Macrophage/Microglia Sirt3 Contributes to the Anti-inflammatory Effects of Resveratrol Against Experimental Intracerebral Hemorrhage in Mice.

Intracerebral hemorrhage (ICH) is a devastating stroke type with high mortality and disability. Inflammatory response induced by macrophages/microglia (M/Ms) activation is one of the leading causes of brain damage after ICH. The anti-inflammatory effects of resveratrol (RSV) have already been evaluated in several models of central nervous system disease. Therefore, we designed the current study to assess the role of RSV in ICH and explore its downstream mechanism related to Sirt3. The autologous artery blood injection was administrated to create an ICH mouse model. M/Ms-specific Sirt3 knockout Sirt3f/f; CX3CR1-Cre (Sirt3 cKO) mouse was used to evaluate the role of Sirt3 on RSV treatment. Neuronal function and hematoma volume were assessed to indicate brain damage. The pro-inflammatory marker (CD16) and cytokine (TNF) were measured to evaluate the inflammatory effects. Our results showed that RSV treatment alleviates neurological deficits, reduces cell death, and increases hematoma clearance on day 7 after ICH. In addition, RSV effectively suppressed CD16+ M/Ms activation and decreased TNF release. In Sirt3 cKO mice, the protective effects of RSV were abolished, indicating the potential mechanism of RSV was partially due to Sirt3 signaling activation. Therefore, RSV could be a promising candidate and therapeutic agent for ICH and Sirt3 could be a potential target to inhibit inflammation.

Top-down stepwise refinement identifies coding and noncoding RNA-associated epigenetic regulatory maps in malignant glioma.

With the emergence of the molecular era and retreat of the histology epoch in malignant glioma, it is becoming increasingly necessary to research diagnostic/prognostic/therapeutic biomarkers and their related regulatory mechanisms. While accumulating studies have investigated coding gene-associated biomarkers in malignant glioma, research on comprehensive coding and noncoding RNA-associated biomarkers is lacking. Furthermore, few studies have illustrated the cross-talk signalling pathways among these biomarkers and mechanisms in detail. Here, we identified DEGs and ceRNA networks in malignant glioma and then constructed Cox/Lasso regression models to further identify the most valuable genes through stepwise refinement. Top-down comprehensive integrated analysis, including functional enrichment, SNV, immune infiltration, transcription factor binding site, and molecular docking analyses, further revealed the regulatory maps among these genes. The results revealed a novel and accurate model (AUC of 0.91 and C-index of 0.84 in the whole malignant gliomas, AUC of 0.90 and C-index of 0.86 in LGG, and AUC of 0.75 and C-index of 0.69 in GBM) that includes twelve ncRNAs, 1 miRNA and 6 coding genes. Stepwise logical reasoning based on top-down comprehensive integrated analysis and references revealed cross-talk signalling pathways among these genes that were correlated with the circadian rhythm, tumour immune microenvironment and cellular senescence pathways. In conclusion, our work reveals a novel model where the newly identified biomarkers may contribute to a precise diagnosis/prognosis and subclassification of malignant glioma, and the identified cross-talk signalling pathways would help to illustrate the noncoding RNA-associated epigenetic regulatory mechanisms of glioma tumorigenesis and aid in targeted therapy.

Intermittent fasting reduces neuroinflammation in intracerebral hemorrhage through the Sirt3/Nrf2/HO-1 pathway.

BACKGROUND: Inflammation contributes to the poor prognosis of intracerebral hemorrhage (ICH). Intermittent fasting (IF) has been shown to be protective against inflammation in multiple pathogenic processes. In the present study, we aimed to investigated the beneficial effects of IF in attenuating neuroinflammation and neurological deficits in a mouse model of ICH and to investigate the underlying mechanism. METHODS: ICH was modeled by intrastriatal injection of autologous blood and IF was modeled by every-other-day feeding in male control mice (C57BL/6), mice with and microglia specific knockout Sirt3f/f;Cx3cr1-Cre (Sirt3 cKO), and Sirt3f/f (wild-type) mice. Brain tissues and arterial blood were harvested at 1, 3, 7 and 28 days after ICH for immunohistochemistry analysis of Iba-1, DARPP-32 and HO-1, morphological analysis by HE staining and inflammatory factor release tests by ELISA. Neurological functions were approached by corner test and cylinder test. Fluorescent double-labeled staining of Iba-1 with CD16, Arg1 or Sirt3 was used to provide direct image of co-expression of these molecules in microglia. TUNEL, cleaved caspase-3 and Nissl staining was performed to evaluate cellular injuries. RESULTS: IF alleviated neurological deficits in both acute and chronic phases after ICH. Morphologically, IF enhanced hematoma clearance, reduced brain edema in acute phase and attenuated striatum atrophy in chronic phase. In addition, IF decreased the numbers of TUNEL+ cells and increased Nissl+ neuron number at day 1, 3 and 7 after ICH. IF suppressed CD16+Iba-1+ microglia activation at day 3 after ICH and reduced inflammatory releases, such as IL-1ß and TNF-α. The above effects of IF were attenuated by microglia Sirt3 deletion partly because of an inhibition of Nrf2/HO-1 signaling pathway. Interestingly, IF increased Iba-1+ microglia number at day 7 which mainly expressed Arg1 while decreased the proinflammatory factor levels. In mice with microglia-specific Sirt3 deletion, the effects of IF on Iba-1+ microglia activation and anti-inflammatory factor expressions were attenuated when compared with wild-type Sirt3f/f mice. CONCLUSIONS: IF protects against ICH by suppressing the inflammatory responses via the Sirt3/Nrf2/HO-1 pathway.

Iduna protects HT22 cells by inhibiting parthanatos: The role of the p53-MDM2 pathway.

Traumatic brain injury (TBI) is common and often fatal in current times. The role of poly(adenosine diphosphate-ribose) polymerase (PARP)-induced cell death (parthanatos) in TBI has not been well studied. Our past study showed that oxidative stress-induced cell death includes parthanatos by confirming the occurrence of PARP activation and nuclear translocation of apoptosis-inducing factor (AIF). As oxidative stress plays a key role in pathological progression after TBI, we believe TBI may also be alleviated by the expression of Iduna, which is the only known endogenous regulator of parthanatos. Thus, a transection model in HT-22 cells was established for present study. Downregulation of Iduna aggravated the cell damage caused by mechanical cell injury, whereas upregulation of Iduna reduced mitochondrial dysfunction induced by mechanical cell injury but exerted no effect on apoptosis associated with mitochondrial dysfunction. By contrast, Iduna prevented parthanatos by reducing PARP activation and nuclear translocation of AIF. We also investigated 2 novel p53-MDM2 pathway inhibitors, AMG 232 and Nutlin-3, which substantially reduced the protective effects of Iduna. These findings indicate that Iduna might prevent TBI by specifically inhibiting parthanatos and promoting mitochondrial function, with the p53-MDM2 pathway playing a critical role.

Establishment and validation of a model for brain injury state evaluation and prognosis prediction.

PURPOSE: Traumatic brain injury (TBI) is one of the leading causes of disability and death in modern times, whose evaluation and prognosis prediction have been one of the most critical issues in TBI management. However, the existed models for the abovementioned purposes were defective to varying degrees. This study aims to establish an ideal brain injury state clinical prediction model (BISCPM). METHODS: This study was a retrospective design. The six-month outcomes of patients were selected as the end point event. BISCPM was established by using the split-sample technology, and externally validated via different tests of comparison between the observed and predicted six-month mortality in validating group. TBI patients admitted from July 2006 to June 2012 were recruited and randomly divided into establishing model group and validating model group. Twenty-one scoring indicators were included in BISCPM and divided into three parts, A, B, and C. Part A included movement, pupillary reflex and diameter, CT parameters, and secondary brain insult factors, etc. Part B was age and part C was medical history of the patients. The total score of part A, B and C was final score of BISCPM. RESULTS: Altogether 1156 TBI patients were included with 578 cases in each group. The score of BISCPM from validating group ranged from 2.75 to 31.94, averaging 13.64 ± 5.59. There was not statistical difference between observed and predicted mortality for validating group. The discrimination validation showed that the BISCPM is superior to international mission for prognosis and analysis of clinical trials (IMPACT) lab model. CONCLUSION: BISCPM is an effective model for state evaluation and prognosis prediction of TBI patients. The use of BISCPM could be of great significance for decision-making in management of TBI.

Minocycline attenuates brain injury and iron overload after intracerebral hemorrhage in aged female rats.

Brain iron overload is involved in brain injury after intracerebral hemorrhage (ICH). There is evidence that systemic administration of minocycline reduces brain iron level and improves neurological outcome in experimental models of hemorrhagic and ischemic stroke. However, there is evidence in cerebral ischemia that minocycline is not protective in aged female animals. Since most ICH research has used male models, this study was designed to provide an overall view of ICH-induced iron deposits at different time points (1 to 28 days) in aged (18-month old) female Fischer 344 rat ICH model and to investigate the neuroprotective effects of minocycline in those rats. According to our previous studies, we used the following dosing regimen (20 mg/kg, i.p. at 2 and 12 h after ICH onset followed by 10 mg/kg, i.p., twice a day up to 7 days). T2-, T2⁎-weighted and T2⁎ array MRI was performed at 1, 3, 7 and 28 days to measure brain iron content, ventricle volume, lesion volume and brain swelling. Immunohistochemistry was used to examine changes in iron handling proteins, neuronal loss and microglial activation. Behavioral testing was used to assess neurological deficits. In aged female rats, ICH induced long-term perihematomal iron overload with upregulated iron handling proteins, neuroinflammation, brain atrophy, neuronal loss and neurological deficits. Minocycline significantly reduced ICH-induced perihematomal iron overload and iron handling proteins. It further reduced brain swelling, neuroinflammation, neuronal loss, delayed brain atrophy and neurological deficits. These effects may be linked to the role of minocycline as an iron chelator as well as an inhibitor of neuroinflammation.

Mitofusin 2 Exerts a Protective Role in Ischemia Reperfusion Injury Through Increasing Autophagy.

BACKGROUND/AIMS: Autophagy is essential for maintaining cellular homeostasis and the survival of terminally differentiated cells as neurons. In this study, we aim to investigate whether mitofusin 2, a mitochondrial fusion protein, mediates autophagy in cerebral ischemia/reperfusion (I/R) injury. METHODS: Primary cultured neurons were treated with oxygen-glucose deprivation/reperfusion to mimic cerebral I/R injury in vitro. Autophagosomes were visualized upon TEM. Autophagy-markers were then detected to monitor autophagy by western-blot and real-time PCR, and the autophagic flux was tracked with a mRFP-GFP-LC3 construct by fluorescence as well as autophagy inhibitors and agonists. The up- and downregulation of Mfn2 were through transfecting a lentivirusexpression vector respectively. And neuronal injury was detected by cell counting kit and TUNEL assay. RESULTS: Results showed I/R increased autophagosome formation and inhibited autolysosome degradation. Furthermore, use of autophagy related agents demonstrated that I/R injury was caused by insufficient autophagy and aggravated by impaired autophagic degradation. The results also indicated that mitofusin 2 could ameliorate I/R injury through increasing autophagosome formation and promoting the fusion of autophagosomes and lysosomes. In contrast, downregulation of mitofusin 2 aggravated the I/R injury by inhibiting autophagosome formation and the fusion of autophagosomes and lysosomes. Additionly, mitofusin 2 overexpression did not lead to autolysosome accumulation induced by I/R. CONCLUSIONS: In summary, this study explicitly demonstrated that mitofusin 2 could ameliorate I/R injury mainly through promoting autophagy, which represented a potential novel strategy for neuroprotection against cerebral I/R damage.

The AMPAR Antagonist Perampanel Attenuates Traumatic Brain Injury Through Anti-Oxidative and Anti-Inflammatory Activity.

Perampanel is a novel α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) antagonist, approved in over 35 countries as an adjunctive therapy for the treatment of seizures. Recently, it was found to exert protective effects against ischemic neuronal injury in vitro. In the present study, we investigated the potential protective effects of perampanel in a traumatic brain injury (TBI) model in rats. Oral administration with perampanel at a dose of 5 mg/kg exerted no major organ-related toxicities. We found that perampanel significantly attenuated TBI-induced brain edema, brain contusion volume, and gross motor dysfunction. The results of Morris water maze test demonstrated that perampanel treatment also improved cognitive function after TBI. These neuroprotective effects were accompanied by reduced neuronal apoptosis, as evidenced by decreased TUNEL-positive cells in brain sections. Moreover, perampanel markedly inhibited lipid peroxidation and obviously preserved the endogenous antioxidant system after TBI. In addition, enzyme-linked immunosorbent assay (ELISA) was performed at 4 and 24 h after TBI to evaluate the expression of inflammatory cytokines. The results showed that perampanel suppressed the expression of pro-inflammatory cytokines TNF-α and IL-1ß, whereas increased the levels of anti-inflammatory cytokines IL-10 and TGF-ß1. These data show that the orally active AMPAR antagonist perampanel affords protection against TBI-induced neuronal damage and neurological dysfunction through anti-oxidative and anti-inflammatory activity.

Downregulation of STIM2 improves neuronal survival after traumatic brain injury by alleviating calcium overload and mitochondrial dysfunction.

Although store-operated calcium entry (SOCE) has been implicated in several neurological disorders, the exact mechanism for its role in traumatic brain injury (TBI) has not been elucidated. In this study, we found that TBI upregulated the expression of a calcium sensor protein called stromal interactive molecule 2 (STIM2); however, the levels of its homologue, STIM1, were unaffected. Both STIM1 and STIM2 are crucial components of SOCE, both in vivo and in vitro. Using shRNA, we discovered that downregulation of STIM2, but not STIM1, significantly improved neuronal survival in both an in vitro and in vivo model of TBI, decreasing neuronal apoptosis, and preserving neurological function. This neuroprotection was associated with alleviating TBI-induced calcium overload and preserving mitochondrial function. Additionally, downregulation of STIM2 not only inhibited Ca(2+) release from the endoplasmic reticulum (ER), but also reduced SOCE-mediated Ca(2+) influx, decreased mitochondrial Ca(2+), restored mitochondrial morphology and improved mitochondrial function, including MMP maintenance, ROS production and ATP synthesis. These results indicate that inhibition of STIM2 can protect neurons from TBI by inhibiting calcium overload and preserving mitochondrial function. This suggests that STIM2 might be an effective interventional target for TBI.

Expression of 58-kD Microspherule Protein (MSP58) is Highly Correlated with PET Imaging of Tumor Malignancy and Cell Proliferation in Glioma Patients.

BACKGROUND/AIMS: The nucleolar 58-kDa microspherule protein (MSP58) has important transcriptional regulation functions and plays a crucial role in the tumorigenesis and progression of cancers. 3'-deoxy-3'-[18F]fluorothymidine (FLT) has emerged as a promising positron emission tomography (PET) tracer for evaluating tumor malignancy and cell proliferation. METHODS: In the present study, the expression of MSP58 was evaluated by immunohistochemistry and the corresponding PET image was examined using FLT-PET in 55 patients with various grades of gliomas. RESULTS: The immunoreactivity score (IRS) of MSP58 increased with tumor grade with grade IV gliomas exhibiting the highest expression and showed a highly significant positive correlation with the Ki-67 index (r = 0.65, P < 0.001). The IRS of MSP58 in the tumor showed a highly significant positive correlation with corresponding FLT uptake value (r = 0.61, P < 0.001). The correlation between MSP58 expression and glioma malignancy was also confirmed by immunofluorescence, RT-PCR and western blot analysis. FLT uptake value also exhibited a highly significant positive correlation with the Ki-67 index (r = 0.59, P < 0.001). Kaplan-Meier analysis revealed that MSP58 expression has a significant prognostic ability for the overall survival time similar to that found in the uptake value of FLT-PET. CONCLUSION: These results indicate that MSP58 plays an important role in cell proliferation and will be one of the potential candidates of molecular therapy targeting proliferation. FLT-PET might be used as an early measure of treatment response in the proliferation-targeted therapy.

Activation of mGluR5 attenuates NMDA-induced neurotoxicity through disruption of the NMDAR-PSD-95 complex and preservation of mitochondrial function in differentiated PC12 cells.

Glutamate-mediated toxicity is implicated in various neuropathologic conditions, and activation of ionotropic and metabotropic glutamate receptors is considered to be the most important mechanism. It has been reported that pharmacological saturation of metabotropic glutamate receptors (mGluRs) can facilitate N-methyl-D-aspartate receptor (NMDAR) related signaling cascades, but the mechanism leading to mGluR-NMDAR interactions in excitotoxic neuronal injury has remained unidentified. In the present study, we investigated the role of mGluR5 in the regulation of N-methyl-D-aspartate (NMDA)-induced excitotoxicity in differentiated PC12 cells. We found that activation of mGluR5 with the specific agonist R,S-2-chloro-5-hydroxyphenylglycine (CHPG) increased cell viability and inhibited lactate dehydrogenase (LDH) release in a dose-dependent manner. CHPG also inhibited an increase in the Bax/Bcl-2 ratio, attenuated cleavage of caspase-9 and caspase-3, and reduced apoptotic cell death after NMDA treatment. The NMDA-induced mitochondrial dysfunction, as indicated by mitochondrial reactive oxygen species (ROS) generation, collapse of mitochondrial membrane potential (MMP), and cytochrome c release, was also partly prevented by CHPG treatment. Furthermore, CHPG blocked the NMDA-induced interaction of NMDAR with postsynaptic density protein-95 (PSD-95), but had no effects on intracellular calcium concentrations. All these results indicated that activation of mGluR5 protects differentiated PC12 cells from NMDA-induced neuronal excitotoxicity by disrupting NMDAR-PSD-95 interaction, which might be an ideal target for investigating therapeutic strategies in various neurological diseases where excitotoxicity may contribute to their pathology.

Sirt3 protects cortical neurons against oxidative stress via regulating mitochondrial Ca2+ and mitochondrial biogenesis.

Oxidative stress is a well-established event in the pathology of several neurobiological diseases. Sirt3 is a nicotinamide adenine nucleotide (NAD+)-dependent protein deacetylase that regulates mitochondrial function and metabolism in response to caloric restriction and stress. This study aims to investigate the role of Sirt3 in H2O2 induced oxidative neuronal injury in primary cultured rat cortical neurons. We found that H2O2 treatment significantly increased the expression of Sirt3 in a time-dependent manner at both mRNA and protein levels. Knockdown of Sirt3 with a specific small interfering RNA (siRNA) exacerbated H2O2-induced neuronal injury, whereas overexpression of Sirt3 by lentivirus transfection inhibited H2O2-induced neuronal damage reduced the generation of reactive oxygen species (ROS), and increased the activities of endogenous antioxidant enzymes. In addition, the intra-mitochondrial Ca2+ overload, but not cytosolic Ca2+ increase after H2O2 treatment, was strongly attenuated after Sirt3 overexpression. Overexpression of Sirt3 also increased the content of mitochondrial DNA (mtDNA) and the expression of mitochondrial biogenesis related transcription factors. All these results suggest that Sirt3 acts as a prosurvival factor playing an essential role to protect cortical neurons under H2O2 induced oxidative stress, possibly through regulating mitochondrial Ca2+ homeostasis and mitochondrial biogenesis.

Aspirin treatment for unruptured intracranial aneurysms: Focusing on its anti-inflammatory role.

Intracranial aneurysms (IAs), as a common cerebrovascular disease, claims a worldwide morbidity rate of 3.2%. Inflammation, pivotal in the pathogenesis of IAs, influences their formation, growth, and rupture. This review investigates aspirin's modulation of inflammatory pathways within this context. With IAs carrying significant morbidity and mortality upon IAs rupture and current interventions limited to surgical clipping and endovascular coiling, the quest for pharmacological options is imperative. Aspirin's role in cardiovascular prevention, due to its anti-inflammatory effects, presents a potential therapeutic avenue for IAs. In this review, we examine aspirin's efficacy in experimental models and clinical settings, highlighting its impact on the progression and rupture risks of unruptured IAs. The underlying mechanisms of aspirin's impact on IAs are explored, with its ability examined to attenuate endothelial dysfunction and vascular injury. This review may provide a theoretical basis for the use of aspirin, suggesting a promising strategy for IAs management. However, the optimal dosing, safety, and long-term efficacy remain to be established. The implications of aspirin therapy are significant in light of current surgical and endovascular treatments. Further research is encouraged to refine aspirin's clinical application in the management of unruptured IAs, with the ultimate aim of reducing the incidence of aneurysms rupture.

Impairment of Autophagic Flux After Hypobaric Hypoxia Potentiates Oxidative Stress and Cognitive Function Disturbances in Mice.

Acute hypobaric hypoxic brain damage is a potentially fatal high-altitude sickness. Autophagy plays a critical role in ischemic brain injury, but its role in hypobaric hypoxia (HH) remains unknown. Here we used an HH chamber to demonstrate that acute HH exposure impairs autophagic activity in both the early and late stages of the mouse brain, and is partially responsible for HH-induced oxidative stress, neuronal loss, and brain damage. The autophagic agonist rapamycin only promotes the initiation of autophagy. By proteome analysis, a screen showed that protein dynamin2 (DNM2) potentially regulates autophagic flux. Overexpression of DNM2 significantly increased the formation of autolysosomes, thus maintaining autophagic flux in combination with rapamycin. Furthermore, the enhancement of autophagic activity attenuated oxidative stress and neurological deficits after HH exposure. These results contribute to evidence supporting the conclusion that DNM2-mediated autophagic flux represents a new therapeutic target in HH-induced brain damage.

Preso enhances mGluR1-mediated excitotoxicity by modulating the phosphorylation of mGluR1-Homer1 complex and facilitating an ER stress after traumatic brain injury.

Glutamate receptor (GluR)-mediated excitotoxicity is an important mechanism causing delayed neuronal injury after traumatic brain injury (TBI). Preso, as a core scaffolding protein of postsynaptic density (PSD), is considered an important regulator during excitotoxicity and TBI and combines with glutamate receptors to form functional units for excitatory glutamatergic neurotransmission, and elucidating the mechanisms of these functional units will provide new targets for the treatment of TBI. As a multidomain scaffolding protein, Preso directly interacts with metabotropic GluR (mGluR) and another scaffold protein, Homer. Because the mGluR-Homer complex plays a crucial role in TBI, modulation of this complex by Preso may be an important mechanism affecting the excitotoxic damage to neurons after TBI. Here, we demonstrate that Preso facilitates the interaction between metabotropic mGluR1 and Homer1 to activate mGluR1 signaling and cause excitotoxic neuronal injury and endoplasmic reticulum (ER) stress after TBI. The regulatory effect of Preso on the mGluR1-Homer1 complex is dependent on the direct association between Preso and this complex and also involves the phosphorylation of the interactive binding sites of mGluR1 and Homer1 by Preso. Further studies confirmed that Preso, as an adaptor of cyclin-dependent kinase 5 (CDK5), promotes the phosphorylation of the Homer1-binding site on mGluR1 by CDK5 and thereby enhances the interaction between mGluR1 and Homer1. Preso can also promote the formation of the mGluR1-Homer1 complex by inhibiting the phosphorylation of the Homer1 hinge region by Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα). Based on these molecular mechanisms, we designed several blocking peptides targeting the interaction between Preso and the mGluR1-Homer1 complex and found that directly disrupting the association between mGluR1 and scaffolding proteins significantly promotes the recovery of motor function after TBI.

Shank3 ameliorates neuronal injury after cerebral ischemia/reperfusion via inhibiting oxidative stress and inflammation.

Shank3, a key molecule related to the development and deterioration of autism, has recently been found to downregulate in the murine brain after ischemia/reperfusion (I/R). Despite this discovery, however, its effects on neuronal injury and the mechanism underlying the effects remain to be clarified. To address this, in this study, based on genetically modified mice models, we revealed that the expression of Shank3 showed a time-dependent change in murine hippocampal neurons after I/R, and that conditional knockout (cko) of Shank3 in neurons resulted in aggravated neuronal injuries. The protective effects of Shank3 against oxidative stress and inflammation after I/R were achieved through direct binding STIM1 and subsequent proteasome-mediated degradation of STIM1. The STIM1 downregulation induced the phosphorylation of downstream Nrf2 Ser40, which subsequently translocated to the nucleus, and further increased the expression of antioxidant genes such as NQO1 and HO-1 in HT22 cells. In vivo, the study has further confirmed that double knockout of Shank3 and Stim1 alleviated oxidative stress and inflammation after I/R in Shank3cko mice. In conclusion, the present study has demonstrated that Shank3 interacts with STIM1 and inhibits post-I/R neuronal oxidative stress and inflammatory response via the Nrf2 pathway. This interaction can potentially contribute to the development of a promising method for I/R treatment.

Id2 epigenetically controls CD8+ T-cell exhaustion by disrupting the assembly of the Tcf3-LSD1 complex.

CD8+ T-cell exhaustion is a state of dysfunction that promotes tumor progression and is marked by the generation of Slamf6+ progenitor exhausted (Texprog) and Tim-3+ terminally exhausted (Texterm) subpopulations. Inhibitor of DNA binding protein 2 (Id2) has been shown to play important roles in T-cell development and CD8+ T-cell immunity. However, the role of Id2 in CD8+ T-cell exhaustion is unclear. Here, we found that Id2 transcriptionally and epigenetically regulates the generation of Texprog cells and their conversion to Texterm cells. Genetic deletion of Id2 dampens CD8+ T-cell-mediated immune responses and the maintenance of stem-like CD8+ T-cell subpopulations, suppresses PD-1 blockade and increases tumor susceptibility. Mechanistically, through its HLH domain, Id2 binds and disrupts the assembly of the Tcf3-Tal1 transcriptional regulatory complex, and thus modulates chromatin accessibility at the Slamf6 promoter by preventing the interaction of Tcf3 with the histone lysine demethylase LSD1. Therefore, Id2 increases the abundance of the permissive H3K4me2 mark on the Tcf3-occupied E-boxes in the Slamf6 promoter, modulates chromatin accessibility at the Slamf6 promoter and epigenetically regulates the generation of Slamf6+ Texprog cells. An LSD1 inhibitor GSK2879552 can rescue the Id2 knockout phenotype in tumor-bearing mice. Inhibition of LSD1 increases the abundance of Slamf6+Tim-3- Texprog cells in tumors and the expression level of Tcf1 in Id2-deleted CD8+ T cells. This study demonstrates that Id2-mediated transcriptional and epigenetic modification drives hierarchical CD8+ T-cell exhaustion, and the mechanistic insights gained may have implications for therapeutic intervention with tumor immune evasion.

Ultra-processed foods and human health: An umbrella review and updated meta-analyses of observational evidence.

BACKGROUND & AIMS: Ultra-processed food (UPF) intake has increased sharply over the last few decades and has been consistently asserted to be implicated in the development of non-communicable diseases. We aimed to evaluate and update the existing observational evidence for associations between ultra-processed food (UPF) consumption and human health. METHODS: We searched Medline and Embase from inception to March 2023 to identify and update meta-analyses of observational studies examining the associations between UPF consumption, as defined by the NOVA classification, and a wide spectrum of health outcomes. For each health outcome, we estimated the summary effect size, 95% confidence interval (CI), between-study heterogeneity, evidence of small-study effects, and evidence of excess-significance bias. These metrics were used to evaluate evidence credibility of the identified associations. RESULTS: This umbrella review identified 39 meta-analyses on the associations between UPF consumption and health outcomes. We updated all meta-analyses by including 122 individual articles on 49 unique health outcomes. The majority of the included studies divided UPF consumption into quartiles, with the lowest quartile being the reference group. We identified 25 health outcomes associated with UPF consumption. For observational studies, 2 health outcomes, including renal function decline (OR: 1.25; 95% CI: 1.18, 1.33) and wheezing in children and adolescents (OR: 1.42; 95% CI: 1.34, 1.49), showed convincing evidence (Class I); and five outcomes were reported with highly suggestive evidence (Class II), including diabetes mellitus, overweight, obesity, depression, and common mental disorders. CONCLUSIONS: High UPF consumption is associated with an increased risk of a variety of chronic diseases and mental health disorders. At present, not a single study reported an association between UPF intake and a beneficial health outcome. These findings suggest that dietary patterns with low consumption of UPFs may render broad public health benefits.

Salvianolic acid B induces apoptosis in human glioma U87 cells through p38-mediated ROS generation.

Salvianolic acid B (SalB), the main water-soluble bioactive compounds isolated from the traditional Chinese medical herb Danshen, has been shown to exert anti-cancer effect in several cancer cell lines. The aim of our study was to investigate the potential anti-cancer effect of SalB in human glioma U87 cells. We found that treatment with SalB significantly decreased cell viability of U87 cells in a dose- and time-dependent manner. SalB also enhanced the intracellular ROS generation and induced apoptotic cell death in U87 cells. Western blot analysis suggested that SalB increased the phosphorylation of p38 MAPK and p53 in a dose-dependent manner. Moreover, blocking p38 activation by specific inhibitor SB203580 or p38 specific siRNA partly reversed the anti-proliferative and pro-apoptotic effects, and ROS production induced by SalB treatment. The anti-tumor activity of SalB in vivo was also demonstrated in U87 xenograft glioma model. All of these findings extended the anti-cancer effect of SalB in human glioma cell lines, and suggested that these inhibitory effects of SalB on U87 glioma cell growth might be associated with p38 activation mediated ROS generation. Thus, SalB might be concerned as an effective and safe natural anticancer agent for glioma prevention and treatment.

Role of Sirtuin 3 in Degenerative Diseases of the Central Nervous System.

An NAD+-dependent deacetylase called Sirtuin 3 (Sirt3) is involved in the metabolic processes of the mitochondria, including energy generation, the tricarboxylic acid cycle, and oxidative stress. Sirt3 activation can slow down or prevent mitochondrial dysfunction in response to neurodegenerative disorders, demonstrating a strong neuroprotective impact. The mechanism of Sirt3 in neurodegenerative illnesses has been elucidated over time; it is essential for neuron, astrocyte, and microglial function, and its primary regulatory factors include antiapoptosis, oxidative stress, and the maintenance of metabolic homeostasis. Neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), may benefit from a thorough and in-depth investigation of Sirt3. In this review, we primarily cover Sirt3's role and its regulation in the nerve cells and the connection between Sirt3 and neurodegenerative disorders.