Chronic Dysfunction Research Articles

Bi-directional neuro-immune dysfunction after chronic experimental brain injury

BackgroundIt is well established that traumatic brain injury (TBI) causes acute and chronic alterations in systemic immune function and that systemic immune changes contribute to posttraumatic neuroinflammation and neurodegeneration. However, how TBI affects bone marrow (BM) hematopoietic stem/progenitor cells chronically and to what extent such changes may negatively impact innate immunity and neurological function has not been examined.MethodsTo further understand the role of BM cell derivatives on TBI outcome, we generated BM chimeric mice by transplanting BM from chronically injured or sham (i.e., 90 days post-surgery) congenic donor mice into otherwise healthy, age-matched, irradiated CD45.2 C57BL/6 (WT) hosts. Immune changes were evaluated by flow cytometry, multiplex ELISA, and NanoString technology. Moderate-to-severe TBI was induced by controlled cortical impact injury and neurological function was measured using a battery of behavioral tests.ResultsTBI induced chronic alterations in the transcriptome of BM lineage−c-Kit+Sca1+ (LSK+) cells in C57BL/6 mice, including modified epigenetic and senescence pathways. After 8 weeks of reconstitution, peripheral myeloid cells from TBI→WT mice showed significantly higher oxidative stress levels and reduced phagocytic activity. At eight months after reconstitution, TBI→WT chimeric mice were leukopenic, with continued alterations in phagocytosis and oxidative stress responses, as well as persistent neurological deficits. Gene expression analysis revealed BM-driven changes in neuroinflammation and neuropathology after 8 weeks and 8 months of reconstitution, respectively. Chimeric mice subjected to TBI at 8 weeks and 8 months post-reconstitution showed that longer reconstitution periods (i.e., time post-injury) were associated with increased microgliosis and leukocyte infiltration. Pre-treatment with a senolytic agent, ABT-263, significantly improved behavioral performance of aged C57BL/6 mice at baseline, although it did not attenuate neuroinflammation in the acutely injured brain.ConclusionsTBI causes chronic activation and progressive dysfunction of the BM stem/progenitor cell pool, which drives long-term deficits in hematopoiesis, innate immunity, and neurological function, as well as altered sensitivity to subsequent brain injury.

Intracellular acidification and glycolysis modulate inflammatory pathway in senescent cells.

Senescent cells accumulate in various organs with ageing, and its accumulation induces chronic inflammation and age-related physiological dysfunctions. Several remodelling of intracellular environments have been identified in senescent cells, including enlargement of cell/nuclear size and intracellular acidification. Although these alterations of intracellular environments were reported to be involved in the unique characteristics of senescent cells, the contribution of intracellular acidification to senescence-associated cellular phenotypes is poorly understood. Here, we identified that the upregulation of TXNIP and its paralog ARRDC4 as a hallmark of intracellular acidification in addition to KGA-type GLS1. These genes were also upregulated in response to senescence-associated intracellular acidification. Neutralization of the intracellular acidic environment ameliorated not only senescence-related upregulation of TXNIP, ARRDC4 and KGA but also inflammation-related genes, possibly through suppression of PDK-dependent anaerobic glycolysis. Furthermore, we found that expression of the intracellular acidification-induced genes, TXNIP and ARRDC4, correlated with inflammatory gene expression in heterogeneous senescent cell population in vitro and even in vivo, implying that the contribution of intracellular pH to senescence-associated cellular features, such as SASP.

Nod-like receptor protein 3 inflammasome-mediated pyroptosis contributes to chronic NaAsO2 exposure-induced fibrotic changes and dysfunction in the liver of SD rats

The metalloid arsenic, known for its toxic properties, is widespread presence in the environment. Our previous research has confirmed that prolonged exposure to arsenic can lead to liver fibrosis injury in rats, while the precise pathogenic mechanism still requires further investigation. In the past few years, the Nod-like receptor protein 3 (NLRP3) inflammasome has been found to play a pivotal role in the occurrence and development of liver injury. In this study, we administered varying doses of sodium arsenite (NaAsO2) and 10 mg/kg.bw MCC950 (a particular tiny molecular inhibitor targeting NLRP3) to Sprague-Dawley (SD) rats for 36 weeks to explore the involvement of NLRP3 inflammasome in NaAsO2-induced liver injury. The findings suggested that prolonged exposure to NaAsO2 resulted in pyroptosis in liver tissue of SD rats, accompanied by the fibrotic injury, extracellular matrix (ECM) deposition and liver dysfunction. Moreover, long-term NaAsO2 exposure activated NLRP3 inflammasome, leading to the release of pro-inflammatory cytokines in liver tissue. After treatment with MCC950, the induction of NLRP3-mediated pyroptosis and release of pro-inflammatory cytokines were significantly attenuated, leading to a decrease in the severity of liver fibrosis and an improvement in liver function. To summarize, those results clearly indicate that hepatic fibrosis and liver dysfunction induced by NaAsO2 occur through the activation of NLRP3 inflammasome-mediated pyroptosis, shedding new light on the potential mechanisms underlying arsenic-induced liver damage.

Protective Role of Dioscin against Doxorubicin-Induced Chronic Cardiotoxicity: Insights from Nrf2-GPX4 Axis-Mediated Cardiac Ferroptosis.

Recent evidence suggests that ferroptosis, an iron-facilitated cell death with excessive lipid peroxidation, is a critical mechanism underlying doxorubicin (DOX)-induced cardiotoxicity (DIC). Although dioscin has been reported to improve acute DIC, direct evidence is lacking to clarify the role of dioscin in chronic DIC and its potential mechanism in cardiac ferroptosis. In this study, we used chronic DIC rat models and H9c2 cells to investigate the potential of dioscin to mitigate DIC by inhibiting ferroptosis. Our results suggest that dioscin significantly improves chronic DIC-induced cardiac dysfunction. Meanwhile, it significantly inhibited DOX-induced ferroptosis by reducing Fe2+ and lipid peroxidation accumulation, maintaining mitochondrial integrity, increasing glutathione peroxidase 4 (GPX4) expression, and decreasing acyl-CoA synthetase long-chain family 4 (ACSL4) expression. Through transcriptomic analysis and subsequent validation, we found that the anti-ferroptotic effects of dioscin are achieved by regulating the nuclear factor-erythroid 2-related factor 2 (Nrf2)/GPX4 axis and Nrf2 downstream iron metabolism genes. Dioscin further downregulates nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) and upregulates expression of frataxin (FXN) and ATP-binding cassette B8 (ABCB8) to limit mitochondrial Fe2+ and lipid peroxide accumulation. However, Nrf2 inhibition diminishes the anti-ferroptotic effects of dioscin, leading to decreased GPX4 expression and increased lipid peroxidation. This study is a compelling demonstration that dioscin can effectively reduce DIC by inhibiting ferroptosis, which is dependent on the Nrf2/GPX4 pathway modulation.

Advances in the Diagnosis and Treatment of Sacral Cysts

Sacral cysts have become a neurological disease that has received widespread attention in recent years. Its etiology and pathogenesis are still unclear, and it is more commonly believed to be the result of the interaction of multiple factors, which leads to clinical symptoms such as chronic low back pain and dysfunction of urinary and fecal functions. The disease is detected and diagnosed by magnetic resonance imaging, and treatment options include conservative treatment, interventional therapy, and surgical removal. However, there is no consensus on the diagnosis and treatment of sacral cysts, which has led to stagnation in the diagnosis and treatment of this disease. This article summarizes the definition, epidemiological characteristics, etiology and pathogenesis, diagnosis and treatment of this disease, in order to provide certain reference for clinical work.

Brain temperature and free water increases after mild COVID-19 infection

The pathophysiology underlying the post-acute sequelae of COVID-19 remains understudied and poorly understood, particularly in healthy adults with a history of mild infection. Chronic neuroinflammation may underlie these enduring symptoms, but studying neuroinflammatory phenomena in vivo is challenging, especially without a comparable pre-COVID-19 dataset. In this study, we present a unique dataset of 10 otherwise healthy individuals scanned before and after experiencing mild COVID-19. Two emerging MR-based methods were used to map pre- to post-COVID-19 brain temperature and free water changes. Post-COVID-19 brain temperature and free water increases, which are indirect biomarkers of neuroinflammation, were found in structures functionally associated with olfactory, cognitive, and memory processing. The largest pre- to post-COVID brain temperature increase was observed in the left olfactory tubercle (p = 0.007, 95% CI [0.48, 3.01]), with a mean increase of 1.75 °C. Notably, the olfactory tubercle is also the region of the primary olfactory cortex where participants with chronic olfactory dysfunction showed the most pronounced increases as compared to those without lingering olfactory dysfunction (adjusted pFDR = 0.0189, 95% CI [1.42, 5.27]). These preliminary insights suggest a potential link between neuroinflammation and chronic cognitive and olfactory dysfunction following mild COVID-19, although further investigations are needed to improve our understanding of what underlies these phenomena.

Recovery of the hibernating cavernosum by penile revascularization

ABSTRACT Objective Chronic ischemia-related cavernous dysfunction is considered irreversible. However, in certain patients, cavernous function appears to recover with penile revascularization. In this study, we investigated a potential cavernous dysfunction reversibility from a clinical perspective. Patients and Methods We involved 93 young patients in the study with arterial erectile dysfunction (ED) (median age: 30 years). Erectile function tests were performed according to the standard operating procedures of the International Society of Sexual Medicine. Among the participants, 63 and 30 displayed pure arteriogenic and mixed vasculogenic (due to both arterial insufficiency and cavernous dysfunction) ED, respectively. Penile revascularization was performed by anastomosing the inferior epigastric artery to the dorsal artery. The ED treatment success was considered from a score of at least 24 on the International Index of Erectile Function-6. Results Our results proved that penile revascularization cured 92.1% and 73.8% of the patients with pure arteriogenic and mixed vasculogenic ED, respectively (Kaplan-Meier method, log-rank test: no significant difference). The required time for curing 50% of the patients was 10.5 and 10.0 months for pure arteriogenic and mixed vasculogenic ED, respectively, indicating no recovery delay in patients with mixed vascular ED. Furthermore, the cavernous dysfunction degree did not influence cavernous function recovery. Conclusion Penile revascularization cured ED in 73.8% of the patients with mixed vasculogenic ED. Cavernous dysfunction appears to be reversible in certain cases. Furthermore, we observed no delay in functional recovery compared to participants with healthy cavernous function. These two discoveries suggest that cavernous function recovery after penile revascularization is similar to the concept of hibernating myocardium in ischemic myocardium. Although cavernous dysfunction is considered irreversible, it could be reversed in multiple cases with blood flow restoration to the cavernous tissue.

Gait kinematics and kinetics in patients with chronic ankle instability and healthy controls: A statistical parametric mapping analysis

BackgroundChronic ankle instability (CAI) is associated with changes in gait biomechanics which may be related to chronic dysfunction. Traditional statistical models may be limited in their ability to assess the complex 3D movement of the lower extremity during gait. Multivariate analysis of the lower extremity kinematics may reveal unique biomechanical differences associated with CAI. Research Question: Do patients with CAI differ from healthy controls in their lower extremity biomechanics and GRF when comparing 3D biomechanics? MethodsThirty-nine young, active adults participated in this study. Data was collected using a 3D motion analysis system while patients walked and jogged. Statistical parametric mapping (SPM) was used to explore 3D GRF, kinematics and kinetics of the of the lower extremity of CAI and healthy patients. ResultsDuring walking, patients with CAI had greater inversion from 68–100% of gait cycle (p < 0.001, mean difference=3.2°). During jogging, patients with CAI had greater inversion from 20–92% (p < 0.001, mean difference=4.6°). Greater plantar flexion moments were found from 65–71% (p = 0.05, mean difference=347.4Nm/kg) and greater eversion moments were found from 95–100% (p = 0.03, mean difference=74.6Nm/kg) in the CAI group. No differences in GRF were found.Significance:Greater inversion may present a potentially injurious position. A faulty position of the rearfoot may require greater muscle function in order to correct the position of the joint resulting in greater eversion moments at the ankle. However, this kinetic change does not appear to correct the ankle position.

Exercise to Mitigate Cerebrovascular Aging: A Geroscience Perspective.

Aging is characterized by a progressive loss of cellular functions that increase the risk of developing chronic diseases, vascular dysfunction, and neurodegenerative conditions. The field of geroscience has identified cellular and molecular hallmarks of aging that may serve as targets for future interventions to reduce the risk of age-related disease and disability. These hallmarks include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Several studies show that exercise may favorably affect these processes and thereby have antiaging properties. The primary mechanisms through which exercise confers protective benefits in the brain are still incompletely understood. To better understand these effects and leverage them to help promote brain health, we present current findings supporting the notion that adaptive responses to exercise play a pivotal role in mitigating the hallmarks of aging and their effects on the aging cerebrovasculature, and ultimately contribute to the maintenance of brain function across the healthspan.

Cell type-specific transforming growth factor-β (TGF-β) signaling in the regulation of salivary gland fibrosis and regeneration

Salivary gland damage and hypofunction result from various disorders, including autoimmune Sjögren's disease (SjD) and IgG4-related disease (IgG4-RD), as well as a side effect of radiotherapy for treating head and neck cancers. There are no therapeutic strategies to prevent the loss of salivary gland function in these disorders nor facilitate functional salivary gland regeneration. However, ongoing aquaporin-1 gene therapy trials to restore saliva flow show promise. To identify and develop novel therapeutic targets, we must better understand the cell-specific signaling processes involved in salivary gland regeneration. Transforming growth factor-β (TGF-β) signaling is essential to tissue fibrosis, a major endpoint in salivary gland degeneration, which develops in the salivary glands of patients with SjD, IgG4-RD, and radiation-induced damage. Though the deposition and remodeling of extracellular matrix proteins are essential to repair salivary gland damage, pathological fibrosis results in tissue hardening and chronic salivary gland dysfunction orchestrated by multiple cell types, including fibroblasts, myofibroblasts, endothelial cells, stromal cells, and lymphocytes, macrophages, and other immune cell populations. This review is focused on the role of TGF-β signaling in the development of salivary gland fibrosis and the potential for targeting TGF-β as a novel therapeutic approach to regenerate functional salivary glands. The studies presented highlight the divergent roles of TGF-β signaling in salivary gland development and dysfunction and illuminate specific cell populations in damaged or diseased salivary glands that mediate the effects of TGF-β. Overall, these studies strongly support the premise that blocking TGF-β signaling holds promise for the regeneration of functional salivary glands.

Acute and Chronic Kidney Dysfunction and Prognosis following Thrombectomy for Ischemic Stroke

Introduction: Patients with chronic kidney disease (CKD) have an increased risk of stroke, and CKD seems associated with worse outcome after a stroke. The main objective of our study RISOTTO was to evaluate the influence of CKD and acute kidney injury (AKI) on the clinical outcome and mortality of ischemic stroke patients after thrombolysis and/or thrombectomy. Methods: This multicenter cohort study included patients in the acute phase of ischemic stroke due to large artery occlusion managed by thrombectomy. Functional outcome at 3 months was assessed by the modified Rankin Scale (mRS). Results: 280 patients were included in the analysis. Fifty-nine patients (22.6%) had CKD. At 3 months, CKD was associated with similar functional prognosis (mRS 3–6: 50.0% vs. 41.7%, p = 0.262) but higher mortality (24.2% versus 9.5%, p = 0.004). In univariate analysis, patients with CKD had a higher burden of white matter hyperintensities (Fazekas score: 1.7 ± 0.8 vs. 1.0 ± 0.8, p = 0.002), lower initial infarct volume with equivalent severity, and lower recanalization success (86.4% vs. 97.0%, p = 0.008) compared to non-CKD patients. Forty-seven patients (20.0%) developed AKI. AKI was associated with poorer 3-month functional outcome (mRS 3–6: 63.8% vs. 49.0%, p = 0.002) and mortality (23.4% versus 7.7%, p = 0.002). In multivariate analysis, AKI appeared as an independent risk factor for poor functional outcome (mRS 3–6: adjOR 2.79 [1.11–7.02], p = 0.029) and mortality (adjOR 2.52 [1.03–6.18], p = 0.043) at 3 months, while CKD was not independently associated with 3-month mortality and poor neurological outcome. Conclusions: AKI is independently associated with poorer functional outcome and increased mortality at 3 months. CKD was not an independent risk factor for 3-month mortality or poor functional prognosis.

Soluble urokinase plasminogen activator receptor (suPAR) in children with obesity or type 1 diabetes as a marker of endothelial dysfunction: a cross-sectional study.

Pediatric obesity and type 1 diabetes mellitus (T1DM) represent two common chronic diseases associated with chronic inflammation, endothelial dysfunction and long-term complications. The aim of the present study was to assess the possible diagnostic and prognostic value of soluble urokinase plasminogen activator receptor (suPAR), a marker of inflammation and impaired endothelial function, in children with the diseases.In this cross-sectional study, children and adolescents with T1DM (N = 41) or obesity (N = 37), aged < 18 years old, and without proteinuria were included, together with children of similar age and without evident morbidity that served as controls (N = 42). Serum samples were obtained during standard outpatient follow up and the urokinase-type plasminogen activator receptor (suPAR) concentrations were measured using a commercially available sandwich ELISA kit (DUP00, R&D systems). Clinical and biochemical indices that were also assessed include body mass index (BMI) z-score, Tanner stages, glycosylated haemoglobin (HbA1c), fasting lipid profile and serum creatinine. Mean serum suPAR levels were significantly higher in patients with obesity compared to patients with T1DM and controls, while children with T1DM had similar suPAR levels to controls. Also, serum suPAR levels showed a negative correlation with age (Spearman rho -0.359, p < 0.001) and serum creatinine levels (Spearman rho -0.334, p = 0.005), and a positive correlation with BMI z-score (Spearman rho 0.354, p = 0.009) in the whole cohort. Conclusion: Serum suPAR may be a useful predictive marker of inflammation or endothelial dysfunction for children with obesity and T1DM, as well as a promising therapeutic target. Further studies are needed in order to clarify whether the reported differences in suPAR levels could reflect a greater impairment of the inflammation status and endothelial function in children with obesity compared to children with T1DM. What is Known: • Paediatric obesity and type 1 diabetes are characterised by chronic inflammation and metabolic dysregulation. • Urokinase plasminogen activator receptor (uPAR) has been proposed as a useful biomarker for chronic inflammation and cardiovascular risk in adults. What is New: • Serum suPAR levels were increased in children and adolescents with obesity compared to those with T1DM and healthy controls; thus, obesity may affect the inflammatory status and endothelial function to a higher degree than T1DM during childhood. • Serum suPAR may serve as a diagnostic and predictive marker of inflammation and endothelial dysfunction for children and adolescents with obesity and T1DM.

Deciphering the Receptor-Mediated Signaling Pathways of Interleukin-19 and Interleukin-20.

Interleukin-19 (IL-19) and Interleukin-20 (IL-20) are inflammatory cytokines belonging to the IL-10 family with immunoregulatory properties. Emerging evidence highlights the importance of association of these cytokines with both immunological and inflammatory disorders, including chronic inflammation, cardiac dysfunction, and cancer. IL-19 and IL-20 bind to the heterodimeric receptor complex and induce multiple downstream signaling cascades by activating the signal transducer and activator of transcription 3 (STAT3), Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), AKT serine/threonine kinase 1 (AKT1), and NFKB inhibitor alpha (NFKBIA), leading to proinflammatory and anti-inflammatory reactions in cancer, inflammation, tumor microenvironment, and infectious diseases. Considering the significant role of these cytokines, we integrated its cellular signaling network by combining multiomics molecular events associated with 56 molecules of induced by IL-19 and 156 molecules of by IL-20. The reactions of these signaling events are classified into enzyme catalysis/post-translational modifications, activation/inhibition events, molecular associations, gene regulations at the mRNA and protein level, and the protein translocation events. We believe that this signaling pathway map would serve as a knowledge base, that aid researchers and clinicians to understand and explore the intricate mechanisms and identify novel signaling components and therapeutic targets for diseases associated with dysregulated IL-19 and IL-20 signaling.

Characteristics and outcomes of youth with functional seizures attending intensive interdisciplinary pain treatment

Functional seizures (FS) can be debilitating and negatively impact quality of life. Yet intervention research for FS is limited, especially for youth. This study examined clinical characteristics and outcomes of youth with FS (13–23 years) presenting to a pediatric intensive interdisciplinary pain treatment (IIPT) program in the midwestern United States. Sixty youth (mean age = 16.5 years; 83.3 % female) met inclusion criteria. At intake, comorbid chronic pain, somatic symptoms, autonomic dysfunction, eating and weight disturbances, and mental health concerns were common. Despite this high symptom burden, youth with FS reported significant improvements in functioning measured with the Functional Disability Inventory, t(53) = 9.80, p <.001, d = 1.32; depression measured with the Center for Epidemiological Studies – Depression Scale for Children, t(53) = 6.76, p <.001, d = 0.91; anxiety measured with the Spence Children’s Anxiety Scale, t(53) = 3.97, p < .001, d = 0.53; and catastrophizing measured with the Pain Catastrophizing Scale for Children, t(53) = 6.44, p <.001, d = 0.86, following completion of the program, suggesting that IIPT may be an effective treatment option for highly disabled and emotionally distressed youth with FS. Future research is needed to continue to refine best practices for youth with FS to reduce suffering and improve outcomes.

HFpEF and sex: understanding the role of sex differences.

Heart failure is a complex clinical syndrome with many etiological factors and complex pathophysiology affecting millions worldwide. Males and females can have distinct clinical presentation and prognosis, and there is an emerging understanding of the factors that highlight the similarities and differences to synthesize and present available data for sex-specific differences in heart failure with preserved ejection fraction (HFpEF). While the majority of data demonstrate more similarities than differences between females and males in terms of heart failure, there are key differences. Data showed that females have a higher risk of developing HFpEF, but a lower risk of mortality and hospitalization. This can be conditioned by different profiles of comorbidities, postmenopausal changes in sex hormone levels, higher levels of inflammation and chronic microvascular dysfunction in females. These factors, combined with different left ventricular dimensions and function, which are more pronounced with age, lead to a higher prevalence of LV diastolic dysfunction at rest and exercise. As a result, females have lower exercise capacity and quality of life when compared to males. Females also have different activities of systems responsible for drug transformation, leading to different efficacy of drugs as well as higher risk of adverse drug reactions. These data prove the necessity for creating sex-specific risk stratification scales and treatment plans.

Beclin 1 Haploinsufficiency Ameliorates High-Fat Diet-Induced Myocardial Injury via Inhibiting Alternative Mitophagy.

Aims: Mitochondrial homeostasis is essential for maintaining redox balance. Besides canonical autophagy, Rab9-dependent alternative autophagy is a crucial mechanism in metabolic cardiomyopathy. Here, we aim to investigate the role of alternative mitophagy and Beclin 1 haploinsufficiency (Beclin 1+/-) in high-fat diet (HFD)-induced metabolic cardiomyopathy. Results: Twenty-four-week HFD impaired glucose tolerance and cardiomyocyte contraction in wild-type mice, both of which were rescued in Beclin 1+/- mice. Beclin 1 haploinsufficiency had little effect on the conventional autophagy mediators (ATG5, LC3 II/LC3 I) but further upregulated Rab9 expression, a marker of alternative autophagy, in response to HFD challenge. Furthermore, either the inhibition of alternative autophagy or Beclin 1 haploinsufficiency abolished palmitic acid (PA)-induced cardiomyocyte contractile anomalies. In vitro, PA overactivated mitophagy, resulting in decreased mitochondrial content in H9C2 cells. These aberrations were alleviated in cells deficient in alternative autophagy but not in cells deficient in conventional autophagy. Mechanistically, HFD promoted reactive oxygen species (ROS) production, activated Rab9-dependent alternative mitophagy, and inhibited mitochondrial biosynthesis. Beclin 1+/- rescued HFD-induced ROS overflow, mitochondrial biogenesis impairment, and prevented Rab9 translocation from the cytoplasm to the mitochondria, thereby inhibiting Rab9-mediated mitophagy overactivation. Innovation: For the first time, this study suggests that prolonged alternative mitophagy exacerbates chronic HFD-induced cardiac dysfunction and supports the protective role of Beclin 1 haploinsufficiency in metabolic cardiomyopathy. This provides additional evidence for a target-based pharmacological intervention. Conclusion: Beclin 1 haploinsufficiency protects against HFD-induced cardiac dysfunction by inhibiting Rab9-dependent alternative mitophagy and ROS production, while promoting mitochondrial biogenesis. Modulating Beclin 1 expression holds promise in preventing chronic HFD-related cardiomyopathy.

Cardiotoxicity risk assessment of anti-cancer drugs and future perspectives

Cardiotoxicity is a serious adverse effect of anti-cancer drugs. Anti-cancer drug-induced cardiotoxicity are arrhythmia, cardiac contractile dysfunction, coronary artery disease, and hypertension, which affect to the quality of life in patients with cancer. In particular, cardiac contractile dysfunction is a life-threatening symptom leading to heart failure, suggesting that it is very important to predict the risk of developing the contractile dysfunction by anti-cancer drugs. Recently, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can be used to assess the risk of drug-induced arrhythmias. This prompts us to evaluate other cardiotoxic effects such as contractility dysfunction and structural toxicity with hiPSC-CMs. Since anti-cancer drug-induced contractility dysfunction are considered to be induced by chronic exposure, we have developed a method to assess chronic contractility dysfunction by imaging analysis of hiPSC-CMs. BMS-986094, which failed in clinical trials due to the occurrence of heart failure, was used as a positive compound. We found that chronic exposure to BMS-986094 decreased the contraction and relaxation velocity in hiPSC-CMs. Doxorubicin was observed to decrease cytotoxicity and both contraction and relaxation velocities in hiPSC-CMs. We are currently further evaluating other anti-cancer drugs with different mode-of-actions using hiPSC-CMs and assess the predictivity and utility of contractile assessment using hiPSC-CMs by comparing with real-world data. Here, we introduce our novel method to assess the chronic contractility of hiPSC-CMs by imaging analysis and discuss the future perspectives for assessing the anti-cancer drug-induced cardiotoxicity.

Enlarged perivascular spaces are associated with white matter injury, cognition and inflammation in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Enlarged perivascular spaces have been previously reported in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, but their significance and pathophysiology remains unclear. We investigated associations of white matter enlarged perivascular spaces with classical imaging measures, cognitive measures and plasma proteins to better understand what enlarged perivascular spaces represent in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and whether radiographic measures of enlarged perivascular spaces would be of value in future therapeutic discovery studies for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Twenty-four individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and 24 age- and sex-matched controls were included. Disease status was determined based on the presence of NOTCH3 mutation. Brain imaging measures of white matter hyperintensity, brain parenchymal fraction, white matter enlarged perivascular space volumes, clinical and cognitive measures as well as plasma proteomics were used in models. White matter enlarged perivascular space volumes were calculated via a novel, semiautomated pipeline, and levels of 7363 proteins were quantified in plasma using the SomaScan assay. The relationship of enlarged perivascular spaces with global burden of white matter hyperintensity, brain atrophy, functional status, neurocognitive measures and plasma proteins was modelled with linear regression models. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and control groups did not exhibit differences in mean enlarged perivascular space volumes. However, increased enlarged perivascular space volumes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy were associated with increased white matter hyperintensity volume (β = 0.57, P = 0.05), Clinical Dementia Rating Sum-of-Boxes score (β = 0.49, P = 0.04) and marginally with decreased brain parenchymal fraction (β = -0.03, P = 0.10). In interaction term models, the interaction term between cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy disease status and enlarged perivascular space volume was associated with increased white matter hyperintensity volume (β = 0.57, P = 0.02), Clinical Dementia Rating Sum-of-Boxes score (β = 0.52, P = 0.02), Mini-Mental State Examination score (β = -1.49, P = 0.03) and marginally with decreased brain parenchymal fraction (β = -0.03, P = 0.07). Proteins positively associated with enlarged perivascular space volumes were found to be related to leukocyte migration and inflammation, while negatively associated proteins were related to lipid metabolism. Two central hub proteins were identified in protein networks associated with enlarged perivascular space volumes: CXC motif chemokine ligand 8/interleukin-8 and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1. The levels of CXC motif chemokine ligand 8/interleukin-8 were also associated with increased white matter hyperintensity volume (β = 42.86, P = 0.03), and levels of C-C motif chemokine ligand 2/monocyte chemoattractant protein 1 were further associated with decreased brain parenchymal fraction (β = -0.0007, P < 0.01) and Mini-Mental State Examination score (β = -0.02, P < 0.01) and increased Trail Making Test B completion time (β = 0.76, P < 0.01). No proteins were associated with all three studied imaging measures of pathology (brain parenchymal fraction, enlarged perivascular spaces, white matter hyperintensity). Based on associations uncovered between enlarged perivascular space volumes and cognitive functions, imaging and plasma proteins, we conclude that white matter enlarged perivascular space volumes may capture pathologies contributing to chronic brain dysfunction and degeneration in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Chronic Liver Disease and Promising Therapeutic Strategy: A Concise Review

Abstract Background: Chronic liver dysfunction (CLD) is a significant global health issue; alcohol use, obesity, drugs, and antibiotic and viral infections contribute to its development. However, changes in gut microbiota composition, primarily as people grow older, can also play a role in initiating and progressing liver dysfunction. Purpose: This review summarizes the altered gut microbiota–mediated chronic liver dysfunction and promising therapeutic strategies for NAFLD, ALD, NASH, and liver cirrhosis. Discussion on the chronic liver disease and its therapeutic aspects: The gut microbiota influences physiological processes, including immune system regulation, by promoting the production of pro-inflammatory markers and elevating the expression of toll-like receptors (TLRs) on hepatocytes, metabolisms of bile acids and choline, alteration in saturated aliphatic organic acid (SCFA) production, and food absorption. These alterations increase intestinal permeability, chronic inflammation, and liver dysfunction. Dysbiosis triggers inflammatory pathways, oxidative stress, and the production of toxic compounds that damage liver cells and promote chronic liver diseases such as alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and cirrhosis. Age-related changes in gut motility, secretory function, and immunological function can further decline beneficial bacterial diversity and abundance and shifts in pathogenic bacterial species’ relative abundance. Conclusion: Dysbiosis resulting from these age-related changes may contribute to the development of CLD. Numerous therapeutic approaches are available to restore the altered gut microbiota and reduce the risk of chronic liver dysfunction.

Beyond Joints: Pulmonary Hypertension in Spondyloarthropathies (Literature review)

Spondyloarthritis (SpA) represents a complex and dynamic spectrum of inflammatory rheumatic diseases. A nuanced understanding of its clinical, genetic, and immunologic aspects is imperative for accurate diagnosis and effective management. The comprehensive literature review reveals a nuanced connection between spondyloarthropathies and pulmonary hypertension (PH), expanding our understanding of these conditions beyond joint pathology. The synthesis of data from various studies provides valuable insights into the complex interplay of factors contributing to the development of PH in individuals with SpA. The reviewed studies consistently indicate a heightened prevalence of elevated arterial blood pressure in the pulmonary artery among patients with ankylosing spondylitis and psoriatic arthritis. However, the limited research on reactive arthritis and other subtypes necessitates further exploration to determine the prevalence and characteristics of pulmonary hypertension across the entire spectrum of SpA. The identified gaps in research emphasize the importance of future studies that encompass the entire SpA spectrum, to provide a more complete understanding of the association with PH. It is crucial to consider all pathogenetic mechanisms, including the impact of chronic persistent inflammation, endothelial dysfunction, and other relevant factors. Recognizing the significance of these mechanisms is vital for comprehensive insights into the complex interplay between both pathologies, guiding the development of targeted interventions and enhancing patient care strategies. This discussion serves as a foundation for future research directions and clinical considerations in the evolving landscape of spondyloarthropathies. This comprehensive overview sets the stage for a deeper exploration of the intricate facets of SpA, including its systemic implications and emerging therapeutic strategies.