Tetranectin knockout mice develop features of Parkinson disease.

BACKGROUND/AIMS: Aggregation of insoluble α-synuclein to form Lewy bodies (LBs) may contribute to the selective loss of midbrain dopaminergic neurons in Parkinson disease (PD). Lack of robust animal models has impeded elucidation of the molecular mechanisms of LB formation and other critical aspects of PD pathogenesis. METHODS: We established a mouse model with targeted deletion of the plasminogen-binding protein tetranectin (TN) gene (TN(-/-)) and measured the behavioral and histopathological features of PD. RESULTS: Aged (15-to 20-month-old) TN(-/-) mice displayed motor deficits resembling PD symptoms, including limb rigidity and both slower ambulation (bradykinesia) and reduced rearing activity in the open field. In addition, these mice exhibited more numerous α-synuclein-positive LB-like inclusions within the substantia nigra pars compacta (SNc) and reduced numbers of SNc dopaminergic neurons than age-matched wild type (WT) mice. These pathological changes were also accompanied by loss of dopamine terminals in the dorsal striatum. CONCLUSION: The TN(-/-) mouse exhibits several key features of PD and so may be a valuable model for studying LB formation and testing candidate neuroprotective therapies for PD and other synucleinopathies.

Oral administration of lysozyme protects against injury of ileum via modulating gut microbiota dysbiosis after severe traumatic brain injury.

Objective: The current study sought to clarify the role of lysozyme-regulated gut microbiota and explored the potential therapeutic effects of lysozyme on ileum injury induced by severe traumatic brain injury (sTBI) and bacterial pneumonia in vivo and in vitro experiments. Methods: Male 6-8-week-old specific pathogen-free (SPF) C57BL/6 mice were randomly divided into Normal group (N), Sham group (S), sTBI group (T), sTBI + or Lysozyme-treated group (L), Normal + Lysozyme group (NL) and Sham group + Lysozyme group (SL). At the day 7 after establishment of the model, mice were anesthetized and the samples were collected. The microbiota in lungs and fresh contents of the ileocecum were analyzed. Lungs and distal ileum were used to detect the degree of injury. The number of Paneth cells and the expression level of lysozyme were assessed. The bacterial translocation was determined. Intestinal organoids culture and co-coculture system was used to test whether lysozyme remodels the intestinal barrier through the gut microbiota. Results: After oral administration of lysozyme, the intestinal microbiota is rebalanced, the composition of lung microbiota is restored, and translocation of intestinal bacteria is mitigated. Lysozyme administration reinstates lysozyme expression in Paneth cells, thereby reducing intestinal permeability, pathological score, apoptosis rate, and inflammation levels. The gut microbiota, including Oscillospira, Ruminococcus, Alistipes, Butyricicoccus, and Lactobacillus, play a crucial role in regulating and improving intestinal barrier damage and modulating Paneth cells in lysozyme-treated mice. A co-culture system comprising intestinal organoids and brain-derived proteins (BP), which demonstrated that the BP effectively downregulated the expression of lysozyme in intestinal organoids. However, supplementation of lysozyme to this co-culture system failed to restore its expression in intestinal organoids. Conclusion: The present study unveiled a virtuous cycle whereby oral administration of lysozyme restores Paneth cell's function, mitigates intestinal injury and bacterial translocation through the remodeling of gut microbiota.

Corticospinal-specific Shh overexpression in combination with rehabilitation promotes CST axonal sprouting and skilled motor functional recovery after ischemic stroke.

Ischemic stroke often leads to permanent neurological impairments, largely due to limited neuroplasticity in adult central nervous system. Here, we first showed that the expression of Sonic Hedgehog (Shh) in corticospinal neurons (CSNs) peaked at the 2nd postnatal week, when corticospinal synaptogenesis occurs. Overexpression of Shh in adult CSNs did not affect motor functions and had borderline effects on promoting the recovery of skilled locomotion following ischemic stroke. In contrast, CSNs-specific Shh overexpression significantly enhanced the efficacy of rehabilitative training, resulting in robust axonal sprouting and synaptogenesis of corticospinal axons into the denervated spinal cord, along with significantly improved behavioral outcomes. Mechanistically, combinatory treatment led to additional mTOR activation in CSNs when compared to that evoked by rehabilitative training alone. Taken together, our study unveiled a role of Shh, a morphogen involved in early development, in enhancing neuroplasticity, which significantly improved the outcomes of rehabilitative training. These results thus provide novel insights into the design of combinatory treatment for stroke and traumatic central nervous system injuries.

Independent risk factors for in-hospital outcome of myasthenic crisis: a prospective cohort study.

Background: Myasthenic crisis (MC) is a life-threatening condition for myasthenia gravis (MG). Therapeutic plasma exchange (TPE) and intravenous immunoglobulin (IVIg) efficaciously treat patients with MC. However, not every MC responds well to rescue therapies, and the determinants for outcome with the evidence from prospective cohorts are still lacking. Objectives: To explore the risk factors for in-hospital outcomes in patients with MC. Methods: Using a national neuromuscular center-based cohort of MG with prospective follow-ups from the crisis to the post-crisis phase, we finally included 90 MC episodes from 76 independent patients who received a standard regimen of rescue therapies. Results: The mean admission age was 52.89 ± 15.72 years. With a female predominance of 63.16% (48/76) and a high proportion of thymoma-associated MG (TMG) of 63.16% (48/76), the overall in-hospital mortality was 2.63% (2/76) and the average duration for mechanical ventilation (MV) use was 17.09 ± 13.36 days (0-53 days). In contrast to the patients with anti-acetylcholine receptor (AChR) antibodies, muscle-specific tyrosine kinase (MuSK)-associated MC exhibited a shorter MV support (5.20 ± 5.07 versus 17.40 ± 13.24 days, p = 0.023), length of intensive care units (ICU) stay (6.00 ± 4.64 versus 19.16 ± 17.54 days, p = 0.046), and hospital stay (16.00 ± 4.12 versus 34.43 ± 20.48 days, p = 0.011). Thymoma [odds ratio (OR): 0.200, 95% confidence interval (CI): 0.058-0.687, p = 0.011], partial pressure of carbon dioxide (PCO2) in blood gas before MV (OR: 1.238, 95% CI: 1.015-1.510, p = 0.035), and pneumonia (OR: 0.204, 95% CI: 0.049-0.841, p = 0.028) were identified as independent risk factors for prolonged MV use. TMG patients with thymoma burden exhibited a notable longer MV use (22.08 ± 17.54 versus 8.88 ± 6.79 days, p = 0.001), a prolonged hospital stay (40.40 ± 26.13 versus 23.67 ± 13.83 days, p = 0.009) compared with non-TMG. Even with complete thymoma resection (R0), TMG exhibited an unfavorable outcome versus non-TMG. Conclusion: With timely rescue therapies and prospective follow-ups, the in-hospital outcome of MCs was substantially improved. Thymoma, PCO2 in blood gas before MV, and pneumonia were identified as independent risk factors for prolonged MV use.

Risk factors for in-hospital outcome of myasthenic crisis Myasthenic crisis (MC) is a life-threatening condition for myasthenia gravis (MG). Therapeutic plasma exchange (TPE) and intravenous immunoglobulin (IVIg) efficaciously treat patients with MC. However, not every MC responds well to rescue therapies, and the determinants for outcome with the evidence from prospective cohorts are still lacking. Using a national neuromuscular center-based cohort of MG with prospective follow-ups from the crisis to the post-crisis phase, we were able to include 90 MC episodes from 76 independent patients who received a standard regimen of rescue therapies. The mean admission age was 52.89±15.72 years. With a female predominance and a high proportion of thymoma-associated MG. The overall in-hospital mortality was 2.63% (2/76) and the average duration for MV use was 17.09±13.36 days (0-53 days). In contrast to the patients with anti-AChR antibodies, MuSK-associated MC exhibited a shorter MV support, length of ICU stay and hospital stay. Thymoma, PCO2 in blood gas before MV, and pneumonia were identified as independent risk factors for prolonged MV use. TMG patients with thymoma burden exhibited a notable longer MV use, a prolonged hospital stay compared with non-TMG. Even with complete thymoma resection (R0), TMG exhibited an unfavorable outcome versus non-TMG. With timely rescue therapies and prospective follow-ups, the in-hospital outcome of MCs was substantially improved. Thymoma, PCO2 in blood gas before MV, and pneumonia.

Prevalence and Clinical Characteristics of Bacterial Pneumonia in Neurosurgical Emergency Center Patients: A Retrospective Study Spanning 13 Years at a Tertiary Center.

Patients with brain injuries are at a heightened susceptibility to bacterial pneumonia, and the timely initiation of empiric antibiotic treatment has been shown to substantially reduce mortality rates. Nevertheless, there is a need for knowledge regarding the resistance and prevalence of pulmonary bacterial infections in this patient population. To address this gap, a retrospective study was conducted at a neurosurgical emergency center, focusing on patients with brain injuries. Among the entire patient population, a total of 739 individuals (18.23%) were identified as having bacterial pneumonia, consisting of 1489 strains of Gram-negative bacteria and 205 strains of Gram-positive bacteria. The resistance of Klebsiella pneumoniae to imipenem exhibited a significant increase, rising from 21.74% in 2009 to 96.67% in 2018, and subsequently reaching 48.47% in 2021. Acinetobacter baumannii displayed resistance rates exceeding 80.0% against multiple antibiotics. The resistance profile of Pseudomonas aeruginosa was relatively low. The proportion of Staphylococcus aureus reached its peak at 18.70% in 2016, but experienced a decline to 7.83% in 2021. The abundance of Gram-negative bacteria exceeded that of Gram-positive bacteria by a factor of 5.96. Klebsiella pneumoniae, Acinetobacter baumannii, and Staphylococcus aureus are prominent pathogens characterized by limited antibiotic choices and scarce treatment alternatives for the isolated strains.

Perioperative Risk Factors Associated with Unplanned Neurological Intensive Care Unit Events Following Elective Infratentorial Brain Tumor Resection.

BACKGROUND: Our aim of this study was to identify risk factors and develop a prediction model for unplanned neurological intensive care unit (NICU) events after elective infratentorial brain tumor resection in order to propose an individualized admission to the NICU tailored to patient needs. METHODS: Patients admitted to our NICU between September 2018 and May 2021 after elective infratentorial brain tumor resection were reviewed. Prolonged NICU stays and unplanned NICU admissions were defined as unplanned NICU events. The prognostic model of unplanned NICU events was developed using a forward stepwise logistic regression analysis, and external validation was evaluated. The C-statistic was used to assess discrimination, and a smooth, nonparametric calibration line was used to assess calibration graphically in the model. RESULTS: Of the 1,710 patients in the development cohort, unplanned NICU events occurred in 162 (9.5%). Based on the lesion type, a Karnofsky Performance Status score <70 at admission, longer duration of surgery, bleeding in the operative area evident on postoperative computed tomography, higher fibrinogen and blood glucose levels at admission, and more intraoperative blood loss were independently associated with unplanned NICU events. The external validation test showed good discrimination (C-statistic = 0.811) and calibration (Hosmer-Lemeshow P = 0.141) for unplanned NICU events. CONCLUSIONS: Several patient and operative characteristics are associated with a greater likelihood of the occurrence of unplanned NICU events. In the future, we may be able to provide better help for the resource allocation of NICUs according to these risk factors and prediction models.

Perioperative risk factors associated with unplanned neurological intensive care unit readmission following elective supratentorial brain tumor resection.

OBJECTIVE: The aim of this study was to describe the clinical and procedural risk factors associated with the unplanned neurosurgical intensive care unit (NICU) readmission of patients after elective supratentorial brain tumor resection and serves as an exploratory analysis toward the development of a risk stratification tool that may be prospectively applied to this patient population. METHODS: This was a retrospective observational cohort study. The electronic medical records of patients admitted to an institutional NICU between September 2018 and November 2021 after elective supratentorial brain tumor resection were reviewed. Demographic and perioperative clinical factors were recorded. A prognostic model was derived from the data of 4892 patients recruited between September 2018 and May 2021 (development cohort). A nomogram was created to display these predictor variables and their corresponding points and risks of readmission. External validation was evaluated using a series of 1118 patients recruited between June 2021 and November 2021 (validation cohort). Finally, a decision curve analysis was performed to determine the clinical usefulness of the prognostic model. RESULTS: Of the 4892 patients in the development cohort, 220 (4.5%) had an unplanned NICU readmission. Older age, lesion type, Karnofsky Performance Status (KPS) < 70 at admission, longer duration of surgery, retention of endotracheal intubation on NICU entry, and longer NICU length of stay (LOS) after surgery were independently associated with an unplanned NICU readmission. A total of 1118 patients recruited between June 2021 and November 2021 were included for external validation, and the model's discrimination remained acceptable (C-statistic = 0.744, 95% CI 0.675-0.814). The decision curve analysis for the prognostic model in the development and validation cohorts showed that at a threshold probability between 0.05 and 0.8, the prognostic model showed a positive net benefit. CONCLUSIONS: A predictive model that included age, lesion type, KPS < 70 at admission, duration of surgery, retention of endotracheal intubation on NICU entry, and NICU LOS after surgery had an acceptable ability to identify elective supratentorial brain tumor resection patients at high risk for an unplanned NICU readmission. These risk factors and this prediction model may facilitate better resource allocation in the NICU and improve patient outcomes.

Characteristics and therapeutic profile of TBI patients who underwent bilateral decompressive craniectomy: experience with 151 cases.

BACKGROUND: Decompressive craniectomy (DC) and intracranial pressure (ICP) monitoring are common approaches to reduce the death rate of Traumatic brain injury (TBI) patients, but the outcomes of these patients are unfavorable, particularly those who receive bilateral DC. The authors discuss their experience using ICP and other potential methods to improve the outcomes of TBI patients who receive bilateral DC. METHODS: Data from TBI patients receiving bilateral DC from Jan. 2008 to Jan. 2022 were collected via a retrospective chart review. Included patients who received unplanned contralateral DC after initial surgery were identified as unplanned secondary surgery (USS) patients. Patients' demographics and baseline medical status; pre-, intra-, and postoperative events; and follow-up visit outcome data were analyzed. RESULTS: A total of 151 TBI patients were included. Patients who underwent USS experienced more severe outcomes as assessed using the 3-month modified Rankin Scale score (P = 0.024). In bilateral DC TBI patients, USS were associated with worsen outcomes, moreover, ICP monitoring was able to lower their death rate and was associated with a lower USS incidence. In USS patients, ICP monitoring was not associated with improved outcomes but was able to lower their mortality rate (2/19, 10.5%, vs. 10/25, 40.0%; P = 0.042). CONCLUSION: The avoidance of USS may be associated with improved outcomes of TBI patients who underwent bilateral DC. ICP monitoring was a potential approach to lower USS rate in TBI patients, but its specific benefits were uncertain.

Validating the incidence of coagulopathy and disseminated intravascular coagulation in patients with traumatic brain injury--analysis of 242 cases.

OBJECTIVES: To estimate the incidence of coagulopathy and disseminated intravascular coagulation (DIC) in patients with traumatic brain injury (TBI) and to investigate its relationship to patient outcome. DESIGN: A prospective observational study. MEASUREMENTS AND MAIN RESULTS: From January 2007 to June 2009, 242 consecutive adult patients with TBI seen in three independent hospitals were recruited. Glasgow Coma Score (GCS) on admission, platelet counts (PLT), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), D-dimer (D-DT) and DIC scores were recorded for each case on admission. Clinical outcome was measured according to the Glasgow Outcome Scale (GOS) at 3 months after injury. Statistical analysis was carried using Student's t-test, one-way analysis of variance (ANOVA), and Tudey test. Coagulation abnormalities were present in approximately 50% of patients with TBI. Prolonged PT and increased D-DT and FIB levels occurred in patients with more severe brain injury and poorer outcome, and these findings were statistically significant. CONCLUSIONS: Coagulation changes, particularly the incidence of DIC, may occur within 6 h after TBI and are more pronounced in patients with severe injuries and poor outcome. PT, D-DT levels and more comprehensively a DIC scores may be useful prognostic indicators in patients with TBI.

Geniposide ameliorates chronic unpredictable mild stress induced depression-like behavior through inhibition of ceramide-PP2A signaling via the PI3K/Akt/GSK3ß axis.

BACKGROUND: Depression is a severe mental disorder. Unfortunately, more than half of patients with major depression disorder cannot achieve remission after initial treatment with an antidepressant. Geniposide, a bioactive iridoid glycoside isolated from Gardenia jasminoides Ellis, can ameliorate depressive-like behaviors in mice. However, the underlying mechanism is still not very clear. METHODS: The pharmacological methods including ELISA, immunofluorescence, and Western blot were used to investigate the role of geniposide on chronic unpredictable mild stress (CUMS)-induced depression mice. RESULTS: In this study, we found that geniposide could inhibit CUMS-induced depressive-like behaviors in mice. Geniposide is able to reduce the levels of ceramide and lower the activity of acid sphingomyelinase (ASM) in hippocampus; besides, ASM inhibitor (amitriptyline) can decrease the concentration of ceramide and ameliorate depressive-like behaviors of mice. Moreover, geniposide can also alleviate CUMS-induced hippocampal neuronal apoptosis and increase the phosphorylated form of PI3K, Akt, and GSK3ß. Additionally, PI3K inhibitor (LY294002) can also abolish the neuroprotective effect of geniposide on hippocampal neurons in vitro. CONCLUSIONS: These results indicate that geniposide exert a potential antidepressant-like effect on CUMS mice, and its effect might be associated with activated PI3K/Akt/GSK3ß signaling, reduced the level of ceramide and hippocampal neuron apoptosis.

[Expression study of DNA translesion synthesis genes in human primary glioma].

OBJECTIVE: To detect the expressions of Rev1, Pol zeta, Pol eta, Pol iota and Pol kappa mRNA in human primary glioma tissues, and to analyze the relationship between the expression and the pathological grade. METHODS: We applied SYBR Green real-time PCR to investigate the mRNA expressions of the 6 genes in 85 primary glioma tissues and 14 normal brain tissues. RESULTS: The expressions of 4 genes including Rev3, Rev7, Pol eta and Pol iota were significantly (P < 0.05) higher in glioma tissues in grade II, III and IV as compared to normal brain tissues. The expressions of Rev1 and Pol kappa were significantly (P < 0.05) higher in grade IV glioma compared to the normal brain tissue. The positive correlation existed (P < 0.01) between the expression of all genes mRNA and the pathologic grade of the human glioma, except for Rev7. CONCLUSION: The up-regulation of DNA translesion synthesis genes, including Rev1, Rev3, Rev7, Pol eta, Pol iota and Pol kappa, may be associated with pathogenesis of glioma.

Comparison of the effects of albumin and crystalloid on mortality among patients with septic shock: systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: This study aimed to compare the effects on mortality of albumin and crystalloid, used for fluid resuscitation among adult patients with septic shock, through conducting a meta-analysis and trial sequential analysis (TSA). DESIGN AND SETTING: Meta-analysis and TSA conducted at Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China. METHODS: Data were collected from several major databases including MEDLINE, EMBASE, Clinical Trials.gov and Cochrane Central Register of Controlled Trials. Studies that compared the effects of albumin therapy versus crystalloid therapy on mortality among adult septic shock patients were eligible for inclusion in the analyses. The study name, year of publication, country of the trial, albumin concentration, type of crystalloid and all reported mortalities at different follow-up endpoints were extracted. RESULTS: Compared with crystalloid, albumin did not decrease all-cause mortality at the final follow-up. However, in TSA, the required information size was not achieved in all groups, which means that the effect size was not definitive and further RCTs are needed to confirm or deny these findings. CONCLUSIONS: Compared with crystalloid solutions, albumin was unable to decrease all-cause mortality. However, TSA indicated that these results could be false-negative. Additional randomized controlled trials are needed to clarify this discrepancy.

Angiotensin-converting enzyme 2 prevents lipopolysaccharide-induced rat acute lung injury via suppressing the ERK1/2 and NF-κB signaling pathways.

Acute respiratory distress syndrome (ARDS) caused by severe sepsis remains a major challenge in intensive care medicine. ACE2 has been shown to protect against lung injury. However, the mechanisms of its protective effects on ARDS are largely unknown. Here, we report that ACE2 prevents LPS-induced ARDS by inhibiting MAPKs and NF-κB signaling pathway. Lentiviral packaged Ace2 cDNA or Ace2 shRNA was intratracheally administrated into the lungs of male SD rats. Two weeks after gene transfer, animals received LPS (7.5 mg/Kg) injection alone or in combination with Mas receptor antagonist A779 (10 µg/Kg) or ACE2 inhibitor MLN-4760 (1 mg/Kg) pretreatment. LPS-induced lung injury and inflammatory response were significantly prevented by ACE2 overexpression and deteriorated by Ace2 shRNA. A779 or MLN-4760 pretreatment abolished the protective effects of ACE2. Moreover, overexpression of ACE2 significantly reduced the Ang II/Ang-(1-7) ratio in BALF and up-regulated Mas mRNA expression in lung, which was reversed by A779. Importantly, the blockade of ACE2 on LPS-induced phosphorylation of ERK1/2, p38 and p50/p65 was also abolished by A779. Whereas, only the ERK1/2 inhibitor significantly attenuated lung injury in ACE2 overexpressing rats pretreated with A779. Our observation suggests that AEC2 attenuates LPS-induced ARDS via the Ang-(1-7)/Mas pathway by inhibiting ERK/NF-κB activation.

Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis prevents lipopolysaccharide-induced apoptosis of pulmonary microvascular endothelial cells by inhibiting JNK/NF-κB pathways.

ACE2 and Ang-(1-7) have important roles in preventing acute lung injury. However, it is not clear whether upregulation of the ACE2/Ang-(1-7)/Mas axis prevents LPS-induced injury in pulmonary microvascular endothelial cells (PMVECs) by inhibiting the MAPKs/NF-κB pathways. Primary cultured rat PMVECs were transduced with lentiviral-borne Ace2 or shRNA-Ace2, and then treated or not with Mas receptor blocker (A779) before exposure to LPS. LPS stimulation resulted in the higher levels of AngII, Ang-(1-7), cytokine secretion, and apoptosis rates, and the lower ACE2/ACE ratio. Ace2 reversed the ACE2/ACE imbalance and increased Ang-(1-7) levels, thus reducing LPS-induced apoptosis and inflammation, while inhibition of Ace2 reversed all these effects. A779 abolished these protective effects of Ace2. LPS treatment was associated with activation of the ERK, p38, JNK, and NF-κB pathways, which were aggravated by A779. Pretreatment with A779 prevented the Ace2-induced blockade of p38, JNK, and NF-κB phosphorylation. However, only JNK inhibitor markedly reduced apoptosis and cytokine secretion in PMVECs with Ace2 deletion and A779 pretreatment. These results suggest that the ACE2/Ang-(1-7)/Mas axis has a crucial role in preventing LPS-induced apoptosis and inflammation of PMVECs, by inhibiting the JNK/NF-κB pathways.

Comparison of the effects of albumin and crystalloid on mortality among patients with septic shock: systematic review with meta-analysis and trial sequential analysis

ABSTRACT BACKGROUND: This study aimed to compare the effects on mortality of albumin and crystalloid, used for fluid resuscitation among adult patients with septic shock, through conducting a meta-analysis and trial sequential analysis (TSA). DESIGN AND SETTING: Meta-analysis and TSA conducted at Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China. METHODS: Data were collected from several major databases including MEDLINE, EMBASE, Clinical Trials.gov and Cochrane Central Register of Controlled Trials. Studies that compared the effects of albumin therapy versus crystalloid therapy on mortality among adult septic shock patients were eligible for inclusion in the analyses. The study name, year of publication, country of the trial, albumin concentration, type of crystalloid and all reported mortalities at different follow-up endpoints were extracted. RESULTS: Compared with crystalloid, albumin did not decrease all-cause mortality at the final follow-up. However, in TSA, the required information size was not achieved in all groups, which means that the effect size was not definitive and further RCTs are needed to confirm or deny these findings CONCLUSIONS: Compared with crystalloid solutions, albumin was unable to decrease all-cause mortality. However, TSA indicated that these results could be false-negative. Additional randomized controlled trials are needed to clarify this discrepancy.

REV3L confers chemoresistance to cisplatin in human gliomas: the potential of its RNAi for synergistic therapy.

The REV3L gene, encoding the catalytic subunit of human polymerase zeta, plays a significant role in the cytotoxicity, mutagenicity, and chemoresistance of certain tumors. However, the role of REV3L in regulating the sensitivity of glioma cells to chemotherapy remains unknown. In this study, we investigated the expression of the REV3L gene in 10 normal brain specimens and 30 human glioma specimens and examined the value of REV3L as a potential modulator of cellular response to various DNA-damaging agents. Reverse transcriptase PCR/real-time PCR analysis revealed that REV3L was overexpressed in human gliomas compared with normal brain tissues. A glioma cell model with stable overexpression of REV3L was used to probe the role of REV3L in cisplatin treatment; upregulation of REV3L markedly attenuated cisplatin-induced apoptosis of the mitochondrial apoptotic pathway. We therefore assessed the REV3L-targeted treatment modality that combines suppression of REV3L expression using RNA interference (RNAi) with the cytotoxic effects of DNA-damaging agents. Downregulation of REV3L expression significantly enhanced the sensitivity of glioma cells to cisplatin, as evidenced by the increased apoptosis rate and marked alterations in the anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xl) and proapoptotic Bcl-2-associated x protein (Bax) expression levels, and reduced mutation frequencies in surviving glioma cells. These results suggest that REV3L may potentially contribute to gliomagenesis and play a crucial role in regulating cellular response to the DNA cross-linking agent cisplatin. Our findings indicate that RNAi targeting REV3L combined with chemotherapy has synergistic therapeutic effects on glioma cells, which warrants further investigation as an effective novel therapeutic regimen for patients with this malignancy.