Causal association and mediating effect of blood biochemical metabolic traits and brain image-derived endophenotypes on Alzheimer's disease.

Background: Recent genetic evidence supports that circulating biochemical and metabolic traits (BMTs) play a causal role in Alzheimer's disease (AD), which might be mediated by changes in brain structure. Here, we leveraged publicly available genome-wide association study data to investigate the intrinsic causal relationship between blood BMTs, brain image-derived phenotypes (IDPs) and AD. Methods: Utilizing the genetic variants associated with 760 blood BMTs and 172 brain IDPs as the exposure and the latest AD summary statistics as the outcome, we analyzed the causal relationship between blood BMTs and brain IDPs and AD by using a two-sample Mendelian randomization (MR) method. Additionally, we used two-step/mediation MR to study the mediating effect of brain IDPs between blood BMTs and AD. Results: Twenty-five traits for genetic evidence supporting a causal association with AD were identified, including 12 blood BMTs and 13 brain IDPs. For BMTs, glutamine consistently reduced the risk of AD in 3 datasets. For IDPs, specific alterations of cortical thickness (atrophy in frontal pole and insular lobe, and incrassation in superior parietal lobe) and subcortical volume (atrophy in hippocampus and its subgroups, left accumbens and left choroid plexus, and expansion in cerebral white matter) are vulnerable to AD. In the two-step/mediation MR analysis, superior parietal lobe, right hippocampal fissure and left accumbens were identified to play a potential mediating role among three blood BMTs and AD. Conclusions: The results obtained in our study suggest that 12 circulating BMTs and 13 brain IDPs play a causal role in AD. Importantly, a subset of BMTs exhibit shared genetic architecture and potentially causal relationships with brain structure, which may contribute to the alteration of brain IDPs in AD.

Systematic druggable genome-wide Mendelian randomization identifies therapeutic targets for sarcopenia.

BACKGROUND: There are no effective pharmacological treatments for sarcopenia. We aim to identify potential therapeutic targets for sarcopenia by integrating various publicly available datasets. METHODS: We integrated druggable genome data, cis-eQTL/cis-pQTL from human blood and skeletal muscle tissue, and GWAS summary data of sarcopenia-related traits to analyse the potential causal relationships between drug target genes and sarcopenia using the Mendelian Randomization (MR) method. Sensitivity analyses and Bayesian colocalization were employed to validate the causal relationships. We also assessed the side effects or additional indications of the identified drug targets using a phenome-wide MR (Phe-MR) approach and investigated actionable drugs for target genes using available databases. RESULTS: MR analysis identified 17 druggable genes with potential causation to sarcopenia in human blood or skeletal muscle tissue. Six of them (HP, HLA-DRA, MAP 3K3, MFGE8, COL15A1, and AURKA) were further confirmed by Bayesian colocalization (PPH4 > 90%). The up-regulation of HP [higher ALM (beta: 0.012, 95% CI: 0.007-0.018, P = 1.2*10-5) and higher grip strength (OR: 0.96, 95% CI: 0.94-0.98, P = 4.2*10-5)], MAP 3K3 [higher ALM (beta: 0.24, 95% CI: 0.21-0.26, P = 1.8*10-94), higher grip strength (OR: 0.82, 95% CI: 0.75-0.90, P = 2.1*10-5), and faster walking pace (beta: 0.03, 95% CI: 0.02-0.05, P = 8.5*10-6)], and MFGE8 [higher ALM (muscle eQTL, beta: 0.09, 95% CI: 0.06-0.11, P = 6.1*10-13; blood pQTL, beta: 0.05, 95% CI: 0.03-0.07, P = 3.8*10-09)], as well as the down-regulation of HLA-DRA [lower ALM (beta: -0.09, 95% CI: -0.11 to -0.08, P = 5.4*10-36) and lower grip strength (OR: 1.13, 95% CI: 1.07-1.20, P = 1.8*10-5)] and COL15A1 [higher ALM (muscle eQTL, beta: -0.07, 95% CI: -0.10 to -0.04, P = 3.4*10-07; blood pQTL, beta: -0.05, 95% CI: -0.06 to -0.03, P = 1.6*10-07)], decreased the risk of sarcopenia. AURKA in blood (beta: -0.16, 95% CI: -0.22 to -0.09, P = 2.1*10-06) and skeletal muscle (beta: 0.03, 95% CI: 0.02 to 0.05, P = 5.3*10-05) tissues showed an inverse relationship with sarcopenia risk. The Phe-MR indicated that the six potential therapeutic targets for sarcopenia had no significant adverse effects. Drug repurposing analysis supported zinc supplementation and collagenase clostridium histolyticum might be potential therapeutics for sarcopenia by activating HP and inhibiting COL15A1, respectively. CONCLUSIONS: Our research indicated MAP 3K3, MFGE8, COL15A1, HP, and HLA-DRA may serve as promising targets for sarcopenia, while the effectiveness of zinc supplementation and collagenase clostridium histolyticum for sarcopenia requires further validation.

MSC-Derived Extracellular Vesicles Alleviate NLRP3/GSDMD-Mediated Neuroinflammation in Mouse Model of Sporadic Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease, with sporadic form being the predominant type. Neuroinflammation plays a critical role in accelerating pathogenic processes in AD. Mesenchymal stem cell (MSC)-derived small extracellular vesicles (MSC-sEVs) regulate inflammatory responses and show great promise for treating AD. Induced pluripotent stem cell (iPSC)-derived MSCs are similar to MSCs and exhibit low immunogenicity and heterogeneity, making them promising cell sources for clinical applications. This study examined the anti-inflammatory effects of MSC-sEVs in a streptozotocin-induced sporadic mouse model of AD (sAD). The intracisternal administration of iPSC-MSC-sEVs alleviated NLRP3/GSDMD-mediated neuroinflammation, decreased amyloid deposition and neuronal apoptosis, and mitigated cognitive dysfunction. Furthermore, it explored the role of miR-223-3p in the iPSC-MSC-sEVs-mediated anti-inflammatory effects in vitro. miR-223-3p directly targeted NLRP3, whereas inhibiting miR-223-3p almost completely reversed the suppression of NLRP3 by MSC-sEVs, suggesting that miR-223-3p may, at least partially, account for MSC-sEVs-mediated anti-inflammation. Results obtained suggest that intracisternal administration of iPSC-MSC-sEVs can reduce cognitive impairment by inhibiting NLRP3/GSDMD neuroinflammation in a sAD mouse model. Therefore, the present study provides a proof-of-principle for applying iPSC-MSC-sEVs to target neuroinflammation in sAD.

Efficient and stable acidic CO2 electrolysis to formic acid by a reservoir structure design.

Electrochemical synthesis of valuable chemicals and feedstocks through carbon dioxide (CO2) reduction in acidic electrolytes can surmount the considerable CO2 loss in alkaline and neutral conditions. However, achieving high productivity, while operating steadily in acidic electrolytes, remains a big challenge owing to the severe competing hydrogen evolution reaction. Here, we show that vertically grown bismuth nanosheets on a gas-diffusion layer can create numerous cavities as electrolyte reservoirs, which confine in situ-generated hydroxide and potassium ions and limit inward proton diffusion, producing locally alkaline environments. Based on this design, we achieve formic acid Faradaic efficiency of 96.3% and partial current density of 471 mA cm-2 at pH 2. When operated in a slim continuous-flow electrolyzer, the system exhibits a full-cell formic acid energy efficiency of 40% and a single pass carbon efficiency of 79% and performs steadily over 50 h. We further demonstrate the production of pure formic acid aqueous solution with a concentration of 4.2 weight %.

Prediction value of neutrophil and eosinophil count at risk of COPD exacerbation.

INTRODUCTION: Predicting acute exacerbations (AEs) in chronic obstructive pulmonary disease (COPD) is crucial. This study aimed to identify blood biomarkers for predicting COPD exacerbations by inflammatory phenotypes. MATERIALS AND METHODS: We analyzed blood cell counts and clinical outcomes in 340 COPD patients aged 20-90 years. Patients were categorized into eosinophilic inflammation (EOCOPD) and non-eosinophilic inflammation (N-EOCOPD) groups. Blood cell counts, eosinophil-to-lymphocyte ratio (ELR), neutrophil-to-lymphocyte ratio (NLR) and neutrophil-to-eosinophil ratio (NER) were calculated. Linear and logistic regression models assessed relationships between health outcomes and blood cell counts. RESULTS: EOCOPD patients had distinct characteristics compared to N-EOCOPD patients. Increased neutrophil % and decreased lymphocyte % were associated with reduced pulmonary function, worse quality of life and more exacerbations, but they did not show statistical significance after adjusting by age, sex, BMI, smoking status, FEV1% and patient's medication. Subgroup analysis revealed a 1.372-fold increase in the OR of AE for every 1 unit increase in NLR in EOCOPD patients (p < .05). In N-EOCOPD patients, every 1% increase in blood eosinophil decreased the risk of exacerbation by 59.6%. CONCLUSIONS: Our study indicates that distinct white blood cell profiles in COPD patients, with or without eosinophilic inflammation, can help assess the risk of AE in clinical settings.

Keratinocyte FABP5-VCP complex mediates recruitment of neutrophils in psoriasis.

One of the hallmarks of intractable psoriasis is neutrophil infiltration in skin lesions. However, detailed molecular mechanisms of neutrophil chemotaxis and activation remain unclear. Here, we demonstrate a significant upregulation of epidermal fatty acid binding protein (E-FABP, FABP5) in the skin of human psoriasis and psoriatic mouse models. Genetic deletion of FABP5 in mice by global knockout and keratinocyte conditional (Krt6a-Cre) knockout, but not myeloid cell conditional (LysM-Cre) knockout, attenuates psoriatic symptoms. Immunophenotypic analysis shows that FABP5 deficiency specifically reduces skin recruitment of Ly6G+ neutrophils. Mechanistically, activated keratinocytes produce chemokines and cytokines that trigger neutrophil chemotaxis and activation in an FABP5-dependent manner. Proteomic analysis further identifies that FABP5 interacts with valosin-containing protein (VCP), a key player in NF-κB signaling activation. Silencing of FABP5, VCP, or both inhibits NF-κB/neutrophil chemotaxis signaling. Collectively, these data demonstrate dysregulated FABP5 as a molecular mechanism promoting NF-κB signaling and neutrophil infiltration in psoriasis pathogenesis.

Gerhardtite as a Precursor to an Efficient CO-to-Acetate Electroreduction Catalyst.

Carbon-carbon coupling electrochemistry on a conventional copper (Cu) catalyst still undergoes low selectivity among many different multicarbon (C2+) chemicals, posing a grand challenge to achieve a single C2+ product. Here, we demonstrate a laser irradiation synthesis of a gerhardtite mineral, Cu2(OH)3NO3, as a catalyst precursor to make a Cu catalyst with abundant stacking faults under reducing conditions. Such structural perturbation modulates electronic microenvironments of Cu, leading to improved d-electron back-donation to the antibonding orbital of *CO intermediates and thus strengthening *CO adsorption. With increased *CO coverage on the defect-rich Cu, we report an acetate selectivity of 56 ± 2% (compared to 31 ± 1% for conventional Cu) and a partial current density of 222 ± 7 mA per square centimeter in CO electroreduction. When run at 400 mA per square centimeter for 40 h in a flow reactor, this catalyst produces 68.3 mmol of acetate throughout. This work highlights the value of a Cu-containing mineral phase in accessing suitable structures for improved selectivity to a single desired C2+ product.

A Chinese medicine called Danggui Longhui may be a new clinically relevant clozapine inducer: Two case reports identified by therapeutic drug monitoring.

BACKGROUND: Danggui Longhui is a traditional Chinese medicine made from the dried root of Angelica sinensis. It is used in psychiatric patients in China to reduce associated constipation. In a population pharmacokinetic model in olanzapine patients from Beijing Anding Hospital, we demonstrate that dangguilonghui tablets doubled olanzapine clearance, indicating the induction of olanzapine metabolism. Olanzapine metabolism is similar to clozapine metabolism. METHODS: Two cases of possible clozapine induction using dangguilonghui tablets 4 g/day were identified in Beijing Anding Hospital. Dividing the minimum therapeutic concentration of 350 ng/mL by the concentration-to-dose (C/D) ratio provides the minimum therapeutic dose. RESULTS: Case 1 was a female smoker on clozapine for 415 days. The mean of 6 clozapine C/D ratios associated with smoking provided a minimum therapeutic dose of 267 mg/day. There were 6 steady-state concentrations on the combination of valproic acid and dangguilonghui tablets, which provided a much higher minimum therapeutic dose of 833 mg/day. Four steady-state clozapine C/D ratios based on smoking and valproate after 4 months of carbamazepine 200 mg/day provided a minimum therapeutic dose of 603 mg/day. Case 2 was a female non-smoker on clozapine for 58 days. She had 3 clozapine C/D ratios on dangguilonghui tablets with a mean of 0.30 ng/mL providing a minimum therapeutic dose of 1167 mg/day. CONCLUSION: Future clinical studies with repeated measures need to replicate the possibility that dangguilonghui tablets are a moderate-to-strong inducer of clozapine metabolism as suggested by these two limited cases.

Short-term mediating effects of PM2.5 on climate-associated COPD severity.

The impact of short-term exposure to environmental factors such as temperature, relative humidity (RH), and fine particulate matter (PM2.5) on chronic obstructive pulmonary disease (COPD) remains unclear. The objective of this study is to investigate PM2.5 as a mediator in the relationship between short-term variations in RH and temperature and COPD severity. A cross-sectional study was conducted on 930 COPD patients in Taiwan from 2017 to 2022. Lung function, COPD Assessment Test (CAT) score, and modified Medical Research Council (mMRC) dyspnea scale were assessed. The mean and differences in 1-day, 7-day, and 30-day individual-level exposure to ambient RH, temperature, and PM2.5 were estimated. The associations between these factors and clinical outcomes were analyzed using linear regression models and generalized additive mixed models, adjusting for age, sex, smoking, and body mass index. In the total season, increases in RH difference were associated with increases in forced expiratory volume in 1 s (FEV1) / forced vital capacity (FVC), while increases in temperature difference were associated with decreases in FEV1 and FEV1/FVC. Increases in PM2.5 mean were associated with declines in FEV1. In the cold season, increases in temperature mean were associated with decreases in CAT and mMRC scores, while increases in PM2.5 mean were associated with declines in FEV1, FVC, and FEV1/FVC. In the warm season, increases in temperature difference were associated with decreases in FEV1 and FEV1/FVC, while increases in RH difference and PM2.5 mean were associated with decreases in CAT score. PM2.5 fully mediated the associations of temperature mean with FEV1/FVC in the cold season. In conclusion, PM2.5 mediates the effects of temperature and RH on clinical outcomes. Monitoring patients during low RH, extreme temperature, and high PM2.5 levels is crucial. Capsule of findings The significance of this study is that an increase in ambient RH and temperature, as well as PM2.5 exposure, were significantly associated with changes in lung function, and clinical symptoms in these patients. The novelty of this study is that PM2.5 plays a mediating role in the association of RH and temperature with COPD clinical outcomes in the short term.

Efficient acidic hydrogen evolution in proton exchange membrane electrolyzers over a sulfur-doped marcasite-type electrocatalyst.

Large-scale deployment of proton exchange membrane (PEM) water electrolyzers has to overcome a cost barrier resulting from the exclusive adoption of platinum group metal (PGM) catalysts. Ideally, carbon-supported platinum used at cathode should be replaced with PGM-free catalysts, but they often undergo insufficient activity and stability subjecting to corrosive acidic conditions. Inspired by marcasite existed under acidic environments in nature, we report a sulfur doping-driven structural transformation from pyrite-type cobalt diselenide to pure marcasite counterpart. The resultant catalyst drives hydrogen evolution reaction with low overpotential of 67 millivolts at 10 milliamperes per square centimeter and exhibits no degradation after 1000 hours of testing in acid. Moreover, a PEM electrolyzer with this catalyst as cathode runs stably over 410 hours at 1 ampere per square centimeter and 60°C. The marked properties arise from sulfur doping that not only triggers formation of acid-resistant marcasite structure but also tailors electronic states (e.g., work function) for improved hydrogen diffusion and electrocatalysis.

Comparison of Humoral Antibody Responses and Seroconversion Rates between Two Homologous ChAdOx1 nCoV-19 and mRNA-1273 Vaccination in Patients Undergoing Maintenance Hemodialysis.

BACKGROUND: Hemodialysis patients are at an increased risk of SARS-CoV-2 infection and are excluded from preauthorization COVID-19 vaccine trials; therefore, their immunogenicity is uncertain. METHODS: To compare the antibody responses to homologous ChAdOx1 and mRNA-1273 SARS-CoV-2 vaccination in hemodialysis patients, 103 age- and sex-matched hemodialysis patients with two homologous prime-boost vaccinations were recruited to detect anti-receptor-binding domain (RBD) IgG levels and seroconversion rates (SCRs) 14 days after a prime dose (PD14), before and 28 days after a boost dose (pre-BD0 and BD28). RESULTS: Both mRNA-1273 and ChAdOx1 vaccinations elicited immunogenicity in study subjects, and the former induced higher anti-RBD IgG levels than the latter. The SCRs of both groups increased over time and varied widely from 1.82% to 97.92%, and were significantly different at PD14 and pre-BD0 regardless of different thresholds. At BD28, the SCRs of the ChAdOx1 group and the mRNA-1273 group were comparable using a threshold ≥ 7.1 BAU/mL (93.96% vs. 97.92%) and a threshold ≥ 17 BAU/mL (92.73% vs. 97.92%), respectively, but they were significantly different using a threshold ≥ 20.2% of convalescent serum anti-RBD levels (52.73% vs. 95.83%). The seroconversion (≥20.2% of convalescent level) at BD28 was associated with mRNA-1273 vaccination after being adjusted for age, sex, body mass index, and the presence of solicited reactogenicity after a prime vaccination. CONCLUSION: Our prospective, observational cohort indicates that a full prime-boost mRNA-1273 vaccination is likely to provide higher immune protection in hemodialysis patients compared to ChAdOx1, and this population with a prime-boost ChAdOx1 vaccination should be prioritized for a third dose.

Sustaining the Activation of EGFR Signal by Inflammatory Cytokine IL17A Prompts Cell Proliferation and EGFR-TKI Resistance in Lung Cancer.

Non-small-cell lung cancer (NSCLC) is a typical inflammation-associated cancer, and lung adenocarcinoma (LUAD) is the most common pathological subtype. Epidermal growth factor (EGF) receptor (EGFR) mutations are the most common driver mutations of LUAD, and they have been identified as important therapeutic targets by EGFR-tyrosine kinase inhibitors (TKIs). The proinflammatory cytokine, interleukin (IL)-17A, and IL-17A-producing cells were reported to be elevated in the tumor microenvironment and peripheral blood of NSCLC patients and to be correlated with tumor progression and poor prognoses. However, the pathophysiological role of IL-17A in NSCLC remains unclear, although some studies suggested its involvement in cancer cell invasion and metastasis. Herein, we observed that expressions of IL-17A and its receptor, IL-17 receptor C (IL-17RC), were elevated in LUAD tissues and were correlated with poor survival in different lung cancer cohorts. In LUAD cells with mutant EGFR, the IL-17A/IL-17RC axis was shown to enhance phosphorylation of EGFR and Met, thereby promoting proliferation and resistance to EGFR-TKIs such as afatinib. In LUAD cells with wild-type (WT) EGFR, we found that the IL-17A/IL-17RC axis enhanced EGF-induced EGFR activation and cell proliferation through causing impairment of EGF-induced EGFR lysosomal degradation. Collectively, our results indicated diverse impacts of the IL-17A/IL-17RC axis on EGFR activation in LUAD cells with WT and mutant EGFR and suggested that developing therapeutic strategies against IL-17A/IL-17RC would be valuable for LUAD treatment.

Overexpressing glyoxalase 1 attenuates acute hyperglycemia-exacerbated neurological deficits of ischemic stroke in mice.

Stress-induced hyperglycemia (SIH) is associated with poor functional recovery and high mortality in patients with acute ischemic stroke (AIS). However, intensive controlling of blood glucose by using insulin was not beneficial in patients with AIS and acute hyperglycemia. This study investigated the therapeutic effects of the overexpression of glyoxalase I (GLO1), a detoxifying enzyme of glycotoxins, on acute hyperglycemia-aggravated ischemic brain injury.  In the present study, adeno-associated viral (AAV)-mediated GLO1 overexpression reduced infarct volume and edema level but did not improve neurofunctional recovery in the mice with middle cerebral artery occlusion (MCAO). AAV-GLO1 infection significantly enhanced neurofunctional recovery in the MCAO mice with acute hyperglycemia but not in the mice with normoglycemia. Methylglyoxal (MG)-modified proteins expression significantly increased in the ipsilateral cortex of the MCAO mice with acute hyperglycemia. AAV-GLO1 infection attenuated the induction of MG-modified proteins, ER stress formation, and caspase 3/7 activation in MG-treated Neuro-2A cells, and reductions in synaptic plasticity and microglial activation were mitigated in the injured cortex of the MCAO mice with acute hyperglycemia. Treatment with ketotifen, a potent GLO1 stimulator, after surgery, alleviated neurofunctional deficits and ischemic brain damage in the MCAO mice with acute hyperglycemia.  Altogether, our data substantiate that, in ischemic brain injury, GLO1 overexpression can alleviate pathologic alterations caused by acute hyperglycemia. Upregulation of GLO1 may be a therapeutic strategy for alleviating SIH-aggravated poor functional outcomes in patients with AIS.

A study on the perioperative effects of obesity on minimally invasive coronary artery bypass grafting and its surgical techniques.

OBJECTIVES: The aim of this study was to discuss the perioperative effects of obesity on minimally invasive coronary artery bypass grafting (CABG) and its surgical techniques. METHODS: A total of 582 patients with multivessel lesion who underwent off-pump CABG by our medical group of Beijing Anzhen Hospital between January 2017 and January 2021 were divided into the minimally invasive cardiac surgery (MICS) group and the conventional group (median sternotomy) according to the surgical method used. The body mass index of the patients was calculated, based on which both groups were divided into obese (≥28 kg/m2) and non-obese subgroups (<28 kg/m2). First, the perioperative data of the obese subgroups of both MICS and conventional groups were compared. Second, the obese and non-obese subgroups were compared in the MICS group. RESULTS: Despite a higher proportion of diabetes in the MICS group, there was no significant difference in preoperative baseline nor in the incidence of major complications within 30 days after surgery between obese subgroups of the MICS and conventional groups. The MICS group had a significantly lower rate of poor wound healing, along with a higher predischarge Barthel Index. Also, the preoperative baseline between the obese and non-obese subgroups of the MICS group exhibited no statistical differences. The obese subgroup had longer postoperative ventilator assistance, while other intraoperative data and postoperative observation indexes exhibited no significant differences. CONCLUSIONS: MICS CABG method is safe and feasible for obese patients with multivessel lesion. Minimally invasive surgery is beneficial to wound healing in obese patients. However, it requires a thorough preoperative evaluation and adequate surgical experience and skills.

Abelmoschus esculentus (Okra) Prevents Insulin Resistance and Restores Neuron Autophagy by Regulating Dipeptidyl Peptidase-4 and Thus Improving Hippocampal Function.

Diabetes is highly linked to the occurrence of Alzheimer disease (AD), which is characterized by beta amyloid peptide (Aß) and hyperphosphorylation of tau (p-tau), and neuron damage particularly in hippocampus. Type 2 diabetes (T2D) is featured by insulin resistance, and phosphorylation of Ser307-IRS-1 is regarded as a resistance marker. Inhibitors of dipeptidyl peptidase-4 (DPP-4) are effective tools for treating T2D. Previously, we reported subfractions of Abelmoschus esculentus (AE, okra) (F1 rich in quercetin glycosides; F2 composed of polysaccharide) attenuated DPP-4 and its downstream signals of insulin resistance, thus preventing Aß-induced neuron damage. Since autophagy could be protective, we now explore if AE works to modulate neuron autophagy by regulating DPP-4 and insulin resistance and, thus, improves the hippocampal function and behavior. We demonstrated that AE subfractions attenuate Aß-induced insulin resistance and the expression of p-tau and normalize the autophagy and survival of hippocampal neurons. The action of AE may be attributed to the downregulation of DPP-4, which plays a critical role in mediating insulin resistance and hinders neuron autophagy. The in vivo findings reveal that the hippocampal insulin resistance appears to link with loss of memory, reduction of curiosity, and depression, whereas treatment with AE significantly improves the insulin sensitivity and hippocampal function. Noteworthy, even at only 5 µg/mL, F2 seems to exhibit a meaningful effect. In conclusion, we suggest that AE attenuates insulin resistance and recovers neuron autophagy which are regulated by DPP-4, thus preventing the damage to the hippocampus, improving recognition and emotion. AE may be an effective adjuvant or supplement to prevent insulin resistance-associated pathogenesis of AD if these results can be confirmed in human clinical trials.

Ability of Local Clearance of Senescent Cells in Ipsilateral Hemisphere to Mitigate Acute Ischemic Brain Injury in Mice.

Senolytic treatment has potential therapeutic efficacy for acute ischemic stroke (AIS). However, the systemic treatment of senolytics may produce off-target side effects and a toxic profile, which affect analysis of the role of acute senescence of neuronal cells in pathogenesis of AIS. We constructed a novel lenti-INK-ATTAC viral vector to introduce INK-ATTAC genes to the ipsilateral brain and locally eliminate senescent brain cells by administering AP20187 to activate caspase-8 apoptotic cascade. In this study, we have found that acute senescence is triggered by middle cerebral artery occlusion (MCAO) surgery, particularly in astrocytes and cerebral endothelial cells (CECs). The upregulation of p16INK4a and senescence-associated secretory phenotype (SASP) factors including matrix metalloproteinase-3, interleukin-1 alpha and -6 were observed in oxygen-glucose deprivation-treated astrocytes and CECs. The systemic administration of a senolytic, ABT-263, prevented the impairment of brain activity from hypoxic brain injury in mice, and significantly improved the neurological severity score, rotarod performance, locomotor activity, and weight loss. The treatment of ABT-263 reduced senescence of astrocytes and CECs in MCAO mice. Furthermore, the localized removal of senescent cells in the injured brain through the stereotaxical injection of lenti-INK-ATTAC viruses generates neuroprotective effects, protecting against acute ischemic brain injury in mice. The content of SASP factors and mRNA level of p16INK4a in the brain tissue of MCAO mice were significantly reduced by the infection of lenti-INK-ATTAC viruses. These results indicate that local clearance of senescent brain cells is a potential therapy on AIS, and demonstrate the correlation between neuronal senescence and pathogenesis of AIS.

Effectiveness of Stereotactic Ablative Radiotherapy for Systemic Therapy Respondents with Inoperable Pulmonary Oligometastases and Oligoprogression.

Stereotactic ablative radiotherapy (SABR) may improve survival in patients with inoperable pulmonary oligometastases. However, the impact of pulmonary oligometastatic status after systemic therapy on SABR outcomes remains unclear. Hence, we investigated the outcomes of SABR in 45 patients with 77 lung tumors and the prognostic value of pulmonary oligoprogression. Eligibility criteria were pulmonary oligometastases (defined as ≤5 metastatic lung tumors), controlled extrapulmonary disease (EPD) after front-line systemic therapy, SABR as primary local treatment for inoperable pulmonary metastases, and consecutive imaging follow-up. Oligometastatic lung tumor was classified into controlled or oligoprogressive status. Overall survival (OS), in-field progression-free survival (IFPFS), out-field progression-free survival (OFPFS), and prognostic variables were evaluated. With 21.8 months median follow-up, the median OS, IFPFS, and OFPFS were 28.3, not reached, and 6.5 months, respectively. Two-year OS, IFPFS, and OFPFS rates were 56.0%, 74.2%, and 17.3%, respectively. Oligoprogressive status (p = 0.003), disease-free interval < 24 months (p = 0.041), and biologically effective dose (BED10) < 100 Gy (p = 0.006) were independently associated with inferior OS. BED10 ≥ 100 Gy (p = 0.029) was independently correlated with longer IFPFS. Oligoprogressive status (p = 0.017) and EPD (p = 0.019) were significantly associated with inferior OFPFS. Grade ≥ 2 radiation pneumonitis occurred in four (8.9%) patients. Conclusively, SABR with BED10 ≥ 100 Gy could provide substantial in-field tumor control and longer OS for systemic therapy respondents with inoperable pulmonary oligometastases. Oligoprogressive lung tumors exhibited a higher risk of out-field treatment failure and shorter OS. Hence, systemic therapy should be tailored for patients with oligoprogression to reduce the risk of out-field treatment failure. However, in the absence of effective systemic therapy, SABR is a reasonable alternative to reduce resistant tumor burden.

Isotopic Fractionation as a Mechanistic Probe in Light-Driven C-H Bond Exchange Reactions.

Here, we report a diagnostic framework for elucidating the mechanisms of photoredox-based hydrogen isotope exchange (HIE) reactions based on hydrogen/deuterium (H/D) fractionation. Traditional thermal HIE methods generally proceed by reversible bond cleavage and bond reformation steps that share a common transition state. However, bond cleavage and bond reformation in light-driven HIE reactions can proceed via multiple, non-degenerate sets of elementary steps, complicating both mechanistic analysis and attendant optimization efforts. Building on classical treatments of equilibrium isotope effects, the fractionation method presented here extracts information regarding the nature of the key bond-forming and bond-breaking steps by comparing the extent of deuterium incorporation into an exchangeable C-H bond in the substrate relative to the H/D isotopic ratio of a solvent reservoir. We show that the extent of fractionation is sensitive to the mechanism of the exchange process and provides a means to distinguish between degenerate and non-degenerate mechanisms for isotopic exchange. In model systems, the mechanisms implied by the fractionation method align with those predicted by thermochemical considerations. We then employed the method to study HIE reactions whose mechanisms are ambiguous on thermodynamic grounds.

Exogenous monocyte myeloid-derived suppressor cells ameliorate immune imbalance, neuroinflammation and cognitive impairment in 5xFAD mice infected with Porphyromonas gingivalis.

BACKGROUND: Periodontitis is closely associated with the pathogenesis of Alzheimer's disease (AD). Porphyromonas gingivalis (Pg), the keystone periodontal pathogen, has been reported in our recent study to cause immune-overreaction and induce cognitive impairment. Monocytic myeloid-derived suppressor cells (mMDSCs) possess potent immunosuppressive function. It is unclear whether mMDSCs-mediated immune homeostasis is impaired in AD patients with periodontitis, and whether exogenous mMDSCs could ameliorate immune-overreaction and cognitive impairment induced by Pg. METHODS: To explore the influence of Pg on cognitive function, neuropathology and immune balance in vivo, 5xFAD mice were treated with live Pg by oral gavage, three times a week for 1 month. The cells of peripheral blood, spleen and bone marrow from 5xFAD mice were treated with Pg to detect the proportional and functional alterations of mMDSCs in vitro. Next, exogenous mMDSCs were sorted from wild-type healthy mice and intravenously injected into 5xFAD mice that were infected with Pg. We used behavioral tests, flow cytometry and immunofluorescent staining to evaluate whether exogenous mMDSCs could ameliorate the cognitive function, immune homeostasis and reduce neuropathology exacerbated by Pg infection. RESULTS: Pg exacerbated cognitive impairment in 5xFAD mice, with the deposition of amyloid plaque and increased number of microglia in the hippocampus and cortex region. The proportion of mMDSCs decreased in Pg-treated mice. In addition, Pg reduced the proportion and the immunosuppressive function of mMDSCs in vitro. Supplement of exogenous mMDSCs improved the cognitive function, and enhanced the proportions of mMDSCs and IL-10+ T cells of 5xFAD mice infected with Pg. At the same time, supplement of exogenous mMDSCs increased the immunosuppressive function of endogenous mMDSCs while decreased the proportions of IL-6+ T cells and IFN-γ+ CD4+ T cells. In addition, the deposition of amyloid plaque decreased while the number of neurons increased in the hippocampus and cortex region after the supplement of exogenous mMDSCs. Furthermore, the number of microglia increased with an increase in the proportion of M2 phenotype. CONCLUSIONS: Pg can reduce the proportion of mMDSCs, induce immune-overreaction, and exacerbate the neuroinflammation and cognitive impairment in 5xFAD mice. Supplement of exogenous mMDSCs can reduce the neuroinflammation, immune imbalance and cognitive impairment in 5xFAD mice infected with Pg. These findings indicate the mechanism of AD pathogenesis and Pg-mediated promotion of AD, and provide a potential therapeutic strategy for AD patients.

Protective effect of antihypertensive drugs on the risk of Parkinson's disease lacks causal evidence from mendelian randomization.

Background: Evidence from observational studies concerning the causal role of blood pressure (BP) and antihypertensive medications (AHM) on Parkinson's disease (PD) remains inconclusive. A two-sample Mendelian randomization (MR) study was performed to evaluate the unconfounded association of genetic proxies for BP and first-line AHMs with PD. Methods: Instrumental variables (IV) from the genome-wide association study (GWAS) for BP traits were used to proxy systolic BP (SBP), diastolic BP, and pulse pressure. SBP-associated variants either located within encoding regions or associated with the expression of AHM targets were selected and then scaled to proxy therapeutic inhibition of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, ß-blockers, calcium channel blockers, and thiazides. Positive control analyses on coronary heart disease (CHD) and stroke were conducted to validate the IV selection. Summary data from GWAS for PD risk and PD age at onset (AAO) were used as outcomes. Results: In positive control analyses, genetically determined BP traits and AHMs closely mimicked the observed causal effect on CHD and stroke, confirming the validity of IV selection methodology. In primary analyses, although genetic proxies identified by "encoding region-based method" for ß-blockers were suggestively associated with a delayed PD AAO (Beta: 0.115; 95% CI: 0.021, 0.208; p = 1.63E-2; per 10-mmHg lower), sensitivity analyses failed to support this association. Additionally, MR analyses found little evidence that genetically predicted BP traits, overall AHM, or other AHMs affected PD risk or AAO. Conclusion: Our data suggest that BP and commonly prescribed AHMs may not have a prominent role in PD etiology.