Apoptosis signal-regulating kinase 1 (Ask1) deficiency alleviates MPP+-induced impairment of evoked dopamine release in the mouse hippocampus

The dopaminergic system is susceptible to dysfunction in numerous neurological diseases, including Parkinson’s disease (PD). In addition to motor symptoms, some PD patients may experience non-motor symptoms, including cognitive and memory deficits. A possible explanation for their manifestation is a disturbed pattern of dopamine release in brain regions involved in learning and memory, such as the hippocampus. Therefore, investigating neuropathological alterations in dopamine release prior to neurodegeneration is imperative. This study aimed to characterize evoked hippocampal dopamine release and assess the impact of the neurotoxin MPP+ using a genetically encoded dopamine sensor and gene expression analysis. Additionally, considering the potential neuroprotective attributes demonstrated by apoptosis signal-regulating kinase 1 (Ask1) in various animal-disease-like models, the study also aimed to determine whether Ask1 knockdown restores MPP+-altered dopamine release in acute hippocampal slices. We applied variations of low- and high-frequency stimulation to evoke dopamine release within different hippocampal regions and discovered that acute application of MPP+ reduced the amount of dopamine released and hindered the recovery of dopamine release after repeated stimulation. In addition, we observed that Ask1 deficiency attenuated the detrimental effects of MPP+ on the recovery of dopamine release after repeated stimulation. RNA sequencing analysis indicated that genes associated with the synaptic pathways are involved in response to MPP+ exposure. Notably, Ask1 deficiency was found to downregulate the expression of Slc5a7, a gene encoding a sodium-dependent high-affinity choline transporter that regulates acetylcholine levels. Respective follow-up experiments indicated that Slc5a7 plays a role in Ask1 deficiency-mediated protection against MPP+ neurotoxicity. In addition, increasing acetylcholine levels using an acetylcholinesterase inhibitor could exacerbate the toxicity of MPP+. In conclusion, our data imply that the modulation of the dopamine-acetylcholine balance may be a crucial mechanism of action underlying the neuroprotective effects of Ask1 deficiency in PD

Potentiation of Schaffer-Collateral CA1 Synaptic Transmission by eEF2K and p38 MAPK Mediated Mechanisms

The elongation factor 2 kinase (eEF2K), likewise known as CaMKIII, has been demonstrated to be involved in antidepressant responses of NMDA receptor antagonists. Even so, it remains open whether direct inhibition of eEF2K without altering up-flow or other signaling pathways affects hippocampal synaptic transmission and neuronal network synchrony. Inhibition of eEF2K by the selective and potent eEF2K inhibitor A-484954 induced a fast pre-synaptically mediated enhancement of synaptic transmission and synchronization of neural network activity. The eEF2K-inhibition mediated potentiation of synaptic transmission of hippocampal CA1 neurons is most notably independent of protein synthesis and does not rely on protein kinase C, protein kinase A or mitogen-activated protein kinase (MAPK) /extracellular signal-regulated protein kinase 1/2. Moreover, the strengthening of synaptic transmission in the response to the inhibition of eEF2K was strongly attenuated by the inhibition of p38 MAPK. In addition, we show the involvement of barium-sensitive and more specific the TWIK-related potassium-1 (TREK-1) channels in the eEF2K-inhibition mediated potentiation of synaptic transmission. These findings reveal a novel pathway of eEF2K mediated regulation of hippocampal synaptic transmission. Further research is required to study whether such compounds could be beneficial for the development of mood disorder treatments with a fast-acting antidepressant response

TiO2, SiO2 and ZrO2 Nanoparticles Synergistically Provoke Cellular Oxidative Damage in Freshwater Microalgae

Metal-based nanoparticles (NPs) are the most widely used engineered nanomaterials. The individual toxicities of metal-based NPs have been plentifully studied. However, the mixture toxicity of multiple NP systems (n ≥ 3) remains much less understood. Herein, the toxicity of titanium dioxide (TiO2) nanoparticles (NPs), silicon dioxide (SiO2) NPs and zirconium dioxide (ZrO2) NPs to unicellular freshwater algae Scenedesmus obliquus was investigated individually and in binary and ternary combination. Results show that the ternary combination systems of TiO2, SiO2 and ZrO2 NPs at a mixture concentration of 1 mg/L significantly enhanced mitochondrial membrane potential and intracellular reactive oxygen species level in the algae. Moreover, the ternary NP systems remarkably increased the activity of the antioxidant defense enzymes superoxide dismutase and catalase, together with an increase in lipid peroxidation products and small molecule metabolites. Furthermore, the observation of superficial structures of S. obliquus revealed obvious oxidative damage induced by the ternary mixtures. Taken together, the ternary NP systems exerted more severe oxidative stress in the algae than the individual and the binary NP systems. Thus, our findings highlight the importance of the assessment of the synergistic toxicity of multi-nanomaterial systems

Presentation_1_Apoptosis signal-regulating kinase 1 (Ask1) deficiency alleviates MPP+-induced impairment of evoked dopamine release in the mouse hippocampus.pdf

The dopaminergic system is susceptible to dysfunction in numerous neurological diseases, including Parkinson’s disease (PD). In addition to motor symptoms, some PD patients may experience non-motor symptoms, including cognitive and memory deficits. A possible explanation for their manifestation is a disturbed pattern of dopamine release in brain regions involved in learning and memory, such as the hippocampus. Therefore, investigating neuropathological alterations in dopamine release prior to neurodegeneration is imperative. This study aimed to characterize evoked hippocampal dopamine release and assess the impact of the neurotoxin MPP+ using a genetically encoded dopamine sensor and gene expression analysis. Additionally, considering the potential neuroprotective attributes demonstrated by apoptosis signal-regulating kinase 1 (Ask1) in various animal-disease-like models, the study also aimed to determine whether Ask1 knockdown restores MPP+-altered dopamine release in acute hippocampal slices. We applied variations of low- and high-frequency stimulation to evoke dopamine release within different hippocampal regions and discovered that acute application of MPP+ reduced the amount of dopamine released and hindered the recovery of dopamine release after repeated stimulation. In addition, we observed that Ask1 deficiency attenuated the detrimental effects of MPP+ on the recovery of dopamine release after repeated stimulation. RNA sequencing analysis indicated that genes associated with the synaptic pathways are involved in response to MPP+ exposure. Notably, Ask1 deficiency was found to downregulate the expression of Slc5a7, a gene encoding a sodium-dependent high-affinity choline transporter that regulates acetylcholine levels. Respective follow-up experiments indicated that Slc5a7 plays a role in Ask1 deficiency-mediated protection against MPP+ neurotoxicity. In addition, increasing acetylcholine levels using an acetylcholinesterase inhibitor could exacerbate the toxicity of MPP+. In conclusion, our data imply that the modulation of the dopamine-acetylcholine balance may be a crucial mechanism of action underlying the neuroprotective effects of Ask1 deficiency in PD.</p

M1-like TAMs are required for the efficacy of PD-L1/PD-1 blockades in gastric cancer

The efficacy of PD-1/PD-L1 blockades is heterogeneous in different molecular subtypes of gastric cancer (GC). In this study, we analyzed relevant clinical trials to identify the molecular subtypes associated with the efficacy of PD-1/PD-L1 blockades, and public datasets, patient samples, and GC cell lines were used for investigating potential mechanisms. We found that GC with EBV-positive, MSI-H/dMMR, TMB-H or PIK3CA mutant subtype had enhanced efficacy of PD-L1/PD-1 blockades. Also, differentially expressed genes of these molecular subtypes shared the same gene signature and functional annotations related to immunity. Meanwhile, CIBERSORT identified that the overlapping landscapes of tumor-infiltrating immune cells in the four molecular subtypes were mainly M1-like macrophages (M1). The relationships between M1 and clinical characteristics, M1, and gene signatures associated with PD-1/PD-L1 blockades also revealed that M1 was associated with improved prognosis and required for the efficacy of PD-L1/PD-1 blockades in GC. We identified that tumor-infiltrating CD68+CD163− macrophages could represent M1 calculated by CIBERSORT in clinical application, and CXCL9, 10, 11/CXCR3 axis was involved in the mechanism of CD68+CD163− macrophages in the enhanced efficacy of PD-L1/PD-1 blockades. In conclusion, CD68+CD163− macrophages are required for the efficacy of PD-L1/PD-1 blockades and expand the applicable candidates in GC patients without the molecular subtypes

Table_1_Aminopeptidase O Protein mediates the association between Lachnospiraceae and appendicular lean mass.XLSX

ObjectiveInvestigating the causal relationship between Lachnospiraceae and Appendicular lean mass (ALM) and identifying and quantifying the role of Aminopeptidase O Protein (AOPEP) as a potential mediator.MethodsThe summary statistics data of gut microbiota composition from the largest available genome-wide association study (GWAS) meta-analysis conducted by the MiBioGen Consortium (n = 13,266). Appendicular lean mass data were obtained from the UK-Biobank (n = 450,243). We conducted bidirectional two-sample Mendelian randomization (MR) analysis using summary-level data from GWAS to investigate the causal relationship between Lachnospiraceae and ALM. Additionally, we employed a drug-targeted MR approach to assess the causal relationship between AOPEP and ALM. Finally, a two-step MR was employed to quantitatively estimate the proportion of the effect of Lachnospiraceae on ALM that is mediated by AOPEP. Cochran's Q statistic was used to quantify heterogeneity among instrumental variable estimates.ResultsIn the MR analysis, it was found that an increase in genetically predicted Lachnospiraceae [OR = 1.031, 95% CI (1.011–1.051), P = 0.002] is associated with an increase in ALM. There is no strong evidence to suggest that genetically predicted ALM has an impact on Lachnospiraceae genus [OR = 1.437, 95% CI (0.785–2.269), P = 0.239]. The proportion of genetically predicted Lachnospiraceae mediated by AOPEP was 34.2% [95% CI (1.3%−67.1%)].ConclusionOur research reveals that increasing Lachnospiraceae abundance in the gut can directly enhance limb muscle mass and concurrently suppress AOPEP, consequently mitigating limb muscle loss. This supports the potential therapeutic modulation of gut microbiota for sarcopenia. Interventions such as drug treatments or microbiota transplantation, aimed at elevating Lachnospiraceae abundance and AOPEP inhibition, synergistically improve sarcopenia in the elderly, thereby enhancing the overall quality of life for older individuals.</p