Cancer disease describes any pathology involving uncontrolled cell growth. As cells duplicate, they can remain localized in defined tissues, forming tumor masses and altering their microenvironmental ...niche, or they can disseminate throughout the body in a metastatic process affecting multiple tissues and organs. As tumors grow and metastasize, they affect normal tissue integrity and homeostasis which signals the body to trigger the acute phase inflammatory response. C-reactive protein (CRP) is a predominant protein of the acute phase response; its blood levels have long been used as a minimally invasive index of any ongoing inflammatory response, including that occurring in cancer. Its diagnostic significance in assessing disease progression or remission, however, remains undefined. By considering the recent understanding that CRP exists in multiple isoforms with distinct biological activities, a unified model is advanced that describes the relevance of CRP as a mediator of host defense responses in cancer. CRP in its monomeric, modified isoform (mCRP) modulates inflammatory responses by inserting into activated cell membranes and stimulating platelet and leukocyte responses associated with acute phase responses to tumor growth. It also binds components of the extracellular matrix in involved tissues. Conversely, CRP in its pentameric isoform (pCRP), which is the form quantified in diagnostic measurements of CRP, is notably less bioactive with weak anti-inflammatory bioactivity. Its accumulation in blood is associated with a continuous, low-level inflammatory response and is indicative of unresolved and advancing disease, as occurs in cancer. Herein, a novel interpretation of the diagnostic utility of CRP is presented accounting for the unique properties of the CRP isoforms in the context of the developing pro-metastatic tumor microenvironment.
Mitochondrial metabolism is an attractive target for cancer therapy
. Reprogramming metabolic pathways could improve the ability of metabolic inhibitors to suppress cancers with limited treatment ...options, such as triple-negative breast cancer (TNBC)
. Here we show that BTB and CNC homology1 (BACH1)
, a haem-binding transcription factor that is increased in expression in tumours from patients with TNBC, targets mitochondrial metabolism. BACH1 decreases glucose utilization in the tricarboxylic acid cycle and negatively regulates transcription of electron transport chain (ETC) genes. BACH1 depletion by shRNA or degradation by hemin sensitizes cells to ETC inhibitors such as metformin
, suppressing growth of both cell line and patient-derived tumour xenografts. Expression of a haem-resistant BACH1 mutant in cells that express a short hairpin RNA for BACH1 rescues the BACH1 phenotype and restores metformin resistance in hemin-treated cells and tumours
. Finally, BACH1 gene expression inversely correlates with ETC gene expression in tumours from patients with breast cancer and in other tumour types, which highlights the clinical relevance of our findings. This study demonstrates that mitochondrial metabolism can be exploited by targeting BACH1 to sensitize breast cancer and potentially other tumour tissues to mitochondrial inhibitors.
C-reactive protein (CRP) is a widely known, hepatically synthesized protein whose blood levels change rapidly and pronouncedly in response to any tissue damaging event associated with an inflammatory ...response. The synthesis and secretion of CRP is stimulated by interleukin-6, an early pleiotropic cytokine released by macrophages, endothelial, and other cells that are activated when localized normal tissue structures are compromised by trauma or disease. Serum CRP levels can change rapidly and robustly from 10-100-fold within 6-72 h of any tissue damaging event. Elevated blood levels correlate with the onset and extent of both activated inflammation and the acute phase biochemical response to the tissue insult. Because its functional bioactivity as the prototypic acute phase reactant has eluded clear definition for decades, diagnosticians of various conditions and diseases use CRP blood levels as a simple index for ongoing inflammation. In many pathologies, which involves many different tissues, stages of disease, treatments, and responses to treatments, its interpretive diagnostic value requires a deeper understanding of the localized tissue processes and events that contribute signals which regulate protective or pathological host defense bioactivities. This report presents concepts that describe how local tissue activation events can lead to a non-proteolytic, conformational rearrangement of CRP into a unique isoform with distinctive solubility, antigenicity, binding reactivities and bioactivities from that protein widely known and measured in serum. By describing factors that control the expression, tissue localization, half-life and pro-inflammatory amplification activity of this CRP isoform, a unifying explanation for the diagnostic significance of CRP measurement in disease is advanced.
The zebrafish (
Danio rerio) is emerging as a promising model organism for experimental studies of stress and anxiety. Here we further validate zebrafish models of stress by analyzing how ...environmental and pharmacological manipulations affect their behavioral and physiological phenotypes. Experimental manipulations included exposure to alarm pheromone, chronic exposure to fluoxetine, acute exposure to caffeine, as well as acute and chronic exposure to ethanol. Acute (but not chronic) alarm pheromone and acute caffeine produced robust anxiogenic effects, including reduced exploration, increased erratic movements and freezing behavior in zebrafish tested in the novel tank diving test. In contrast, ethanol and fluoxetine had robust anxiolytic effects, including increased exploration and reduced erratic movements. The behavior of several zebrafish strains was also quantified to ascertain differences in their behavioral profiles, revealing high-anxiety (leopard, albino) and low-anxiety (wild type) strains. We also used LocoScan (CleverSys Inc.) video-tracking tool to quantify anxiety-related behaviors in zebrafish, and dissect anxiety-related phenotypes from locomotor activity. Finally, we developed a simple and effective method of measuring zebrafish physiological stress responses (based on a human salivary cortisol assay), and showed that alterations in whole-body cortisol levels in zebrafish parallel behavioral indices of anxiety. Collectively, our results confirm zebrafish as a valid, reliable, and high-throughput model of stress and affective disorders.
Approximately 20% of patients infected with SARS-CoV-2 (COVID-19) develop potentially life-threatening pathologies involving hyperinflammation, cytokine storm, septic shock complications, coagulation ...dysfunction, and multiple organ failure. Blood levels of the prototypic acute phase reactant, C-reactive protein (CRP), which is hepatically synthesized and released in response to interleukin-6 stimulation, is markedly elevated in patients with COVID-19. Markedly high CRP levels correlate with poor prognosis for survival. Insights into CRP structure-function relationships have uncovered both pro- and anti-inflammatory isoforms that may be used to monitor the extent of tissue damage associated with COVID-19 pathologies and prognoses. Herein, rationale is given for interpretation of CRP blood levels as a simple, rapid, and cost-effective way to assess disease severity and help guide therapeutic options in COVID-19 patients.
C-reactive protein (CRP) was first recognized in the 1940s as a protein that appeared in blood during acute episodes of infectious disease. Its presence and pharmacodynamics were found in essentially ...all diseases that involved tissue damage and inflammation. Identified as a major component of the innate, unlearned immunity, it became a useful diagnostic marker for the extent of inflammation during disease exacerbation or remission. Efforts to define its true biological role has eluded clear definition for over a half-century. Herein, a unifying concept is presented that explains both pro-inflammatory and anti-inflammatory activities of CRP. This concept involves the recognition and understanding that CRP can be induced to undergo a pronounced, non-proteolytic reorganization of its higher-level protein structures into conformationally distinct isomers with distinctive functional activities. This process occurs when the non-covalently associated globular subunits of the pentameric isoform ("pCRP") are induced to dissociate into a monomeric isoform ("mCRP"). mCRP consistently and potently provides pro-inflammatory activation and amplification activities. pCRP provides weak anti-inflammatory activities consistent with low-level chronic inflammation. mCRP can spontaneously form in purified pCRP reagents in ways that are not immediately recognized during purification and certification analyses. By now understanding the factors that influence pCRP dissociate into mCRP, many published reports investigating CRP as a biological response modifier of host defense can be reevaluated to include a discussion of how each CRP isoform may have affected the generated results. Specific attention is given to
and
studies of CRP as an anti-cancer agent.
Growing evidence suggests that the immune component of the tumor microenvironment (TME) may be highly involved in the progression of high-grade serous ovarian cancer (HGSOC), as an immunosuppressive ...TME is associated with worse patient outcomes. Due to the poor prognosis of HGSOC, new therapeutic strategies targeting the TME may provide a potential path forward for preventing disease progression to improve patient survival. One such postulated approach is the repurposing of the type 2 diabetes medication, metformin, which has shown promise in reducing HGSOC tumor progression in retrospective epidemiological analyses and through numerous preclinical studies. Despite its potential utility in treating HGSOC, and that the immune TME is considered as a key factor in the disease's progression, little data has definitively shown the ability of metformin to target this component of the TME. In this brief review, we provide a summary of the current understanding of the effects of metformin on leukocyte function in ovarian cancer and, coupled with data from other related disease states, posit the potential mechanisms by which the drug may enhance the anti-tumorigenic effects of immune cells to improve HGSOC patient survival.
The role of phospholipid signaling in ovarian cancer is poorly understood. Sphingosine-1-phosphate (S1P) is a bioactive metabolite of sphingosine that has been associated with tumor progression ...through enhanced cell proliferation and motility. Similarly, sphingosine kinases (SPHK), which catalyze the formation of S1P and thus regulate the sphingolipid rheostat, have been reported to promote tumor growth in a variety of cancers. The findings reported here show that exogenous S1P or overexpression of SPHK1 increased proliferation, migration, invasion, and stem-like phenotypes in ovarian cancer cell lines. Likewise, overexpression of SPHK1 markedly enhanced tumor growth in a xenograft model of ovarian cancer, which was associated with elevation of key markers of proliferation and stemness. The diabetes drug, metformin, has been shown to have anticancer effects. Here, we found that ovarian cancer patients taking metformin had significantly reduced serum S1P levels, a finding that was recapitulated when ovarian cancer cells were treated with metformin and analyzed by lipidomics. These findings suggested that in cancer the sphingolipid rheostat may be a novel metabolic target of metformin. In support of this, metformin blocked hypoxia-induced SPHK1, which was associated with inhibited nuclear translocation and transcriptional activity of hypoxia-inducible factors (HIF1α and HIF2α). Further, ovarian cancer cells with high SPHK1 were found to be highly sensitive to the cytotoxic effects of metformin, whereas ovarian cancer cells with low SPHK1 were resistant. Together, the findings reported here show that hypoxia-induced SPHK1 expression and downstream S1P signaling promote ovarian cancer progression and that tumors with high expression of SPHK1 or S1P levels might have increased sensitivity to the cytotoxic effects of metformin. IMPLICATIONS: Metformin targets sphingolipid metabolism through inhibiting SPHK1, thereby impeding ovarian cancer cell migration, proliferation, and self-renewal.
Abstract
Autism spectrum disorder (ASD) is a neurological disorder that manifests during early development, impacting individuals through their ways of communicating, social behaviors, and their ...ability to perform day-to-day activities. There have been different proposed mechanisms on how ASD precipitates within a patient, one of which being the impact cytokines have on fetal development once a mother’s immune system has been activated (referred to as maternal immune activation, MIA). The occurrence of ASD has long been associated with elevated levels of several cytokines, including interleukin-6 (IL-6) and interferon gamma (IFN-γ). These proinflammatory cytokines can achieve high systemic levels in response to immune activating pathogens from various extrinsic sources. Transfer of cytokines such as IL-6 across the placental barrier allows accumulation in the fetus, potentially inducing neuroinflammation and consequently altering neurodevelopmental processes. Individuals who have been later diagnosed with ASD have been observed to have elevated levels of IL-6 and other proinflammatory cytokines during gestation. Moreover, the outcome of MIA has been associated with neurological effects such as impaired social interaction and an increase in repetitive behavior in animal models, supporting a mechanistic link between gestational inflammation and development of ASD-like characteristics. The present review attempts to provide a concise overview of the available preclinical and clinical data that suggest cross-talk between IL-6 and IFN-γ through both extrinsic and intrinsic factors as a central mechanism of MIA that may promote the development of ASD.
ATP and reactive oxygen species (ROS) are signaling molecules that control cellular function and phenotype. Mitochondria produce both ATP and ROS. Since the electrons needed to generate either ATP or ...ROS originate from NADH/FADH2, the mechanism through which electrons flow towards oxygen determines yields and whether ATP or ROS prevails. Alterations in the electron flow impact cells dramatically, such as by supporting specialization (which requires high ATP) or imposing dedifferentiation. High ROS, facilitated by enzymes such as superoxide dismutase 2 (SOD2) that enhance mitochondrial hydrogen peroxide (mtH2O2), are normally linked to dedifferentiation of somatic cells. Here we propose that combined high mtH2O2 and mitochondrial unfolded protein response (UPRmt) activation are essential for somatic dedifferentiation programs and the acquisition of stem-like properties in reparative processes and disease.
Reactive oxygen species (ROS) levels are key determinants of cellular plasticity and modulate phenotypic transitions through signaling.
Mitochondrial ROS (mtROS) and ATP levels are part of a mitochondrial switch system regulating differentiation/dedifferentiation cycles (cellular phenotypes).
The electron flow through mitochondria controls metabolism and signaling, maintaining cellular specialized functions or promoting dedifferentiation.
Buffering ROS levels is essential to stabilize cellular states operating at high ROS levels to simultaneously enable redox signaling and mitigate damage that can compromise cell survival.
The mitochondrial unfolded protein response (UPRmt) is an indispensable and complex response that allows cells to buffer ROS and exist at high-ROS steady-state levels.
High superoxide dismutase 2 (SOD2) and activation of the UPRmt characterize cells with high phenotypic plasticity.
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