Inverted Classroom Teaching of Physiology in Basic Medical Education: Bibliometric Visual Analysis.

Background: Over the last decade, there has been growing interest in inverted classroom teaching (ICT) and its various forms within the education sector. Physiology is a core course that bridges basic and clinical medicine, and ICT in physiology has been sporadically practiced to different extents globally. However, students' and teachers' responses and feedback to ICT in physiology are diverse, and the effectiveness of a modified ICT model integrated into regular teaching practice in physiology courses is difficult to assess objectively and quantitatively. Objective: This study aimed to explore the current status and development direction of ICT in physiology in basic medical education using bibliometric visual analysis of the related literature. Methods: A bibliometric analysis of the ICT-related literature in physiology published between 2000 and 2023 was performed using CiteSpace, a bibliometric visualization tool, based on the Web of Science database. Moreover, an in-depth review was performed to summarize the application of ICT in physiology courses worldwide, along with identification of research hot spots and development trends. Results: A total of 42 studies were included for this bibliometric analysis, with the year 2013 marking the commencement of the field. University staff and doctors working at affiliated hospitals represent the core authors of this field, with several research teams forming cooperative relationships and developing research networks. The development of ICT in physiology could be divided into several stages: the introduction stage (2013-2014), extensive practice stage (2015-2019), and modification and growth stage (2020-2023). Gopalan C is the author with the highest citation count of 5 cited publications and has published 14 relevant papers since 2016, with a significant surge from 2019 to 2022. Author collaboration is generally limited in this field, and most academic work has been conducted in independent teams, with minimal cross-team communication. Authors from the United States published the highest number of papers related to ICT in physiology (18 in total, accounting for over 43% of the total papers), and their intermediary centrality was 0.24, indicating strong connections both within the country and internationally. Chinese authors ranked second, publishing 8 papers in the field, although their intermediary centrality was only 0.02, suggesting limited international influence and lower overall research quality. The topics of ICT in physiology research have been multifaceted, covering active learning, autonomous learning, student performance, teaching effect, blended teaching, and others. Conclusions: This bibliometric analysis and literature review provides a comprehensive overview of the history, development process, and future direction of the field of ICT in physiology. These findings can help to strengthen academic exchange and cooperation internationally, while promoting the diversification and effectiveness of ICT in physiology through building academic communities to jointly train emerging medical talents.

Recapitulation of Structure-Function-Regulation of Blood-Brain Barrier under (Patho)Physiological Conditions.

The blood-brain barrier (BBB) is a remarkable and intricate barrier that controls the exchange of molecules between the bloodstream and the brain. Its role in maintaining the stability of the central nervous system cannot be overstated. Over the years, advancements in neuroscience and technology have enabled us to delve into the cellular and molecular components of the BBB, as well as its regulation. Yet, there is a scarcity of comprehensive reviews that follow a logical framework of structure-function-regulation, particularly focusing on the nuances of BBB regulation under both normal and pathological conditions. This review sets out to address this gap by taking a historical perspective on the discovery of the BBB and highlighting the major observations that led to its recognition as a distinct brain barrier. It explores the intricate cellular elements contributing to the formation of the BBB, including endothelial cells, pericytes, astrocytes, and neurons, emphasizing their collective role in upholding the integrity and functionality of the BBB. Furthermore, the review delves into the dynamic regulation of the BBB in physiological states, encompassing neural, humoral, and auto-regulatory mechanisms. By shedding light on these regulatory processes, a deeper understanding of the BBB's response to various physiological cues emerges. This review also investigates the disruption of the BBB integrity under diverse pathological conditions, such as ischemia, infection, and toxin exposure. It elucidates the underlying mechanisms that contribute to BBB dysfunction and explores potential therapeutic strategies that aim to restore the BBB integrity and function. Overall, this recapitulation provides valuable insights into the structure, functions, and regulation of the BBB. By integrating historical perspectives, cellular elements, regulatory mechanisms, and pathological implications, this review contributes to a more comprehensive understanding of the BBB and paves the way for future research and therapeutic interventions.

Physiology education and teaching in Chinese mainland medical schools: the status quo and the changes over the past two decades.

Physiology is a critical subject that bridges basic and clinical medicine. The reform of physiology education is crucial to improving the quality of teaching and supporting student learning; however, there is a lack of comprehensive data documenting the current state of physiology education in medical programs in China. This study conducted an online survey among experienced teachers from the top 100 medical schools in the Chinese mainland in 2022. A total of 89 valid questionnaires were included in this study. In 57.3% of the surveyed medical schools, 70% of the physiology teachers have a Ph.D. degree, while the number of faculty members with a medical background has tended to decrease in 53.9% of the surveyed medical schools. Of the 89 medical schools, 62 have implemented physiology course integration, with 69.4% of the respondents believing that curriculum integration could enhance students' knowledge acquisition and application. The lecture hours per term are 50-70 and 71-90 in 49.4% and 42.7% of the 89 medical schools, respectively. The ratio of course duration of lecture to laboratory was 2:1 in 47.2% of the surveyed medical schools, while the ratio was between 1:1 and 2:1 in 47.2% of the surveyed medical schools, and only 5.6% of medical schools opted for a 1:1 course arrangement. For teaching methods, about 60% of medical schools used problem-based learning, case-based learning, and task-based learning (PBL/CBL/TBL) for clinical medicine students only, and 25.4% of medical schools applied PBL/CBL/TBL to all students. This study is conducive to promoting dialogue and communication among physiology teachers, administrators, and researchers.NEW & NOTEWORTHY This study conducted a nationwide survey of the top 100 medical schools in the Chinese mainland in 2022 to provide first-hand data on the current situation and changes in physiology education and teaching in the Chinese mainland with focuses on the faculty composition, curriculum integration, teaching methods, and assessment modes, which is a microcosm of the reform and development of the medical education in the Chinese mainland, hoping to improve the quality of preclinical medical education.

Autophagy and Apoptosis in Acute Brain Injuries: From Mechanism to Treatment.

Significance: Autophagy and apoptosis are two important cellular mechanisms behind brain injuries, which are severe clinical situations with increasing incidences worldwide. To search for more and better treatments for brain injuries, it is essential to deepen the understanding of autophagy, apoptosis, and their interactions in brain injuries. This article first analyzes how autophagy and apoptosis participate in the pathogenetic processes of brain injuries respectively and mutually, then summarizes some promising treatments targeting autophagy and apoptosis to show the potential clinical applications in personalized medicine and precision medicine in the future. Recent Advances: Most current studies suggest that apoptosis is detrimental to brain recovery. Several studies indicate that autophagy can cause unnecessary death of neurons after brain injuries, while others show that autophagy is beneficial for acute brain injuries (ABIs) by facilitating the removal of damaged proteins and organelles. Whether autophagy is beneficial or detrimental in ABIs depends on many factors, and the results from different research groups are diverse or even controversial, making this topic more appealing to be explored further. Critical Issues: Neuronal autophagy and apoptosis are two primary pathological processes in ABIs. How they interact with each other and how their regulations affect the outcome and prognosis of brain injuries remain uncertain, making these answers more critical. Future Directions: Insights into the interplay between autophagy and apoptosis and the accurate regulations of their balance in ABIs may promote personalized and precise treatments in the field of brain injuries. Antioxid. Redox Signal. 38, 234-257.

Therapeutic Effect of Platelet-Rich Fibrin Transplant on Formation of Thin Endometrium.

OBJECTIVES: Thin endometrium is a common problem encountered in the field of assisted reproductive technology. We explored the effects of platelet-rich fibrin in a thin endometrium rat model. MATERIALS AND METHODS: Twenty Sprague-Dawley rats were randomly divided into 2 groups. For the thin endometrium group, endometria of left uteri were injected with ethanol. For the experimental group, platelet-rich fibrin was sutured onto the left uteri of endometria injected with ethanol. Right uteri were kept as the normal (control) group. Two weeks after platelet-rich fibrin transplant, uteri were sampled for histology, immunohistochemistry, Western blot, and real-time reverse transcription-polymerase chain reaction. RESULTS: Endometrium thicknesses in normal, thin endometrium, and experimental groups were 632.2 ± 38.28, 434.80 ± 41.37, and 603.0 ± 40.93 µm, respectively. Endometrium thickness in the experi-mental group was significantly increased versus the thin endometrium group (P = .011). Immunohistochemical examination showed that expression levels of cytokeratin 18, vimentin, and leukemia inhibitory factor in the experimental group were significantly higher versus the thin endometrium group (P < .001, P < .006, and P = .001, respectively). In Western blot analysis, cytokeratin 18, integrin ß3, leukemia inhibitory factor, and vimentin protein expressions were slightly higher in the experimental and normal groups versus the thin endometrium group. Real-time reverse transcription-polymerase chain reaction showed significantly higher octamer-binding transcription factor 4 mRNA levels in the experimental group versus the thin endometrium group (P < .001). Interleukin 6 and matrix metalloproteinase 9 mRNA levels were significantly upregulated in the experimental group versus the thin endometrium group (P= .004 and P < .001, respectively). Interleukin 1ß mRNA expression was significantly lower in the experimental group versus the thin endometrium group (P < .007). CONCLUSIONS: Application of platelet-rich fibrin has a therapeutic effect on thin endometrium in rats. Our results provide new insight on clinical treatment of thin endometrium.

Phosphorylation of 5-LOX: The Potential Set-point of Inflammation.

Inflammation secondary to tissue injuries serves as a double-edged sword that determines the prognosis of tissue repair. As one of the most important enzymes controlling the inflammation process by producing leukotrienes, 5-lipoxygenase (5-LOX, also called 5-LO) has been one of the therapeutic targets in regulating inflammation for a long time. Although a large number of 5-LOX inhibitors have been explored, only a few of them can be applied clinically. Surprisingly, phosphorylation of 5-LOX reveals great significance in regulating the subcellular localization of 5-LOX, which has proven to be an important mechanism underlying the enzymatic activities of 5-LOX. There are at least three phosphorylation sites in 5-LOX jointly to determine the final inflammatory outcomes, and adjustment of phosphorylation of 5-LOX at different phosphorylation sites brings hope to provide an unrecognized means to regulate inflammation. The present review intends to shed more lights into the set-point-like mechanisms of phosphorylation of 5-LOX and its possible clinical application by summarizing the biological properties of 5-LOX, the relationship of 5-LOX with neurodegenerative diseases and brain injuries, the phosphorylation of 5-LOX at different sites, the regulatory effects and mechanisms of phosphorylated 5-LOX upon inflammation, as well as the potential anti-inflammatory application through balancing the phosphorylation-depended set-point.

Tanshinone IIA Suppresses Proliferation and Inflammatory Cytokine Production of Synovial Fibroblasts from Rheumatoid Arthritis Patients Induced by TNF-α and Attenuates the Inflammatory Response in AIA Mice.

Rheumatoid arthritis (RA) is a chronic and progressive autoimmune disease in which activated RA fibroblast-1ike synoviocytes (RA-FLSs) are one of the main factors responsible for inducing morbidity. Previous reports have shown that RA-FLSs have proliferative features similar to cancer cells, in addition to causing cartilage erosion that eventually causes joint damage. Thus, new therapeutic strategies and drugs that can effectively contain the abnormal hyperplasia of RA-FLSs and restrain RA development are necessary for the treatment of RA. Tanshinone IIA (Tan IIA), one of the main phytochemicals isolated from Salvia miltiorrhiza Bunge, is capable of promoting RA-FLS apoptosis and inhibiting arthritis in an AIA mouse model. In addition, RA patients treated at our clinic with Tan IIA showed significant improvements in their clinical symptoms. However, the details of the molecular mechanism by which Tan IIA effects RA are unknown. To clarify this mechanism, we evaluated the antiproliferative and inhibitory effects of proinflammatory factor production caused by Tan IIA to RA-FLSs. We demonstrated that Tan IIA can restrict the proliferation, migration, and invasion of RA-FLSs in a time- and dose-dependent manner. Moreover, Tan IIA effectively suppressed the increase in mRNA expression of some matrix metalloproteinases and proinflammatory factors induced by TNF-α in RA-FLSs, resulting in inflammatory reactivity inhibition and blocking the destruction of the knee joint. Through the integration of network pharmacology analyses with the experimental data obtained, it is revealed that the effects of Tan IIA on RA can be attributed to its influence on different signaling pathways, including MAPK, AKT/mTOR, HIF-1, and NF-kB. Taken together, these data suggest that the compound Tan IIA has great therapeutic potential for RA treatment.

Active Monomer RTR-1 Derived from the Root of Rhodomyrtus t omentosa Induces Apoptosis in Gastric Carcinoma Cells by Inducing ER Stress and Inhibiting the STAT3 Signaling Pathway.

PURPOSE: Rhodomyrtus tomentosa, a flowering plant from the Myrtaceae family, is considered  an antitumour substance with versatile biological and pharmacological activities. RTR-1 is an active monomer purified from the root of Rhodomyrtus tomentosa. However, the detail of mechanism involving in RTR-1 anti-cancer activity remains to be elucidated, and the effect on gastric cancer cells is unknown. METHODS: Cell proliferation was determined by MTT and clone formation assay. The effect of RTR-1 on cell cycle distribution and apoptosis was analysed utilizing flow cytometry, respectively. Moreover, Western blotting was used to detect the expression of cell cycle- and apoptosis-related protein. RESULTS: Based on MTT and clone formation assay, we noticed that RTR-1 inhibited the proliferation of gastric carcinoma (BGC823 and SGC7901) cells in a dose- and time-dependent manner. Furthermore, the results of flow cytometry and Western blotting showed that RTR-1 induced cell cycle arrest in the G2/M phase through the ATM-Chk2-p53-p21 signaling pathway and induced cell apoptosis by inhibiting the signal transducers and activators of transcription 3 (STAT3) pathway and activating the endoplasmic reticulum stress (ER stress) pathway. CONCLUSION: Taken together, these results demonstrate that RTR-1 induces cell cycle arrest and promotes apoptosis in gastric carcinoma, indicating its potential application for gastric cancer therapy.

Investigation of Water-Sensitivity Damage for Tight Low-Permeability Sandstone Reservoirs.

Tight sandstone reservoir has been characterized by low permeability and porosity, developed micro-nanopore throats, strong capillary forces, and high content of clay minerals. It is vulnerable to damage caused by water sensitivity during the processes of reservoir development, which significantly impedes the hydrocarbon production. Hence, it is important to analyze the damage mechanism of water sensitivity to avoid the production decrease. However, the conventional steady-state method is time-consuming and inaccurate for evaluating the water-sensitivity damage in tight low-permeability reservoirs. Aiming at this problem, this paper introduced pressure transmission test (PTT), a time-saving and accurate method, to quantitatively evaluate the degree of damage by water sensitivity. Moreover, lithofacies analysis methods, consisting of computed tomography (CT) scanning, scanning electron microscopy (SEM), and X-ray diffraction (XRD), are also used to evaluate the reservoir properties, which can provide a basis for analyzing the potential damage factors. The CT scanning results show that the developed micropore throat in the target reservoirs has poor connectivity. The XRD results indicate that the target reservoir mainly consists of a mixed-layer illite/smectite and smectite, which is consistent with the observation by SEM experiments. The results of PTT show that the ultimate average damage rate of water sensitivity is approximately 62.94%, attributed to the medium-strong water sensitivity. Compared with the conventional steady-state method measuring the outlet flow of the core, this method can reduce the experimental errors merely by recording the pressure data varying with time. Moreover, it is also applicable for evaluating other types of formation sensitivity damage, such as alkali and acid sensitivity damage for low-permeability reservoirs.

Neurotrophin-3 provides neuroprotection via TrkC receptor dependent pErk5 activation in a rat surgical brain injury model.

BACKGROUND: Surgical brain injury (SBI) which occurs due to the inadvertent injury inflicted to surrounding brain tissue during neurosurgical procedures can potentiate blood brain barrier (BBB) permeability, brain edema and neurological deficits. This study investigated the role of neurotrophin 3 (NT-3) and tropomyosin related kinase receptor C (TrkC) against brain edema and neurological deficits in a rat SBI model. METHODS: SBI was induced in male Sprague Dawley rats by partial right frontal lobe resection. Temporal expression of endogenous NT-3 and TrkC was evaluated at 6, 12, 24 and 72 h after SBI. SBI rats received recombinant NT-3 which was directly applied to the brain surgical injury site using gelfoam. Brain edema and neurological function was evaluated at 24 and 72 h after SBI. Small interfering RNA (siRNA) for TrkC and Rap1 was administered via intracerebroventricular injection 24 h before SBI. BBB permeability assay and western blot was performed at 24 h after SBI. RESULTS: Endogenous NT-3 was decreased and TrkC expression increased after SBI. Topical administration of recombinant NT-3 reduced brain edema, BBB permeability and improved neurological function after SBI. Recombinant NT-3 administration increased the expression of phosphorylated Rap1 and Erk5. The protective effect of NT-3 was reversed with TrkC siRNA but not Rap1 siRNA. CONCLUSIONS: Topical application of NT-3 reduced brain edema, BBB permeability and improved neurological function after SBI. The protective effect of NT-3 was possibly mediated via TrkC dependent activation of Erk5.

Multiple mechanisms underlying neuroprotection by secretory phospholipase A2 preconditioning in a surgically induced brain injury rat model.

BACKGROUND: Intra-operative bleeding, post-operative brain edema and neuroinflammation are major complications in patients with surgical brain injury (SBI). Phospholipase A2 (PLA2) is the upstream enzyme which initiates the PLA2, 5-lipoxygenase (5-LOX) and leukotriene B4 (LTB4) inflammatory pathway. We hypothesized PLA2preconditioning (PPC) prior to SBI can activate endogenous anti-inflammatory responses to protect against SBI. This study evaluated if PPC can ameliorate neurosurgical complications and elucidated PPC-mediated possible protective mechanisms in a rat SBI model. METHODS: Total 105 adult male Sprague Dawley rats were used for this study. SBI was induced by partial resection of the right frontal lobe. PLA2 or 0.9% NaCl was injected via rats' tail vein for 3 consecutive days prior to SBI. For mechanism study, a selective PLA2 inhibitor, Manoalide and 5-LOX inhibitor, Zileuton were injected intravenously with PPC to elucidate the role of PLA2 and 5-LOX in PPC-mediated anti-inflammatory effects. Brain water content (BWC) and lung water content, neurological tests, ELISA, western blot, immunohistochemistry, white blood cells (WBC) count, and spectrophotometric assay for intra-operative hemorrhage volume were evaluated. RESULTS: First, PPC reduced brain water content, intra-operative bleeding, and improved neurological function after SBI. Second, PPC decreased 5-LOX expression and brain leukocyte infiltration, while increasing glial fibrillary acidic protein (GFAP) expression in the peri-resection brain tissue after SBI. Third, PPC induced peripheral inflammation represented by mild pulmonary inflammation and increased peripheral blood WBC count and LTB4 level. Lastly, PPC increased blood glucose concentration and glucocorticoid levels after SBI. In addition, PPC mediated above-mentioned changes were partially reversed by administration of PLA2 inhibitor, Manoalide and 5-LOX inhibitor, Zileuton. CONCLUSIONS: PPC conferred neuroprotection against SBI via multi-target involvement induced anti-inflammatory mechanisms.

Naja sputatrix Venom Preconditioning Attenuates Neuroinflammation in a Rat Model of Surgical Brain Injury via PLA2/5-LOX/LTB4 Cascade Activation.

Inflammatory preconditioning is a mechanism in which exposure to small doses of inflammatory stimuli prepares the body against future massive insult by activating endogenous protective responses. Phospholipase A2/5-lipoxygenase/leukotriene-B4 (PLA2/5-LOX/LTB4) axis is an important inflammatory signaling pathway. Naja sputatrix (Malayan spitting cobra) venom contains 15% secretory PLA2 of its dry weight. We investigated if Naja sputatrix venom preconditioning (VPC) reduces surgical brain injury (SBI)-induced neuroinflammation via activating PLA2/5-LOX/LTB4 cascade using a partial frontal lobe resection SBI rat model. Naja sputatrix venom sublethal dose was injected subcutaneously for 3 consecutive days prior to SBI. We observed that VPC reduced brain edema and improved neurological function 24 h and 72 h after SBI. The expression of pro-inflammatory mediators in peri-resection brain tissue was reduced with VPC. Administration of Manoalide, a PLA2 inhibitor or Zileuton, a 5-LOX inhibitor with VPC reversed the protective effects of VPC against neuroinflammation. The current VPC regime induced local skin inflammatory reaction limited to subcutaneous injection site and elicited no other toxic effects. Our findings suggest that VPC reduces neuroinflammation and improves outcomes after SBI by activating PLA2/5-LOX/LTB4 cascade. VPC may be beneficial to reduce post-operative neuroinflammatory complications after brain surgeries.

Correlation Between Subacute Sensorimotor Deficits and Brain Edema in Rats after Surgical Brain Injury.

No matter how carefully a neurosurgical procedure is performed, it is intrinsically linked to postoperative deficits resulting in delayed healing caused by direct trauma, hemorrhage, and brain edema, termed surgical brain injury (SBI). Cerebral edema occurs several hours after SBI and is a major contributor to patient morbidity, resulting in increased postoperative care. Currently, the correlation between functional recovery and brain edema after SBI remains unknown. Here we examine the correlation between neurological function and brain water content in rats 42 h after SBI. SBI was induced in male Sprague-Dawley rats via frontal lobectomy. Twenty-four hours post-ictus animals were subjected to four neurobehavior tests: composite Garcia neuroscore, beam walking test, corner turn test, and beam balance test. Animals were then sacrificed for right-frontal brain water content measurement via the wet-dry method. Right-frontal lobe brain water content was found to significantly correlate with neurobehavioral deficits in the corner turn and beam balance tests: the number of left turns (percentage of total turns) for the corner turn test and distance traveled for the beam balance test were both inversely proportional with brain water content. No correlation was observed for the composite Garcia neuroscore or the beam walking test.

Recombinant Slit2 attenuates neuroinflammation after surgical brain injury by inhibiting peripheral immune cell infiltration via Robo1-srGAP1 pathway in a rat model.

BACKGROUND AND PURPOSE: Peripheral immune cell infiltration to the brain tissue at the perisurgical site can promote neuroinflammation after surgical brain injury (SBI). Slit2, an extracellular matrix protein, has been reported to reduce leukocyte migration. This study evaluated the effect of recombinant Slit2 and the role of its receptor roundabout1 (Robo1) and its downstream mediator Slit-Robo GTPase activating protein 1 (srGAP1)-Cdc42 on peripheral immune cell infiltration after SBI in a rat model. METHODS: One hundred and fifty-three adult male Sprague-Dawley rats (280-350 g) were used. Partial resection of right frontal lobe was performed to induce SBI. Slit2 siRNA was administered by intracerebroventricular injection 24h before SBI. Recombinant Slit2 was injected intraperitoneally 1h before SBI. Recombinant Robo1 used as a decoy receptor was co-administered with recombinant Slit2. srGAP1 siRNA was administered by intracerebroventricular injection 24h before SBI. Post-assessments included brain water content measurement, neurological tests, ELISA, Western blot, immunohistochemistry, and Cdc42 activity assay. RESULTS: Endogenous Slit2 was increased after SBI. Robo1 was expressed by peripheral immune cells. Endogenous Slit2 knockdown worsened brain edema after SBI. Recombinant Slit2 administration reduced brain edema, neurological deficits, and pro-inflammatory cytokines after SBI. Recombinant Slit2 reduced peripheral immune cell markers cluster of differentiation 45 (CD45) and myeloperoxidase (MPO), as well as Cdc42 activity in the perisurgical brain tissue which was reversed by recombinant Robo1 co-administration and srGAP1 siRNA. CONCLUSIONS: Recombinant Slit2 improved outcomes by reducing neuroinflammation after SBI, possibly by decreasing peripheral immune cell infiltration to the perisurgical site through Robo1-srGAP1 mediated inhibition of Cdc42 activity. These results suggest that Slit2 may be beneficial to reduce SBI-induced neuroinflammation.

IDH1 mutation-associated long non-coding RNA expression profile changes in glioma.

Isocitrate dehydrogenase 1 (IDH1) mutation is an important prognostic marker in glioma. However, its downstream effect remains incompletely understood. Long non-coding RNAs (lncRNAs) are emerging as important regulators of tumorigenesis in a number of human malignancies, including glioma. Here, we investigated whether and how lncRNA expression profiles would differ between gliomas with or without IDH1 mutation. By using our previously reported lncRNA mining approach, we performed lncRNA profiling in three public glioma microarray datasets. The differential lncRNA expression analysis was then conducted between mutant-type and wild-type IDH1 glioma samples. Comparison analysis identified 14 and 9 lncRNA probe sets that showed significantly altered expressions in astrocytic and oligodendroglial tumors, respectively (fold change ≥ 1.5, false discovery rate ≤ 0.1). Moreover, the differential expressions of these lncRNAs could be confirmed in the independent testing sets. Functional exploration of the lncRNAs by analyzing the lncRNA-protein interactions revealed that these IDH1 mutation-associated lncRNAs were involved in multiple tumor-associated cellular processes, including metabolism, cell growth and apoptosis. Our data suggest the potential roles of lncRNA in gliomagenesis, and may help to understand the pathogenesis of gliomas associated with IDH1 mutation.

Phosphoinositide 3-Kinase Gamma Contributes to Neuroinflammation in a Rat Model of Surgical Brain Injury.

Neuroinflammation plays an important role in the pathophysiology of surgical brain injury (SBI). Phosphoinositide 3-kinase gamma (PI3Kγ), predominately expressed in immune and endothelial cells, activates multiple inflammatory responses. In the present study, we investigated the role of PI3Kγ and PI3Kγ-activated phosphodiesterase 3B (PDE3B) in neuroinflammation in a rat model of SBI. One hundred and fifty-two male Sprague Dawley rats (weight 280-350 g) were subjected to a partial right frontal lobe corticotomy model of SBI. A PI3Kγ pharmacological inhibitor (AS252424 or AS605240) was administered intraperitoneally. PI3Kγ siRNA, human recombinant active-PI3Kγ protein, or human recombinant active-PDE3B protein were administered intracerebroventricularly. Post-SBI assessments included neurobehavioral tests, brain water content, Western blot, and immunohistochemistry. Endogenous PI3Kγ levels were increased within peri-resection brain tissues after SBI, accompanied by increased brain water content and neurological functional deficits. There was a trend toward increased endogenous PDE3B phosphorylation after SBI. The selective PI3Kγ inhibitors AS252424 and AS605240 reduced brain water content surrounding corticotomy and improved neurological function after SBI. SBI increased and PI3Kγ inhibitor decreased levels of myeloperoxidase, cluster of differentiation 3, mast cell degranulation, E-selectin, and IL-1 in peri-resection brain tissues. Direct administration of human recombinant active-PI3Kγ protein and active-PDE3B protein countered the protective effect of AS252424. PI3Kγ siRNA reduced PI3Kγ levels, decreased brain water content within peri-resection brain tissues, and improved neurological function after SBI. Collectively, our findings suggest that PI3Kγ contributed to neuroinflammation after SBI. The use of selective PI3Kγ inhibitors may be a novel approach to ameliorating SBI via their anti-inflammation effects. Significance statement: Life-saving or elective neurosurgeries often involve unavoidable damages to neighboring, nondiseased brain tissues. Such surgical brain injury (SBI) is attributable exclusively to the neurosurgical procedure itself and may cause postoperative complications that exacerbate neurological function. Although the importance of this medical problem is fully acknowledged, intraoperative administration of adjunctive treatment such as steroids and mannitol to patients undergoing neurosurgery appear not to be efficient remedies for SBI. To date, the issue of perioperative neuroprotection specifically against SBI has not been well studied. Using a clinically relevant rat model of SBI, we are exploring a new neuroprotective strategy targeting phosphoinositide 3-kinase gamma (PI3Kγ). PI3Kγ activates multiple inflammatory responses. By attenuating neuroinflammation, selective PI3Kγ inhibition would limit postoperative complications and benefit neurological outcomes.

Comparison between self-assembling peptide nanofiber scaffold (SAPNS) and fibrin sealant in neurosurgical hemostasis.

RADA16-I is a synthetic type I self-assembling peptide nanofiber scaffold (SAPNS) which may serve as a novel biocompatible hemostatic agent. Its application in neurosurgical hemostasis, however, has not been explored. Although RADA16-I is nontoxic and nonimmunogenic, its intrinsic acidity may potentially provoke inflammation in the surgically injured brain. We conducted an animal study to compare RADA16-I with fibrin sealant, a commonly used agent, with the hypothesis that the former would be a comparable alternative. Using a standardized surgical brain injury model, 30 Sprague-Dawley rats were randomized into three treatment groups: RADA16-I, fibrin sealant or gelatin sponge (control). Animals were sacrificed on day 3 and 42. Astrocytic and microglial infiltrations within the cerebral parenchyma adjacent to the operative site were significantly lower in the RADA16-I and fibrin sealant groups than control. RADA16-I did not cause more cellular inflammatory response despite its acidity when compared with fibrin sealant. Immunohistochemical studies showed infiltration by astrocytes and microglia into the fibrin sealant and RADA16-I grafts, suggesting their potential uses as tissue scaffolds. RADA16-I is a promising candidate for further translational and clinical studies that focus on its applications as a safe and effective hemostat, proregenerative nanofiber scaffold as well as drug and cell carrier.

What's New in Traumatic Brain Injury: Update on Tracking, Monitoring and Treatment.

Traumatic brain injury (TBI), defined as an alteration in brain functions caused by an external force, is responsible for high morbidity and mortality around the world. It is important to identify and treat TBI victims as early as possible. Tracking and monitoring TBI with neuroimaging technologies, including functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), positron emission tomography (PET), and high definition fiber tracking (HDFT) show increasing sensitivity and specificity. Classical electrophysiological monitoring, together with newly established brain-on-chip, cerebral microdialysis techniques, both benefit TBI. First generation molecular biomarkers, based on genomic and proteomic changes following TBI, have proven effective and economical. It is conceivable that TBI-specific biomarkers will be developed with the combination of systems biology and bioinformation strategies. Advances in treatment of TBI include stem cell-based and nanotechnology-based therapy, physical and pharmaceutical interventions and also new use in TBI for approved drugs which all present favorable promise in preventing and reversing TBI.

Correlation between subacute sensorimotor deficits and brain water content after surgical brain injury in rats.

Brain edema is a major contributor to poor outcome and reduced quality of life after surgical brain injury (SBI). Although SBI pathophysiology is well-known, the correlation between cerebral edema and neurological deficits has not been thoroughly examined in the rat model of SBI. Thus, the purpose of this study was to determine the correlation between brain edema and deficits in standard sensorimotor neurobehavior tests for rats subjected to SBI. Sixty male Sprague-Dawley rats were subjected to either sham surgery or surgical brain injury via partial frontal lobectomy. All animals were tested for neurological deficits 24 post-SBI and fourteen were also tested 72 h after surgery using seven common behavior tests: modified Garcia neuroscore (Neuroscore), beam walking, corner turn test, forelimb placement test, adhesive removal test, beam balance test, and foot fault test. After assessing the functional outcome, animals were euthanized for brain water content measurement. Surgical brain injury resulted in significantly elevated frontal lobe brain water content 24 and 72 h after surgery compared to that of sham animals. In all behavior tests, significance was observed between sham and SBI animals. However, a correlation between brain water content and functional outcome was observed for all tests except Neuroscore. The selection of behavior tests is critical to determine the effectiveness of therapeutics. Based on this study's results, we recommend using beam walking, the corner turn test, the beam balance test, and the foot fault test since correlations with brain water content were observed at both 24 and 72 h post-SBI.

Ischemic conditioning-induced endogenous brain protection: Applications pre-, per- or post-stroke.

In the area of brain injury and neurodegenerative diseases, a plethora of experimental and clinical evidence strongly indicates the promise of therapeutically exploiting the endogenous adaptive system at various levels like triggers, mediators and the end-effectors to stimulate and mobilize intrinsic protective capacities against brain injuries. It is believed that ischemic pre-conditioning and post-conditioning are actually the strongest known interventions to stimulate the innate neuroprotective mechanism to prevent or reverse neurodegenerative diseases including stroke and traumatic brain injury. Recently, studies showed the effectiveness of ischemic per-conditioning in some organs. Therefore the term ischemic conditioning, including all interventions applied pre-, per- and post-ischemia, which spans therapeutic windows in 3 time periods, has recently been broadly accepted by scientific communities. In addition, it is extensively acknowledged that ischemia-mediated protection not only affects the neurons but also all the components of the neurovascular network (consisting of neurons, glial cells, vascular endothelial cells, pericytes, smooth muscle cells, and venule/veins). The concept of cerebroprotection has been widely used in place of neuroprotection. Intensive studies on the cellular signaling pathways involved in ischemic conditioning have improved the mechanistic understanding of tolerance to cerebral ischemia. This has added impetus to exploration for potential pharmacologic mimetics, which could possibly induce and maximize inherent protective capacities. However, most of these studies were performed in rodents, and the efficacy of these mimetics remains to be evaluated in human patients. Several classical signaling pathways involving apoptosis, inflammation, or oxidation have been elaborated in the past decades. Newly characterized mechanisms are emerging with the advances in biotechnology and conceptual renewal. In this review we are going to focus on those recently reported methodological and mechanistic discoveries in the realm of ischemic conditioning. Due to the varied time differences of ischemic conditioning in different animal models and clinical trials, it is important to define optimal timing to achieve the best conditioning induced neuroprotection. This brings not only an opportunity in the treatment of stroke, but challenges as well, as data is just becoming available and the procedures are not yet optimized. The purpose of this review is to shed light on exploiting these ischemic conditioning modalities to protect the cerebrovascular system against diverse injuries and neurodegenerative disorders.