Asta Literature Retrieval: Pathophysiology and clinical mechanisms of capillary leak syndrome. Core disease mechanisms, molecular and cellular p...

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

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] The Role of Failing Autonomic Nervous System on Life-Threatening Idiopathic Systemic Capillary Leak Syndrome

• Authors: R. Colombo, M. Wu, E. Catena, Andrea Perotti, T. Fossali et al.
• Year: 2018
• Venue: Frontiers in Medicine
• URL: https://www.semanticscholar.org/paper/e50246bc8ebff0c9cdbed7db9ced5b3acea49c50
• DOI: 10.3389/fmed.2018.00111
• PMID: 29732372
• PMCID: 5919959
• Citations: 6
• Summary: This work reports ANS activity during acute phase and recovery from a severe ISCLS shock and speculate on the possibility that autonomic mechanisms underlie the pathogenesis of attacks.
• Evidence snippets:
• Snippet 1 (score: 0.393) > Systemic capillary leak syndrome (SCLS) is a rare condition causing recurrent episodes of potentially fatal hypovolemic shock first described by Clarkson et al. (1). Since then, 500 cases have been reported, most of them secondary to malignancies or chemotherapy, 168 out of 500 classified as idiopathic (2). The underlying pathological mechanism is mainly unknown. Several alterations in cytokine pathways and cell-mediated immune response have been associated with SCLS also in its idiopathic form [idiopathic systemic capillary leak syndrome (ISCLS)] (3)(4)(5)(6) leading to abrupt endothelial barrier dysfunction (7). The resulting shift of fluids and proteins from the intravascular to the interstitial compartment causes the hypovolemic shock that characterizes disease recurrences. > Recurrences can be divided into three distinct phases: prodromal, leak, and post leak phase (7). Capillary leakage leads to hemoconcentration, hypoalbuminemia, generalized edema, and refractory hypovolemic shock with subsequent complications (8). ISCLS is often misdiagnosed as polycythemia vera or sepsis. > Because of its low incidence, both pathophysiology and therapy of ISCLS are mainly unknown and still controversial. Moreover, the autonomic nervous modulation during ISCLS attacks has never been studied. We report the first description of autonomic nervous system (ANS) modulation during the course of an acute crisis in a patient affected by ISCLS.

[2] Analyzing IL-2-induced vascular leakage with an irAOP as tool

• Authors: Patricia Gogesch, Samira Ortega Iannazzo, Tamara Zimmermann, Remi Villenave, Katherina Sewald et al.
• Year: 2024
• Venue: Journal of Immunotoxicology
• URL: https://www.semanticscholar.org/paper/22985cec0e6ca544859269cc107f98f52c69f61f
• DOI: 10.1080/1547691X.2024.2369123
• PMID: 39655495
• Citations: 5
• Summary: An overview of the development of VL from an immunological perspective in the context of high-dose IL-2 immunotherapy is provided and an irAOP for IL-2-mediated vascular leakage is generated with the aim to identify gaps and possible biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.389) > The systemic capillary leak syndrome, also known as Clarkson's Disease, is a severe form of vascular leakage (VL) first reported in 1960 (Clarkson et al. 1960). In the clinics, systemic VL occurs as ischemic disease or as secondary disease induced by previous conditions and is associated with a dramatic lethal rate of 20 -30% (Bichon et al. 2021). Despite the high mortality, VL is under-diagnosed and its incidence is uncertain due to the nonspecific manifestations (Shin et al. 2018;Jeong et al. 2019), emphasizing its critical clinical impact. VL in general is a phenomenon, which is associated with inflammatory conditions such as acute respiratory distress syndrome, asthma, pancreatitis, sepsis, systemic sclerosis, diabetes, or infectious diseases (Bruni et al. 2018). It also occurs in context of graft-vs-host-disease, surgical procedures, and as a severe side-effect of immunomodulatory therapies (Jeong et al. 2019;Bichon et al. 2021). > The concept of adverse outcome pathways (AOPs) was developed for the risk assessment of chemicals and the analyses of their modes of action (MoA). They are used as a toxicological tool to generate a framework for the organization of pathwaybased data and mechanisms (Villeneuve et al. 2014;Knapen et al. 2018). An AOP describes a sequence of events starting with a molecular initiating event (MIE), followed by a series of key events (KEs), which are causally linked to the adverse outcome. Per definition, KEs have to be observable and/or measurable. They are connected by key event relationships (KERs), finally resulting in an adverse outcome (Spinu et al. 2019). This concept finds more and more application in different fields and results are publicly available e.g. in the AOP-wiki (Society for Advancement of AOPs). Despite the fact that one MIE and MoA can result in different adverse outcomes, an AOP generally focuses on one adverse outcome and its underlying mechanism.

[3] Uremic Toxins, Oxidative Stress, Atherosclerosis in Chronic Kidney Disease, and Kidney Transplantation

• Authors: E. Wojtaszek, U. Ołdakowska-Jedynak, M. Kwiatkowska, Tomasz Glogowski, J. Małyszko
• Year: 2021
• Venue: Oxidative Medicine and Cellular Longevity
• URL: https://www.semanticscholar.org/paper/7c34f2c5e03c4892f2d9bbd0469a1d79016bbede
• DOI: 10.1155/2021/6651367
• PMID: 33628373
• PMCID: 7895596
• Citations: 73
• Influential citations: 2
• Summary: The impact of uremic toxins on vascular dysfunction in CKD patients and kidney transplant recipients was discussed and special attention was paid to the role of native and transplanted kidney function.
• Evidence snippets:
• Snippet 1 (score: 0.362) > It would be worth to mention that AKI contributes to the initiation and progression of CKD, and vice versa CKD predisposes to AKI [190][191][192].AKI and CKD are interconnected syndromes.The accumulating data from basic and clinical research indicates that renal hypoxia is associated with CKD, AKI to CKD continuum, and AKI on top of CKD.Tubulointerstitial hypoxia is a key player in the pathophysiology of CKD and AKI to CKD transition [193][194][195][196][197][198].Capillary rarefaction after AKI episode results in tubulointerstitial fibrosis, and damaged tubular epithelial cells that fail to redifferentiate may contribute to capillary rarefaction and thus aggravating hypoxia [193,194,199].Moreover, hypoxia induces diverse epigenetic changes such as chromosome conformation, DNA methylation, or histone modification [199].The mechanisms involved in the susceptibility of AKI and impairment of recovery from AKI in CKD patients remain largely unexplained.Multiple mechanisms at epigenetic, signaling, cellular, and tissue levels may be involved [200][201][202].Briefly, oxidative stress is a key mechanism in the pathogenesis and progression of CKD and impaired renal regeneration after AKI episodes.Therapeutic strategies targeting hypoxia have been shown to be effective in blocking the progression to CKD and possibly AKI protection [192,193,199]. > In CKD, the retention of a variety of metabolites, due to a decrease in their renal clearance and/or a rise in their synthesis, is found.These compounds could be small and water soluble, lipophilic and/or protein bound, or larger and in the middlemolecule range.Several solutes have been shown to exert biological activity, on cells and metabolic processes, leading to uremic syndrome.

[4] 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: 37
• 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: 0.362) > 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.

[5] In vitro Study of the Antagonistic Effect of Low-dose Liquiritigenin on Gemcitabine-induced Capillary Leak Syndrome in Pancreatic Adenocarcinoma via Inhibiting ROS- Mediated Signalling Pathways.

• Authors: Wei Wu, Q. Xia, Ruijie Luo, Ziqi Lin, P. Xue
• Year: 2015
• Venue: Asian Pacific journal of cancer prevention : APJCP
• URL: https://www.semanticscholar.org/paper/c49a41612019f18b31e5aa2f5b502254cc65c398
• DOI: 10.7314/APJCP.2015.16.10.4369
• PMID: 26028101
• Citations: 11
• Influential citations: 1
• Summary: Low-dose liquiritigenin might be beneficial to prevent the occurrence of gemcitabine-induced CLS in pancreatic adenocarcinoma via inhibiting reactive oxygen species (ROS)- mediated signalling pathways.
• Evidence snippets:
• Snippet 1 (score: 0.359) > Gemcitabine (Gemcitabine), a synthetic pyrimidine nucleoside, could block DNA synthesis and inhibit RNA synthesis to some extent. It is used as the standard chemotherapy for pancreatic adenocarcinoma in stage II, III and IV, although it's primarily palliative (Lau et al., 2012). As a severe result of the attack by gemcitabineinduced cytotoxicity for capillary endothelial cells (CECs), capillary leak syndrome (CLS) has been reported in several cases (De Pas et al., 2001;Pulkkanen et al., 2003;Biswas et al., 2004;Dahan et al., 2007). CLS, a serious disorder characterized by capillary hyperpermeability and albumin leak, is initiated by damaging CECs and their conjunctions that lead to RESEARCH ARTICLE dysfunction of capillary endothelial barrier (Stein et al., 2012). Clinically, administration of glucocorticoids and fluid resuscitation as well as discontinuation of gemcitabine can potentially reduce the mortality of CLS (Casadei et al., 2013). Nevertheless, Gemcitabine-induced cytotoxicity to CECs shows non-dose-dependence and individual difference. Progressive disease in some cases maintains a rapid development, which quickly results in ischemia-reperfusion injury and causes multiple organ failure (Stein et al., 2012), but at this time, the effect of all treatments on reversing progression is still limited. Hence, we proposed that prior-preventive measures should be implemented to prevent the occurrence of gemcitabineinduced CLS. Analysis on the action mechanism for gemcitabine indicated that two active metabolites of gemcitabine injured mitochondria to cause massive generation and transmembrane transport of ROS, and then that triggered ROS-mediated signalling pathways to induce the damage to cells in proliferative cycles (Chen et al., 2014). We inferred that gemcitabine-induced dysfunction of capillary endothelial barrier was primarily initiated by the downstream events in ROS-mediated signal transduction pathways.

[6] Navigating Drug-Induced Lung Disease (DILD): A Comprehensive Review on Management and Prevention Strategies

• Authors: Srinivasulareddy Annareddy, B. Ghewade, Ulhas S Jadhav, Pankaj B Wagh
• Year: 2024
• Venue: Cureus
• URL: https://www.semanticscholar.org/paper/0b389cda78d09ed43d6169972b6b2948590d3a59
• DOI: 10.7759/cureus.69954
• PMID: 39445304
• PMCID: 11496594
• Citations: 1
• Influential citations: 1
• Summary: This review provides a comprehensive overview of DILD, focusing on its definition, pathophysiology, and clinical implications, and examines future research directions and emerging therapies, aiming to enhance the understanding and management of DILD.
• Evidence snippets:
• Snippet 1 (score: 0.352) > The pathophysiology of drug-induced lung injury (DILI) is complex, involving various mechanisms that can lead to pulmonary complications. These mechanisms can be broadly categorized into two main types: direct toxicity and immune-mediated toxicity [1]. Direct toxicity occurs when a drug or its metabolites cause cellular damage without involving the immune system. This can happen through several pathways, such as producing reactive metabolites, oxidative stress, and direct cellular injury. For example, drugs like bleomycin can generate reactive oxygen species (ROS), leading to oxidative stress, cell injury, and apoptosis. Additionally, certain drugs can directly damage alveolar epithelial cells or endothelial cells, causing inflammation and pulmonary edema [13]. Immune-mediated lung injury involves an abnormal immune response triggered by drug exposure. This can manifest through allergic reactions, where drugs act as haptens and bind to proteins, eliciting an immune response. This can result in drug-induced pneumonitis, characterized by the infiltration of immune cells and cytokine release. Some medications can also induce systemic cytokine release, causing lung inflammation and damage, such as capillary leakage and pulmonary edema [14]. Genetic factors significantly influence susceptibility to drug-induced lung injury. Variability in drug metabolism and immune response can lead to idiosyncratic reactions, which are unpredictable and not dose-dependent. Genetic polymorphisms in genes encoding drug-metabolizing enzymes can affect the production of toxic metabolites, while preexisting lung conditions or genetic predispositions may increase the risk of developing DILI. Differences in immune system function among individuals can also result in varying responses to drugs, with some patients experiencing severe immune-mediated lung injury while others do not [15]. Understanding the pathophysiology of drug-induced lung injury, including the influence of genetic predisposition and idiosyncratic reactions, is crucial for identifying at-risk patients and developing effective prevention and management strategies. Ongoing research is essential to elucidate these mechanisms further and improve clinical outcomes for patients affected by drug-induced lung injury [16].

[7] The systemic capillary leak syndrome following COVID-19 vaccine

• Authors: Chengjie Zhao, R. Xue, Kaile Zhao, Ruoyan Lei, Mingyi Zhao et al.
• Year: 2024
• Venue: Human Vaccines & Immunotherapeutics
• URL: https://www.semanticscholar.org/paper/fa48249482b9cfea398548b4749257b699fee2de
• DOI: 10.1080/21645515.2024.2372149
• PMID: 39171563
• PMCID: 11346542
• Citations: 3
• Summary: Case reports of SCLS induced by COVID-19 vaccines are summarized and discussed to raise awareness of COVID-19 vaccine-associated rare diseases and the urgency to reconsider the safety of COVID-19 vaccines is highlighted.
• Evidence snippets:
• Snippet 1 (score: 0.347) > The COVID-19 pandemic, which erupted globally in 2019, has become one of the most significant health crises of this century. Since the outbreak of the COVID-19 pneumonia in 2020, vaccines have been developed and have proven to be highly effective in preventing and treating the disease. 1,2 The COVID-19 vaccines are mainly classified into four types based on the development process, including the mRNA vaccine (BNT162b2), the non-replicating adenovirus vector-based DNA vaccines (AZD1222/ChAdOx1), the inactivated virus vaccine (CoronaVac) and subunit vaccines. 3,4 Although the safety and efficacy of these vaccines in preventing and treating COVID-19 pneumonia have been demonstrated, a certain number of patients have experienced adverse reactions post-vaccination, including capillary leak syndrome and anaphylaxis. 5 he systemic capillary leak syndrome (SCLS) refers to a disease characterized by increased permeability of capillaries to proteins, causing protein-rich fluid to flow from inside the blood vessels to the tissue space, 6,7 which has been categorized several types, including idiopathic(Clarkson), drug-induced and others. The specific and definitive treatment guidelines for the various subtypes remain to be further defined. The prominent features of SCLS are hypotension, hemoconcentration and hypoalbuminemia. 8 SCLS can be triggered by a variety of disorders. When capillary leak syndrome occurs in the context of hematologic malignancy treatment and the shared pathophysiology of these disorders is to cause a surge in systemic cytokine storms, resulting in capillary endothelial cell injury on the cellular level, 9 thereby increasing capillary permeability and leading to the exudation of intravascular material. The role of mediators other than cytokines is not well known. ][12] Although the causal relationship and specific mechanism between COVID-19 vaccination and the pathogenesis of SCLS have not been fully elucidated, the occurrence of rare adverse reactions post-vaccination has garnered significant clinical attention.

[8] 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: 0.346) > 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

[9] TAFRO Syndrome with Renal Thrombotic Microangiopathy: Insights into the Molecular Mechanism and Treatment Opportunities

• Authors: K. Tu, P. Fan, Tai-Di Chen, W. Chuang, Chao-Yi Wu et al.
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/e64fdaca40a5c6a70fb0a75c7ad42095a154aaca
• DOI: 10.3390/ijms22126286
• PMID: 34208103
• PMCID: 8230834
• Citations: 9
• Influential citations: 1
• Summary: The aim of this review article is to summarize the latest knowledge of molecular mechanisms behind the TAFRO syndrome and their potential role in renal damage.
• Evidence snippets:
• Snippet 1 (score: 0.341) > The prothrombotic state is secondary to endothelial injury of the involved vasculature [39]. > Although attributed to different molecular mechanisms, TTP and HUS still overlap with each other in terms of clinical presentations.Nowadays, many diseases resemble TTP or HUS, with presentations of MAHA and/or pathological features of endothelial injury.All these diseases are collectively referred to as "TMA syndromes" [40].Some of these diseases have little pathological evidence of endothelial injury (e.g., TTP), and others have no clinical or laboratory features of MAHA (e.g., anti-VEGF-related renal TMA [41]). > The kidney is the major organ involved in patients with TMA syndromes.It is not yet clear why renal vasculature is so vulnerable to endothelial injury.The unique architecture of glomerular capillaries may account for this susceptibility.Glomerular capillaries are composed of thin and loose fenestrated vascular endothelium.Glycocalyx synthesized by the vascular endothelium forms a charge-selective filtration barrier of the glomerular basement membrane.VEGF is the major cytokine that maintains the integrity and functionality of the vascular endothelium [42].In vitro evidence suggests that in glomerular capillaries, VEGF induces the fenestrate formation of the vascular endothelium.The glomerular endothelium has surface receptors for the vascular endothelial growth factor (VEGF-R).The primary source of VEGF nursing the glomerular endothelial cell are visceral epithelial cells, podocytes, rather than the circulating VEGF [43].Breakdown of VEGF backflow from podocytes to endothelial cells could result in endothelial damage of glomerular capillary [44].This unique feature is only present in the renal vasculature.Although the mechanism has not been clarified yet, this may provide a possible explanation of renal susceptibility to endothelial injury. > We summarized the diseases known as TMA syndrome and the proposed mechanism of renal thrombotic microangiopathy (Table 2).

[10] From molecular signatures to predictive biomarkers: modeling disease pathophysiology and drug mechanism of action

• Authors: A. Heinzel, P. Perco, G. Mayer, R. Oberbauer, A. Lukas et al.
• Year: 2014
• Venue: Frontiers in Cell and Developmental Biology
• URL: https://www.semanticscholar.org/paper/36d6c03a528c1358c0ae5b667cca5ce73b2fbee5
• DOI: 10.3389/fcell.2014.00037
• PMID: 25364744
• PMCID: 4207010
• Citations: 23
• Summary: This work exemplifies a computational workflow for expanding from statistics-based association analysis toward deriving molecular pathway and process models for characterizing phenotypes and drug mechanism of action, in turn providing precision medicine hypotheses utilizing predictive biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.339) > In such scenario a biomarker needs to serve as proxy of key mechanistic factors characterizing and driving a disease on a patient-specific level, combined with educating on the specific interference of disease mechanism with drug mechanism of action. For capturing these constraints a detailed molecular map of a clinical phenotype and its interference with a drug mechanism of action is needed, and here integration of Omics profiling adds to identifying such mechanisms (Fechete et al., 2011;Mühlberger et al., 2012). > An a priori stratification of patients based on an appropriately chosen biomarker panel reflecting the pathophysiology of a given patient (group) allowing to determine a match with a specific drug's mechanism of action appears as promising approach. As recently discussed by Himmelfarb et al. fresh approaches are critical in finding therapies to kidney disease benefiting patients, outlining the importance of improving the translational aspect in clinical research (Himmelfarb and Tuttle, 2013). Here, omics technologies have added significantly to the data landscape characterizing chronic kidney disease, however, in a first instance mainly expanding the candidate set of apparently relevant processes and pathways, going in hand with a large number of biomarker candidates, which individually hamper clinically relevant assessment on disease progression (Fechete et al., 2011;Hellemons et al., 2012). > Integrative approaches in the realm of Systems Biology have been proposed for reaching a consensus description of chronic kidney disease pathophysiology, including molecular models of DN as well as of the reno-cardial axis (He et al., 2012;Komorowsky et al., 2012;Mayer et al., 2012;Heinzel et al., 2013). Still, a translation process needs to be followed, joining disease pathophysiology, stratification markers allowing enrichment strategies, combined with on a molecular mechanistic level matching drugs for allowing precision medicine (Mirnezami et al., 2012). In this work we exemplify such procedure on DN being the major clinical presentation leading to end stage renal disease.

[11] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

• Authors: P. Mesdom, R. Colle, É. Lebigot, S. Trabado, Eric Deflesselle et al.
• Year: 2020
• Venue: Current Neuropharmacology
• URL: https://www.semanticscholar.org/paper/79368e365458486de96794333613c12a6063bf54
• DOI: 10.2174/1570159X17666191021141057
• PMID: 31631822
• PMCID: 7327943
• Citations: 12
• Summary: This review highlights the great and still underused potential of HDF, which stands out as a very promising tool in the understanding of MDD and AD mechanisms of action.
• Evidence snippets:
• Snippet 1 (score: 0.339) > Background: Human dermal fibroblasts (HDF) can be used as a cellular model relatively easily and without genetic engineering. Therefore, HDF represent an interesting tool to study several human diseases including psychiatric disorders. Despite major depressive disorder (MDD) being the second cause of disability in the world, the efficacy of antidepressant drug (AD) treatment is not sufficient and the underlying mechanisms of MDD and the mechanisms of action of AD are poorly understood. Objective The aim of this review is to highlight the potential of HDF in the study of cellular mechanisms involved in MDD pathophysiology and in the action of AD response. Methods The first part is a systematic review following PRISMA guidelines on the use of HDF in MDD research. The second part reports the mechanisms and molecules both present in HDF and relevant regarding MDD pathophysiology and AD mechanisms of action. Results HDFs from MDD patients have been investigated in a relatively small number of works and most of them focused on the adrenergic pathway and metabolism-related gene expression as compared to HDF from healthy controls. The second part listed an important number of papers demonstrating the presence of many molecular processes in HDF, involved in MDD and AD mechanisms of action. Conclusion The imbalance in the number of papers between the two parts highlights the great and still underused potential of HDF, which stands out as a very promising tool in our understanding of MDD and AD mechanisms of action

[12] Network expression analysis identifies and experimentally validates the involvement of Fosb in acute kidney injury

• Authors: Xiaoyan Tang, C. Shen, Chunqiu Liu, Jianya Gao
• Year: 2025
• Venue: FASEB BioAdvances
• URL: https://www.semanticscholar.org/paper/ae3a7edbdb3a68a658fb479d1bfcbb293b0d6937
• DOI: 10.1096/fba.2024-00201
• PMID: 40212808
• PMCID: 11980807
• Citations: 2
• Summary: PI network analysis revealed Fosb as a significantly upregulated hub gene in AKI, with experimental validation demonstrating its substantial upregulation in patients with acute tubular necrosis, HR‐induced HK‐2 cells injury and ischemia–reperfusion injury (IRI) mice.
• Evidence snippets:
• Snippet 1 (score: 0.338) > Acute kidney injury (AKI) is a common clinical syndrome with complex mechanisms, and its molecular mechanisms have not been fully elucidated. 3 Therefore, there is an urgent need for relevant research to identify potential biomarkers and reveal molecular mechanisms, which are of significant importance for clinical practice. In this study, a systematic analysis of the gene expression profiles was conducted on 82 samples of AKI and 66 samples from the reference control group. A total of 1265 significantly DEGs were identified. Subsequently, pathway and molecular function enrichment analysis was performed through GSEA and GO analysis to identify enriched molecular pathways and functions. Additionally, GO and KEGG pathway analysis of DEGs identified enriched molecular functions and pathways. WGCNA confirmed that most DEGs were involved in modules significantly associated with AKI, especially the upregulated hub gene Fosb. Furthermore, PPI network hub gene analysis revealed potential genes associated with AKI, with Fosb identified as a hub gene. We then validated the expression of Fosb in human, mouse, and cell line models. Moreover, we confirmed the inhibitory effect of Fosb on apoptosis and inflammation in human proximal renal tubule cells in vitro. > The occurrence of AKI is influenced by various causes, such as ischemia, toxic substances, reduced renal perfusion, and inflammation, 30 leading to differences in its pathophysiology and molecular mechanisms. GSEA analysis revealed that AKI involves multiple pathways, including DNA repair, apoptosis, and adipogenesis. In cancer patients, chemotherapy is one of the main treatment modalities, which includes DNA-damaging agents such as platinum-based drugs. 31 Therefore, the DNA repair pathway suggests that we can study the mechanisms of AKI by obtaining biopsy samples from systemic chemotherapy patients. In our analysis, in addition to Fosb, we found that F2R like trypsin receptor 1 (F2RL1) was also significantly upregulated in AKI, consistent with previous research report, 32 suggesting that targeting F2RL1 may be a novel therapeutic option for patients with cisplatininduced AKI.

[13] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

• Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
• Year: 2012
• Venue: Croatian Medical Journal
• URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
• DOI: 10.3325/cmj.2012.53.529
• PMID: 23275318
• PMCID: 3541579
• Citations: 28
• Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
• Evidence snippets:
• Snippet 1 (score: 0.337) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[14] Nasopharyngeal Carcinoma Signaling Pathway: An Update on Molecular Biomarkers

• Authors: W. Tulalamba, T. Janvilisri
• Year: 2012
• Venue: International Journal of Cell Biology
• URL: https://www.semanticscholar.org/paper/307cb9186444d9dad6e2e3b53763be0de76de186
• DOI: 10.1155/2012/594681
• PMID: 22500174
• PMCID: 3303613
• Citations: 93
• Influential citations: 5
• Summary: The molecular signaling pathways in the NPC are discussed for the holistic view of NPC development and progression and the important insights toward NPC pathogenesis may offer strategies for identification of novel biomarkers for diagnosis and prognosis.
• Evidence snippets:
• Snippet 1 (score: 0.337) > In the pregenomic eras, highly integrated and complex circuitry of molecular signaling in NPC pathogenesis was only partially understood. Over the past decade, the knowledge of the molecular mechanisms in NPC carcinogenesis has been rapidly accumulated. Dysregulation and abnormal protein expression of molecules in certain signaling pathways involved in cellular functions including proliferation, adhesion, survival, and apoptosis has been demonstrated in the NPC cells. Detailed information on the complex network in signaling pathway leading to a coordinated pattern of gene expression and regulation in NPC will undoubtedly provide important clues to develop novel prognostic and therapeutic strategies for this cancer. Refining molecular markers into clinically relevant assays may assist in the detection of NPC in asymptomatic patients, as well as stage classification and monitoring disease progression and treatments. Furthermore, selective regulation of particular proteins targeting cancer cell proliferation, invasion, and apoptosis is a hopeful prospect for future anticancer therapy that slow disease progression and improve survival.

[15] 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: 0.334) > 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.

[16] Lactate metabolism and lactylation in kidney diseases: insights into mechanisms and therapeutic opportunities

• Authors: Yuhua Cheng, Linjuan Guo
• Year: 2025
• Venue: Renal Failure
• URL: https://www.semanticscholar.org/paper/6208b88884af543f7c97d2e70ed6b727dcfb4f58
• DOI: 10.1080/0886022X.2025.2469746
• PMID: 40012230
• PMCID: 11869332
• Citations: 11
• Summary: A review examines the role of lactate esters, especially lactylation, in kidney diseases, with a focus on their regulatory mechanisms and potential as therapeutic targets.
• Evidence snippets:
• Snippet 1 (score: 0.334) > Lactate metabolism and its post-translational modifications, particularly lactylation, play critical roles in the pathophysiology of various kidney diseases, including AKI, DKD, and ccRCC (Figure 1). The kidney's ability to metabolize lactate is crucial for maintaining renal function under normal conditions. However, in pathological states, impaired lactate metabolism leads to its accumulation, exacerbating renal dysfunction and disease progression. For more details on lactate metabolism and kidney diseases, refer to previous reviews [2,3,25]. > Lactylation influences gene transcription, protein function, and cellular metabolism, contributing to inflammatory responses, mitochondrial dysfunction, and tumor progression. > Understanding the mechanisms of lactate metabolism and lactylation in kidney diseases opens new avenues for therapeutic interventions. Targeting these metabolic pathways could mitigate renal injury and improve patient outcomes. Future research should focus on elucidating the specific pathways and molecular targets affected by lactate and lactylation and developing inhibitors to modulate these processes. Clinical trials are necessary to validate the efficacy and safety of these therapies. Overall, the lactate-lactylation axis is a promising target for novel therapeutic strategies aimed at treating kidney diseases and improving renal health.

[17] Recent Evidences of Epigenetic Alterations in Chronic Obstructive Pulmonary Disease (COPD): A Systematic Review

• Authors: R. Ragusa, Pasquale Bufano, A. Tognetti, M. Laurino, Chiara Caselli
• Year: 2025
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/2660cdbbe1f205c631fe890e5c6a3c8d9b81ce5f
• DOI: 10.3390/ijms26062571
• PMID: 40141213
• PMCID: 11942187
• Citations: 4
• Summary: A systematic review of the latest knowledge on epigenetic modifications that characterize COPD, summarizing epigenetic factors that could serve as potential novel biomarkers and therapeutic targets for the treatment of COPD patients.
• Evidence snippets:
• Snippet 1 (score: 0.333) > The papers included were clustered according to epigenetic mechanisms involved in COPD (molecular and cellular processes, as biomarker or therapeutic target). Tables 4-9 describe the extracted information, including the following: Study = name of first author et al., year; Country (Region) = where the study took place; Number of participants = sample size; Type of sample = biological sample employed; Gene affected = gene or group of genes whose expression can be "regulated" by epigenetic mechanisms; Epigenetic alteration = type of epigenetic alteration observed in the presence of disease; Activity in COPD = involvement of epigenetic elements in different molecular and cellular mechanisms associated with COPD; and Role of epigenetic mechanisms = epigenetic modifications that can be used to explain the pathophysiology of COPD or as biomarkers and therapeutic targets.

[18] Clinical metabolomics in type 2 diabetes mellitus: from pathogenesis to biomarkers

• Authors: Chuanxin Liu, Hetao Chen, Yujin Ma, Lei Zhang, Lulu Chen et al.
• Year: 2025
• Venue: Frontiers in Endocrinology
• URL: https://www.semanticscholar.org/paper/36f8d26a208b7b96763df2e9aa3211e440031c0e
• DOI: 10.3389/fendo.2025.1501305
• PMID: 40070584
• PMCID: 11893406
• Citations: 11
• Summary: The results facilitate understanding the pathophysiology and mechanism of type 2 diabetes mellitus and supports research in accurate diagnosis, risk prediction, curative effect, distinct stages, and prognosis judgment of T2DM.
• Evidence snippets:
• Snippet 1 (score: 0.332) > The metabolome is sensitive to a variety of genetic and environmental stimuli and susceptible to genetic, environmental, and gut microbiome pressures, so subtle differences between individuals can lead to large perturbations in metabolite concentrations and fluxes (15, 24). At present, cystatin C has become an ideal endogenous marker for evaluating glomerular filtration function because it is not affected by sex, age or muscle mass (25). In addition, more and more evidence shows that serum CysC is involved in the pathological process of vascular remodeling and neovascularization, which is closely related to the occurrence and development of diabetic microangiopathy (26). > Eighty-four papers were included in this review and obtained through database searches, namely, PubMed, Cochrane Library, China national knowledge internet(CNKI), General Purpose, and VIP Database. The keywords for the searches were "metabolomics" and "type 2 diabetes mellitus" and its complications. The papers were incorporated by reading and summarizing the literature according to the classification standards (27). The profound analysis of clinical differential metabolites identified in type 2 diabetes and its complications were conducted concerning composition, frequency of category, sample type, and pathways to explore the pathological mechanism of type 2 diabetes and its complications to provide a systematic basis for clinical diagnosis, risk stratification, comprehending disease progression, prognosis assessment, and drug efficacy. Our goal is to apply metabolomics to clinical diagnostic biomarkers, metabolic mechanisms, and prognostic observations, and early diagnosis can be made through metabolites to avoid progression to more serious complications.

[19] Investigating the role of NPR1 in dilated cardiomyopathy and its potential as a therapeutic target for glucocorticoid therapy

• Authors: Yaomeng Huang, Tongxin Li, Shichao Gao, Shuyu Li, Xiaoran Zhu et al.
• Year: 2023
• Venue: Frontiers in Pharmacology
• URL: https://www.semanticscholar.org/paper/be229f6f2059faab4c97ec0a04bd055adab9dfe1
• DOI: 10.3389/fphar.2023.1290253
• PMID: 38026943
• PMCID: 10662320
• Citations: 3
• Summary: Natriuretic peptide receptor 1 (NPR1) was identified as a core gene associated with DCM through bioinformatics analysis and led to substantial improvements in cardiac and renal function, accompanied by an upregulation of NPR1 expression.
• Evidence snippets:
• Snippet 1 (score: 0.330) > Multiple pathways and molecules are involved in this process; however, the detailed underlying mechanisms remain unclear. In recent years, with the development of high-throughput sequencing and gene chip technologies, the use of bioinformatics technology to explore the occurrence, development, and prognosis of diseases has become a hot topic for scholars worldwide (Hwang et al., 2018;Nayor et al., 2019;Rinschen et al., 2019;Sturm et al., 2019;Montaner et al., 2020). > The present study aimed to use bioinformatics technology to screen for DCM-related genes and investigate their mechanisms, with the purpose of revealing the pathogenesis of DCM and seeking treatment methods. The GSE3586 dataset, containing expression profiles related to DCM, was selected from the Gene Expression Omnibus (GEO) database. This study aimed to predict the core genes that may play crucial roles in disease progression at the molecular level through the enrichment of relevant molecular pathways associated with DCM. Furthermore, the phenotype of the core genes was validated to further support the results of the bioinformatics analysis through basic and clinical experiments. Additionally, the role of glucocorticoids in DCM treatment is discussed in this article with the purpose of providing a theoretical and experimental basis for exploring the pathogenesis of DCM and elucidating therapeutic methods. This study also provides a theoretical reference for the interpretation, early diagnosis, and treatment of DCM.

[20] Diabetic Retinopathy: Mechanism, Diagnosis, Prevention, and Treatment

• Authors: M. Al-Shabrawey, Wenbo Zhang, D. McDonald
• Year: 2015
• Venue: BioMed Research International
• URL: https://www.semanticscholar.org/paper/91c249a6b9bbec6bab48140b5e5a1e537045895d
• DOI: 10.1155/2015/854593
• PMID: 25866817
• PMCID: 4383145
• Citations: 42
• Influential citations: 2
• Summary: The current special issue through a number of investigators and experts in the field of DR presents both research and review articles that highlight novel pathways implicated in the development of DR and review the pathophysiology and management of DR.
• Evidence snippets:
• Snippet 1 (score: 0.323) > Diabetic retinopathy (DR) is the most common complication of diabetes and remains a major cause of preventable blindness. Anatomical and functional changes occur in various retinal cells including retinal endothelial cells, neurons, and retinal pigment epithelium prior to clinical symptoms of the disease. Early changes include appearance of microaneurysms, leukocyte adhesion, apoptosis of vascular (endothelial cells and pericytes), and neuronal cells. The changes progress to involve breakdown of the inner and outer blood retinal barriers causing diabetic macular edema, the most leading cause of vision loss in DR. Capillary degeneration and development of acellular capillaries lead to impairment of retinal perfusion and subsequent hypoxia and retinal neovascularization, the hallmark of proliferative diabetic retinopathy (PDR). There are several therapeutic strategies to manage the DR including laser photocoagulation, anti-VEGF, and triamcinolone intraocular injection. These therapeutic interventions are still limited by significant side effects. Therefore, there is still an urgent need to find out new therapies to limit the diminution or loss of vision in diabetic patients. The current special issue through a number of investigators and experts in the field of DR presents both research and review articles that highlight novel pathways implicated in the development of DR and review the pathophysiology and management of DR. > Novel Mechanisms of Diabetic Retinopathy. Effective therapeutic approaches to restore sight in diabetic patients with clinically identifiable retinopathy are still lacking and in this issue S. Z. Safi et al. provide a timely review of current thinking in field. Firstly, using several scientific databases (PubMed, Ovid MEDLINE, SPORTDiscus, and EMBASE databases) they have reviewed the literature focusing on the molecular mechanisms involved in the pathogenesis of DR and, secondly on emerging strategies under consideration for development of future pharmacological interventions. Initially, they described the major pathways widely recognized to be involved in disease, namely, the polyol pathway, activation of protein kinase C (KPC) isoforms, increased hexosamine pathway flux and increased advanced glycation end-product

Notes

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