OBOX regulates mouse zygotic genome activation and early development.

Zygotic genome activation (ZGA) activates the quiescent genome to enable the maternal-to-zygotic transition1,2. However, the identity of transcription factors that underlie mammalian ZGA in vivo remains elusive. Here we show that OBOX, a PRD-like homeobox domain transcription factor family (OBOX1-OBOX8)3-5, are key regulators of mouse ZGA. Mice deficient for maternally transcribed Obox1/2/5/7 and zygotically expressed Obox3/4 had a two-cell to four-cell arrest, accompanied by impaired ZGA. The Obox knockout defects could be rescued by restoring either maternal and zygotic OBOX, which suggests that maternal and zygotic OBOX redundantly support embryonic development. Chromatin-binding analysis showed that Obox knockout preferentially affected OBOX-binding targets. Mechanistically, OBOX facilitated the 'preconfiguration' of RNA polymerase II, as the polymerase relocated from the initial one-cell binding targets to ZGA gene promoters and distal enhancers. Impaired polymerase II preconfiguration in Obox mutants was accompanied by defective ZGA and chromatin accessibility transition, as well as aberrant activation of one-cell polymerase II targets. Finally, ectopic expression of OBOX activated ZGA genes and MERVL repeats in mouse embryonic stem cells. These data thus demonstrate that OBOX regulates mouse ZGA and early embryogenesis.

Analysis of Genome Architecture during SCNT Reveals a Role of Cohesin in Impeding Minor ZGA.

Somatic cell nuclear transfer (SCNT) can reprogram a somatic nucleus to a totipotent state. However, the re-organization of 3D chromatin structure in this process remains poorly understood. Using low-input Hi-C, we revealed that, during SCNT, the transferred nucleus first enters a mitotic-like state (premature chromatin condensation). Unlike fertilized embryos, SCNT embryos show stronger topologically associating domains (TADs) at the 1-cell stage. TADs become weaker at the 2-cell stage, followed by gradual consolidation. Compartments A/B are markedly weak in 1-cell SCNT embryos and become increasingly strengthened afterward. By the 8-cell stage, somatic chromatin architecture is largely reset to embryonic patterns. Unexpectedly, we found cohesin represses minor zygotic genome activation (ZGA) genes (2-cell-specific genes) in pluripotent and differentiated cells, and pre-depleting cohesin in donor cells facilitates minor ZGA and SCNT. These data reveal multi-step reprogramming of 3D chromatin architecture during SCNT and support dual roles of cohesin in TAD formation and minor ZGA repression.

Polycomb Group Proteins Regulate Chromatin Architecture in Mouse Oocytes and Early Embryos.

In mammals, chromatin organization undergoes drastic reorganization during oocyte development. However, the dynamics of three-dimensional chromatin structure in this process is poorly characterized. Using low-input Hi-C (genome-wide chromatin conformation capture), we found that a unique chromatin organization gradually appears during mouse oocyte growth. Oocytes at late stages show self-interacting, cohesin-independent compartmental domains marked by H3K27me3, therefore termed Polycomb-associating domains (PADs). PADs and inter-PAD (iPAD) regions form compartment-like structures with strong inter-domain interactions among nearby PADs. PADs disassemble upon meiotic resumption from diplotene arrest but briefly reappear on the maternal genome after fertilization. Upon maternal depletion of Eed, PADs are largely intact in oocytes, but their reestablishment after fertilization is compromised. By contrast, depletion of Polycomb repressive complex 1 (PRC1) proteins attenuates PADs in oocytes, which is associated with substantial gene de-repression in PADs. These data reveal a critical role of Polycomb in regulating chromatin architecture during mammalian oocyte growth and early development.

Reprogramming of Meiotic Chromatin Architecture during Spermatogenesis.

Chromatin organization undergoes drastic reconfiguration during gametogenesis. However, the molecular reprogramming of three-dimensional chromatin structure in this process remains poorly understood for mammals, including primates. Here, we examined three-dimensional chromatin architecture during spermatogenesis in rhesus monkey using low-input Hi-C. Interestingly, we found that topologically associating domains (TADs) undergo dissolution and reestablishment in spermatogenesis. Strikingly, pachytene spermatocytes, where synapsis occurs, are strongly depleted for TADs despite their active transcription state but uniquely show highly refined local compartments that alternate between transcribing and non-transcribing regions (refined-A/B). Importantly, such chromatin organization is conserved in mouse, where it remains largely intact upon transcription inhibition. Instead, it is attenuated in mutant spermatocytes, where the synaptonemal complex failed to be established. Intriguingly, this is accompanied by the restoration of TADs, suggesting that the synaptonemal complex may restrict TADs and promote local compartments. Thus, these data revealed extensive reprogramming of higher-order meiotic chromatin architecture during mammalian gametogenesis.

The landscape of RNA Pol II binding reveals a stepwise transition during ZGA.

Zygotic genome activation (ZGA) is the first transcription event in life1. However, it is unclear how RNA polymerase is engaged in initiating ZGA in mammals. Here, by developing small-scale Tn5-assisted chromatin cleavage with sequencing (Stacc-seq), we investigated the landscapes of RNA polymerase II (Pol II) binding in mouse embryos. We found that Pol II undergoes 'loading', 'pre-configuration', and 'production' during the transition from minor ZGA to major ZGA. After fertilization, Pol II is preferentially loaded to CG-rich promoters and accessible distal regions in one-cell embryos (loading), in part shaped by the inherited parental epigenome. Pol II then initiates relocation to future gene targets before genome activation (pre-configuration), where it later engages in full transcription elongation upon major ZGA (production). Pol II also maintains low poising at inactive promoters after major ZGA until the blastocyst stage, coinciding with the loss of promoter epigenetic silencing factors. Notably, inhibition of minor ZGA impairs the Pol II pre-configuration and embryonic development, accompanied by aberrant retention of Pol II and ectopic expression of one-cell targets upon major ZGA. Hence, stepwise transition of Pol II occurs when mammalian life begins, and minor ZGA has a key role in the pre-configuration of transcription machinery and chromatin for genome activation.

Widespread Enhancer Dememorization and Promoter Priming during Parental-to-Zygotic Transition.

The epigenome plays critical roles in controlling gene expression and development. However, how the parental epigenomes transit to the zygotic epigenome in early development remains elusive. Here we show that parental-to-zygotic transition in zebrafish involves extensive erasure of parental epigenetic memory, starting with methylating gametic enhancers. Surprisingly, this occurs even prior to fertilization for sperm. Both parental enhancers lose histone marks by the 4-cell stage, and zygotic enhancers are not activated until around zygotic genome activation (ZGA). By contrast, many promoters remain hypomethylated and, unexpectedly, acquire histone acetylation before ZGA at as early as the 4-cell stage. They then resolve into either activated or repressed promoters upon ZGA. Maternal depletion of histone acetyltransferases results in aberrant ZGA and early embryonic lethality. Finally, such reprogramming is largely driven by maternal factors, with zygotic products mainly contributing to embryonic enhancer activation. These data reveal widespread enhancer dememorization and promoter priming during parental-to-zygotic transition.

Cobalt-Mediated Defect Engineering Endows High Reversible Amorphous VS4 Anode for Advanced Sodium-Ion Storage.

Metal sulfides are promising anode materials for sodium-ion batteries (SIBs) due to their structural diversity and high theoretical capacity, but the severe capacity decay and inferior rate capability caused by poor structural stability and sluggish kinetics impede their practical applications. Herein, a cobalt-doped amorphous VS4 wrapped by reduced graphene oxide (i.e., Co0.5-VS4/rGO) is developed through a Co-induced defect engineering strategy to boost the kinetics performances. The as-prepared Co0.5-VS4/rGO demonstrates excellent rate capacities over 10 A g-1 and superior cycling stability at 5 A g-1 over 1600 cycles, which is attributed to the defects formed by Co doping, the formed amorphous structure and the robust rGO substrate. The great features of Co0.5-VS4/rGO anode are further confirmed in sodium-ion capacitors when the active carbon cathode is used. Additionally, the relationships between metal doping, the derived defects, the amorphous structure, and the sodium storage of VS4 are uncovered. This work provides deep insights into preparing amorphous functional materials and also probes the potential applications of metal sulfide-based electrode materials for advanced batteries.

Publisher Correction: Chromatin analysis in human early development reveals epigenetic transition during ZGA.

In this Letter, the 'Open chromatin' label in Fig. 4a should have been centred above the first three columns, and the black horizontal line underneath the label should have been removed. In addition, there should have been a vertical black line between the last two sets of panels for consistency. Minor changes have also been made to Fig. 1 and to the legend of Fig. 3. These errrors have been corrected online, and see Supplementary Information to the accompanying Amendment for the original Fig. 4.

Chromatin analysis in human early development reveals epigenetic transition during ZGA.

Upon fertilization, drastic chromatin reorganization occurs during preimplantation development 1 . However, the global chromatin landscape and its molecular dynamics in this period remain largely unexplored in humans. Here we investigate chromatin states in human preimplantation development using an improved assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) 2 . We find widespread accessible chromatin regions in early human embryos that overlap extensively with putative cis-regulatory sequences and transposable elements. Integrative analyses show both conservation and divergence in regulatory circuitry between human and mouse early development, and between human pluripotency in vivo and human embryonic stem cells. In addition, we find widespread open chromatin regions before zygotic genome activation (ZGA). The accessible chromatin loci are readily found at CpG-rich promoters. Unexpectedly, many others reside in distal regions that overlap with DNA hypomethylated domains in human oocytes and are enriched for transcription factor-binding sites. A large portion of these regions then become inaccessible after ZGA in a transcription-dependent manner. Notably, such extensive chromatin reorganization during ZGA is conserved in mice and correlates with the reprogramming of the non-canonical histone mark H3K4me3, which is uniquely linked to genome silencing3-5. Taken together, these data not only reveal a conserved principle that underlies the chromatin transition during mammalian ZGA, but also help to advance our understanding of epigenetic reprogramming during human early development and in vitro fertilization.

Resetting Epigenetic Memory by Reprogramming of Histone Modifications in Mammals.

Polycomb group proteins and the related histone modification H3K27me3 can maintain the silencing of key developmental regulators and provide cellular memory. However, how such an epigenetic state is reprogrammed and inherited between generations is poorly understood. Using an ultra-sensitive approach, STAR ChIP-seq, we investigated H3K27me3 across 14 developmental stages along mouse gametogenesis and early development. Interestingly, highly pervasive H3K27me3 is found in regions depleted of transcription and DNA methylation in oocytes. Unexpectedly, we observed extensive loss of promoter H3K27me3 at Hox and other developmental genes upon fertilization. This is accompanied by global erasure of sperm H3K27me3 but inheritance of distal H3K27me3 from oocytes. The resulting allele-specific H3K27me3 patterns persist to blastocysts before being converted to canonical forms in postimplantation embryos, where both H3K4me3/H3K27me3 bivalent promoter marks are restored at developmental genes. Together, these data revealed widespread resetting of epigenetic memory and striking plasticity of epigenome during gametogenesis and early development.

Isoform Switch of TET1 Regulates DNA Demethylation and Mouse Development.

The methylcytosine oxidase TET proteins play important roles in DNA demethylation and development. However, it remains elusive how exactly they target substrates and execute oxidation. Interestingly, we found that, in mice, the full-length TET1 isoform (TET1e) is restricted to early embryos, embryonic stem cells (ESCs), and primordial germ cells (PGCs). By contrast, a short isoform (TET1s) is preferentially expressed in somatic cells, which lacks the N terminus including the CXXC domain, a DNA-binding module that often recognizes CpG islands (CGIs) where TET1 predominantly occupies. Unexpectedly, TET1s can still bind CGIs despite the fact that its global chromatin binding is significantly reduced. Interestingly, global chromatin binding, but not targeted binding at CGIs, is correlated with TET1-mediated demethylation. Finally, mice with exclusive expression of Tet1s failed to erase imprints in PGCs and displayed developmental defects in progeny. These data show that isoform switch of TET1 regulates epigenetic memory erasure and mouse development.

The Effect of Central Sensitization on Postoperative Neurocognitive Dysfunction in Hospitalized Elderly Patients: A Prospective Cohort Clinical Trial.

OBJECTIVE: To investigate whether central sensitization (CS) in elderly patients was a predictive risk factor for postoperative neurocognitive dysfunction (PNCD). METHODS: One hundred and thirty-three aged patients undergoing total knee arthroplasty (TKA) who received femoral nerve block and general anesthesia were recruited in this research and prospectively assigned into two groups according to the Central Sensitization Inventory (CSI) score: group C (n = 106, CSI score less than 40) and group CS (n = 27, CSI score higher than 40). Scores of Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Confusion Assessment Method (CAM), Numerical Rating Scale (NRS) and Quality of recovery-40 (QoR-40) questionnaires were assessed. Basic information and clinical records of all participants were also collected. RESULTS: PNCD occurred in 24 (22.6%) of patients in group C and 16 (59.3%) in group CS (p < .05). Multivariate logistic regression analysis revealed that patients with CSI score ≥40 before surgery exhibited higher risk of PNCD after adjustment for other risk factors (p < .05). Compared to group C, the pre- and post-operative NRS scores, pain duration, the WOMAC score, and propofol consumptions for anesthesia induction were significantly increased in group CS (p < .05). CONCLUSION: Hospitalized elderly patients with clinical symptoms of CS scores may have increased risk of PNCD following TKA.

taVNS Alleviates Sevoflurane-Induced Cognitive Dysfunction in Aged Rats Via Activating Basal Forebrain Cholinergic Neurons.

Postoperative cognitive dysfunction (POCD) is a common complication of central nervous system after anesthesia or surgery. Sevoflurane, an inhalation anesthetic, may inhibit cholinergic pathway that induce neuronal death and neuroinflammation, ultimately leading to POCD. Transauricular vagus nerve stimulation (taVNS) has neuroprotective effects in POCD rats, but the mechanisms related to cholinergic system have not been revealed. Sprague-Dawley rats were anesthetized with sevoflurane to construct the POCD model. The immunotoxin 192-IgG-saporin (192-sap) selectively lesioned cholinergic neurons in the basal forebrain, which is the major source of cholinergic projections to hippocampus. After lesion, rats received 5 days of taVNS treatment (30 min per day) starting 24 h before anesthesia. Open field test and Morris water maze were used to test the cognitive function. In this study, rats exposed to sevoflurane exhibited cognitive impairment that was attenuated by taVNS. In addition, taVNS treatment activated cholinergic system in the basal forebrain and hippocampus, and downregulated the expression of apoptosis- and necroptosis-related proteins, such as cleaved Caspase-3 and p-MLKL, in the hippocampus. Meanwhile, the activation of Iba1+ microglial by sevoflurane was reduced by taVNS. 192-sap blocked the cholinergic system activation in the basal forebrain and hippocampus and inhibited taVNS-mediated neuroprotection and anti-inflammation effects in the hippocampus. Generally, our study indicated that taVNS might alleviate sevoflurane-induced hippocampal neuronal apoptosis, necroptosis and microglial activation though activating cholinergic system in the basal forebrain.

Melatonin attenuates lung ischemia-reperfusion injury through SIRT3 signaling-dependent mitophagy in type 2 diabetic rats.

Background: Lung ischemia-reperfusion injury (LIRI) remains the major cause of primary lung dysfunction after lung transplantation. Diabetes mellitus (DM) is an independent risk factor for morbidity and mortality following lung transplantation. Mitochondrial dysfunction is recognized as a key mediator in the pathogenesis of diabetic LIRI. Melatonin has been reported to be a safe and potent preserving mitochondrial function agent. This study aimed at investigating the potential therapeutic effect and mechanisms of melatonin on diabetic LIRI. Methods: High-fat-diet-fed streptozotocin-induced type 2 diabetic rats were exposed to melatonin, with or without administration of the SIRT3 short hairpin ribonucleic acid (shRNA) plasmid following a surgical model of ischemia-reperfusion injury of the lung. Lung function, inflammation, oxidative stress, cell apoptosis, and mitochondrial function were examined. Results: The SIRT3 signaling and mitophagy were suppressed following diabetic LIRI. Treatment with melatonin markedly induced mitophagy and restored SIRT3 expression. Melatonin treatment also attenuated subsequent diabetic LIRI by improving lung functional recovery, suppressing inflammation, decreasing oxidative damage, diminishing cell apoptosis, and preserving mitochondrial function. However, either administration of SIRT3 shRNA or an autophagy antagonist 3-methyladenine (3-MA) suppressing mitophagy, and compromised the protective action of melatonin. Conclusion: Data indicated that melatonin attenuates diabetic LIRI through activation of SIRT3 signaling-mediated mitophagy.

Allelic reprogramming of 3D chromatin architecture during early mammalian development.

In mammals, chromatin organization undergoes drastic reprogramming after fertilization. However, the three-dimensional structure of chromatin and its reprogramming in preimplantation development remain poorly understood. Here, by developing a low-input Hi-C (genome-wide chromosome conformation capture) approach, we examined the reprogramming of chromatin organization during early development in mice. We found that oocytes in metaphase II show homogeneous chromatin folding that lacks detectable topologically associating domains (TADs) and chromatin compartments. Strikingly, chromatin shows greatly diminished higher-order structure after fertilization. Unexpectedly, the subsequent establishment of chromatin organization is a prolonged process that extends through preimplantation development, as characterized by slow consolidation of TADs and segregation of chromatin compartments. The two sets of parental chromosomes are spatially separated from each other and display distinct compartmentalization in zygotes. Such allele separation and allelic compartmentalization can be found as late as the 8-cell stage. Finally, we show that chromatin compaction in preimplantation embryos can partially proceed in the absence of zygotic transcription and is a multi-level hierarchical process. Taken together, our data suggest that chromatin may exist in a markedly relaxed state after fertilization, followed by progressive maturation of higher-order chromatin architecture during early development.

Effect of pre-infusion of hypertonic saline on postoperative delirium in geriatric patients undergoing shoulder arthroscopy: a randomized controlled trial.

BACKGROUND: Neuroinflammation may be a potential mechanism of postoperative delirium (POD) in geriatric patients, and hypertonic saline (HS) has immunomodulatory properties. The purpose of this study was to investigate whether HS could reduce the incidence of POD in elderly patients and its effect on neutrophil activation and inflammatory cytokine expression. METHODS: We studied the effect of pre-infusion of 4 mL/kg 3% hypertonic saline vs. 4 mL/kg 0.9% normal saline on POD in patients undergoing shoulder arthroscopy in a prospective, randomized, double-blind, controlled trial. Neutrophil surface molecules (CD11b, CD66b and CD64) were analyzed by flow cytometry. Circulating concentrations of inflammatory factors IL-1ß, IL-6, TNF-α and neurological damage factor S100ß were assessed by enzyme immunoassay. The Confusion Assessment Method-Chinese Revision (CAM-CR) was applied for the assessment of POD 1-3 days after surgery. RESULTS: The incidence of POD in group H was significantly lower than that in group N (7.14% vs 26.83%, P = 0.036). The expression levels of inflammatory cytokines ( IL-6 and TNF-α) and neutrophil surface markers (CD11b and CD66b) were significantly lower in group H than in group N at 24 h after surgery (P = 0.018, P < 0.001, P < 0.001, P = 0.024). There were no significant differences in postoperative pain, nausea and vomiting, infection, phlebitis, and patients satisfaction between the two groups. CONCLUSION: Pre-infusion of HS can reduce the incidence of POD and the immune-inflammatory response. TRIAL REGISTRATION: Chinese Clinical Trial Registry (14/4/2022, registration number: ChiCTR2200058681.

Bicarbonate ringer's solution could improve the intraoperative acid-base equilibrium and reduce hepatocellular enzyme levels after deceased donor liver transplantation: a randomized controlled study.

BACKGROUND: Bicarbonate Ringer's (BR) solution is a direct liver and kidney metabolism-independent HCO3- buffering system. We hypothesized that BR solution would be more effective in improving acid-base equilibrium and more conducive to better liver function than Acetate Ringer's (AR) solution in conventional orthotopic liver transplantation (OLT) patients. METHODS: Sixty-nine adult patients underwent OLT. Patients in the bicarbonate and acetate groups received BR solution or AR solution as infused crystalloids and graft washing solution, respectively. The primary outcome was the effect on pH and base excess (BE) levels. The secondary outcome measures were the incidence and volume of intraoperative 5% sodium bicarbonate infusion and laboratory indicates of liver and kidney function. RESULTS: The pH and absolute BE values changed significantly during the anhepatic phase and immediately after transplanted liver reperfusion in the bicarbonate group compared with the acetate group (all P < 0.05). The incidence and volume of 5% sodium bicarbonate infusion were lower in the bicarbonate group than in the acetate group (all P < 0.05). The aspartate transaminase (AST) level at 7 postoperative days and the creatine level at 30 postoperative days were significantly higher in the acetate group than in the bicarbonate group (all P < 0.05). CONCLUSION: Compared with AR solution, BR solution was associated with improved intraoperative acid-base balance and potentially protected early postoperative liver graft function and reduced late-postoperative renal injury.

Oxygen Vacancy and Interface Effect Adjusted Hollow Dodecahedrons for Efficient Oxygen Evolution Reaction.

Metal-organic frameworks (MOFs) with special morphologies provide the geometric morphology and composition basis for the construction of platforms with excellent catalytic activity. In this work, cobalt-cerium composite oxide hollow dodecahedrons (Co/Cex-COHDs) with controllable morphology and tunable composition are successfully prepared via a high-temperature pyrolysis strategy using Co/Ce-MOFs as self-sacrificial templates. The construction of the hollow structure can expose a larger surface area to provide abundant active sites and pores to facilitate the diffusion of substances. The formation and optimization of phase interface between Co3O4 and CeO2 regulate the electronic structure of the catalytic site and form a fast channel favorable to electron transport, thereby enhancing the electrocatalytic oxygen evolution activity. Based on the above advantages, the optimized Co/Ce0.2-COHDs obtained an enhanced oxygen evolution reaction (OER) performance.

Unraveling the Intercorrelation Between Micro/Mesopores and K Migration Behavior in Hard Carbon.

Pore-structure design with increased ion-diffusion ability is usually regarded as an effective strategy to improve K-storage performance in hard carbon (HC). However, the relationship between porous structure and K+ migration behavior remains unclear and requires further exploration. Herein, a series of chemically activated hard carbon spheres (denoted as AHCSs) with controllable micro/mesopores structure are successfully synthesized to explore intercorrelation between micro/mesopores and K migration behavior. The experimental results indicate AHCSs have two different K+ storage ways, that is, adsorption behavior at high potential region and intercalation process at low potential region. These behaviors are closely related to the pores structure evolution: the micropores afford extra active sites for efficient K-ions adsorption, and therefore positive correlation between micropores and adsorption-contributed capacity is confirmed; the mesopores permit more K-ions intercalation/deintercalation by offering adequate pathways, and as a result positive correlations between mesopores and intercalation-contributed capacity as well as initial Coulombic efficiency are revealed. All these together contribute to achieving excellent reversible capacity, and exceptional rate capability with an ultra-long cycle lifespan in PIBs, and simultaneously exhibit a high energy density as well as considerable cycling stability for potassium-ion full cells. These results promote a fundamental understanding of K+ migration behaviors in hard carbon.

Necrostatin-1 Against Sevoflurane-Induced Cognitive Dysfunction Involves Activation of BDNF/TrkB Pathway and Inhibition of Necroptosis in Aged Rats.

Postoperative cognitive dysfunction (POCD) induced by anesthesia or surgery has become a common complication in the aged population. Sevoflurane, a clinical inhalation anesthetic, could stimulate calcium overload and necroptosis to POCD. In addition, necroptosis inhibitor necrostatin-1 (Nec-1) alleviated cognitive impairment caused by multiple causes, including postoperative cognitive impairment. However, whether Nec-1 exerts a neuroprotective effect on POCD via calcium and necroptosis remains unclear. We anesthetized Sprague-Dawley rats with sevoflurane to construct the POCD model and to explore the mechanism underlying neuroprotective effects of Nec-1 in POCD. Rats were treated with Nec-1 (6.25 mg/kg) 1 h prior to anesthesia. Open field test and Morris water maze were employed to detect the cognitive function. In this study, rats exposed to sevoflurane displayed cognitive dysfunction without changes in spontaneous activity; however, the sevoflurane-induced POCD could be relieved by Nec-1 pretreatment. Nec-1 decreased sevoflurane-induced calcium overload and calpain activity in the hippocampus. In addition, Nec-1 alleviated the expression of p-RIPK1, RIPK1, p-RIPK3, RIPK3, p-MLKL and MLKL. Furthermore, Nec-1 remarkably increased BDNF and p-TrkB/TrkB expression in the hippocampus of aged rats. Ultimately, our research manifests evidence that Nec-1 may play a neuroprotective role against sevoflurane-induced cognitive impairment via the increase of BDNF/TrkB and suppression of necroptosis-related pathway.