Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Murine typhus. Core disease mechanisms, molecular and cellular pathways, i...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Adipose Tissue Serves as a Reservoir for Recrudescent Rickettsia prowazekii Infection in a Mouse Model

• Authors: Y. Bechah, C. Paddock, C. Capo, J. Mege, D. Raoult
• Year: 2010
• Venue: PLoS ONE
• URL: https://www.semanticscholar.org/paper/5b757f7f13338d7b2b37b23bec2b4a4dec01c792
• DOI: 10.1371/journal.pone.0008547
• PMID: 20049326
• PMCID: 2797295
• Citations: 54
• Influential citations: 1
• Summary: A murine model for Brill-Zinsser disease is described, and PCR and cell culture are used to show transient rickettsemia in mice treated with dexamethasone, suggesting a role for adipose tissue as a potential reservoir for dormant infections with R. prowazekii.
• Evidence snippets:
• Snippet 1 (score: 0.445) > Brill-Zinsser disease, the relapsing form of epidemic typhus, typically occurs in a susceptible host years or decades after the primary infection; however, the mechanisms of reactivation and the cellular reservoir during latency are poorly understood. Herein we describe a murine model for Brill-Zinsser disease, and use PCR and cell culture to show transient rickettsemia in mice treated with dexamethasone >3 months after clinical recovery from the primary infection. Treatment of similarly infected mice with cyclosporine failed to produce recrudescent bacteremia. Therapy with doxycycline for the primary infection prevented recrudescent bacteremia in most of these mice following treatment with dexamethasone. Rickettsia prowazekii (the etiologic agent of epidemic typhus) was detected by PCR, cell culture, and immunostaining methods in murine adipose tissue, but not in liver, spleen, lung, or central nervous system tissues of mice 4 months after recovery from the primary infection. The lungs of dexamethasone-treated mice showed impaired expression of β-defensin transcripts that may be involved in the pathogenesis of pulmonary lesions. In vitro, R. prowazekii rickettsiae infected and replicated in the murine adipocyte cell line 3T3-L1. Collectively these data suggest a role for adipose tissue as a potential reservoir for dormant infections with R. prowazekii.

[2] Immunization with an Autotransporter Protein of Orientia tsutsugamushi Provides Protective Immunity against Scrub Typhus

• Authors: Na-Young Ha, Prashant Sharma, Gwanghun Kim, Yuri Kim, C. Min et al.
• Year: 2015
• Venue: PLoS Neglected Tropical Diseases
• URL: https://www.semanticscholar.org/paper/a60b6105d1ac156de381571a55e7e01c1e38ee57
• DOI: 10.1371/journal.pntd.0003585
• PMID: 25768004
• PMCID: 4359152
• Citations: 53
• Summary: It is demonstrated that ScaA functions as a bacterial adhesion factor, and anti-ScaA antibody significantly neutralizes bacterial infection of host cells, the most promising result of scrub typhus vaccination trials against infection of heterologous strains in mouse models thus far.
• Evidence snippets:
• Snippet 1 (score: 0.438) > Intradermal or intravenous inoculation of the pathogen partially represented the specific pathology of human scrub typhus [64,65]. An infection model using O. tsutsugamushi-infected mites to mimic the natural transmission was also shown that the species of infected chigger and their O. tsutsugamushi genotypes produced different clinical presentations in ICR mice [63]. Previously, diverse strains of mice showed differential morbidity and mortality to the infection with specific strains of O. tsutsugamushi [67,68]. Therefore, various factors such as infection routes and genetic backgrounds of host and the pathogen may affect the susceptibility and disease severity of scrub typhus. In the current study, we used C57BL/6 inbred mice model after intraperitoneal injection of O. tsutsugamushi strains, which resulted in 100% mortality when unimmunized. Valid models in C57BL/6 mice also open the opportunity to study genes involved in the mechanisms of immunity and pathogenesis by the use of gene knockout mice [69]. The development of animal models that accurately portray human scrub typhus is an important step toward standing and managing disease [65,66]. Although there are differences in target cells of O. tsutsugamushi infection and the disease progression depending on the route of infection and the genotypes, these models closely parallels the clinical course and pathological legions described from lethal scrub typhus in human and, therefore, may provide valuable tools to characterize the molecular and cellular factors responsible for immunological pathogenesis of scrub typhus [65]. Further studies on the bacterial virulence mechanisms [39,70,71] and the underlying mechanisms of immunological pathogenesis in human scrub typhus patients [72] should also be followed to improve our understanding for the weak and transient immunity against the bacterial infection in human and to facilitate the development of effective vaccine for scrub typhus.

[3] Brain transcriptomics reveal the activation of neuroinflammation pathways during acute Orientia tsutsugamushi infection in mice

• Authors: Yuejin Liang, Aditi, Florence Onyoni, Hui Wang, Casey A Gonzales et al.
• Year: 2023
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/335df2a4d6bd62b526fd0e93e19de6409b3d9f1e
• DOI: 10.3389/fimmu.2023.1194881
• PMID: 37426673
• PMCID: 10326051
• Citations: 13
• Summary: New insights into neuroinflammation in scrub typhus are provided, highlighting the impact of excessive IFN responses, microglial activation, and BBB dysregulation on disease pathogenesis.
• Evidence snippets:
• Snippet 1 (score: 0.421) > Scrub typhus, an acute febrile illness caused by Orientia tsutsugamushi (Ot), is prevalent in endemic areas with one million new cases annually. Clinical observations suggest central nervous system (CNS) involvement in severe scrub typhus cases. Acute encephalitis syndrome (AES) associated with Ot infection is a major public health problem; however, the underlying mechanisms of neurological disorder remain poorly understood. By using a well-established murine model of severe scrub typhus and brain RNA-seq, we studied the brain transcriptome dynamics and identified the activated neuroinflammation pathways. Our data indicated a strong enrichment of several immune signaling and inflammation-related pathways at the onset of disease and prior to host death. The strongest upregulation of expression included genes involved in interferon (IFN) responses, defense response to bacteria, immunoglobulin-mediated immunity, IL-6/JAK-STAT signaling, and TNF signaling via NF-κB. We also found a significant increase in the expression of core genes related to blood-brain barrier (BBB) disruption and dysregulation in severe Ot infection. Brain tissue immunostaining and in vitro infection of microglia revealed microglial activation and proinflammatory cytokine production, suggesting a crucial role of microglia in neuroinflammation during scrub typhus. This study provides new insights into neuroinflammation in scrub typhus, highlighting the impact of excessive IFN responses, microglial activation, and BBB dysregulation on disease pathogenesis.

[4] Polarized lung inflammation and Tie2/angiopoietin-mediated endothelial dysfunction during severe Orientia tsutsugamushi infection

• Authors: Brandon Trent, Yuejin Liang, Yan Xing, Marisol Esqueda, Yang Wei et al.
• Year: 2019
• Venue: PLoS Neglected Tropical Diseases
• URL: https://www.semanticscholar.org/paper/62282ec13f746479908b29c99da28cc9d675b9f8
• DOI: 10.1101/723387
• PMID: 32119672
• PMCID: 7067486
• Citations: 24
• Summary: This first detailed investigation of lung cellular immune responses during acute O. tsutsugamushi infection uncovers specific biomarkers for vascular dysfunction and M1-skewed inflammatory responses, highlighting future therapeutic research for the control of this neglected tropical disease.
• Evidence snippets:
• Snippet 1 (score: 0.421) > Orientia tsutsugamushi infection can cause acute lung injury and high mortality in humans; however, the underlying mechanisms are unclear. Here, we tested a hypothesis that dysregulated pulmonary inflammation and Tie2-mediated endothelial malfunction contribute to lung damage. Using a murine model of lethal O. tsutsugamushi infection, we demonstrated pathological characteristics of vascular activation and tissue damage: 1) a significant increase of ICAM-1, VEGFR2, and angiopoietin-2 (Ang2) proteins in inflamed tissues and lung-derived endothelial cells (EC), 2) a progressive loss of endothelial quiescent and junction proteins (Ang1, VE-cadherin/CD144, occuludin), and 3) a profound impairment of Tie2 receptor at the transcriptional and functional levels. In vitro infection of primary human EC cultures and serum Ang2 proteins in scrub typhus patients support our animal studies, implying endothelial dysfunction in severe scrub typhus. Flow cytometric analyses of lung-recovered cells further revealed that pulmonary macrophages (MΦ) were polarized toward an M1-like phenotype (CD80+CD64+CD11b+Ly6G-) during the onset of disease and prior to host death, which correlated with the significant loss of CD31+CD45- ECs and M2-like (CD206+CD64+CD11b+Ly6G-) cells. In vitro studies indicated extensive bacterial replication in M2-type, but not M1-type, MΦs, implying the protective and pathogenic roles of M1-skewed responses. This is the first detailed investigation of lung cellular immune responses during acute O. tsutsugamushi infection. It uncovers specific biomarkers for vascular dysfunction and M1-skewed inflammatory responses, highlighting future therapeutic research for the control of this neglected tropical disease. Author Summary Scrub typhus is a life-threatening disease, infecting an estimated one million people yearly. Acute lung injury is the most common clinical observation; however, its pathogenic biomarkers and mechanisms of progression remain unknown. Here, we used a lethal infection mouse model that parallels certain aspects of severe scrub typhus, primary human

[5] LifeTime and improving European healthcare through cell-based interceptive medicine

• Authors: N. Rajewsky, G. Almouzni, S. Gorski, S. Aerts, I. Amit et al.
• Year: 2020
• Venue: Nature
• URL: https://www.semanticscholar.org/paper/d626a4acb560c1ef16ea394cb4dccf277882d119
• DOI: 10.1038/s41586-020-2715-9
• PMID: 32894860
• PMCID: 7656507
• Citations: 138
• Influential citations: 2
• Summary: The LifeTime initiative is an ambitious, multidisciplinary programme that aims to improve healthcare by tracking individual human cells during disease processes and responses to treatment in order to develop and implement cell-based interceptive medicine in Europe over the next decade.
• Evidence snippets:
• Snippet 1 (score: 0.407) > , a major challenge is a lack of understanding of the early events in disease onset to enable the development of disease-modifying therapies. The lack of access to longitudinal samples from patients necessitates the establishment of cohorts of patient-derived disease models to understand the cellular heterogeneity associated with disease. The discovery of pathways and biomarkers that will allow the stratification of patients on the basis of the cellular mechanisms that drive a disease will make it possible to design new clinical trials to reevaluate drugs that were previously tested without such stratification, and to broaden the drug target portfolio. > As seen during the coronavirus disease 2019 (COVID-19) pandemic, it is important to be able to understand infection mechanisms and the host response in order to rapidly identify the most likely effective treatment for an infection. At the same time, the continuous rise of antimicrobial resistance requires the discovery of new therapeutic strategies. A key medical challenge for infectious diseases is to understand the cellular response to infections and to develop precision, immune-based therapeutic strategies to combat infections. > Chronic inflammatory diseases impose a high burden owing to their long-term debilitating consequences, which result from the structural destruction of affected organs or tissues. Current therapies treat the symptoms but do not cure or fully control the chronic inflammatory pathophysiology. While different targeted therapies exist, they are expensive and their success is limited by high rates of non-response to treatment. Consequently, there is an urgent need to explore and understand how cellular heterogeneity contributes to the pathology of inflammatory diseases 61 and how this relates to the predicted course of disease and the response of a patient to one of the numerous available therapies. > Many cardiovascular and metabolic diseases lack effective therapies owing to a lack of knowledge of their underlying causes and the link between abnormal cardiac cell structure or function and pathophysiology. The identified medical priority is to understand the cellular and molecular mechanisms involved, in order to enable early diagnosis and the design of new mechanism-based therapies for precise clinical treatment. > The LifeTime disease roadmaps can be divided broadly into three phases 7 : first, immediate research into the identified medical challenges using established, scaled single-cell technologies, computational tools and disease models; second, the development of new technologies that are required

[6] Polygenic autoimmune disease risk alleles impacting B cell tolerance act in concert across shared molecular networks in mouse and in humans

• Authors: I. T. Harley, K. Allison, R. Scofield
• Year: 2022
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/9f9ca9f9572375dba54d174099ba68be2a8ec2a0
• DOI: 10.3389/fimmu.2022.953439
• PMID: 36090990
• PMCID: 9450536
• Citations: 9
• Summary: The synthesis and analysis of the current state of the art in understanding of human risk alleles in two prototypical autoimmune diseases – systemic lupus erythematosus and type 1 diabetes along with spontaneous murine disease models show that there is substantial overlap between the molecular networks that define these disease states across species.
• Evidence snippets:
• Snippet 1 (score: 0.394) > Importantly, both of these disease states have long been modeled with mouse strains that spontaneously develop disease features that closely resemble several of the key phenotypes and pathophysiologies of the human diseases being modeled. Because of the long history of investigation of the cellular and molecular mechanisms of these models, we expect that models of these two diseases are likely to have a more complete list of the genetic contributors and understanding of the relevant cellular and molecular mechanisms leading to murine autoimmune disease. > To address this overlap, we also synthesize what is known regarding the function of putative causal genes across murine models of both systemic autoimmune pathologies (SLE and T1D) and autoreactive B cell tolerance. We discuss several plausible potential explanations for the non-monotonic relationship between currently known human and murine autoimmune risk alleles. Through this analysis, we show that the molecular networks comprised of putative human and murine risk alleles for B-cell dependent autoimmunity and autoimmune pathology substantially overlap. Finally, we propose a framework for steps toward more successful translation of findings from murine model systems to clinical application in humans.

[7] Prioritizing Molecular Biomarkers in Asthma and Respiratory Allergy Using Systems Biology

• Authors: Lucía Cremades-Jimeno, M. D. de Pedro, M. López-Ramos, J. Sastre, P. Mínguez et al.
• Year: 2021
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/d8ca6e130adec2dfa39545eb1763827d9450e4f5
• DOI: 10.3389/fimmu.2021.640791
• PMID: 33936056
• PMCID: 8081895
• Citations: 13
• Influential citations: 1
• Summary: This study has enabled it to prioritize biomarkers depending on the functionality associated with each disease and with specific molecular motifs, which could improve the definition and usefulness of new molecular biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.386) > Firstly, the molecular characterization of the three pathophysiological processes of interest (respiratory allergy, allergic asthma, and nonallergic asthma) was performed using the Therapeutic Performance Mapping System (TPMS) technology (Anaxomics Biotech, Barcelona, Catalonia, Spain) (31). Briefly, systems biology generates models that are able to reproduce the behavior of a disease in a patient, thus identifying the key genes, proteins, or metabolites in the development of the disease. A dictionary has been created to translate clinical and medical terms into molecular biology data, effectively linking the molecular and the clinical words. This dictionary, called the Biological Effectors Database (BED), relates biological processes (adverse events of drugs, drug indications, diseases, etc.) with the proteins most closely associated with them. Thus, the dictionary acts as a translator of clinical phenotypes into terms comprehensible for protein networks, and conversely allows for the translation of molecular measures toward clinical outcomes. The BED is structured hierarchically, where the biggest level is the entire disease, which is divided into different pathophysiological molecular motifs, which in turn contain the proteins involved in the development of the disease. The motifs are classified into two levels depending on their respective implication, i.e. causal motifs, which are directly related to the onset or pathophysiology of the condition, and symptomatic (manifestative) motifs, which are a consequence of the disease. > In the present study, respiratory allergy, allergic asthma, and non-allergic asthma have been characterized at the molecular level. Therefore, the analysis of high throughput data by means of TPMS allows for identification of those proteins closely associated with the disease of interest and can provide a mechanistic rationale for their involvement. The effector proteins of the manifestative and causal molecular motifs of these three diseases have been identified through bibliographic review and curate data. Figure 1 summarizes the workflow used for this study.

[8] Differential Regulation of Interferon Signaling Pathways in CD4+ T Cells of the Low Type-2 Obesity-Associated Asthma Phenotype

• Authors: Fahd Alhamdan, L. Marsh, F. Pedersen, B. A. Alhamwe, C. Thölken et al.
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/64e368bc44d989aa672152b1812fa77c44e3189c
• DOI: 10.3390/ijms221810144
• PMID: 34576307
• PMCID: 8469911
• Citations: 23
• Summary: The specific activation of interferon (IFN)-stimulated genes associated with IFN-related signaling and viral infection pathways might provide a novel view of the molecular mechanisms associated with the development of the low type-2 obesity-associated asthma phenotype, which is a step ahead in theDevelopment of new stratified therapeutic approaches.
• Evidence snippets:
• Snippet 1 (score: 0.385) > Over the last decades, non-communicable diseases (NCDs) have become the major cause of death worldwide, especially after the development of effective anti-infectious measures of prevention (vaccines) and treatment (antibiotics) [1][2][3]. Moreover, they represent a huge burden on the healthcare system and economic situation [4,5]. Prevalence and incidence of NCDs are still further increasing along with ongoing urbanization, industrialization, and globalization of unhealthy diet and lifestyles [6,7]. According to the World Health Organization (WHO), the rapid increase in the NCDs is mainly driven by various risk factors including tobacco, harmful use of alcohol, and obesity [8]. Furthermore, different NCDs and their major risk factors seem to have substantially overlapping underlying mechanisms, often involving immunometabolic alterations [9,10]. Combinations of certain NCDs and associated risk factors can create separate specific disease entities, classified as a clinical subtype or phenotype [11]. > Obesity is a key risk factor underlying a variety of major NCDs, including asthma [10,12]. The comorbidity of obesity and asthma is referred to as obesity-associated asthma [13,14]. Various associated clinical characteristics of obesity and asthma have been described. The major obesity-associated asthma phenotype is characterized as "late-onset, severe and difficult to treat, type-2 low inflammation disease and presenting mostly in women" [15][16][17]. While these detailed clinical characteristics strictly define this particular phenotype of asthma, the specific underlying cellular and molecular mechanisms of this phenotype are still only poorly understood. > Gene expression alterations, especially in cells critically involved in disease development, represent a major molecular contributor to the pathophysiology of chronic inflammatory diseases such as asthma. Subsets of CD4 + T cells, such as Th1, Th2, and Th17 have been shown to differentially contribute to the initiation and perpetuation of specific asthma phenotypes [18,19]. Certain biological pathways and cellular processes play an essential role in the polarization of the CD4 + T cells subtypes [20].

[9] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

• Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
• Year: 2025
• Venue: Journal of Veterinary Internal Medicine
• URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
• DOI: 10.1111/jvim.70139
• PMID: 40492724
• PMCID: 12150350
• Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
• Evidence snippets:
• Snippet 1 (score: 0.384) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[10] Solving the Evidence Interpretability Crisis in Health Technology Assessment: A Role for Mechanistic Models?

• Authors: E. Courcelles, J. Boissel, J. Massol, I. Klingmann, R. Kahoul et al.
• Year: 2022
• Venue: Frontiers in Medical Technology
• URL: https://www.semanticscholar.org/paper/877d5b1b75599745f704a9c8371f74601ff17e2f
• DOI: 10.3389/fmedt.2022.810315
• PMID: 35281671
• PMCID: 8907708
• Citations: 6
• Summary: Light is shed on different stakeholder's contributions and needs in the appraisal phase and how mechanistic modeling strategies and reporting can contribute to this effort to implement mechanistic models central in the evidence generation, synthesis, and appraisal of HTA so that the totality of mechanistic and clinical evidence can be leveraged by all relevant stakeholders.
• Evidence snippets:
• Snippet 1 (score: 0.379) > A second limitation in HTA is the fact that currently population (and sometimes stratified) medicine is pursued during clinical Uncertainty not completely addressed in competent authority assessment report Example use of MIDD relevant to address uncertainty potentially also during HTA What is the optimal dosage in the clinical context? > Physiologically based pharmacokinetic models can investigate dosing-regimens relevant for regulatory review and product labels (9) and can also mimic real-life adherence to prescribed treatment regimens (see also below) or pharmacology-relevant characteristics of special populations as well as drug-drug interactions. > What is the duration of the effectiveness, especially with chronic use of a treatment? > Mechanistic models can predict the long-term disease progression by extrapolation of shorter-term findings under the constraints of how the components of the system function (and these constraints convey biological plausibility by design). An example is the use of a mechanism-based disease progression model for comparison of long-term effects of pioglitazone, metformin, and gliclazide on disease processes underlying Type 2 Diabetes Mellitus (10). Another example is prediction of long-term outcomes by short-term marker data as demonstrated by a semi-mechanistic approach in context of osteoporosis treatment (11). > What is the efficacy for relevant clinical outcomes? > Mechanistic models combined with pharmacometric approaches can translate findings for one outcome to a range of other outcomes. An example of survival modeling on the back of a mechanistic description is the modeling framework for CD19-Specific CAR-T cell immunotherapy using a quantitative systems pharmacology model (12). > What is the size of the clinical effect dependent on patient characteristics and extrinsic factors? > Data-driven modeling techniques can capture correlation within clinical data. Describing the clinical effect of a drug can also be based on mechanistic considerations. Such models either (a) link disease phenotypes to increasingly granular mathematical representations of pathophysiologic processes (top-down approach) or (b) derive functional, computable cellular networks from the molecular building blocks of genes and proteins to elucidate the impact of pathologic or therapeutic alterations on network operating states and hence clinical phenotype (bottom-up) [

[11] In Vitro Disease Models of the Endocrine Pancreas

• Authors: Marko Milojević, Jan Rožanc, Jernej Vajda, Laura Činč Ćurić, Eva Paradiž et al.
• Year: 2021
• Venue: Biomedicines
• URL: https://www.semanticscholar.org/paper/607e4baf1df4c1c06656a07d617a408d29b1a3e8
• DOI: 10.3390/biomedicines9101415
• PMID: 34680532
• PMCID: 8533367
• Citations: 9
• Summary: This review provides an overview of in vitro models and focuses specifically on in vitro disease models of the endocrine pancreas and diabetes, with an emphasis on islets of Langerhans and beta cell dysfunction.
• Evidence snippets:
• Snippet 1 (score: 0.378) > The fundamental goal of biomedical research is to decipher the molecular mechanisms of human disease in order to develop more effective or even new models for diagnosis, prevention, and therapeutic approaches.Due to ethical and other concerns, basic research on human (patho)physiology requires in vitro approaches.Current experiments generally rely on cell cultures and animal models (e.g., transgenic mice).While these are useful for certain aspects of disease modelling because they replicate disease phenotypes similar those observed in humans, it is becoming increasingly clear that basic genetic and molecular mechanisms may differ greatly between humans and other animals due to species-specific differences.For example, a recent systematic study of 5554 human genes and 4918 murine analogues showed that, in acute inflammatory stress responses changes in murine gene expression correlate poorly with those observed in humans [1].Moreover, it is difficult to identify and independently vary the crucial molecular and cellular factors that contribute to disease in whole-animal models.This is probably the reason that many drugs fail to show efficacy and safety when translated from animal studies to human clinical trials [2]. > The inadequacies of animal models to adequately recapitulate human disease, coupled with the associated ethical constraints and requirements to study disease pathogenesis under controlled conditions, have given rise to a new field at the interface of tissue engineering and pathophysiology, focused on the development of in vitro models of disease.These are defined as synthetic alternative experimental systems that contain living human cells and mimic tissue-and organ-level pathophysiology in vitro by taking advantage of recent advances in tissue engineering, microfabrication, and microfluidics [3][4][5].When developing an in vitro disease model, some of the basic elements to consider are the source and type of cells, chemical and physical stimuli that promote the simulated cell phenotype, and additionally, when developing a 3D in vitro model, scaffold structure, fabrication process, and building blocks.The micro-and macro-environmental conditions of the in vitro models should be designed to mimic the characteristics of native or pathologically altered tissues.These include nutrient and metabolite concentrations, pH, and gas and mechanical gradients [6,7].

[12] Enhancer Associated Long Non-coding RNA Transcription and Gene Regulation in Experimental Models of Rickettsial Infection

• Authors: I. Chowdhury, H. Narra, Abha Sahni, K. Khanipov, Y. Fofanov et al.
• Year: 2019
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/1876042af6ccbd1f2bdceb52dd936c5c0de2a45a
• DOI: 10.3389/fimmu.2018.03014
• PMID: 30687302
• PMCID: 6333757
• Citations: 15
• Influential citations: 2
• Summary: This work has profiled the expression of host lncRNAs during infection of susceptible mice with R. conorii as a model closely mimicking the pathogenesis of human spotted fever rickettsioses, and provides very first experimental evidence suggesting altered expression of pulmonary lnc RNAs and elncRNA-mediated regulation of PCGs involved in immunity and during host interactions with pathogenic ricksettsiae.
• Evidence snippets:
• Snippet 1 (score: 0.373) > Arthropod-borne Rickettsia species include obligate intracellular, Gram-negative bacteria known to cause spotted fever and typhus groups of rickettsial dieases in humans (1). The clinical spectrum of spotted fever group (SFG) rickettsioses varies in severity from mild to fatal cases of Rocky Mountain spotted fever (RMSF) caused by Rickettsia rickettsii, Mediterranean spotted fever (MSF) due to R. conorii, and Queensland tick typhus following infection with R. australis (1). A majority of human rickettsial diseases involve transmission from arthropod vectors, for example naturally circulating infected ticks in case of R. rickettsii and R. conorii. Due mainly to the predilection of pathogenic rickettsiae to target endothelial cells lining the microvasculature in their mammalian hosts and cell-to-cell spread during the course of infection (1,2), a prominent feature of pathogenesis is the innate immune activation and inflammatory perturbations of microvascular endothelium, leading to complications such as ocular inflammation or retinitis, myocarditis, endocarditis, pulmonary, and cerebral edema due to fluid imbalance associated with the derangements of endothelial barrier, and multi-organ failure in severe cases (1)(2)(3)(4)(5)(6). Employing both patient samples and established experimental models of infection, a number of studies have delved into the definition of host responses during rickettsial infections (7,8), but the mechanisms underlying the activation and regulation of such immune mechanisms remain largely unknown. > Functional annotation of the mammalian genome (FANTOM) and Encyclopedia of DNA Elements (ENCODE) projects have challenged the central dogma of molecular biology by suggesting that non-protein-coding regions carry multiple overlapping codes that profoundly affect gene expression and other cellular processes.

[13] Understanding the Pathogenesis of Cardiac Complications in Patients with Propionic Acidemia and Exploring Therapeutic Alternatives for Those Who Are Not Eligible or Are Waiting for Liver Transplantation

• Authors: Evelina Maines, M. Moretti, Nicola Vitturi, G. Gugelmo, I. Fasan et al.
• Year: 2023
• Venue: Metabolites
• URL: https://www.semanticscholar.org/paper/cde4b45d074c2b77caef9eb4e98c21bb412d8ead
• DOI: 10.3390/metabo13040563
• PMID: 37110221
• PMCID: 10143878
• Citations: 3
• Summary: This review summarizes the current knowledge of the pathogenetic mechanisms underlying cardiac complications of propionic acidemia and the available and potential pharmacological options for the prevention or the treatment of cardiac complications in PA and provides a critical discussion of the related therapeutic options.
• Evidence snippets:
• Snippet 1 (score: 0.371) > PA is a complex and heterogeneous disease involving multiple cellular pathways beyond the primary enzyme defect. Therefore, it is unlikely that a single mechanism may cause cardiac complications. > Since the heart is a highly energy-demanding organ, altered energy metabolism in the myocardium is considered a major driver of pathological cardiac manifestations in PA. Indeed, cardiac involvement, in the form of CM or arrhythmia, is common in several energy metabolism disorders, including mitochondrial electron transport defects [103] and fatty acid oxidation disorders [104]. > In addition, since cell energy is mostly obtained thanks to the mitochondria, especially via the TCA cycle and electron transport chain, pathogenetic mechanisms targeting these pathways have been extensively investigated as potential causes of cardiac disease in PA. > Since cardiac complications are observed in vivo despite good metabolic control and without a correlation with the metabolic severity, mechanisms other than the accumulation of toxic compounds have been suggested as causative. Deficiency of nutrients, intermediates or cofactors, mitochondrial ultrastructural changes, and increased oxidative stress can all contribute to the development of cardiac complications. Intriguing new hypotheses are emerging involving miRNA signatures and epigenetic mechanisms. miRNA expression in PA is influenced by the age of the patients and by the tissue under consideration. Clearly, multiple factors regulate the molecular adaptations to PA. All these mechanisms add to the complex pattern of the phenotypes and may mediate the chronic changes associated with the natural history of the disease [64]. > The knowledge of these pathogenetic mechanisms comes from preclinical studies, exploiting a variety of experimental models such as: [1] in vitro systems, namely patientderived cells, immortalized cell lines, or mouse cells (treated or not treated with propionate); [2] the Pcca −/− (A138T) mice, with an estimated PCC activity of 2% [105]. > The murine model is a robust tool for studying the pathophysiology of PA, and it allows the characterization of the cardiac phenotype [30,37]. However, mouse models have some limitations, reflecting the structural and physiological differences between mouse and human hearts [106,107]. In vitro disease models based on iPSCs offer unprecedented opportunities.

[14] New therapeutic targets in rare genetic skeletal diseases

• Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
• Year: 2015
• Venue: Expert Opinion on Orphan Drugs
• URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
• DOI: 10.1517/21678707.2015.1083853
• PMID: 26635999
• PMCID: 4643203
• Citations: 38
• Influential citations: 1
• Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.370) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[15] Targeting Hepatic Stellate Cells for the Prevention and Treatment of Liver Cirrhosis and Hepatocellular Carcinoma: Strategies and Clinical Translation

• Authors: Hao Xiong, Jinsheng Guo
• Year: 2025
• Venue: Pharmaceuticals
• URL: https://www.semanticscholar.org/paper/76e92127053136900f7e3f10e2c9278251ced5d2
• DOI: 10.3390/ph18040507
• PMID: 40283943
• PMCID: 12030350
• Citations: 10
• Summary: HSC-targeted approaches using specific surface markers and receptors may enable the selective delivery of drugs, oligonucleotides, and therapeutic peptides that exert optimized anti-fibrotic and anti-HCC effects.
• Evidence snippets:
• Snippet 1 (score: 0.368) > Significant progress has been made in elucidating the cellular and molecular mechanisms of liver fibrosis; however, only a few findings have been successfully translated into clinical applications. Firstly, the high cost of drug development and target validation necessitates prolonged timelines and substantial financial investment. Secondly, as regulatory requirements become more stringent, there is an increasing demand for drugs with well-defined clinical efficacy and safety profiles. Moreover, the efficacy observed in animal models often fails to fully translate to clinical settings due to differences in pharmacokinetics, extracellular matrix (ECM) cross-linking, and disease pathophysiology. Despite advancements in anti-fibrotic drug development, accurately identifying ideal noninvasive biomarkers for fibrotic activity and establishing consensus on optimal clinical endpoints remain significant challenges [113,114]. > Currently, addressing the underlying cause remains the only proven strategy to halt or reverse liver fibrosis progression, while the development of effective anti-fibrotic therapies continues to pose a major challenge in liver disease management. Over the past few decades, substantial progress has been made in elucidating the cellular and molecular mechanisms underlying liver fibrosis. Liver fibrosis is a complex pathological change involving multiple cells, factors, and pathways, and the study of the cellular and molecular mechanisms of its occurrence and development provides an important theoretical basis and therapeutic target for clinical drug development. It is anticipated that improved animal models and well-designed clinical trials will facilitate the successful translation of anti-fibrotic research into effective clinical treatments in the near future.

[16] Therapies for Mitochondrial Disease: Past, Present, and Future

• Authors: Megan Ball, Nicole J. Van Bergen, A. Compton, David R. Thorburn, S. Rahman et al.
• Year: 2025
• Venue: Journal of Inherited Metabolic Disease
• URL: https://www.semanticscholar.org/paper/196ee50a950f29bc4134cfb8fe6bdfa9a3a1468b
• DOI: 10.1002/jimd.70065
• PMID: 40714961
• PMCID: 12301291
• Citations: 4
• Summary: The latest developments in the pursuit to identify effective treatments for mitochondrial disease are examined and the barriers impeding their success in translation to clinical practice are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.367) > Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA‐encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre‐molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA‐based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

[17] Case Report: Murine typhus complicated by symmetrical peripheral gangrene: first report and diagnostic insights from metagenomic next-generation sequencing

• Authors: Hengling Zhu, Linhui Hu, Zaiming Feng, Zichen Zhang, Heng Zhu et al.
• Year: 2026
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/e871813598fcfd37d44c299851cefa3764b40981
• DOI: 10.3389/fimmu.2025.1746919
• PMID: 41624871
• PMCID: 12855535
• Summary: First reported case of murine typhus complicated by symmetrical peripheral gangrene (SPG), in which metagenomic next-generation sequencing (mNGS) enabled rapid diagnosis and guided timely doxycycline therapy, establishes its potential to cause life-threatening multiorgan failure.
• Evidence snippets:
• Snippet 1 (score: 0.366) > In resource-limited settings where advanced molecular tools like mNGS are unavailable, clinicians must rely on a combination of classical laboratory methods and high clinical suspicion. Conventional serological tests, such as the Indirect Immunofluorescence Assay (IFA), remain the diagnostic gold standard, although their utility is often hampered by the requirement for paired serum samples to demonstrate a four-fold rise in antibody titers. For earlier detection, conventional polymerase chain reaction (PCR) targeting specific genes (e.g., gltA or ompB) can be highly effective if performed during the rickettsemic phase. Notably, our case demonstrates that the Weil-Felix test, despite its well-documented limitations in sensitivity and specificity, remains a valuable and accessible screening tool. As shown in our patient, a significant seroconversion of Proteus OX19 (from negative to 1:320) can provide retrospective confirmation of the diagnosis at a fraction of the cost of genomic sequencing. Clinicians should therefore prioritize serial serological testing and, where available, specific PCR assays to bridge the diagnostic gap in endemic regions. > In summary, our case presents three key innovations that advance the understanding and management of murine typhus. First, it enriches the scarce clinical data on severe murine typhus in China's subtropical regions, highlighting agricultural occupational exposure as a context-specific risk factor. Second, it expands the spectrum of misleading early symptoms-such as isolated abdominal pain-and documents a rare, severe progression pathway, challenging the notion that multiple comorbidities are required for life-threatening outcomes. Third, it is the first to link SPG to murine typhus, elucidating its unique pathophysiology and demonstrating the value of mNGS as a rapid diagnostic tool. Beyond these contributions, the case emphasizes that timely molecular diagnostics are critical for managing rickettsial infections in critically ill patients with atypical manifestations, ultimately providing guidance for clinicians in endemic regions to improve diagnostic accuracy, optimize treatment timing, and recognize rare complications. Further studies with larger patient cohorts are warranted to validate these findings, explore additional risk factors and symptom patterns, and deepen our understanding of the mechanisms underlying severe murine typhus.

[18] Cross-species transcriptomics translation reveals a role for the unfolded protein response in Mycobacterium tuberculosis infection

• Authors: Krista M. Pullen, Ryan Finethy, Seung-Hyun B Ko, Charlotte J. Reames, Christopher M Sassetti et al.
• Year: 2025
• Venue: NPJ Systems Biology and Applications
• URL: https://www.semanticscholar.org/paper/ed564fd15af058b6d20c30e7b8ebf978e1688f31
• DOI: 10.1038/s41540-024-00487-6
• PMID: 39955299
• PMCID: 11830044
• Citations: 3
• Summary: This work confirmed that the infection-induced unfolded protein response in Mycobacterium tuberculosis-infected mouse macrophages modulates immune functions in Mycobacterium tuberculosis-infected mouse macrophages.
• Evidence snippets:
• Snippet 1 (score: 0.363) > Numerous studies have identified similarities in blood transcriptomic signatures of tuberculosis (TB) phenotypes between mice and humans, including type 1 interferon production and innate immune cell activation. However, murine infection pathophysiology is distinct from human disease. We hypothesized that this is partly due to differences in the relative importance of biological pathways across species. To address this animal-to-human gap, we applied a systems modeling framework, Translatable Components Regression, to identify the axes of variation in the preclinical data most relevant to human TB disease state. Among the pathways our cross-species model pinpointed as highly predictive of human TB phenotype was the infection-induced unfolded protein response. To validate this mechanism, we confirmed that this cellular stress pathway modulates immune functions in Mycobacterium tuberculosis-infected mouse macrophages. Our work demonstrates how systems-level computational models enhance the value of animal studies for elucidating complex human pathophysiology.

[19] Chemotherapy and Mechanisms of Resistance in Breast Cancer

• Authors: A. Oliveira, R. E. Santos, F. F. O. Rodrigues
• Year: 2012
• Venue: Unknown venue
• URL: https://www.semanticscholar.org/paper/502a86d8bcd7208be6f539fcceba631f82f25a7d
• DOI: 10.5772/24629
• Summary: The addition of adjuvant polychemotherapy in advanced breast cancer showed gain by controlling survival of micrometastases in patients with lymph nodes affected by cancer or not.
• Evidence snippets:
• Snippet 1 (score: 0.362) > The main reasons responsible for treatment failure in cancer patients are the mechanisms of drug resistance and emergence of disseminated disease (Terek et al, 2003). We identified two types of resistance most relevant to BC: primary resistance, which corresponds to the clinical situation where the patient showed no response to therapy, and secondary or acquired resistance in which, initially, there is an observed response and a subsequent failure of the treatment regimen (Kroger et al, 1999). Several mechanisms may cause the phenotype of multidrug resistance to chemotherapy drugs and are well characterized in in vitro experiments, including alterations in systemic pharmacology (pharmacokinetics and metabolism), extracellular mechanisms (tumor environment, multicellular drug resistance), and cellular mechanisms (cellular pharmacology, activation and inactivation of drugs, modification of specific targets and regulatory pathways of apoptosis) (Leonessa et al, 2003, Riddick et al, 2005. Identification of factors that affect cell metabolism, which are related to drug resistance, will enable the identification of which patients are at particular risk of treatment failure. Among the biochemical and molecular mechanisms of drug resistance, we stress: changes in the activity of topoisomerase II, alterations in the DNA repair mechanism, overexpression of P-glycoprotein; high intracellular concentrations of enzymes purification of cellular metabolism -among them enzymes the family of glutathione S-transferases (GSTs) and changes in the mechanisms of signaling via c-Jun N-terminal kinase 1 (JNK1) -and "apoptosis signal-regulating kinase (ASK1) required for activation of the" mitogenactivated protein (MAP kinases) in apoptosis and cellular restoration. These pathways are also mediated by proteins encoded by genes of GSTs (O'Brien, Tew, 1996;Burg, Mulder, 2002, L'Ecuyer et al, 2004). Different response rates to particular chemotherapy regimens, as observed in patient groups with the same biological characteristics and stage, suggest the existence of different mechanisms of drug resistance, probably induced by genetic alterations (Hayes, Pulford, 1995;O'Brien , Tew, 1996;Pakunlu et al, 2003). Among the mechanisms of purification of cellular metabolism involved in the

[20] Clinical proteomic analysis of scrub typhus infection

• Authors: E. C. Park, Sang-Yeop Lee, S. Yun, Chi‐Won Choi, Hayoung Lee et al.
• Year: 2018
• Venue: Clinical Proteomics
• URL: https://www.semanticscholar.org/paper/5385810d209800ae76dda94ccaa3b5b6f9379b39
• DOI: 10.1186/s12014-018-9181-5
• PMID: 29449793
• PMCID: 5812041
• Citations: 14
• Summary: The first proteomic study of clinical serum samples from scrub typhus patients identified changes in protein expression upon infection with O. tsutsugamushi and following antibiotic treatment, and normal expression was largely rescued by antibiotic treatment.
• Evidence snippets:
• Snippet 1 (score: 0.358) > Clinical Proteomics been as high as 50% [8]. Therefore, early diagnosis of scrub typhus is essential to prevent complications and to reduce the mortality rate. > The main goal of proteomic studies is to elucidate protein expression and identify changes under the influence of biological perturbations such as diseases or drug treatment [9,10]. The information obtained from such analyses provides valuable information on pathophysiology and potential diagnostic biomarkers of disease [11]. Since the genome sequence of O. tsutsugamushi was published [12], several proteomic studies have focused on identifying proteins. The first proteomic analysis involved 2D liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based comparison of protein expression, and 14 proteins were shown to be differentially expressed in antibiotic-sensitive and -insensitive O. tsutsugamushi [13]. Kishimoto and colleagues also performed shotgun proteomics analysis of O. tsutsugamushi, which revealed specific characteristics of this obligate intracellular bacterial species, and identified potential immunogenic factors such as type IV secretion system proteins [14]. More recently, comprehensive analysis of global gene and protein expression in O. tsutsugamushi in fibroblasts and macrophages showed how the pathogen responds in different types of host cells [15]. > Although previous proteomic studies on O. tsutsugamushi provided some evidence about the pathophysiology of scrub typhus, information about diagnostic markers is lacking. Currently, complement fixation is one the earliest tests for diagnosis of scrub typhus [2,16,17]. At present, there is no diagnostic test of pathogenic antigen generated by O. tsutsugamushi. Moreover, proteomic analysis of O. tsutsugamushi directly isolated from scrub typhus patients has not been successfully performed, presumably because O. tsutsugamushi proteins are present at low concentrations in the blood. In the present study, as the first step in proteomic analysis of scrub typhus patients, we investigated the serum proteome to elucidate physiological changes caused by infection, both before and after antibiotic treatment.

Notes

• This provider combines search_papers_by_relevance with snippet_search.
• No synthesis or second-stage model call is performed.