Pathophysiological Impact Research Articles

"Pathophysiological Impact of Chronic exposure of Cefalexin Antibiotic Residue above the MRL level in Mice"

"Pathophysiological Impact of Chronic exposure of Cefalexin Antibiotic Residue above the MRL level in Mice"

Navigating the Neurobiology of Parkinson's: The Impact and Potential of α-Synuclein.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease worldwide; therefore, since its initial description, significant progress has been made, yet a mystery remains regarding its pathogenesis and elusive root cause. The widespread distribution of pathological α-synuclein (αSyn) aggregates throughout the body raises inquiries regarding the etiology, which has prompted several hypotheses, with the most prominent one being αSyn-associated proteinopathy. The identification of αSyn protein within Lewy bodies, coupled with genetic evidence linking αSyn locus duplication, triplication, as well as point mutations to familial Parkinson's disease, has underscored the significance of αSyn in initiating and propagating Lewy body pathology throughout the brain. In monogenic and sporadic PD, the presence of early inflammation and synaptic dysfunction leads to αSyn aggregation and neuronal death through mitochondrial, lysosomal, and endosomal functional impairment. However, much remains to be understood about αSyn pathogenesis, which is heavily grounded in biomarkers and treatment strategies. In this review, we provide emerging new evidence on the current knowledge about αSyn's pathophysiological impact on PD, and its presumable role as a specific disease biomarker or main target of disease-modifying therapies, highlighting that this understanding today offers the best potential of disease-modifying therapy in the near future.

Accurate low and high grade glioma classification using free water eliminated diffusion tensor metrics and ensemble machine learning

Glioma, a predominant type of brain tumor, can be fatal. This necessitates an early diagnosis and effective treatment strategies. Current diagnosis is based on biopsy, prompting the need for non invasive neuroimaging alternatives. Diffusion tensor imaging (DTI) is a promising method for studying the pathophysiological impact of tumors on white matter (WM) tissue. Single-shell DTI studies in brain glioma patients have not accounted for free water (FW) contamination due to tumors. This study aimed to (a) assess the efficacy of a two-compartment DTI model that accounts for FW contamination and (b) identify DTI-based biomarkers to classify low-grade glioma (LGG) and high-grade glioma (HGG) patients. DTI data from 86 patients (LGG n = 39, HGG n = 47) were obtained using a routine clinical imaging protocol. DTI metrics of tumorous regions and normal-appearing white matter (NAWM) were evaluated. Advanced stacked-based ensemble learning was employed to classify LGG and HGG patients using both single- and two-compartment DTI model measures. The DTI metrics of the two-compartment model outperformed those of the standard single-compartment DTI model in terms of sensitivity, specificity, and area under the curve of receiver operating characteristic (AUC-ROC) score in classifying LGG and HGG patients. Four features (out of 16 features), namely fractional anisotropy (FA) of the edema and core region and FA and mean diffusivity of the NAWM region, showed superior performance (sensitivity = 92%, specificity = 90%, and AUC-ROC = 90%) in classifying LGG and HGG. This demonstrates that both tumorous and NAWM regions may be differentially affected in LGG and HGG patients. Our results demonstrate the significance of using a two-compartment DTI model that accounts for FW contamination by improving diagnostic accuracy. This improvement may eventually aid in planning treatment strategies for glioma patients.

Microsatellite instability at U2AF-binding polypyrimidic tract sites perturbs alternative splicing during colorectal cancer initiation

BackgroundMicrosatellite instability (MSI) due to mismatch repair deficiency (dMMR) is common in colorectal cancer (CRC). These cancers are associated with somatic coding events, but the noncoding pathophysiological impact of this genomic instability is yet poorly understood. Here, we perform an analysis of coding and noncoding MSI events at the different steps of colorectal tumorigenesis using whole exome sequencing and search for associated splicing events via RNA sequencing at the bulk-tumor and single-cell levels.ResultsOur results demonstrate that MSI leads to hundreds of noncoding DNA mutations, notably at polypyrimidine U2AF RNA-binding sites which are endowed with cis-activity in splicing, while higher frequency of exon skipping events are observed in the mRNAs of MSI compared to non-MSI CRC. At the DNA level, these noncoding MSI mutations occur very early prior to cell transformation in the dMMR colonic crypt, accounting for only a fraction of the exon skipping in MSI CRC. At the RNA level, the aberrant exon skipping signature is likely to impair colonic cell differentiation in MSI CRC affecting the expression of alternative exons encoding protein isoforms governing cell fate, while also targeting constitutive exons, making dMMR cells immunogenic in early stage before the onset of coding mutations. This signature is characterized by its similarity to the oncogenic U2AF1-S34F splicing mutation observed in several other non-MSI cancer.ConclusionsOverall, these findings provide evidence that a very early RNA splicing signature partly driven by MSI impairs cell differentiation and promotes MSI CRC initiation, far before coding mutations which accumulate later during MSI tumorigenesis.

A systematic review and meta-analysis of cortisol levels in Plasmodium infections

Malaria has complex interactions with host physiology, including alterations in cortisol levels. Cortisol, a key hormone in the stress response, is known to be dysregulated in various infectious diseases. This systematic review and meta-analysis aimed to elucidate the relationship between Plasmodium infection and cortisol levels, shedding light on the intricate interplay between the parasite and the host’s endocrine system. The methodological protocol for assessing cortisol levels in malaria patients was registered in PROSPERO (CRD42024496578), a widely recognized international prospective register of systematic reviews. This registration ensures transparency and minimizes the risk of bias in our research. A comprehensive search strategy was employed across major databases, including Embase, PubMed, Scopus, and Medline, to include studies that reported cortisol levels in infected patients. The qualitative synthesis was undertaken to synthesize the difference in cortisol levels between malaria-infected and uninfected individuals. The meta-analysis employed the random effects model in the quantitative synthesis to calculate the effect estimate. The review included a total of 20 studies, with a substantial number conducted in Africa, followed by Asia and South America. Most included studies (13/20, 65%) reported higher cortisol levels in infected patients than in uninfected patients. The meta-analysis confirmed significantly higher cortisol levels in infected patients compared to uninfected individuals (P < 0.0001, standardized mean difference (SMD): 1.354, 95% confidence interval: 0.913 to 1.795, I2: 88.3%, across 15 studies). Notably, the method for cortisol measurement and the type of blood sample used (serum or plasma) were significant moderators in the analysis, indicating that these factors may influence the observed relationship between Plasmodium infection and cortisol levels. The systematic review and meta-analysis confirmed that Plasmodium infection is associated with increased cortisol levels, highlighting the intricate relationship between the disease and the host stress response. These findings underscore the potential of cortisol as a supplementary biomarker for understanding the pathophysiological impact of malaria. By providing insights into the stress-related mechanisms of malaria, this comprehensive understanding can inform future research and potentially enhance disease management and treatment strategies, particularly in regions heavily burdened by malaria.

Somatic RAP1B gain-of-function variant underlies isolated thrombocytopenia and immunodeficiency.

The ubiquitously expressed small GTPase Ras-related protein 1B (RAP1B) acts as a molecular switch that regulates cell signaling, cytoskeletal remodeling, and cell trafficking and activates integrins in platelets and lymphocytes. The residue G12 in the P-loop is required for the RAP1B-GTPase conformational switch. Heterozygous germline RAP1B variants have been described in patients with syndromic thrombocytopenia. However, the causality and pathophysiological impact remained unexplored. We report a boy with neonatal thrombocytopenia, combined immunodeficiency, neutropenia, and monocytopenia caused by a heterozygous de novo single nucleotide substitution, c.35G>A (p.G12E) in RAP1B. We demonstrate that G12E and the previously described G12V and G60R were gain-of-function variants that increased RAP1B activation, talin recruitment, and integrin activation, thereby modifying late responses such as platelet activation, T cell proliferation, and migration. We show that in our patient, G12E was a somatic variant whose allele frequency decreased over time in the peripheral immune compartment, but remained stable in bone marrow cells, suggesting a differential effect in distinct cell populations. Allogeneic hematopoietic stem cell transplantation fully restored the patient's hemato-immunological phenotype. Our findings define monoallelic RAP1B gain-of-function variants as a cause for constitutive immunodeficiency and thrombocytopenia. The phenotypic spectrum ranged from isolated hematological manifestations in our patient with somatic mosaicism to complex syndromic features in patients with reported germline RAP1B variants.

Non-neuronal cell-derived acetylcholine, a key modulator of the vascular endothelial function in health and disease.

Vascular endothelial cells play an important role in regulating peripheral circulation by modulating arterial tone in the microvasculature. Elevated intracellular Ca2+ levels are required in endothelial cells to induce smooth muscle relaxation via endothelium-dependent mechanisms such as nitric oxide production, prostacyclin, and endothelial cell hyperpolarization. It is well established that exogenous administration of acetylcholine can increase intracellular Ca2+ concentrations, followed by endothelium-dependent vasodilation. Although endogenous acetylcholine's regulation of vascular tone remains debatable, recent studies have reported that endogenously derived acetylcholine, but not neuronal cell-derived acetylcholine, is a key modulator of endothelial cell function. In this minireview, we summarize the current knowledge of the non-neuronal cholinergic system (NNCS) in vascular function, particularly vascular endothelial cell function, which contributes to blood pressure regulation. We also discuss the possible pathophysiological impact of endothelial NNCS, which may induce the development of vascular diseases due to endothelial dysfunction, and the potential of endothelial NNCS as a novel therapeutic target for endothelial dysfunction in the early stages of metabolic syndrome, diabetes, and hypertension.

Oxidative stress: A driving force in CKD induced heart failure

Background: Several clinical investigations have shown that individuals with renal impairment are more likely to experience heart failure. Cardiac remodeling happens relatively early in the course of kidney injury, yet research into identification of common markers of cardiorenal signaling remains insuffcient. This may be because studies conducted in small animal models do not accurately reflect the complexity of the disease. To bridge the translational gap, we developed a swine model for chronic kidney disease (CKD) Aim: We employed proteome studies to clarify the pathophysiological impact of chronic kidney disease (CKD) on the heart and correlate to cardiac function and perfusion in order to offer mechanistic insights. Methods: We used microspheres to embolise both kidneys of swine at 10-12 weeks of age while sham operated swine served as controls. Post 6 months, we performed pressure volume loops to assess cardiac function, while coronary flow reserve (CFR) was measured by intracoronary infusion of adenosine in control and CKD. (LC-MS-MS based proteomic analyses of left ventricular tissue was performed. Paraffn embedded myocardium and kidney tissues were histologically examined for interstitial fibrosis and oxidative stress. Results: Renal embolization resulted in mild chronic kidney injury as evidenced by increased fibrosis staining and urinary NGAL (24±4 vs 48±9 pg/ml). Hemodynamic parameters showed increased wall stress (20±3 vs 40±7 ml*mmHg/g) as well as increase of end diastolic volume (1.5±0.1 vs 1.9±0.1 ml/kg) indicating dilation of the left ventricle in CKD. Quantitative proteomic analysis detected significant differences in the left ventricle of the controls when compared to those with CKD and STRING pre-ranked functional analysis showed enrichments in pathways related to reactive oxygen species. Furthermore, we detected alterations of pathways associated with remodeling of the extracellular matrix (ECM), Oxidative stress and ECM remodeling were confirmed histologically. Interestingly, in CKD we found that mitochondrial proteins like cytochrome oxidase (MT-CO2) and ATP5 synthase subunit were downregulated suggesting mitochondrial dysfunction which was associated with higher basal coronary blood flow (0.48±0.05 vs 0.87±0.11 ml/min/g). Conclusions: Our proteomic data in swine model provides strong evidence that mild CKD can induce early alterations in mitochondrial function along with oxidative stress and ECM remodeling. Thus, we aim to further our understanding by applying our proteomic findings in conjunction with functional hemodynamic data in this swine model of cardiorenal disease. German Center for Cardiovascular Research (DZHK81Z0600207 to D.M. and P.S.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Investigating Sea-Level Brain Predictors for Acute Mountain Sickness: A Multimodal MRI Study before and after High-Altitude Exposure.

Acute mountain sickness is a series of brain-centered symptoms that occur when rapidly ascending to high altitude. Predicting acute mountain sickness before high-altitude exposure is crucial for protecting susceptible individuals. The present study aimed to evaluate the feasibility of predicting acute mountain sickness after high-altitude exposure by using multimodal brain MR imaging features measured at sea level. We recruited 45 healthy sea-level residents who flew to the Qinghai-Tibet Plateau (3650 m). We conducted T1-weighted structural MR imaging, resting-state fMRI, and arterial spin-labeling perfusion MR imaging both at sea level and high altitude. Acute mountain sickness was diagnosed for 5 days using Lake Louise Scoring. Logistic regression with Least Absolute Shrinkage and Selection Operator logistic regression was performed for predicting acute mountain sickness using sea-level MR imaging features. We also validated the predictors by using MR images obtained at high altitude. The incidence rate of acute mountain sickness was 80.0%. The model achieved an area under the receiver operating characteristic curve of 86.4% (sensitivity = 77.8%, specificity = 100.0%, and P < .001) in predicting acute mountain sickness At sea level, valid predictors included fractional amplitude of low-frequency fluctuations (fALFF) and degree centrality from resting-state fMRI, mainly distributed in the somatomotor network. We further learned that the acute mountain sickness group had lower levels of fALFF in the somatomotor network at high altitude, associated with smaller changes in CSF volume and higher Lake Louise Scoring, specifically relating to fatigue and clinical function. Our study found that the somatomotor network function detected by sea-level resting-state fMRI was a crucial predictor for acute mountain sickness and further validated its pathophysiologic impact at high altitude. These findings show promise for pre-exposure prediction, particularly for individuals in need of rapid ascent, and they offer insight into the potential mechanism of acute mountain sickness.

Unraveling interindividual variation of trimethylamine N-oxide and its precursors at the population level.

Trimethylamine N-oxide (TMAO) is a circulating microbiome-derived metabolite implicated in the development of atherosclerosis and cardiovascular disease (CVD). We investigated whether plasma levels of TMAO, its precursors (betaine, carnitine, deoxycarnitine, choline), and TMAO-to-precursor ratios are associated with clinical outcomes, including CVD and mortality. This was followed by an in-depth analysis of their genetic, gut microbial, and dietary determinants. The analyses were conducted in five Dutch prospective cohort studies including 7834 individuals. To further investigate association results, Mendelian Randomization (MR) was also explored. We found only plasma choline levels (hazard ratio [HR] 1.17, [95% CI 1.07; 1.28]) and not TMAO to be associated with CVD risk. Our association analyses uncovered 10 genome-wide significant loci, including novel genomic regions for betaine (6p21.1, 6q25.3), choline (2q34, 5q31.1), and deoxycarnitine (10q21.2, 11p14.2) comprising several metabolic gene associations, for example, CPS1 or PEMT. Furthermore, our analyses uncovered 68 gut microbiota associations, mainly related to TMAO-to-precursors ratios and the Ruminococcaceae family, and 16 associations of food groups and metabolites including fish-TMAO, meat-carnitine, and plant-based food-betaine associations. No significant association was identified by the MR approach. Our analyses provide novel insights into the TMAO pathway, its determinants, and pathophysiological impact on the general population.

Indicators of intracardiac haemodynamics in patients with chronic coronary syndrome with concomitant coronavirus disease (COVID-19)

the nature of cardiovascular damage caused by SARS-CoV-2 coronavirus infection due to acute severe respiratory distress syndrome is associated with high mortality. However, the pathophysiological impact of COVID-19 (C19) on intracardiac haemodynamics remains unknown. The aim of our study was to evaluate intracardiac haemodynamics in patients with chronic coronary syndrome (CCS) in combination with coronavirus disease (COVID-19). The prospective study included: 30 patients with CAD with a negative PCR test for COVID-19 (1Agroup), 38 patients with CAD with a positive PCR test for COVID-19 (1Bgroup), of whom 12 were diagnosed with an increase in the level of troponin I (1B/T+), 26 patients had a normal level of troponin I (1B/T-). As a comparison, 30 patients with COVID-19 with PCR(+), without signs of CAD - group 2, as well as 30 healthy volunteers without signs of CAD and with negative PCR were studied. Clinical and laboratory data, treatment, and intracardiac haemodynamics were assessed by echocardiography in all groups. The left ventricular myocardial mass index, left ventricular end-diastolic volume, right ventricular size, and pulmonary artery systolic pressure were highest in the group of CAD with COVID-19 with a positive troponin test (1B/T+), compared with the (1B/T-) group, also in the (1B/T+) group, the ejection fraction and total longitudinal strain by speckle tracking were lower than in the (1B/T-) group. When compared with group 1A, LVEF was lower in the (1B/T+) group, and STla was higher in the (1B/T+) group. When comparing the indicators of group 1A and (1B/T-), a similar pattern of changes in intracardiac haemodynamics was noted: LV myocardial mass index, right ventricular diameter, systolic pressure in the pulmonary artery were higher, while longitudinal strain was slightly lower in (1B/T-) than in group 1A. When comparing the echocardiography parameters of patients in the (1B/T+) subgroup with group 2, larger left ventricular end-diastolic volume, left atrium, left ventricular myocardial mass index were found in (1B/T+), but the ejection fraction was lower in (1B/T+), while the right ventricular size and pulmonary artery systolic pressure were slightly higher than in group 2. In the subgroup (1B/T-), the nature of the changes was similar, but the size of the RV and PASP did not differ from those in group 2. The echocardiographic parameters of group 1A differed from those of group 2 by higher values of LVEF, LVEDV, LVMMS and lower EF, but the size of the RV and PASP were larger in patients with COVID-19. Cardiac damage associated with SARS-CoV-2 in patients with concomitant CAD has an effect on the myocardium, which is manifested in an increase in left ventricular EF due to increased preload, at the expense of a decrease in global strain and systolic function of the LV myocardium, due to the direct cytotoxic effect of SARS-CoV-2 on the one hand, and destabilisation of existing atherosclerotic plaques, as well as hypoxia and worsening of endothelial dysfunction on the other. An increase in the size of the right ventricle is associated with an increase in peripheral vascular resistance in the small circle as a consequence of increased systolic pressure in the pulmonary artery in covidassociated pneumonia. The impact of SARS-CoV-2 infection on the heart is associated with cardiovascular risk factors and the severity of the inflammatory process.

Hibifolin protected pro-inflammatory response and oxidative stress in LPS-induced acute lung injury through antioxidative enzymes and the AMPK2/Nrf-2 pathway.

ALI is a grave medical ailment that manifests as abrupt inflammation of the lungs and diminished oxygen levels. It poses a considerable challenge to the medical fraternity, with elevated rates of morbidity and mortality. Our research endeavors to investigate the potential of hibifolin, a flavonoid glucuronide, imbued with potent antioxidant properties, and its molecular mechanism to combat LPS-induced ALI in mice. The study utilized ICR mice to create an ALI model induced by LPS. Prior to LPS administration, hibifolin was given at 10, 30, or 50 mg/kg, or dexamethasone was given at 1 mg/kg to assess its preventative impact. Changes in lung tissue, pulmonary edema, and lipid peroxidation were analyzed using H&E stain assay, lung wet/dry ratio assay, and MDA formation assay, respectively. Activity assay kits were used to measure MPO activity and antioxidative enzymes (SOD, CAT, GPx) activity in the lungs. Western blot assay was used to determine the phosphorylation of Nrf-2 and AMPK2 in the lungs. Hibifolin demonstrated a concentration-dependent improvement in LPS-induced histopathologic pulmonary changes. This treatment notably mitigated pulmonary edema, lipid peroxidation, and MPO activity in ALI mice. Additionally, hibifolin successfully restored antioxidative enzyme activity in the lungs of ALI mice. Moreover, hibifolin effectively promoted Nrf-2 phosphorylation and reinstated AMPK2 phosphorylation in the lungs of ALI mice. The results indicate that hibifolin could effectively alleviate the pathophysiological impact of LPS-induced ALI. This is likely due to its antioxidative properties, which help to restore antioxidative enzyme activity and activate the AMPK2/Nrf2 pathway. These findings are valuable in terms of enhancing our knowledge of ALI treatment and pave the way for further investigation into hibifolin as a potential therapeutic option for lung injuries.

Systemic Vascular Resistance and Myocardial Work Analysis in Hypertrophic Cardiomyopathy and Transthyretin Cardiac Amyloidosis with Preserved Left Ventricular Ejection Fraction.

Background: The pathophysiological impact of systemic vascular resistance (SVR) and pressure-strain loop-derived global myocardial work index (GWI) in hypertrophic cardiomyopathy (HCM) and transthyretin cardiac amyloidosis (ATTR) has been randomly investigated. Methods: Both SVR and GWI were assessed in outpatients consecutively referred at two Italian cardiology departments for heart failure with preserved left ventricular ejection fraction (LVEF), affected by either nonobstructive HCM or wild-type ATTR. Based on relevant cross-tabulations, the patients were gathered into 4 functional classes according to cut-off values of 1440 dyne/s/cm-5 for SVR, and 1576 mm Hg% for GWI, as suggested by previous studies. Results: A total of 60 patients, 30 in each group, aged 61 ± 16 years, with 78% males, were studied. HCM patients were younger than those with ATTR and in a better clinical condition (23% HCM vs. 77% ATTR were NYHA class II-III, p < 0.001). Overall, 51 patients (85%) showed a high SVR, 21/30 HCM (70%), and 30 ATTR (100%) (p < 0.005). Both SVR and GWI (expressions of ventricular-arterial coupling) were impaired in 43% of HCM patients (showing greater LV concentric hypertrophy) and 93% of ATTR patients (in advanced NYHA functional class) (p < 0.001). Conclusions: A substantial percentage of present study population showed impaired SVR and/or GWI, despite preserved LVEF. The proposed classification may shed further light on the pathophysiological and clinical characteristics of such hypertrophic phenotypes.

Alteration of LARGE1 abundance in patients and a mouse model of 5q-associated spinal muscular atrophy

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by recessive pathogenic variants affecting the survival of motor neuron (SMN1) gene (localized on 5q). In consequence, cells lack expression of the corresponding protein. This pathophysiological condition is clinically associated with motor neuron (MN) degeneration leading to severe muscular atrophy. Additionally, vulnerability of other cellular populations and tissues including skeletal muscle has been demonstrated. Although the therapeutic options for SMA have considerably changed, treatment responses may differ thus underlining the persistent need for validated biomarkers. To address this need and to identify novel marker proteins for SMA, we performed unbiased proteomic profiling on cerebrospinal fluid derived (CSF) from genetically proven SMA type 1–3 cases and afterwards performed ELISA studies on CSF and serum samples to validate the potential of a novel biomarker candidates in both body fluids. To further decipher the pathophysiological impact of this biomarker, immunofluorescence studies were carried out on spinal cord and skeletal muscle derived from a 5q-SMA mouse model. Proteomics revealed increase of LARGE1 in CSF derived from adult patients showing a clinical response upon treatment with nusinersen. Moreover, LARGE1 levels were validated in CSF samples of further SMA patients (type 1–3) by ELISA. These studies also unveiled a distinguishment between groups in improvement of motor skills: adult patients do present with lowered level per se at baseline visit while no elevation upon treatment in the pediatric cohort can be observed. ELISA-based studies of serum samples showed no changes in the pediatric cohort but unraveled elevated level in adult patients responding to future intervention with nusinersen, while non-responders did not show a significant increase. Additional immunofluorescence studies of LARGE1 in MN and skeletal muscle of a SMA type 3 mouse model revealed an increase of LARGE1 during disease progression. Our combined data unraveled LARGE1 as a protein dysregulated in serum and CSF of SMA-patients (and in MN and skeletal muscle of SMA mice) holding the potential to serve as a disease marker for SMA and enabling to differentiate between patients responding and non-responding to therapy with nusinersen.

Human serum-derived α-synuclein auto-antibodies mediate NMDA receptor-dependent degeneration of CNS neurons

BackgroundPresence of autoantibodies against α-synuclein (α-syn AAb) in serum of the general population has been widely reported. That such peripheral factors may be involved in central nervous system pathophysiology was demonstrated by detection of immunoglobulins (IgGs) in cerebrospinal fluid and brain of Parkinson’s disease (PD) patients. Thus, blood-borne IgGs may reach the brain parenchyma through an impaired blood-brain barrier (BBB).FindingsThe present study aims to evaluate the patho-physiological impact of α-syn AAbs on primary brain cells, i.e., on spontaneously active neurons and on astrocytes. Exposure of neuron-astrocyte co-cultures to human serum containing α-syn AAbs mediated a dose-dependent reduction of spontaneous neuronal activity, and subsequent neurodegeneration. Removal specifically of α-syn AAbs from the serum prevented neurotoxicity, while purified, commercial antibodies against α-syn mimicked the neurodegenerative effect. Mechanistically, we found a strong calcium flux into neurons preceding α-syn AAbs-induced cell death, specifically through NMDA receptors. NMDA receptor antagonists prevented neurodegeneration upon treatment with α-syn (auto)antibodies. α-syn (auto)antibodies did not affect astrocyte survival. However, in presence of α-syn, astrocytes reacted to α-syn antibodies by secretion of the chemokine RANTES.ConclusionThese findings provide a novel basis to explain how a combination of BBB impairment and infiltration of IgGs targeting synuclein may contribute to neurodegeneration in PD and argue for caution with α-syn immunization therapies for treatment of PD.

Crosstalk with renal proximal tubule cells drives acidosis-induced inflammatory response and dedifferentiation of fibroblasts via p38-singaling

BackgroundTubulointerstitial kidney disease associated microenvironmental dysregulation, like acidification, inflammation and fibrosis, affects tubule cells and fibroblasts. Micromilieu homeostasis influences intracellular signaling and intercellular crosstalk. Cell–cell communication in turn modulates the interstitial microenvironment. We assessed the impact of acidosis on inflammatory and fibrotic responses in proximal tubule cells and fibroblasts as a function of cellular crosstalk. Furthermore, cellular signaling pathways involved were identified.MethodsHK-2 (human proximal tubule) and CCD-1092Sk (human fibroblasts), in mono and coculture, were exposed to acidic or control media for 3 or 48 h. Protein expression of inflammation markers (TNF, TGF-ß and COX-2), dedifferentiation markers (N-cadherin, vinculin, ß-catenin and vimentin), fibrosis markers (collagen III and fibronectin) and phospho- as well as total MAPK levels were determined by western blot. Secreted collagen III and fibronectin were measured by ELISA. The impact of MAPK activation was assessed by pharmacological intervention. In addition, necrosis, apoptosis and epithelial permeability were determined.ResultsIndependent of culture conditions, acidosis caused a decrease of COX-2, vimentin and fibronectin expression in proximal tubule cells. Only in monoculture, ß-Catenin expression decreased and collagen III expression increased in tubule cells during acidosis. By contrast, in coculture collagen III protein expression of tubule cells was reduced. In fibroblasts acidosis led to an increase of TNF, COX-2, vimentin, vinculin, N-cadherin protein expression and a decrease of TGF-ß expression exclusively in coculture. In monoculture, expression of COX-2 and fibronectin was reduced. Collagen III expression of fibroblasts was reduced by acidosis independent of culture conditions.In coculture, acidosis enhanced phosphorylation of ERK1/2, JNK1/2 and p38 transiently in proximal tubule cells. In fibroblasts, acidosis enhanced phosphorylation of p38 in a sustained and very strong manner. ERK1/2 and JNK1/2 were not affected in fibroblasts. Inhibition of JNK1/2 and p38 under coculture conditions reduced acidosis-induced changes in fibroblasts significantly.ConclusionsOur data show that the crosstalk between proximal tubule cells and fibroblasts is crucial for acidosis-induced dedifferentiation of fibroblasts into an inflammatory phenotype. This dedifferentiation is at least in part mediated by p38 and JNK1/2. Thus, cell–cell communication is essential for the pathophysiological impact of tubulointerstitial acidosis.

Pathogenesis of pelvic endometriomas: Lessons learned from surgical management

Background: There is a relatively poor understanding of the pathogenesis of pelvic endometriomas, as is the whole subject of endometriosis. The pathophysiological basis of endometriosis remains enigmatic, especially for endometriomas. Diagnostic acumen has remained low; therefore, a standardized objective treatment approach is elusive. &#x0D; Objective: To elucidate possible pathogenetic processes and collate them with clinical and treatment outcomes.&#x0D; Results: This is a relatively neglected pathologic process that affects the ovary. It is a composite component of pelvic peritoneal endometriosis with a heavier predilection toward the ovary as the target organ. Infertility is a very common outcome because of reduced ovarian reserve and the inflammatory processes that often accompany the pelvic peritoneal component. Endometriomas are very common, as reflected by the finding that 17-44% of patients with ovarian cysts have endometriomas, and endometriomas constitute 35% of benign ovarian cysts. &#x0D; Conclusion: The propensity of the condition, coupled with the pathophysiological impact, dictates a need for a better understanding of pathogenesis and conservative treatment that targets fertility preservation.

Obesity hypoventilation syndrome, literature review.

Obesity is a global health concern that has been increasing over the years, and it is associated with several pathophysiological changes affecting the respiratory system, including alveolar hypoventilation. Obesity hypoventilation syndrome (OHS) is one of the six subtypes of sleep-hypoventilation disorders. It is defined as the presence of obesity, chronic alveolar hypoventilation leading to daytime hypercapnia and hypoxia, and sleep-disordered breathing. The existence of a sleep disorder is one of the characteristics that patients with OHS present. Among them, 90% of patients have obstructive sleep apnea (OSA), and the remaining 10% of patients with OHS have non-obstructive sleep hypoventilation without OSA or with mild OSA. This review aims to provide a comprehensive understanding of the epidemiological and pathophysiological impact of OHS and to highlight its clinical features, prognosis, and severity, as well as the available treatment options.

Crosstalk between CD8+ T cells and mesenchymal stromal cells in intestine homeostasis and immunity.

The intestine represents the most complex cellular network in the whole body. It is constantly faced with multiple types of immunostimulatory agents encompassing from food antigen, gut microbiome, metabolic waste products, and dead cell debris. Within the intestine, most T cells are found in three primary compartments: the organized gut-associated lymphoid tissue, the lamina propria, and the epithelium. The well-orchestrated epithelial-immune-microbial interaction is critically important for the precise immune response. The main role of intestinal mesenchymal stromal cells is to support a structural framework within the gut wall. However, recent evidence from stromal cell studies indicates that they also possess significant immunomodulatory functions, such as maintaining intestinal tolerance via the expression of PDL1/2 and MHC-II molecules, and promoting the development of CD103+ dendritic cells, and IgA+ plasma cells, thereby enhancing intestinal homeostasis. In this review, we will summarize the current understanding of CD8+ T cells and stromal cells alongside the intestinal tract and discuss the reciprocal interactions between T subsets and mesenchymal stromal cell populations. We will focus on how the tissue residency, migration, and function of CD8+ T cells could be potentially regulated by mesenchymal stromal cell populations and explore the molecular mediators, such as TGF-β, IL-33, and MHC-II molecules that might influence these processes. Finally, we discuss the potential pathophysiological impact of such interaction in intestine hemostasis as well as diseases of inflammation, infection, and malignancies.

Reparative potential of bone tissue and associated influencing factors

The aim of the sthudy. To study the influence of general and local factors on the regenerative potential of bone tissue to optimize augmentation mechanisms in the treatment of jaw atrophy. The influence of general and local factors on the regenerative potential of the bone during the augmentation operation of the alveolar process (part) of the jaw in 68 patients was studied. The survival rate of dental implants and the incidence of complications after completion of dental rehabilitation in the long-term follow-up period (more than 5 years) were evaluated. 18 indicators were studied, which were evaluated by qualitative and quantitative methods. The study of the effect of indicators on regeneration was carried out using an accurate Fischer test for conjugacy tables. The assessment of the strength of the influence was calculated as the ratio of the chances of developing an unfavorable outcome of bone grafting and dental implantation. He highest chances of developing adverse outcomes were found in smoking patients with diabetes mellitus, high body mass index, low survival of bone walls, severe bone atrophy (5.6 and higher class according to Cawood & Howell), three-dimensional bone defect, in the absence of 3 or more bone walls, the presence of subcompensated and decompensated psychological state the patient. In the course of histological examination, the influence of these factors on the mechanisms of reparative osteogenesis morphologically manifested a lower degree of progress of regenerative processes and a lower degree of maturity of bone tissue. To reduce the chances of developing an unfavorable outcome, in the presence of negative general and local factors, it is not advisable to use dental implantation simultaneously with bone augmentation procedures. In order to reduce the pathophysiological impact of negative factors during sinus lifting, increase the proportion of autosteal material for potentiating the metabolic activity of bone tissue, as well as prescribe antioxidant, antihypoxant and membrane stabilizing therapy before surgery and in the early postoperative period.