[Background] Herpesvirus infections can induce diverse visual impairments with permanent sequelae, yet systematic data on their clinical spectrum and outcomes remain scarce. [Methods] We conducted a single-center retrospective cohort study at the Department of Neurology, Beijing Tongren Hospital, Capital Medical University. Thirteen consecutive patients (19 affected eyes) with herpesvirus-related visual impairment admitted between January 2016 and January 2025 were enrolled. Demographic data, clinical manifestations, etiological tests (polymerase chain reaction [PCR], metagenomic next-generation sequencing [mNGS], serology), neuroimaging, treatment regimens, and visual outcomes were analyzed. [Results] The cohort had a mean age of 50.4 years (range 31–66), with male predominance (84.6%, 11/13). Varicella zoster virus (VZV) was the leading pathogen (76.9%, 10/13), followed by herpes simplex virus type 1 (HSV-1), Epstein–Barr virus (EBV), and pseudorabies virus (PRV). Eight patients (61.5%) developed optic neuritis (ON) secondary to VZV infection, and five patients (38.5%) suffered from acute retinal necrosis (ARN), which was caused by VZV (n = 2), HSV-1 (n = 2), and PRV (n = 1). Bilateral involvement occurred in 46.2% (6/13) of patients. ARN was associated with the most severe visual loss. At the disease nadir, 46.2% of patients (6/13) presented with no light perception (NLP). Notably, five of these six NLP cases were diagnosed with ARN. Etiological confirmation was achieved in only 38.5% (5/13) of cases. mNGS of cerebrospinal and vitreous fluid, alongside aqueous humor PCR, are pivotal for diagnosing HSV-1/EBV mixed infections and rare PRV infection. All patients received antiviral therapy, 11 of whom (84.6%) were treated with intravenous antiviral agents. Glucocorticoids were administered as combination therapy to all patients. However, only one of eight VZV–ON eyes showed genuine visual improvement. In VZV–ARN, the initially involved eyes stayed NLP at final follow-up, while the fellow eyes recovered vision. Still, all non-VZV ARN patients had persistent bilateral NLP during follow-up. [Conclusions] Herpesvirus-associated visual impairment is dominated by VZV, manifests as ON or ARN, and carries a high risk of severe permanent vision loss—particularly in ARN. The emergence of zoonotic PRV underscores the need for heightened clinical vigilance. Diagnostic delays and insufficient interdisciplinary collaboration contribute substantially to poor outcomes.

Sleep is essential for brain homeostasis, in part by supporting glymphatic clearance through sleep-related oscillations. However, the relationship between putative glymphatic metrics and coupled sleep rhythm disruption, and their combined role in Alzheimer’s disease (AD) progression, remains poorly understood. We analyzed data from 75 individuals, 54 with AD and 21 cognitively normal (CN) controls, including sleep electroencephalography (EEG), magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) AD biomarkers, and two-year longitudinal cognitive assessments. Putative glymphatic metrics was evaluated using choroid plexus (CP) volume, perivascular spaces (PVSs), diffusion tensor imaging along the perivascular space (DTI-ALPS) index, and blood oxygen level-dependent signal coupled to CSF signal (BOLD-CSF coupling). Coupled sleep rhythm was assessed via slow oscillation (SO)-theta and SO-spindle couplings. Correlation and mediation analyses explored associations between these MRI-derived indices and coupled sleep oscillations, and least absolute shrinkage and selection operator (LASSO) regression was used to predict AD progression. Compared to CN controls, individuals with AD had reduced DTI-ALPS index and BOLD-CSF coupling (p < 0.05), along with disrupted SO-spindle coupling (p = 0.029). Across all participants, lower global BOLD-CSF coupling correlated with misaligned SO-theta burst coupling (r = 0.311, p = 0.018), and reduced DTI-ALPS was associated with misaligned SO-spindle coupling (r = 0.370, p = 0.008). In the AD group, DTI-ALPS remained correlated with SO-spindle misalignment (r = 0.376, p = 0.028). Mediation analysis revealed that SO-spindle misalignment contributed to cognitive decline through its effect on DTI-ALPS. Importantly, combining putative glymphatic and sleep EEG metrics effectively predicted AD progression. Our findings suggest that disruptions in surrogates marker of glymphatic clearance and coupled sleep rhythms are jointly associated with AD-related cognitive decline. These metrics offer a promising framework for predicting disease progression and understanding neurodegenerative mechanisms in AD.

Autism spectrum disorder (ASD) is a type of neurodevelopmental disorder that occurs most frequently in early childhood, affecting approximately 1% of the global population. Currently, the elusive nature of the pathological mechanisms underlying ASD precludes the existence of a definitive, effective treatment approach. In this study, we have successfully generated a novel ASD rat model utilizing CRISPR/Cas9 technology, offering a promising platform for further investigation and potential therapeutic interventions. The model is characterized by two crucial point mutations occurring at key enzyme cleavage sites of brain-derived neurotrophic factor (BDNF), thereby causing disruptions in enzyme cleavage processes. The phenotypes of this rat model faithfully recapitulate the salient deficits frequently encountered in ASD patients, exhibiting impairments in social behavior, cognition, and anxiety, along with neuronal abnormalities with key brain regions, notably the hippocampus (HPC) and medial prefrontal cortex (mPFC). Through preliminary RNA-seq analysis, we found changes in gene expression patterns related to synapses and neuronal excitability in these areas, providing new insights into the pathogenesis of ASD. Furthermore, our utilization of 7,8-dihydroxyflavone (7,8-DHF), a robust enhancer for the upregulation of both BDNF and TrkB mRNA and simultaneously activates the BDNF-TrkB signaling pathway, appears to strengthen the BDNF-TrkB signaling cascade. This intervention modifies firing patterns of neuronal spikes and synaptic transmission, which may contribute to the amelioration of ASD-like social interaction behavior exhibited in BDNFmet/leu rats. Our research not only deepens our understanding of the pathogenesis of ASD, but also present encouraging avenue for early intervention strategies and treatments.

Calcium overload drives neuronal cell death, but its mechanisms remain unclear. Previous studies in Drosophila implicated tousled-like kinase (TLK) in this process. Here, we investigated TLK2, the mammalian homolog, in calcium overload-induced neuronal death. We found that calcium overload enhances TLK2 expression, multimerization, and phosphorylation, increasing its kinase activity. Inhibiting TLK2 via RNA interference or a small-molecule inhibitor reduced neuronal death, while TLK2 overexpression triggered nuclear envelope (NE) rupture, nuclear enlargement, multinucleation, and cell cycle reentry markers. A protein complex involving TLK2, dynein light chain LC8, and myosin IIA was linked to NE disruption. In mouse models of glaucoma, TLK2 contributed to retinal ganglion cell degeneration, connecting calcium overload to neurodegeneration. We propose "CaToptosis" (Calcium-induced Tousled-like kinase-mediated cell death) as a distinct neuronal death pathway.

BACKGROUND:Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a rare disease with a high disability rate, characterized by acute-to-subacute psychiatric and/or neurological symptoms. Continuous intrathecal antibody synthesis does not correlate with the active phase of encephalitis and antibody titers do not directly reflect the severity of the condition. Currently, there is a lack of biomarkers for disease monitoring. This study focuses on finding novel peripheral blood biomarkers that can accurately monitor the severity of anti-NMDAR encephalitis. METHODS:Peripheral blood samples were collected from patients with anti-NMDAR encephalitis, including those with acute-phase (autoimmune encephalitis (AE)-a group) and stable-phase (AE-s group) autoimmune encephalitis. Healthy individuals were included as controls (HC group). We isolated exosomal microRNAs (miRNAs) from the samples and screened differentially expressed miRNAs through next-generation sequencing. The sequencing results were validated using quantitative real-time qPCR (RT-qPCR). Furthermore, we conducted a correlation analysis between the expression levels of the screened miRNAs and clinical severity. Finally, we performed functional pathway analysis to explore the underlying mechanisms in anti-NMDAR encephalitis. RESULTS:We found that exosomal miR-432-5p, miR-4433b-5p, and miR-599 exhibited significant differences between patients with anti-NMDAR encephalitis and healthy controls, as well as at various phases of the disease. The expression of miR-432-5p and miR-4433b-5p were negatively correlated with clinical severity. We further identified that key pathways including rhythmic processes and glutamatergic signaling play significant roles in the pathogenesis of anti-NMDAR encephalitis. CONCLUSIONS:Our research indicated that exosomal miR-432-5p, miR-4433b-5p, and miR-599 were correlated with the severity of anti-NMDAR encephalitis and can serve as potential biomarkers for disease monitoring. Moreover, the key functional pathways predicted by these miRNAs may play crucial roles in disease progression.

Serotonin receptor subtype 1 A (5-HTR1A) is a critical therapeutic target for neuropsychiatric disorders. Crataegus pinnatifida Bge. (hawthorn) exhibits potent antidepressant-like effects via 5-HTR1A activation, yet its bioactive constituents remain unidentified. Herein, we engineered 5-HTR1A-haloalkane dehalogenase fusion protein and immobilized it on 6-bromohexanoic acid-functionalized microspheres to establish affinity-based screening platform. Bioactivity-guided isolation identified malic acid and chlorogenic acid as 5-HTR1A ligands, and their binding energies were-12.9 kcal/mol and-44.7 kcal/mol, respectively. In vitro assays demonstrated that chlorogenic acid significantly protected PC12 cells from corticosterone-induced damage at concentrations as low as 2.5 mu M (p = 0.0305), whereas malic acid exhibited comparable effects at 20 mu M. Both compounds effectively counteracted corticosterone-induced reductions in serotonin, dopamine, and BDNF levels likely through interactions with 5-HTR1A. Collectively, these findings suggest that malic acid and chlorogenic acid are stable, high-affinity 5-HTR1A ligands with significant neuroprotective potential, making them promising lead compounds for developing novel 5-HTR1A-targeted therapeutics.

Terazosin (TZ), a well-known antagonist of the α1-adrenergic receptor (α1-AR), has demonstrated protective effects on vascular endothelial cells (ECs) and reduced vascular stiffness in clinical studies. Endothelial dysfunction and oxidative stress are central drivers of cardiometabolic diseases such as diabetes, where sustained ROS burden accelerates EC senescence and barrier failure. These findings suggest its potential role in combating vascular aging and atherosclerosis; however, the underlying mechanisms remain partially understood. In this study, we investigated whether TZ can prevent atherosclerosis in ApoE-/- mice fed a high-cholesterol diet and aimed to elucidate the mechanisms involved. Our results showed that TZ significantly reduced plaque size, EC senescence, vascular permeability, and reactive oxygen species (ROS) levels, effectively inhibiting atherosclerosis independently of α1-AR signaling. In cultured primary human umbilical vein ECs (HUVECs), TZ inhibited EC senescence via the Pgk1/Hsp90 pathway. It enhanced the interaction between Hsp90 and the antioxidant enzyme peroxiredoxin 1 (Prdx1), leading to lower ROS levels-a key driver of cellular senescence. These findings were confirmed in atherosclerotic ApoE-/- mice. Furthermore, senescent ECs exhibited increased levels of vascular endothelial growth factor A (VEGFA) and decreased levels of angiostatin, contributing to higher vascular permeability and exacerbating atherosclerosis. TZ effectively reversed these changes. Overall, our study demonstrates that TZ primarily alleviates EC senescence and atherosclerosis through the Pgk1/Hsp90/Prdx1 pathway, highlighting Pgk1 activation as a strategy that may also mitigate endothelial dysfunction and oxidative stress in broader cardiometabolic contexts (e.g., diabetes), suggesting that TZ is a promising senomorphic agent for treating vascular aging and atherosclerosis in clinical settings and that Pgk1-targeted interventions could have implications beyond atherosclerosis.

Background Severe autoimmune encephalitis (AE) can cause significant neurological deficits, status epilepticus, status dystonicus, and even death, which can be life-threatening to patients. Accurate risk stratification for severe AE progression is critical for optimizing therapeutic strategies. The comprehensive prediction models for severe AE based on routine clinical data and laboratory indicators remain lacking. Objective To develop and validate a prediction model for severe AE to optimize individualized treatment. Methods We collected clinical data and laboratory examination results from 207 patients with confirmed AE. The study population was divided into development and validation cohort. A prediction model for severe AE was constructed using a nomogram and was rigorously validated both internally and externally. Severe AE was defined as modified Rankin Scale (mRS) > 2 and Clinical Assessment Scale for Encephalitis (CASE) > 4. Results The variables ultimately included in the nomogram for the severe AE predictive model were age, psychiatric and/or behavioral abnormalities, seizures, decreased level of consciousness, cognitive impairment, involuntary movements, autonomic dysfunction, and increased intrathecal IgG synthesis rate. It demonstrated excellent discriminative capacity and calibration through internal-external validation. Conclusion The prediction model has highly feasibility in clinical practice, and holds promise as an important tool for risk assessment and guiding individualized treatment in patients with AE.

Neuroinflammation and oxidative stress contribute to the progression of sepsis-associated encephalopathy (SAE). Angiotensin-converting enzyme 2 (ACE2) is considered to be a neuroprotective factor due to its anti-inflammatory and antioxidant properties. However, the role of ACE2 on myeloid cells in regulating SAE and the underlying mechanism warrants further exploration. SAE was induced in ACE2 transgenic (TG), knockout (KO), and bone marrow (BM) chimeric mice by cecal ligation and puncture (CLP). The expression levels of apoptosis-, oxidation- and neuroinflammation-associated mediators and morphological changes were monitored by quantitative real-time PCR analyses and histological examinations in the cortex of septic mice. The contents of angiotensin (Ang) II and Ang-(1–7) along with the activity of ACE2 were examined with commercial kits. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and Sestrin2 was detected by immunoblotting analysis. Our results indicated that the expression of cortical ACE2 was significantly reduced in the early phase of CLP-induced sepsis. Moreover, ACE2 overexpression in TG mice conferred neuroprotection against sepsis, as evidenced by alleviated neuronal apoptosis, oxidative stress, and proinflammatory M1-like microglial polarization, accompanied by upregulation of the Ang-(1–7), Nrf2, and Sestrin2 protein levels. Conversely, ACE2 deficiency in KO mice exacerbated SAE. The neuroprotective effects of ACE2 were further confirmed in wild-type mice transplanted with ACE2-TG and KO BM cells. Therefore, our data suggest that myeloid ACE2 exerts a protective role in the pathogenesis of SAE, potentially by activating Ang-(1–7)-Nrf2/sestrin2 signaling pathway, and highlight that upregulating ACE2 expression and activity may represent a promising approach for the treatment of SAE in patients with sepsis.

Abdominal aortic aneurysm (AAA), a vascular degenerative disease, is a potentially life-threatening condition characterised by the loss of vascular smooth muscle cells (VSMCs), degradation of extracellular matrix (ECM), inflammation, and oxidative stress. Despite the severity of AAA, effective drugs for treatment are scarce. At low doses, terazosin (TZ) exerts antiapoptotic and anti-inflammatory effects in several diseases, but its potential to protect against AAA remains unexplored. Herein, we investigated the effects of TZ in two AAA animal models: Angiotensin II (Ang II) infusion in Apoe(-/-) mice and calcium chloride application in C57BL/6J mice. Mice were orally administered with TZ (100 or 1000 mu g/kg/day). The in vivo results indicated that low-dose TZ alleviated AAA formation in both models. Low-dose TZ significantly reduced aortic pulse wave velocity without exerting an apparent antihypertensive effect in the Ang II-induced AAA model. Paternally expressed gene 3 (Peg3) was identified via RNA sequencing as a novel TZ target. PEG3 expression was significantly elevated in both mouse and human AAA tissues. TZ suppressed PEG3 expression and reduced the abundance of matrix metalloproteinases (MMP2/MMP9) in the tunica media. Functional experiments and molecular analyses revealed that TZ (10 nM) treatment and Peg3 knockdown effectively prevented Ang II-induced VSMC senescence and apoptosis in vitro. Thus, Peg3, a novel target of TZ, mediates inflammation-induced VSMC apoptosis and senescence. Lowdose TZ downregulates Peg3 expression to attenuate AAA formation and ECM degradation, suggesting a promising therapeutic strategy for AAA.

With the progress of medical and health conditions, the incidence and mortality of encephalitis and meningitis caused by traditional pathogens have decreased. However, due to the change of pathogen spectrum of neurological infection, the improvement of detection methods of neurological infection pathogens and the emergence of new evidence of pathogens causing neurodegenerative diseases, it is necessary to rethink the clinical characteristics and diagnosis and treatment of neurological infectious diseases (NID). At the same time, post-infectious/para-infectious nervous system diseases (PPINDs) that do not directly enter the central nervous system are increasing after the SARS-CoV-2 epidemic. Therefore, we propose to attach importance to the disciplinary characteristics and discipline construction of Infectious Neurology with NID and PPINDs as the two major themes, and to improve the diagnosis and treatment of NID and PPINDs through multi-disciplinary cooperation and specialized training.

The accumulation of α-synuclein (α-syn), a key protein in Parkinson's disease (PD), contributes to progressive neuronal damage associated with mitochondrial dysfunction and interactions with various proteins. However, the precise mechanism by which α-syn affects energy metabolism remains unclear. In our study, we used human α-syn (hα-syn) transgenic mice, which exhibit progressive neuronal decline. Through an immunoprecipitation assay specific to hα-syn, we identified an enzyme in the mitochondrial tricarboxylic acid (TCA) cycle as a binding partner—mitochondrial aconitase 2 (ACO2), which converts citrate to isocitrate. Hα-syn increasingly interacted with ACO2 in mitochondria as mice aged, correlating with a progressive decrease in ACO2 activity. The overexpression of ACO2 and the addition of isocitrate, a downstream metabolite of ACO2, were observed to alleviate hα-syn-induced mitochondrial dysfunction and cytotoxicity. Furthermore, we designed an interfering peptide to block the interaction between ACO2 and hα-syn, which showed therapeutic effects in reducing hα-syn toxicity in vitro and in vivo. Our research establishes a direct link between α-syn and the TCA cycle and identifies ACO2 as a promising therapeutic target for improving mitochondrial function and reducing α-syn neurotoxicity in PD.

Enhanced recovery after surgery (ERAS) has been successfully integrated into a diverse array of surgical fields to improve the quality and efficacy of treatment intervention. Nonetheless, the application of the ERAS protocol for patients with diabetic foot ulcer (DFU) subsequent to undergoing surgical procedures has not been previously explored. Therefore, this study aimed to investigate the effect of an enhanced recovery protocol on perioperative outcomes in patients with DFU following surgical procedures. A retrospective analysis was conducted on 112 patients with DFU who underwent surgery between January 2020 and December 2021 at a tertiary referral care center. In total, 57 patients received standard perioperative care (the non-ERAS group), and 55 patients received ERAS care (the ERAS group). The primary outcomes included the length of stay (LOS), wound healing time, patient satisfaction, and costs, serving as the basis for assessing the effectiveness of the two approaches. Secondary outcomes included preoperative anxiety (APAIS score), nutritional status (PG-SGA), pain (NRS score), the incidence of lower-extremity deep vein thrombosis (DVT), the reduction in lower-limb circumference, and the activity of daily living scale (Barthel Index). The ERAS group exhibited significantly shorter LOS (11.36 vs. 26.74 days; P < 0.001) and lower hospital costs (CNY 62,165.27 vs. CNY 118,326.84; P < 0.001), as well as a higher patient satisfaction score and Barthel Index score (P < 0.05). Additionally, we found a lower APAIS score, incidence of DVT, and circumference reduction in lower limbs in the ERAS group compared to the non-ERAS group (P < 0.05). In comparison, the wound healing time, nutritional status, and pain levels of participants in both groups showed no significant difference (P > 0.05). By reducing the LOS and hospital costs, and by minimizing perioperative complications, the ERAS protocol improves the quality and efficacy of treatment intervention in patients with DFU who underwent surgical procedures.Trial registration number: ChiCTR 2200064223 (Registration Date: 30/09/2022).

To estimate the associations of circulating levels of cytokines with the risk of Neuromyelitis optica spectrum disorders (NMOSD).

Sepsis-induced acute liver injury (ALI) is common in intensive care units. Angiotensin-converting enzyme 2 (ACE2) plays a vital role in hepatic fibrosis and steatosis; however, its role in sepsis-induced ALI remains unclear. This study found that hepatic ACE2 expression in cecal ligation and puncture (CLP)-treated mice significantly decreased 24 h after CLP. ACE2-transgenic (TG) mice exhibited a significant improvement in CLP-induced ALI, accompanied by the inhibition of hepatocyte apoptosis, oxidative stress, and inflammation, while ACE2-knockout mice demonstrated an opposite trend. During sepsis-induced ALI, ACE2-TG could also elevate the Ang-(1–7) and Mas receptor (MasR) levels in liver tissues. Interestingly, the MasR inhibitor A779 abrogated the favorable effects of ACE2 on CLP-induced ALI. In a bone marrow transplantation experiment, the ACE2-TG transplantation group showed significantly improved inflammation and liver dysfunction, less hepatocyte apoptosis, and reduced oxidative stress after CLP compared with the wild-type transplantation group. In contrast, the ACE2-knockout group showed poor inflammatory response and liver dysfunction, significantly more hepatocyte apoptosis, and elevated oxidative stress than the wild-type transplantation group after CLP. ACE2 protects against sepsis-induced ALI by inhibiting hepatocyte apoptosis, oxidative stress, and inflammation via the Ang-(1–7)–Mas receptor axis. Thus, targeting ACE2 may be a promising novel strategy for preventing and treating sepsis-induced ALI.

Parkinson's disease (PD) is characterized by α-synuclein aggregation in dopaminergic (DA) neurons, which are sensitive to oxidative stress. Mitochondria aconitase 2 (ACO2) is an essential enzyme in the tricarboxylic acid cycle that orchestrates mitochondrial and autophagic functions to energy metabolism. Though widely linked to diseases, its relation to PD has not been fully clarified. Here we revealed that the peripheral ACO2 activity was significantly decreased in PD patients and associated with their onset age and disease durations. The knock-in mouse and Drosophila models with the A252T variant displayed aggravated motor deficits and DA neuron degeneration after 6-OHDA and rotenone-induction, and the ACO2 knockdown or blockade cells showed features of mitochondrial and autophagic dysfunction. Moreover, the transcription of autophagy-related genes LC3 and Atg5 was significantly downregulated via inhibited histone acetylation at the H3K9 and H4K5 sites. These data provided multi-dimensional evidences supporting the essential roles of ACO2, and as a potential early biomarker to be used in clinical trials for assessing the effects of antioxidants in PD. Moreover, ameliorating energy metabolism by targeting ACO2 could be considered as a potential therapeutic strategy for PD and other neurodegenerative disorders.

Brain aging may accelerate after rodents reach middle age. However, the endogenous mediator that promotes this acceleration is unknown. We predict that the mediator may be expressed after an organism reaches middle age and dysregulates mitochondrial function. In the neurons of wild-type Drosophila (flies), we observed that mitochondria were fragmented in aged flies, and this fragmentation was associated with mitochondrial calcium overload. In a previous study, we found that mitochondrial fragmentation induced by calcium overload was reversed by the loss of Vimar , which forms a complex with Miro. Interestingly, Vimar expression was increased after the flies reached middle age. Overexpression of Vimar in neurons resulted in premature aging and mitochondrial calcium overload. In contrast, downregulation of Vimar in flies older than middle age promoted healthy aging. As the mouse homolog of Vimar, RAP1GDS1 expression was found to be increased after mice reached middle age; RAP1GDS1 -transgenic and RAP1GDS1 -knockdown mice displayed similar responses to flies with overexpressed and reduced Vimar expression, respectively. This research provides genetic evidence of a conserved endogenous mediator that promotes accelerated brain aging.

Sepsis-induced cardiomyopathy (SIC), caused by a dysregulated host response to infection, is a major contributor to high mortality. Angiotensin-converting enzyme 2 (ACE2), a crucial component of the renin-angiotensin system (RAS), has protective effects against several cardiovascular diseases, such as myocardial infarction and heart failure. However, the role of ACE2 in the pathogenesis of SIC and underlying mechanisms remain unknown. The present study was designed to examine the effects of ACE2 activation or inhibition on SIC in C57BL/6 mice. The ACE2 activator diminazene aceturate (DIZE) and ACE2 inhibitor MLN-4760 were applied for treatment. Myocardial function, inflammatory response, oxidative stress, apoptosis and mitochondrial biogenesis were investigated. Major assays were echocardiography, H&E staining, immunofluorescence staining, DHE staining, TUNEL staining, Western blot, qPCR analysis, ELISA and corresponding kits. We confirmed that ACE2 was markedly downregulated in septic heart tissues. Pharmacological activation of ACE2 by DIZE ameliorated cecal ligation puncture (CLP)-induced mortality, cardiac dysfunction, inflammatory response, oxidative stress and the cardiomyocyte apoptosis by promoting MasR-Sirt1-mediated mitochondrial biogenesis. In contrast, SIC was aggravated via inhibiting MasR-Sirt1-mediated mitochondrial biogenesis by the use of ACE2 inhibitor MLN-4760. Consequently, activation of ACE2 may protect against SIC by promoting MasR-Sirt1-mediated mitochondrial biogenesis.

The prevention of protein condensates has emerged as a new drug target to treat diverse neurodegenerative disorders. We previously reported that terazosin (TZ), a prescribed antagonist of the α1 adrenergic receptor, is an activator of phosphoglycerate kinase 1 (Pgk1) and Hsp90. In this study, we aimed to determine whether TZ prevents the formation of diverse pathological condensates in cell cultures and animal disease models. In primary neuron culture, TZ treatment reduced both the protein density and abundance of fused in sarcoma (FUS)-P525L-GFP, a disease-associated mutant form of FUS. Regarding the mechanism, we found that increased intracellular ATP levels were critical for the reduction in protein aggregate density. In addition, Hsp90 activation by TZ enhanced Hsp90 interaction with ULK1, a master regulator of autophagy. Through in vivo studies, we examined neuron-specific overexpression of tau in Drosophila, mouse models of APP/PS1 Alzheimer's disease (AD), and a rat model of multiple system atrophy (MSA) via the viral expression of α-synuclein in the striatum. TZ prevented and reversed the formation of pathological protein condensates. Together, our results suggest that activation of Pgk1 in cytosol may dissolve pathological protein aggregates via increased ATP levels and degrade these proteins via autophagy; the FUS-P525L degradation pathway in nucleus is unclear.