[Corrigendum] Incremental load training improves renal fibrosis by regulating the TGF­ß1/TAK1/MKK3/p38MAPK signaling pathway and inducing the activation of autophagy in aged mice.

Following the publication of the above article, an interested reader drew to the authors' attention that, for the immunofluorescence staining experiments shown in Fig. 3A on p. 1681, the 'E­cadherin / YC' and 'E­cadherin / OC' data panels were overlapping, such that they may have been derived from the same original source; moreover, with the transmission electron microscopic images shown in Fig. 6G on p. 1683, the 'OC' and 'OY' panels were similarly overlapping. After having re­examined their figures, the authors have realized that the data shown for the 'E­cadherin / YC' experiment in Fig. 3A and the 'OC' experiment in Fig. 6G were selected incorrectly. The authors were able, however, to identify the correct data for both of these figures, and the revised versions of Figs. 3 and 6 are shown on the next page. Note that the errors made during the assembly of these figures did not affect the overall conclusions reported in the paper. All the authors agree with the publication of this corrigendum, and are grateful to the Editor of International Journal of Molecular Medicine for allowing them the opportunity to publish this. They also apologize to the readership for any inconvenience caused. [International Journal of Molecular Medicine 44: 1677­1686, 2019; DOI: 10.3892/ijmm.2019.4344].

Retracted: Caffeine Treatment Promotes Differentiation and Maturation of Hypoxic Oligodendrocytes via Counterbalancing Adenosine 1 Adenosine Receptor-Induced Calcium Overload.

The Editors of Medical Science Monitor wish to inform you that the above manuscript has been retracted from publication due to concerns with the credibility and originality of the study, the manuscript content, and the Figure images. Reference: Ting Cao, Teng Ma, Yang Xu, Yanping Tian, Qiyan Cai, Baichuan Li, Hongli Li. Caffeine Treatment Promotes Differentiation and Maturation of Hypoxic Oligodendrocytes via Counterbalancing Adenosine 1 Adenosine Receptor-Induced Calcium Overload. Med Sci Monit, 2019; 25: 1729-1739. DOI: 10.12659/MSM.915147.

Evaluation of a prerequisite course of histology implementation for Chinese students of eight-year medical programme: a mixed quantitative survey.

BACKGROUND: Due to insufficient basic medical knowledge and inappropriate learning strategies, students of 8-year medical programme encountered many obstacles in the initial stage of basic medicine learning. This study was to determine whether a prerequisite course can improve basic medicine learning performance and adjust learning strategies to adapt to basic medicine learning. METHODS: A prerequisite course of histology was constructed by a two-round modified Delphi study. Seventy-four students of 8-year medical programme were subjected to two groups: the prerequisite course group (PC group) and non-prerequisite course group (NPC group). The PC group take part in the prerequisite course by student-centred blended learning approach but NPC group not. The PC and NPC group underwent requisite histology teaching activities after prerequisite course. Examination of the prerequisite course and requisite histology course were carried out. Effect of the prerequisite course was evaluated by an empirical method using a questionnaire-based approach. RESULTS: The results of examinations showed students' scores of the PC group were significantly higher than those of students of NPC group in both prerequisite course and requisite histology examinations (P < 0.05). The results of questionnaires showed that students were satisfied with the prerequisite course, which was beneficial for uptake in medical knowledge, cultivation of clinical thinking and scientific research ability and adaptation in learning strategies (P < 0.01). Furthermore, our prerequisite course is conducive to subsequent courses learning, especially for pathology (P < 0.01). CONCLUSION: Our prerequisite course could effectively supplement knowledge of basic medicine, improve clinical thinking and scientific research ability and adapt their learning strategies. These findings suggest that the prerequisite course is useful and should be introduced in medical curriculum reform at the early stages of basic medical training.

Patients with venous thromboembolism after spontaneous intracerebral hemorrhage: a review.

BACKGROUND: Patients with spontaneous intracerebral hemorrhage (ICH) have a higher risk of venous thromboembolism (VTE) and in-hospital VTE is independently associated with poor outcomes for this patient population. METHODS: A comprehensive literature search about patients with VTE after spontaneous ICH was conducted using databases MEDLINE and PubMed. We searched for the following terms and other related terms (in US and UK spelling) to identify relevant studies: intracerebral hemorrhage, ICH, intraparenchymal hemorrhage, IPH, venous thromboembolism, VTE, deep vein thrombosis, DVT, pulmonary embolism, and PE. The search was restricted to human subjects and limited to articles published in English. Abstracts were screened and data from potentially relevant articles was analyzed. RESULTS: The prophylaxis and treatment of VTE are of vital importance for patients with spontaneous ICH. Prophylaxis measures can be mainly categorized into mechanical prophylaxis and chemoprophylaxis. Treatment strategies include anticoagulation, vena cava filter, systemic thrombolytic therapy, catheter-based thrombus removal, and surgical embolectomy. We briefly summarized the state of knowledge regarding the prophylaxis measures and treatment strategies of VTE after spontaneous ICH in this review, especially on chemoprophylaxis and anticoagulation therapy. Early mechanical prophylaxis, especially with intermittent pneumatic compression, is recommended by recent guidelines for patients with spontaneous ICH. While decision-making on chemoprophylaxis and anticoagulation therapy evokes debate among clinicians, because of the concern that anticoagulants may increase the risk of recurrent ICH and hematoma expansion. Uncertainty still exists regarding optimal anticoagulants, the timing of initiation, and dosage. CONCLUSION: Based on current evidence, we deem that initiating chemoprophylaxis with UFH/LMWH within 24-48 h of ICH onset could be safe; anticoagulation therapy should depend on individual clinical condition; the role of NOACs in this patient population could be promising.

Prostatic fluid exosome-mediated microRNA-155 promotes the pathogenesis of type IIIA chronic prostatitis.

BACKGROUND: The latest research has shown that exosomes play an important role in cell-to-cell communication and are closely related to the occurrence of many chronic inflammatory diseases. However, no studies have clarified whether exosomes are involved in the pathogenesis of aseptic inflammation, type IIIA chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS-A). This study aimed to explore the relationship between prostatic fluid exosomes and CP/CPPS-A and reveal new pathogenesis. METHODS: Our group collected prostatic fluid samples from CP/CPPS-A patients and normal adult men. Electron microscope, quantitative PCR (qPCR), Western Blot, nanoparticle tracking analysis, hematoxylin-and-eosin (HE) staining, immunofluorescence staining and miRNA-155 functional analysis were used to verify the role of exosomes in CP/CPPS-A in vivo and in vitro. RESULTS: Exosomes were abundantly enriched in the prostatic fluid of CP/CPPS-A patients and selectively overloaded with microRNA-155 (miRNA-155). These exosomes were taken up by prostatic stromal cells in large quantities. They activated interleukin (IL)-8 and tumor necrosis factor-alpha (TNF-α) expression in vitro, and the integrity of the exosomes' plasma membrane is a necessary condition for information transmission by exosomes. In in vivo experiments, histological results showed that prostatic fluid exosomes induced prostatitis in rats. Also, immunofluorescence staining showed excessive activation of IL-8, TNF-α, and inducible nitric oxide synthase (iNOS). CONCLUSIONS: Exosomes in the prostatic fluid and the miRNA-155 contained therein were may be involved with the pathogenesis of CP/CPPS-A.

DNA Hypermethylation Induced by L-Methionine Leads to Oligodendroglial and Myelin Deficits and Schizophrenia-Like Behaviors in Adolescent Mice.

Increasing evidence has demonstrated that in addition to dysfunction of neuronal circuitry, oligodendroglial dysfunction and/or disruption of white matter integrity are found in the brains of patients with schizophrenia. DNA methylation, a well-established risk factor for schizophrenia, has been demonstrated to cause neuronal dysfunction; however, whether dysregulation of DNA methylation contributes to oligodendroglial/myelin deficits in the pathogenesis of schizophrenia remains unclear. In the present study, by using L-methionine-treated mice, we confirmed that mice with DNA hypermethylation exhibited an anxious phenotype, impaired sociability, and sensorimotor gating deficits. Notably, DNA hypermethylation in oligodendroglial cells led to dysregulation of multiple oligodendroglia-specific transcription factors, which indicated disruption of the transcriptional architecture. Furthermore, DNA hypermethylation caused a reduction of oligodendroglial lineage cells and myelin integrity in the frontal white matter of mice. Taken together, these results indicate that DNA hypermethylation leads to oligodendroglial and/or myelin deficits, which may, at least in part, contribute to schizophrenia-like behaviors in mice. This study provides new insights into the possibility that precise modulation of DNA methylation status in oligodendroglia could be beneficial for the white matter pathology in schizophrenia.

Current use of rivaroxaban in elderly patients with venous thromboembolism (VTE).

Venous thromboembolism (VTE), which is characterized by pulmonary embolism and deep vein thrombosis, has become a serious public concern. Notably, over half of the patients with VTE are over 70 years of age, but elderly patients are at high risk of anti-coagulation and bleeding, which increase with age. Moreover, risk factors and frailty also show a difference between elderly patients and ordinary patients diagnosed with VTE. Rivaroxaban is a direct inhibitor of activated factor Xa and has the advantage of predictable pharmacodynamics and pharmacokinetics, no coagulation monitoring, and few drug interactions. As a first-line therapy for VTE, this drug is more advantageous than traditional therapy and exhibits good efficacy and safety for ordinary patients. However, the effectiveness and safety of rivaroxaban in elderly patients have not been fully elucidated. This article reviewed the use of rivaroxaban in elderly patients, including drug interactions, monitoring, reversal agents of rivaroxaban, and the use of small dosages of rivaroxaban in elderly patients.

Aerobic exercise training decreases cognitive impairment caused by demyelination by regulating ROCK signaling pathway in aging mice.

Recent studies have discovered a strong link between physical exercise and the prevention of neuro-degenerative symptoms, especially in elderly subjects, nonetheless, the exact underlying mechanism remains unclear. In this study, we hypothesized that aerobic exercise training may have a protective effect on myelin sheath in aged mice by regulating the ROCK signal pathway, which is considered as a crucial mechanism for decreasing apoptosis and promoting regeneration. Briefly, C57/BL aged mice underwent an exercise training (5 days/week, lasting 6 weeks). Memory and cognitive impairment were examined using Novel object recognition (NOR) test and Morris water maze test (MWM). Demyelination was explored using Luxol fast blue staining and transmission electron microscopy in the corpus callosum (CC), and the expression of ROCK and apoptotic protein were analyzed via western blot. We demonstrated the impairment of memory and cognitive and the decrease of myelin sheath thickness in aged mice. In addition, severe demyelination was observed in aged mice, accompanied with increased expression of RhoA, ROCK, ATF3, and Caspase 3, and reduced expression of MBP, Olig2, and NG2. Aerobic exercise training improved behavioral functions, increased the expression of MBP and myelin sheath thickness, reduced apoptosis and promoted myelination. To sum up, our data indicate that aerobic exercise training protects demyelination from aging-related white matter injury, which is associated with the up-regulation of ROCK signal pathway.

Inhibition of RhoA/ROCK Pathway in the Early Stage of Hypoxia Ameliorates Depression in Mice via Protecting Myelin Sheath.

Neuroplasticity and connectivity in the central nervous system (CNS) are easily damaged after hypoxia. Long-term exposure to an anoxic environment can lead to neuropsychiatric symptoms and increases the likelihood of depression. Demyelination is an important lesion of CNS injury that may occur in depression. Previous studies have found that the RhoA/ROCK pathway is upregulated in neuropsychiatric disorders such as multiple sclerosis, stroke, and neurodegenerative diseases. Therefore, the chief aim of this study is to explore the regulatory role of the RhoA/ROCK pathway in the development of depression after hypoxia by behavioral tests, Western blotting, immunostaining as well as electron microscopy. Results showed that HIF-1α, S100ß, RhoA/ROCK, and immobility time in FST were increased, sucrose water preference ratio in SPT was decreased, and the aberrant activity of neurocyte and demyelination occurred after hypoxia. After the administration of Y-27632 and fluoxetine in hypoxia, these alterations were improved. Lingo1, a negative regulatory factor, was also overexpressed after hypoxia and its expression was decreased when the pathway blocked. However, fluoxetine had no effect on the expression of Lingo1. Then, we demonstrated that demyelination was associated with failures of oligodendrocyte precursor cell proliferation and differentiation and increased apoptosis of oligodendrocytes. Collectively, our data indicate that the RhoA/ROCK pathway plays a vital role in the initial depression during hypoxia. Blocking this pathway in the early stage of hypoxia can enhance the effectiveness of antidepressants, rescue myelin damage, and reduce the expression of the negative regulatory protein of myelination. The findings provide new insight into the prophylaxis and treatment of depression.

Aerobic Endurance Exercise Ameliorates Renal Vascular Sclerosis in Aged Mice by Regulating PI3K/AKT/mTOR Signaling Pathway.

Renal vascular sclerosis caused by aging plays an important role in the occurrence and development of chronic kidney disease. Clinical studies have confirmed that endurance exercise is able to delay the aging of skeletal muscle and brain tissue. However, to date, few studies have assessed whether endurance exercise is able to improve the occurrence of renal vascular sclerosis caused by natural aging and its related mechanisms. In this study, we investigated the protective effect of aerobic endurance exercise on renal vascular sclerosis in aged mice and its effect on the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. The results suggested that aerobic endurance exercise preserved kidney morphology and renal function. Glomerular basement membrane thickness was evidently increased, podocyte foot processes were effaced in aged mice, and aerobic endurance exercise significantly ameliorated the overall lesion range. The protein expression of vascular endothelial growth factor (VEGF) and JG12 was lower in the senile control group (OC group). The protein expression of VEGF and JG12 was significantly increased after aerobic endurance exercise. Furthermore, aerobic endurance exercise resulted in downregulation of Bax, Caspase 3, IL-6, and senescent cells and upregulation of Bcl-2. The upregulation of PI3K and its downstream signal molecules AKT and mTOR after aerobic endurance exercise was further observed. Our observations indicated that aerobic endurance exercise may inhibit renal vascular sclerosis in aged mice by regulating the PI3K/AKT/mTOR signaling pathway.

Incremental load training improves renal fibrosis by regulating the TGF­ß1/TAK1/MKK3/p38MAPK signaling pathway and inducing the activation of autophagy in aged mice.

Recent studies have confirmed that kidney tissue fibrosis is closely linked to the natural aging of organs. One of its major characteristics is the reduction of autophagic activity. However, to date, few studies have assessed whether incremental load training is able to improve the occurrence of renal fibrosis caused by natural aging and the underlying mechanisms. In the present study involving male C57/BL mice, an elderly exercise group (OY group) was subjected to progressive load­increasing rotary­bar training (5 days/week, lasting for 6 weeks), with an elderly control group (OC group) and a young control group (YC group) used as controls. Renal fibrosis and autophagy­associated indicators were assessed by Masson's staining, reverse transcription­quantitative PCR analysis, western blotting, immunofluorescence and transmission electron microscopy. The results suggested that collagen deposition in the basal part of the renal tubular epithelium and glomeruli in the OY group was significantly lower than that in the OC group. In the OC group, the protein expression levels of E­cadherin, Beclin 1 and light chain 3 were significantly decreased, and increases in α­smooth muscle actin­positive signals were observed in the glomerular matrix and renal capsule wall. Furthermore, the expression of transforming growth factor (TGF)­ß1 and its downstream signaling molecules TGF­ß­activated kinase 1 (TAK1), mitogen­activated protein kinase (MAPK) kinase (MKK3) and p38MAPK were downregulated following training. The present study confirmed that incremental load training may improve renal fibrosis in aged mice by regulating the TGF­ß1/TAK1/MMK3/p38MAPK signaling pathway and inducing the activation of autophagy to reduce the synthesis of extracellular matrix and delay the epithelial­mesenchymal transition. The present study provides a novel experimental basis for the intervention of incremental load training to prevent senile renal fibrosis.

Demyelination contributes to depression comorbidity in a rat model of chronic epilepsy via dysregulation of Olig2/LINGO-1 and disturbance of calcium homeostasis.

Depression is the most common comorbidity among patients with epilepsy. Despite prior assumptions that antiepileptic drugs are to blame, more and more pathological studies have shown that latent neurological alterations associated with white matter injury and demyelination may underlie this link. However, whether disturbances in cerebral myelination contribute to the initiation of depression in epilepsy remains unclear. In the present study, we investigated the connection between demyelination disorders and the development of depression comorbidity in epilepsy. We first induced spontaneous recurrent epilepticus seizure (SRS) in young rats with pilocarpine. We then established depressive behaviors by recurrent forced swimming test and evaluate the depression state by sucrose preference test. The ratio of depression comorbidity in SRS rats was then calculated. Next, myelination in SRS-Depressed (SRS-D) rats was explored via PCR, western blotting, and immunohistochemistry for the key myelin promotion factor, Olig2 and inhibition factor, LINGO-1. Finally, in situ RNA hybridization of NCX3, one of the dominant Ca2+ extrusion proteins in oligodendrocytes (OLs) was performed to explore whether Ca2+ homeostasis of OLs was disturbed in epilepsy-induced hypoxic conditions and involved in the epilepsy-depression comorbidity. Our results revealed that one-quarter of the SRS rats displayed typical depressive behaviors, which were defined as SRS-D rats. In SRS-D rats, severe demyelination was also observed, accompanied with reduced expression of MBP, Olig2, and NCX3 and increased expression of LINGO-1 in the cingulate gyrus. In SRS-Non depressed rats, no significant changes were found from the control animals. This work provides new insights into the demyelination in epilepsy-depression comorbidity, which involves dysregulation of Olig2/LINGO-1 and disturbance of Ca2+ homeostasis.

Caffeine Treatment Promotes Differentiation and Maturation of Hypoxic Oligodendrocytes via Counterbalancing Adenosine 1 Adenosine Receptor-Induced Calcium Overload.

BACKGROUND We aimed to explore the involvement of adenosine 1 adenosine receptor (A1AR) in hypoxia-induced poor differentiation of oligodendrocytes (OLs), and the underlying mechanism of caffeine treatment in hypoxic injuries. MATERIAL AND METHODS Real-time polymerase chain reaction (RT-PCR) was used to assess the alterations of AR expression in cultured hypoxic OLs with or without caffeine treatment. Then, intracellular alterations of Ca²âº concentrations ([Ca²âº) were detected by confocal Fluo-3 imaging. The subsequent changes of myelin related protein expression were determined by western blot and immunofluorescence. RESULTS Three hours after hypoxia, significantly upregulated expression of A1AR was observed, accompanied with significantly decreased expression of oligodendrocyte transcription factor (Olig2). In addition, either hypoxia stimulation or 100 µM adenosine induced apparent elevation of resting [Ca²âº] in cultured OLs. However, pretreatment with DPCPX (A1AR selective antagonist) or caffeine abolished the [Ca²âº] increase, and the subsequent adenosine of high dose induced Ca²âº activity in developing OLs. Furthermore, caffeine or DPCPX improved the expression MBP and CNPase proteins after hypoxia stimulation, which resulted in the morphological maturation of OLs. CONCLUSIONS Caffeine treatment exerted protective effects on neonatal hypoxia injuries. It prevented Ca²âº overload injury, kept Ca²âº homeostasis in hypoxic developing OLs, and facilitated optimal expression of myelin related proteins by inhibiting A1AR in vitro. This study also provided experimental evidence for clinical application of caffeine in early treatment of neonatal hypoxia, and highlighted the potential significance of A1AR in anti-hypoxic drug discovery.

Catalpol Inhibits Ischemia-Induced Premyelinating Oligodendrocyte Damage through Regulation of Intercellular Calcium Homeostasis via Na⁺/Ca2+ Exchanger 3.

The heightened vulnerability of premyelinating oligodendrocytes (PreOLs) in response to hypoxia⁻ischemia may contribute to perinatal white matter injury and subsequent neurobehavioral dysfunction. Intracellular Ca2+ overload is considered a crucial mechanism predisposing PreOLs to ischemic injury. We previously reported that catalpol, an iridoid glycoside extracted from Rehmannia root, inhibits intracellular Ca2+ overload of PreOLs in an in vitro ischemia model. However, the exact underlying mechanisms remain elusive. In the present study, we aimed to investigate the protective effects of catalpol on PreOLs and to explore the underlying mechanisms involved in the modulation of intracellular Ca2+ homeostasis. Postnatal day 2 (P2) Sprague-Dawley (SD) rats subjected to bilateral common carotid artery ligation followed by exposure to 8% oxygen for 10 min were used as a rat model of neonatal hypoxia⁻ischemia. We found that catalpol significantly improved behavioral functions and prevented PreOL loss and myelination deficit after hypoxia⁻ischemia. Our in vitro studies also confirmed the direct effects of catalpol on oxygen-glucose deprivation (OGD)-induced cell death and arrested maturation of PreOLs. Moreover, we demonstrated that catalpol significantly inhibited intracellular Ca2+ overload and promoted the expression of Na⁺/Ca2+ exchanger 3 (NCX3). Finally, we found that catalpol significantly reduced mitochondrial damage and subsequent extracellular signal-regulated kinase 1/2 (ERK1/2) and poly-ADP-ribose polymerase-1 (PARP-1) activation. Treatment with NCX3-preferring inhibitor 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea (KB-R7943) significantly reversed the protective effects of catalpol on PreOLs under OGD. Overall, our data suggest that catalpol protects PreOLs from ischemic injury through regulation of intercellular Ca2+ homeostasis via upregulation of NCX3 activity.

Modified task-based learning program promotes problem-solving capacity among Chinese medical postgraduates: a mixed quantitative survey.

BACKGROUND: Despite great advances, China's postgraduate education faces many problems, for example traditional lecture-based learning (LBL) method provides fewer oppotunities to apply knowledge in a working situation. Task-based learning (TBL) is an efficient strategy for increasing the connections among skills, knowledge and competences. This study aimed to evaluate the effect of a modified TBL model on problem-solving abilities among postgraduate medical students in China. METHODS: We allocated 228 first-year postgraduate students at Third Military Medical University into two groups: the TBL group and LBL group. The TBL group was taught using a TBL program for immunohistochemistry. The curriculum consisted of five phases: task design, self-learning, experimental operations, discussion and summary. The LBL group was taught using traditional LBL. After the course, learning performance was assessed using theoretical and practical tests. The students' preferences and satisfaction of TBL and LBL were also evaluated using questionnaires. RESULTS: There were notable differences in the mean score rates in the practical test (P < 0.05): the number of high scores (>80) in the TBL group was higher than that in the LBL group. We observed no substantial differences in the theoretical test between the two groups (P > 0.05). The questionnaire results indicated that the TBL students were satisfied with teaching content, teaching methods and experiment content. The TBL program was also beneficial for the postgraduates in completing their research projects. Furthermore, the TBL students reported positive effects in terms of innovative thinking, collaboration, and communication. CONCLUSIONS: TBL is a powerful educational strategy for postgraduate education in China. Our modified TBL imparted basic knowledge to the students and also engaged them more effectively in applying knowledge to solve real-world issues. In conclusion, our TBL established a good foundation for the students' future in both medical research and clinical work.

Catalpol Protects Pre-Myelinating Oligodendrocytes against Ischemia-induced Oxidative Injury through ERK1/2 Signaling Pathway.

The vulnerability of pre-myelinating oligodendrocytes (PreOLs) to ischemic injury plays an important role in the pathogenesis and progression of perinatal white matter injury. Although oxidative stress is thought to be a major pathogenic mechanism predisposing the PreOLs to injury, no effective therapies have been identified to date. The present study aimed to investigate the direct protective effects of catalpol, a potent antioxidant and free radical scavenger, on ischemia-induced oxidative damage in PreOLs and to explore whether the ERK1/2 signaling pathway contributed to the protection provided by catalpol. Primary cultures of PreOLs exposed to oxygen-glucose deprivation (OGD) followed by reperfusion were used as an in vitro model of ischemia. Pretreatment with 0.5 mM catalpol for 1 h prior to OGD treatment significantly reversed ischemia-induced apoptosis in PreOLs and myelination deficits by inhibiting intracellular Ca2+ increase, reducing mitochondrial damage, and ameliorating overproduction of reactive oxygen species (ROS). The expression levels of phosphorylated ERK1/2 (p-ERK1/2) and activated poly-ADP-ribose polymerase-1 (PARP-1) were also markedly decreased by catalpol treatment. Blocking the ERK1/2 signaling pathway with the MEK inhibitor U0126 and catalpol significantly protected PreOLs from ROS-mediated apoptosis under OGD. Taken together, these results suggest that catalpol protects PreOLs against ischemia-induced oxidative injury through ERK1/2 signaling pathway. Catalpol may be a candidate for treating ischemic white matter damage.

Lead Poisoning Disturbs Oligodendrocytes Differentiation Involved in Decreased Expression of NCX3 Inducing Intracellular Calcium Overload.

Lead (Pb) poisoning has always been a serious health concern, as it permanently damages the central nervous system. Chronic Pb accumulation in the human body disturbs oligodendrocytes (OLs) differentiation, resulting in dysmyelination, but the molecular mechanism remains unknown. In this study, Pb at 1 µM inhibits OLs precursor cells (OPCs) differentiation via decreasing the expression of Olig 2, CNPase proteins in vitro. Moreover, Pb treatment inhibits the sodium/calcium exchanger 3 (NCX3) mRNA expression, one of the major means of calcium (Ca(2+)) extrusion at the plasma membrane during OPCs differentiation. Also addition of KB-R7943, NCX3 inhibitor, to simulate Pb toxicity, resulted in decreased myelin basic protein (MBP) expression and cell branching. Ca(2+) response trace with Pb and KB-R7943 treatment did not drop down in the same recovery time as the control, which elevated intracellular Ca(2+) concentration reducing MBP expression. In contrast, over-expression of NCX3 in Pb exposed OPCs displayed significant increase MBP fluorescence signal in positive regions and CNPase expression, which recovered OPCs differentiation to counterbalance Pb toxicity. In conclusion, Pb exposure disturbs OLs differentiation via affecting the function of NCX3 by inducing intracellular calcium overload.

4,4'-Diisothiocyanostilbene-2,2'-disulfonic Acid (DIDS) Ameliorates Ischemia-Hypoxia-Induced White Matter Damage in Neonatal Rats through Inhibition of the Voltage-Gated Chloride Channel ClC-2.

Chronic cerebral hypoperfusion is believed to cause white matter lesions (WMLs), leading to cognitive impairment. Previous studies have shown that inflammation and apoptosis of oligodendrocytes (OLs) are involved in the pathogenesis of WMLs, but effective treatments have not been studied. In this study, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), a chloride (Cl-) channel blocker, was injected into chronic cerebral ischemia-hypoxia rat models at different time points. Our results showed that DIDS significantly reduced the elevated mRNA levels and protein expression of chloride channel 2 (ClC-2) in neonatal rats induced by ischemia-hypoxia. Meanwhile, DIDS application significantly decreased the concentrations of reactive oxygen species (ROS); and the mRNA levels of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha TNF-α in neonatal rats with hypoxic-ischemic damage. Myelin staining was weaker in neonatal rats with hypoxic-ischemic damage compared to normal controls in corpus callosum and other white matter, which was ameliorated by DIDS. Furthermore, the elevated number of caspase-3 and neural/glial antigen 2 (NG-2) double-labeled positive cells was attenuated by DIDS after ischemia anoxic injury. Administration of DIDS soon after injury alleviated damage to OLs much more effectively in white matter. In conclusion, our study suggests that early application of DIDS after ischemia-hypoxia injury may partially protect developing OLs.

Catalpol promotes oligodendrocyte survival and oligodendrocyte progenitor differentiation via the Akt signaling pathway in rats with chronic cerebral hypoperfusion.

Chronic cerebral hypoperfusion is thought to induce white matter lesions (WMLs), which contribute to cognitive impairment. Although inflammation and oligodendrocyte apoptosis are believed to be involved in the pathogenesis of WMLs, effective therapies have not been identified yet. This study investigated whether catalpol, an iridoid glycoside, can alleviate WMLs by promoting oligodendrocyte survival and oligodendrocyte progenitor differentiation via the Akt signaling pathway in rats with chronic cerebral hypoperfusion. A rat model of chronic cerebral hypoperfusion was created through permanent occlusion of bilateral common carotid arteries. Catalpol (5mg/kg) or saline was intraperitoneally administered daily for 10 days following the operation. On the 30th day after surgery, inflammation, oligodendrocyte apoptosis, and myelin damage in the ischemic white matter were more severe and evident than in the sham control group. Treatment with catalpol significantly suppressed white matter inflammation and attenuated oligodendrocyte apoptosis and myelin damage. The expression of phosphorylated Akt (p-Akt) and the number of mature oligodendrocytes were also markedly increased by catalpol treatment, and these effects were reversed by the PI3K inhibitor LY294002. In conclusion, catalpol attenuates hypoperfusion-induced WMLs by promoting oligodendrocyte survival and oligodendrocyte progenitor differentiation through the Akt signaling pathway. Our results suggest that catalpol may be a candidate for treating cerebrovascular WMLs.