MBP Levels Research Articles

Remote ischemic preconditioning plays a neuroprotective role in cerebral ischemia-reperfusion mice by inhibiting mitophagy

Remote ischemic preconditioning (RIPC) represents a clinically feasible method for safeguarding vital organs against ischemic injury. However, its specific role in cerebral ischemia-reperfusion (I/R) injury remains to be definitively elucidated. In this study, we investigated the neuroprotective effects of RIPC on mice at 7 days post-cerebral I/R and its involvement in mitophagy and mitochondrial dysfunction. Cerebral I/R led to impaired brain function, as well as structural and functional damage to mitochondria. Notably, RIPC treatment ameliorated the neurological dysfunction induced by cerebral I/R. Compared with the I/R group, the expression levels of NeuN, MBP, PDH, and Tom20 were significantly elevated in the RIPC + I/R group. Furthermore, mitochondria in the RIPC + I/R group exhibited more intact structure compared to those in the I/R group. In mice subjected to I/R injury, RIPC treatment markedly increased ATP content, ADP content, TAN level and glucose uptake while upregulating expression levels of Parkin, Pink1 and P62 proteins; it also reduced both the volume of ischemic foci and the number of mitochondrial autophagosomes along with decreasing LC3B II/I ratio. In conclusion, RIPC may exert a neuroprotective role by inhibiting excessive mitophagy during subacute stages following an ischemic stroke.

DHA and EPA alleviate depressive-like behaviors in chronic sleep-deprived mice: Involvement of iron metabolism, oligodendrocyte-lipids peroxidation and the LCN2-NLRP3 signaling axis

Mounting evidence suggests that eicosapentaenoic acid (EPA) is superior to docosahexaenoic acid (DHA) in the treatment of depression, but the underlying mechanisms remain elusive. In the present study, the effect of DHA and EPA on depressive-like behaviors was investigated in chronic sleep-deprived (CSD) mice. Following the administration of EPA or DHA, investigations were conducted on depression-like behavior, myelin damage, iron dyshomeostasis, oligodendrocyte-lipids peroxidation, and neuroinflammation. As anticipated, EPA was more effective than DHA in ameliorating CSD-induced depression by increasing center preference and immobility time and concurrently shortening immobility latency. Both DHA and EPA mitigated myelin damage with EPA demonstrating superior benefits characterized by higher levels of Olig2, MBP, and FTH, as well as decreased oligodendrocyte-lipid peroxidation. The inhibition of activated astrocytes and the associated LCN2-NLRP3 signaling pathway was observed following both EPA and DHA supplementation. However, the inhibitory effect was more pronounced with EPA. Additionally, EPA outperformed DHA in mitigating microglial activation and M1/M2 polarization imbalance. Overall, this present study provides valuable insights into the anti-depressive effects of DHA and EPA, highlighting their role in inhibiting oligodendrocyte-lipids peroxidation and the LCN2-NLRP3 axis and corroborating the superiority of EPA in mediating antidepressant effects.

Inhibition of GZMB activity ameliorates cognitive dysfunction by reducing demyelination in diabetic mice

BackgroundDiabetic cognitive dysfunction (DCD) has attracted increased attention, but its precise mechanism remains to be explored. Oligodendrocytes form myelin sheaths that wrap around axons. Granzyme B (GZMB) can cause axonal degeneration of the central nervous system. However, the role of GZMB in diabetic cognitive dysfunction (DCD) has not been reported. This study aimed to investigate whether GZMB promotes demyelination and participates in DCD by regulating the endoplasmic reticulum stress function of oligodendrocytes. MethodsStreptozotocin was injected intraperitoneally to establish a diabetic model in C57BL/6 mice. The mice were randomly divided into four groups: control group, diabetic group, diabetic + SerpinA3N group, and diabetic + saline treatment group. We performed the Morris water maze test to assess the learning and memory abilities of the mice. An immunofluorescence assay was performed to detect the expression sites of GZMB and OLIG2 in the hippocampal CA1 region. Luxol Fast Blue staining and electron microscopy were performed to detect the myelin number and myelin plate densities. Immunohistochemistry was used to detect the expression levels of MBP and CNPase. Protein blotting was used to assess the expression levels of GZMB, PERK, p-PERK, eIF2α, p-eIF2α, NLRP3, Caspase-1, GSDMD-N, IL-1β, and IL-18 as well as MBP and CNPase. ResultsThe GZMB inhibitor SerpinA3N reduces escape latency and increases the traversing platforms and residence time in the target area, improving DCD in mice. It also reduces endoplasmic reticulum stress in hippocampal oligodendrocytes and focal prolapse, further promoting MBP and CNPase expression and reducing demyelination. ConclusionsOur findings suggest that inhibition of GZMB activity modulates oligodendrocyte endoplasmic reticulum stress and pyroptosis, reduces demyelination, and ameliorates diabetes-related cognitive impairment.

Association of phthalates exposure and sex steroid hormones with late-onset preeclampsia: a case-control study

BackgroundThis study aimed to investigate the relationship between phthalates exposure and estrogen and progesterone levels, as well as their role in late-onset preeclampsia.MethodsA total of 60 pregnant women who met the inclusion and exclusion criteria were recruited. Based on the diagnosis of preeclampsia, participants were divided into two groups: normotensive pregnant women (n = 30) and pregnant women with late-onset preeclampsia (n = 30). The major metabolites of phthalates (MMP, MEP, MiBP, MBP, MEHP, MEOHP, MEHHP) and sex steroid hormones (estrogen and progesterone) were quantified in urine samples of the participants.ResultsNo significant differences were observed in the levels of MMP, MEP, MiBP, MBP, MEHP, MEOHP, and MEHHP between women with preeclampsia and normotensive pregnant women (P > 0.05). The urinary estrogen showed a negative correlation with systolic blood pressure (rs= -0.46, P < 0.001) and diastolic blood pressure (rs= -0.47, P < 0.001). Additionally, the urinary estrogen and progesterone levels were lower in women with preeclampsia compared to those in normotensive pregnant women (P < 0.05). After adjusting for confounding factors, we observed a significant association between reduced urinary estrogen levels and an increased risk of preeclampsia (aOR = 0.09, 95%CI = 0.02–0.46). Notably, in our decision tree model, urinary estrogen emerged as the most crucial variable for identifying pregnant women at a high risk of developing preeclampsia. A positive correlation was observed between urinary progesterone and MEHP (rs = 0.36, P < 0.05) in normotensive pregnant women. A negative correlation was observed between urinary estrogen and MEP in pregnant women with preeclampsia (rs= -0.42, P < 0.05).ConclusionsPhthalates exposure was similar in normotensive pregnant women and those with late-onset preeclampsia within the same region. Pregnant women with preeclampsia had lower levels of estrogen and progesterone in their urine, while maternal urinary estrogen was negatively correlated with the risk of preeclampsia and phthalate metabolites (MEP).Trial registrationRegistration ID in Clinical Trials: NCT04369313; registration date: 30/04/2020.

Effects of apelin on neonatal brain neurogenesis in L-NAME-induced maternal preeclampsia

The aim of this study was to investigate the possible protective effects of apelin, which is known to have antioxidant and anti-inflammatory effects, on changes in neurogenesis in newborns of pregnant rats with L-NAME-induced preeclampsia. Wistar albino female rats were divided into four experimental groups: Control, Apelin, Preeclampsia and Preeclampsia + Apelin. Blood pressure was measured on the 5th, 11th and 17th days of gestation, urine protein was analyzed from urine samples collected for 24 h on the 6th, 12th and 18th days and serum creatinine was analyzed from serum samples. Maternal kidney and placenta tissues were obtained to establish the preeclampsia model, and neonatal brain tissues including the cortex, hippocampus and cerebellum regions were obtained to investigate neurogenesis and examined by histological and immunohistochemical methods. The number of newborns, body weight and brain weight of the newborns were measured. eNOS, IL-10, nNOS and NO levels in the brain analyzed via ELISA. Mean arterial pressure, urine protein and serum creatinine increased in the preeclampsia. Newborn weight decreased in the Preeclampsia group, the values in the Preeclampsia + Apelin group were closer to the Control and Apelin groups. In the Preeclampsia group, edema and dilatation in the proximal and distal tubules of kidneys, perivillous fibrin deposition and increase in syncytial nodules of placenta were observed. VEGF immunoreactivity decreased and iNOS immunoreactivity increased in both kidney and placenta. In neonatal brain tissue examinations, cytotoxic edema accompanied by thinning of cortex, delayed migration and lower cell counts in the hippocampus, and increase in intercellular spaces and EGL thickening in the cerebellum were observed in the preeclampsia. Expression of NeuN, GFAP, MBP, IL-10, eNOS, nNOS and NO levels decreased, whereas expression of Iba-1 increased in the preeclampsia. In the Preeclampsia + Apelin group, these findings were similar to the Control and Apelin groups. Apelin administration was found to be beneficial for preventing the adverse consequences of preeclampsia, but further experimental and clinical studies are needed to better understand these effects.

Comparison of the Expression Levels of MBP and GFAP Following the Induction of Neuronal Demyelination with Ethidium Bromide in Male and Female Rats

Comparison of the Expression Levels of MBP and GFAP Following the Induction of Neuronal Demyelination with Ethidium Bromide in Male and Female Rats

Differential Effect of Chronic Morphine on Neuronal Degeneration in Male vs. Female Mice.

Opioid abuse in the United States has been increasing at an alarming rate over the past 20 years. Sex differences are documented for the rates of opioid-related overdoses, abuse patterns, and drug-induced physiological effects. In our previous study, we demonstrated that chronic oxycodone administration in young female rats is associated with neurodegeneration in the brain. Males and females are susceptible to neurodegenerative diseases via differing mechanisms. To investigate whether opioid exposure affects males and females differently, we treated young mice with chronic morphine. We observed that females had stronger antinociceptive responses to acute morphine and showed a delayed development of tolerance. Males had a higher basal Bax level in the brain that correlated with a higher number of apoptotic cells. Morphine increased Bax levels in both males and females without affecting the numbers of apoptotic cells. Morphine increased activated caspase 3 in axons and increased the MBP level in plasma only in females, suggesting a demyelination process. Our data suggest that males are protected from demyelination by having a higher basal BDNF level. Altogether, our results suggest that males and females have different molecular signaling underlying their patterns in the development of morphine tolerance and drug-induced neuronal degeneration.

Exposure to the pharmaceutical buspirone alters locomotor activity, anxiety-related behaviors, and transcripts related to serotonin signaling in larval zebrafish (Danio rerio)

Buspirone is a pharmaceutical used to treat general anxiety disorder by acting on the dopaminergic and serotoninergic system. Buspirone, like many human pharmaceuticals, has been detected in municipal wastewater; however, the environmental exposure risks are unknown for this psychoactive compound. We studied the effects of buspirone on the behavior of zebrafish, focusing on locomotor and anxiolytic behavior. We also measured transcripts associated with oxidative stress, neurotoxicity, and serotonin signaling to identify potential mechanisms underlying the behavioral changes. Concentrations ranged from environmentally relevant (nM) to physiologically active concentrations typical of human pharmaceuticals (μM). Buspirone treatment did not impact survival, nor did it induce deformities in zebrafish treated for 7 days up to 10 μM. There was a positive relationship between locomotor activity and buspirone concentration in dark periods of the visual motor response test. In the light-dark preference test, both the average time per visit to the dark zone and the percent cumulative duration in the dark zone were increased by 1 μM buspirone. Transcript levels of ache, manf, and mbp were decreased in larvae, while the expression of gap43 was increased following exposure to buspirone, indicating potential neurotoxic effects. There was also reduced expression of serotonin-related genes encoding receptors, transporters, and biosynthesis enzymes (i.e., 5ht1aa, sertb, and tph1a). These data increase understanding of the behavioral and molecular responses in zebrafish following waterborne exposure to neuroactive pharmaceuticals like buspirone.

Altered serum levels of neuronal proteins and antibodies to them in occupational diseases of the nervous system.

Aclinical and immunological examination of men with occupational pathology, including vibration disease (VD), occupational sensorineural hearing loss (SHL), and chronic mercury intoxication (CMI), was carried out. The comparison group consisted of men comparable in age and total work experience. Serum concentrations of neurotrophins (S100β, MBP, BDNF) and antibodies (ABs) to S100β and MBP proteins were determined by enzyme-linked immunosorbent assay. An increase in the level of the S100β protein was shown in CMI, VD, and a tendency for its increase was found in SHL. In parallel, an increase in AB to the S100β protein in VD and SHL and a decrease in AB in CMI were noted. A comparative assessment of MBP levels indicated a pronounced increase in its serum concentrations in patients with CMI and VD versus the comparison group. At the same time, an increase in the level of serum ABs to MBP in individuals with VD and SHL, and a decrease in patients with CMI were noted. In patients with CMI, a significant decrease in the BDNF concentration was found, while in SHL and VD, no statistically significant differences were found in comparison with the comparison group. The results obtained confirm importance of assessing serum concentrations of neurotrophic proteins and ABs to them in the case of occupational damage to the nervous system caused by exposure to physical and chemical factors.

DHA and EPA Alleviate Epileptic Depression in PTZ-Treated Young Mice Model by Inhibiting Neuroinflammation through Regulating Microglial M2 Polarization and Improving Mitochondrial Metabolism.

Depression is the most common complication of childhood epilepsy, leading to a poor prognosis for seizure control and poor quality of life. However, the molecular mechanisms underlying epileptic depression have not been completely elucidated. Increasing evidence suggests that oxidative stress and neuroinflammation are major contributors to depression. The positive effects of dietary supplementation with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on depression have been previously reported. However, knowledge regarding the effects of EPA and DHA in managing depressive symptoms in pediatric patients with epilepsy is limited. Therefore, this study aims to investigate the effects of EPA and DHA on epileptic depression in a pentylenetetrazole (PTZ)-treated young mouse model. Three-week-old mice were fed a DHA- or EPA-enriched diet for 21 days and treated with PTZ (35 mg/kg, i.p.) every other day for a total of 10 times. EPA was more effective than DHA at alleviating PTZ-induced depressive symptoms. Pathological results revealed that DHA and EPA significantly improved neuronal degeneration in the hippocampus. Analysis of the mechanism revealed that DHA and EPA mitigated PTZ-induced myelin damage by increasing the protein levels of CNPase, Olig2, and MBP. Furthermore, both DHA and EPA reduced neuroinflammation by promoting microglial M2 polarization and suppressing the LCN2-NLRP3 inflammasome pathway. Notably, EPA polarized microglia towards the M2 phenotype. In addition, DHA and EPA decreased oxidative stress by inhibiting NOX2 and enhancing mitochondrial metabolism through the increased expression of mitochondrial respiratory chain complex I-V proteins. These findings suggest that DHA and EPA can be used as effective interventions to improve depression in children with epilepsy, with EPA being a particularly favorable option.

Serum Levels of S100B Protein and Myelin Basic Protein as a Potential Biomarkers of Recurrent Depressive Disorders.

Nowadays, nervous tissue damage proteins in serum are considered promising drug targets and biomarkers of Mood Disorders. In a cross-sectional naturalistic study, the S100B, MBP and GFAP levels in the blood serum were compared between two diagnostic groups (patients with Depressive Episode (DE, n = 28) and patients with Recurrent Depressive Disorder (RDD, n = 21)), and healthy controls (n = 25). The diagnostic value of serum markers was assessed by ROC analysis. In the DE group, we did not find changed levels of S100B, MBP and GFAP compared with controls. In the RDD group, we found decreased S100B level (p = 0.011) and increased MBP level (p = 0.015) in comparison to those in healthy controls. Provided ROC analysis indicates that MBP contributes to the development of a DE (AUC = 0.676; 95%Cl 0.525-0.826; p = 0.028), and S100B and MBP have a significant effect on the development of RDD (AUC = 0.732; 95%Cl 0.560-0.903; p = 0.013 and AUC = 0.712; 95%Cl 0.557-0.867; p = 0.015, correspondingly). The study of serum markers of nervous tissue damage in patients with a current DE indicates signs of disintegration of structural and functional relationships, dysfunction of gliotransmission, and impaired secretion of neurospecific proteins. Modified functions of astrocytes and oligodendrocytes are implicated in the pathophysiology of RDD.

Necrostatin-1s Suppresses RIPK1-driven Necroptosis and Inflammation in Periventricular Leukomalacia Neonatal Mice.

Periventricular leukomalacia (PVL), a predominant form of brain injury in preterm survivors, is characterized by hypomyelination and microgliosis and is also the major cause of long-term neurobehavioral abnormalities in premature infants. Receptor-interacting protein kinase 1 (RIPK1) plays a pivotal role in mediating cell death and inflammatory signaling cascade. However, very little is known about the potential effect of RIPK1 in PVL and the underlying mechanism. Herein, we found that the expression level of RIPK1 was drastically increased in the brain of PVL neonatal mice models, and treatment of PVL neonatal mice with Necrostatin-1s (Nec-1s), an inhibitor of RIPK1, greatly ameliorated cerebral ischemic injury, exhibiting an increase of body weights, reduction of cerebral infarct size, neuronal loss, and occurrence of necrosis-like cells, and significantly improved the long-term abnormal neurobehaviors of PVL. In addition, Nec-1s significantly suppressed hypomyelination and promoted the differentiation of oligodendrocyte precursor cells (OPCs), as demonstrated by the increased expression levels of MBP and Olig2, the decreased expression level of GPR17, a significant increase in the number of CC-1-positive cells, and suppression of myelin ultrastructure impairment. Moreover, the mechanism of neuroprotective effects of Nec-1s against PVL is closely associated with its suppression of the RIPK1-mediated necrosis signaling molecules, RIPK1, PIPK3, and MLKL. More importantly, inhibition of RIPK1 could reduce microglial inflammatory injury by triggering the M1 to M2 microglial phenotype, appreciably decreasing the levels of M1 marker CD86 and increasing the levels of M2 markers Arg1 or CD206 in PVL mice. Taken together, inhibition of RIPK1 markedly ameliorates the brain injury and long-term neurobehavioral abnormalities of PVL mice through the reduction of neural cell necroptosis and reversing neuroinflammation.

Retrospective study on the correlation between serum MIF level and the condition and prognosis of patients with traumatic head injury.

This study aimed to investigate the correlation between serum levels of macrophage migration inhibitory factor (MIF) and the condition and prognosis of patients with traumatic brain injury (TBI). A retrospective study design was used, and the clinical data of 131 TBI patients from February 2019 to January 2022 were analyzed. Patients were divided into mild (13-15 points), moderate (9-12 points), or severe (3-8 points) groups according to their Glasgow Coma Scale (GCS) score after admission. The serum levels of BDNF, MIF, and MBP in the three groups were compared, and their correlation with the severity of TBI was analyzed. Patients were then separated into a good prognosis group (4-5 points) and a poor prognosis group (≤3 points) based on their Glasgow Prognostic Score (GOS) after 6 months of follow-up. The predictive power of serum indexes and combined detection on prognosis was analyzed. Patients were classified into a mild group (n = 63), moderate group (n = 47), and severe group (n = 21) based on their GCS, with a significant difference noted in serum levels of MIF, MBP, and BDNF among patients with different degrees of severity (all P < 0.001). The MIF, MBP, and BDNF levels were lower in the mild group compared to the moderate (all P < 0.001) and severe group (all P < 0.001). Additionally, the MIF and BDNF levels in the moderate group were lower compared to the severe group (P = 0.011, P = 0.002). Patients with mild severity had lower serum MIF, MBP, and BDNF levels than those with other degrees, and these indexes were positively correlated with the severity of TBI (all P < 0.001, r = 0.62, r = 0.48, r = 0.58). Based on the GOS, patients were divided into a good prognosis group (n = 107) and a poor prognosis group (n = 24), with the levels of MIF, MBP, and BDNF in the good prognosis group being significantly lower than those in the poor prognosis group (P < 0.001, P = 0.007, P = 0.003). The area under the curve (AUC) of MIF was higher than that of MBP and BDNF in predicting the prognosis of TBI patients; however, the statistical differences were not significant (MIF vs. MBP, P = 0.239; MIF vs. BDNF, P = 0.211; BDNF vs. MBP, P = 0.899). The center line has a large displacement, CT annular cisterna compression, increased white blood cell count, MBP and BDNF were risk factors for prognosis in TBI patients (P = 0.005, P = 0.001, P = 0.005, P = 0.033, P = 0.044). The serum levels of MIF, MBP, and BDNF in TBI patients were positively correlated with the severity of the disease, and MBP, BDNF levels had predictive value in determining patient prognosis.

Honokiol-Rich Magnolia officinalis Bark Extract Attenuates Trauma-Induced Neuropathic Pain.

Neuropathic pain (NP) affects about 8% of the general population. Current analgesic therapies have limited efficacy, making NP one of the most difficult to treat pain conditions. Evidence indicates that excessive oxidative stress can contribute to the onset of chronic NP and several natural antioxidant compounds have shown promising efficacy in NP models. Thus, this study aimed to investigate the pain-relieving activity of honokiol (HNK)-rich standardized extract of Magnolia officinalis Rehder & E. Wilson bark (MOE), well known for its antioxidant and anti-inflammatory properties, in the spared nerve injury (SNI) model. The molecular mechanisms and efficacy toward neuroinflammation were investigated in spinal cord samples from SNI mice and LPS-stimulated BV2 microglia cells. MOE and HNK showed antioxidant activity. MOE (30 mg/kg p.o.) produced an antiallodynic effect in SNI mice in the absence of locomotor impairment, reduced spinal p-p38, p-JNK1, iNOS, p-p65, IL-1ß, and Nrf2 overexpression, increased IL-10 and MBP levels and attenuated the Notch signaling pathway by reducing Jagged1 and NEXT. These effects were prevented by the CB1 antagonist AM251. HNK reduced the proinflammatory response of LPS-stimulated BV2 and reduced Jagged1 overexpression. MOE and HNK, by modulating oxidative and proinflammatory responses, might represent interesting candidates for NP management.

Hemodynamic parameters in patients undergoing surgery for pheochromocytoma/paraganglioma: a retrospective study

BackgroundPheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors characterized by hemodynamic instability, caused by the paroxysmal release of catecholamines. Patients may develop cardiovascular complications in the perioperative phase due to the massive release of catecholamines, particularly during anesthetic induction and surgical manipulation of the tumor. The aim of this retrospective study was to evaluate the risk factors involved in perioperative hemodynamic instability in patients who underwent surgery for chromaffin tumors.MethodsForty patients (median age 55 [36.50–64.50]) undergone surgery for PHEO/abdominal PGL from January 2011 to December 2016 at the AOU Careggi (Florence, Italy) were retrospectively evaluated. Systolic, diastolic, and mean blood pressure were considered at baseline and during surgery. Patients with blood pressure steadily < 140/90 mmHg before surgery were considered “adequately prepared”. A preoperative therapy with doxazosin, a selective alpha-1 blocker, was started in all patients for at least 14 days prior to the surgery. The presence of hemodynamic instability was reported.ResultsComparing males and females, a significant difference in doxazosin daily dose (p = 0.018), systolic blood pressure (p = 0.048), and in the proportion of adequately prepared patients (p = 0.031) emerged. A positive correlation between preoperative daily dose of doxazosin, tumor size (B = 0.60, p < 0.001), and urinary normetanephrine levels (B = 0.64, p < 0.001) was also observed. Hemodynamic instability occurred in 30.0% of patients. The absence of adequate preparation (p = 0.012) before surgery, urinary normetanephrine levels (NMNur p = 0.039), and surgery time (minutes) (p = 0.021) resulted as risk factors of hemodynamic instability in our series. The use of intraoperative drugs was higher in patients with hemodynamic instability (p < 0.001). A pre-surgical SBP level of > 133 mmHg (OR = 6 CI95% 1.37–26.20, p = 0.017) and an intraoperative SBP and MBP levels of > 127 mmHg (OR = 28.80 CI95% 2.23–371.0, p = 0.010) and > 90 mmHg (OR = 18.90 CI95% 1.82–196.0, p = 0.014), respectively, were identified as effective thresholds to recognize patients at higher risk of HI.ConclusionsA preoperative therapy with alpha-blockers is useful, but not sufficient to avoid surgical risks. Patients with higher pre-surgical levels of NMNur, pre-surgical SBP > 133 mmHg, and/or intraoperative SBP > 127 mmHg and MBP > 90 mmHg, should be carefully monitored. A multidisciplinary approach is indispensable to optimize the management of PHEOs/abdominal PGLs in order to reduce surgical complications.

Association of a mixture of phthalates and phenols with frailty among middle-aged and older adults: A population-based cross-sectional study

BackgroundFrailty is a complex geriatric syndrome caused by degenerative changes in the body or various chronic diseases. The use of personal care and consumer products is associated with a wide range of health outcomes, but its relationship with frailty remains unknown. Therefore, our primary aim was to explore the potential links between exposure to phenols and phthalates, either separately or in combination, and frailty. MethodsThe exposure levels of phthalates and phenols were evaluated through the measurement of metabolites in urine samples. Frailty state was assessed by a 36-item frailty index with values ≥ 0.25 indicating frailty. Weighted logistic regression was used to explore the relationship between individual chemical exposure and frailty. In addition, multi-pollutant strategies (WQS, Qgcomp, BKMR) were used to examine the joint effect of chemical mixture on frailty. A series of subgroup analyses and sensitivity analyses were conducted as well. ResultsIn the multivariate logistic regression model, each unit increase in natural log-transformed BPA (OR: 1.21; 95%CI: 1.04, 1.40), MBP (OR: 1.25; 95%CI: 1.07, 1.46), MBzP (OR: 1.18; 95%CI: 1.03, 1.36), and MiBP (OR: 1.19; 95%CI: 1.03, 1.37) were significantly associated with higher odds of frailty. The results of the WQS and Qgcomp indicated that increasing quartiles of chemical mixture was associated with odds of frailty with ORs of 1.29 (95%CI: 1.01, 1.66) and 1.37 (95%CI: 1.06, 1.76). The weight of MBzP is dominant in both the WQS index and the positive weight of Qgcomp. In the BKMR model, the cumulative effect of chemical mixture was positively correlated with the prevalence of frailty. ConclusionsIn summary, higher levels of BPA, MBP, MBzP, and MiBP are significantly associated with higher odds of frailty. Our study provides preliminary evidence that phenol and phthalate biomarker mixture is positively associated with frailty, with MBzP contributing most to the positive association.

Post-mortem detection of neuronal and astroglial biochemical markers in serum and urine for diagnostics of traumatic brain injury.

Currently available epidemiological data shows that traumatic brain injury (TBI) represents one of the leading causes of death that is associated with medico-legal practice, including forensic autopsy, criminological investigation, and neuropathological examination. Attention focused on TBI research is needed to advance its diagnostics in ante- and post-mortem cases with regard to identification and validation of novel biomarkers. Recently, several markers of neuronal, astroglial, and axonal injury have been explored in various biofluids to assess the clinical origin, progression, severity, and prognosis of TBI. Despite clinical usefulness, understanding their diagnostic accuracy could also potentially help translate them either into forensic or medico-legal practice, or both. The aim of this study was to evaluate post-mortem pro-BDNF, NSE, UCHL1, GFAP, S100B, SPTAN1, NFL, MAPT, and MBP levels in serum and urine in TBI cases. The study was performed using cases (n = 40) of fatal head injury and control cases (n = 20) of sudden death. Serum and urine were collected within ∼ 24h after death and compared using ELISA test. In our study, we observed the elevated concentration levels of GFAP and MAPT in both serum and urine, elevated concentration levels of S100B and SPTAN1 in serum, and decreased concentration levels of pro-BDNF in serum compared to the control group. The obtained results anticipate the possible implementation of performed assays as an interesting tool for forensic and medico-legal investigations regarding TBI diagnosis where the head injury was not supposed to be the direct cause of death.

Role of IL-6 in the immunopathogenesis of mild, moderate and severe TBI

Traumatic brain injury (TBI) results in a significant inflammatory burden that increase the production of inflammatory mediators and biomarkers. The immune system plays a key role in the pathogenesis of traumatic brain injury. Neuroinflammatory mediators released from resident glia (activated microglia and astrocytes) inside the brain recruit immune cells where cytokines are small soluble proteins that confer instructions and mediate communication among immune and non-immune cells. Interleukin-6 (IL-6) is a proinflammatory cytokine known to be elevated after trauma, and a major contributor to the inflammatory response following TBI. Previous studies have investigated associations between IL-6 and outcome following TBI, but to date, studies have been inconsistent in their conclusions. The purpose of the current study was to assessment of cerebrospinal fluid (CSF) interleukin-6 (IL-6) and MBP levels in patients with TBI. Samples of cerebrospinal fluid of 85 patients with TBI were examined. Concentrations IL-6 were measured via xMAP multiplexing technology. The control was the course of CSF in patients with concussion. An increased content was found in all patients with traumatic brain injury: 19.59 pg/mL in the group with mild traumatic brain injury; 103.6 pg/mL in the group with moderate traumatic brain injury; and 2225 pg/mL in the group with severe traumatic brain injury load versus 2.58 pg/mL in the control group. A direct correlation was found with the presence of basic myelin proteins in the cerebrospinal fluid, which indicates the degree of damage and neurodegeneration processes. Identification of the features of IL-6 content in patients with brain injury may indicate its important role in the course of disease. It also requires additional more detailed study, including comparison with IL-6 content in peripheral blood.

Repeated exposure to 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP) accelerates ligand-independent activation of estrogen receptors in long-term estradiol-deprived MCF-7 cells

It was previously identified that there may be an active metabolite of bisphenol A (BPA), 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP). An in vitro system was developed to detect MBP toxicity to the Michigan Cancer Foundation-7 (MCF-7) cells that had been repeatedly exposed to a low dose of the metabolite. MBP profoundly activated estrogen receptor (ER)-dependent transcription as a ligand, with an EC50 of 2.8 nM. Women are continuously exposed to numerous estrogenic environmental chemicals; but their susceptibility to these chemicals may be significantly altered after menopause. Long-term estrogen-deprived (LTED) cells, which display ligand-independent ER activation, are a postmenopausal breast cancer model derived from MCF-7 cells. In this study, we investigated the estrogenic effects of MBP on LTED cells in a repeated exposure in vitro model. The results suggest that i) nanomolar levels of MBP reciprocally disrupt the balanced expression of ERα and ERβ proteins, leading to the dominant expression of ERβ, ii) MBP stimulates ERs-mediated transcription without acting as an ERβ ligand, and iii) MBP utilizes mitogen-activated protein kinase and phosphatidylinositol-3 kinase signaling to evoke its estrogenic action. Moreover, the repeated exposure strategy was effective for detecting low-dose estrogenic-like effects caused by MBP in LTED cells.

Potassium channels at the crossroads of neuroinflammation and myelination in experimental models of multiple sclerosis

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS), characterized by the presence of localized demyelinating lesions accompanied by an inflammatory reaction, evidently leading to neurodegeneration. A number of ion channels have been implicated in the progression of MS, most notably in cell types involved in the immune response. In the present study, we investigated the implication of two ion channel isoforms, Kv1.1 and Kv1.3, in experimental models of neuroinflammation and demyelination. Immunohistochemical staining of brain sections from the mouse cuprizone model displayed high levels Kv1.3 expression. In an astroglial cellular model of inflammation, stimulation with LPS resulted also in a higher expression of Kv1.1 and Kv1.3, while the introduction of 4-Aminopyridine (4-AP) exacerbated the release of pro-inflammatory chemokine CXCL10. In the oligodendroglial cellular model of demyelination, the alteration in expression levels of Kv1.1 and Kv1.3 may be correlated with that of MBP levels. Indirect co-culture was attempted to further understand the communication between astrocytes and oligodendrocytes, The addition of reactive astrocytes’ secretome significantly inhibited the production of MBP, this inhibition was accompanied by an alteration in the expression of Kv1.1 and Kv1.3. The addition of 4-AP in this case did not alleviate the decrease in MBP production. In conclusion, the use of 4-AP generated controversial results, suggesting 4-AP may be used in the early stages of the disease or in the remission phases to stimulate myelination, yet in induced toxic inflammatory environment, 4-AP exacerbated this effect.