) ◽  
pp. 2243-2262
Author(s):  
Danlin Liu ◽  
Gavin Richardson ◽  
Fehmi M. Benli ◽  
Catherine Park ◽  
João V. de Souza ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Cardiovascular System ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Molecular Targets ◽  
Therapeutic Interventions ◽  
Low Grade ◽  
Cardiovascular Research ◽  
Inflammatory Processes ◽  
Ach Receptors

Abstract In the elderly population, pathological inflammation has been associated with ageing-associated diseases. The term ‘inflammageing’, which was used for the first time by Franceschi and co-workers in 2000, is associated with the chronic, low-grade, subclinical inflammatory processes coupled to biological ageing. The source of these inflammatory processes is debated. The senescence-associated secretory phenotype (SASP) has been proposed as the main origin of inflammageing. The SASP is characterised by the release of inflammatory cytokines, elevated activation of the NLRP3 inflammasome, altered regulation of acetylcholine (ACh) nicotinic receptors, and abnormal NAD+ metabolism. Therefore, SASP may be ‘druggable’ by small molecule therapeutics targeting those emerging molecular targets. It has been shown that inflammageing is a hallmark of various cardiovascular diseases, including atherosclerosis, hypertension, and adverse cardiac remodelling. Therefore, the pathomechanism involving SASP activation via the NLRP3 inflammasome; modulation of NLRP3 via α7 nicotinic ACh receptors; and modulation by senolytics targeting other proteins have gained a lot of interest within cardiovascular research and drug development communities. In this review, which offers a unique view from both clinical and preclinical target-based drug discovery perspectives, we have focused on cardiovascular inflammageing and its molecular mechanisms. We have outlined the mechanistic links between inflammageing, SASP, interleukin (IL)-1β, NLRP3 inflammasome, nicotinic ACh receptors, and molecular targets of senolytic drugs in the context of cardiovascular diseases. We have addressed the ‘druggability’ of NLRP3 and nicotinic α7 receptors by small molecules, as these proteins represent novel and exciting targets for therapeutic interventions targeting inflammageing in the cardiovascular system and beyond.

Emotion-Oriented Coping Style Predicts Self-Harm in Response to Acute Psychiatric Hospitalization

Crisis ◽  
2020 ◽  
pp. 1-7
Author(s):  
Jacqueline M. Frei ◽  
Vladimir Sazhin ◽  
Melissa Fick ◽  
Keong Yap
Keyword(s):  
Borderline Personality Disorder ◽  
Personality Disorder ◽  
Psychiatric Hospitalization ◽  
Coping Styles ◽  
Psychiatric Inpatients ◽  
Borderline Personality ◽  
Self Report ◽  
Therapeutic Interventions ◽  
Coping Behaviors ◽  
Self Harm

Abstract. Psychiatric hospitalization can cause significant distress for patients. Research has shown that to cope with the stress, patients sometimes resort to self-harm. Given the paucity of research on self-harm among psychiatric inpatients, a better understanding of transdiagnostic processes as predictors of self-harm during psychiatric hospitalization is needed. The current study examined whether coping styles predicted self-harm after controlling for commonly associated factors, such as age, gender, and borderline personality disorder. Participants were 72 patients (mean age = 39.32 years, SD = 12.29, 64% male) admitted for inpatient treatment at a public psychiatric hospital in Sydney, Australia. Participants completed self-report measures of coping styles and ward-specific coping behaviors, including self-harm, in relation to coping with the stress of acute hospitalization. Results showed that younger age, diagnosis of borderline personality disorder, and higher emotion-oriented coping were associated with self-harm. After controlling for age and borderline personality disorder, higher levels of emotion-oriented coping were found to be a significant predictor of self-harm. Findings were partially consistent with hypotheses; emotion-oriented but not avoidance-oriented coping significantly predicted self-harm. This finding may help to identify and provide psychiatric inpatients who are at risk of self-harm with appropriate therapeutic interventions.

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