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BackgroundThere is limited research on the relationship between Systemic Oxidative Stress (SOS) status and inflammatory indices. Adding onto existing literature, this study aimed to examine the association between dietary Oxidative Balance Score (OBS) and lifestyle OBS (which make up the overall OBS), and Cardiovascular Disease (CVD) prevalence at different Systemic Immune Inflammation Index (SII) and Systemic Inflammatory Response Index (SIRI) levels.MethodsThis study involved 9,451 subjects selected from the National Health and Nutrition Examination Survey (NHANES) 2007–2018. The OBS comprised 20 dietary and lifestyle factors. Statistical methods included Weighted Linear Regression Analysis (WLRA), Logistic Regression Analysis (LRA), Sensitivity Analysis (SA), and Restricted Cubic Spline (RCS) analysis.ResultsThe multivariate WLRA revealed that OBS was significantly negatively correlated with both SII (β = −5.36, p < 0.001) and SIRI (β = −0.013, p < 0.001) levels. In SA, removing any single OBS component had no significant effect on the WLRA results of SII and SIRI. Further subgroup analyses revealed that OBS was more impactful in lowering SII in women than in men. Additionally, OBS was more significantly negatively correlated with SII and SIRI in the low-age group than in the high-age group. Moreover, RCS analysis confirmed this linear relationship. Compared to dietary OBS, lifestyle OBS exerted a more significant effect on Coronary Artery Disease (CAD) (OR: 0.794, p = 0.002), hypertension (OR: 0.738, p

AbstractIntroduction There is a dearth of comprehensive studies on the association between serum electrolyte and adverse short-term prognosis of Chinese patients with acute decompensated heart failure (ADHF).Patients and methods A total of 5166 patients with ADHF were divided into four serum electrolyte-related study populations (potassium (n = 5145), sodium (n = 5135), chloride (n = 4966), serum total calcium (STC) (n = 4143)) under corresponding exclusions. Different logistic regression models were utilized to gauge the association between these electrolytes or the number of electrolyte abnormalities and the risk of a composite of all-cause mortality or 30-day heart failure (HF) readmission.Results In multivariable adjusted analysis, patients with potassium below 3.5 mmol/L (odds ratios (ORs) 1.45; 95% confidence interval (CI):1.07–1.95), 4.01–4.50 mmol/L (OR: 1.29, CI: 1.02–1.62), 4.51–5.00 mmol/L (OR: 1.43, CI: 1.08–1.90) and above 5.00 mmol/L (OR: 1.74, CI: 1.21–2.51) had an increased risk of outcome when compared with potassium at 3.50–4.00 mmol/L. Sodium levels were inversely related to the risk of a composite outcome (

BackgroundInflammation serves as a key pathologic mediator in the progression of infections and various diseases, involving significant alterations in the gut microbiome and metabolism. This study aims to probe into the potential causal relationships between gut microbial taxa and human blood metabolites with various serum inflammatory markers (CRP, SAA1, IL-6, TNF-α, WBC, and GlycA) and the risks of seven common infections (gastrointestinal infections, dysentery, pneumonia, bacterial pneumonia, bronchopneumonia and lung abscess, pneumococcal pneumonia, and urinary tract infections).MethodsTwo-sample Mendelian randomization (MR) analysis was performed using inverse variance weighted (IVW), maximum likelihood, MR-Egger, weighted median, and MR-PRESSO.ResultsAfter adding other MR models and sensitivity analyses, genus Roseburia was simultaneously associated adversely with CRP (Beta IVW = −0.040) and SAA1 (Beta IVW = −0.280), and family Bifidobacteriaceae was negatively associated with both CRP (Beta IVW = −0.034) and pneumonia risk (Beta IVW = −0.391). After correction by FDR, only glutaroyl carnitine remained significantly associated with elevated CRP levels (Beta IVW = 0.112). Additionally, threonine (Beta IVW = 0.200) and 1-heptadecanoylglycerophosphocholine (Beta IVW = −0.246) were found to be significantly associated with WBC levels. Three metabolites showed similar causal effects on different inflammatory markers or infectious phenotypes, stearidonate (18:4n3) was negatively related to SAA1 and urinary tract infections, and 5-oxoproline contributed to elevated IL-6 and SAA1 levels. In addition, 7-methylguanine showed a positive correlation with dysentery and bacterial pneumonia.ConclusionThis study provides novel evidence confirming the causal effects of the gut microbiome and the plasma metabolite profile on inflammation and the risk of infection. These potential molecular alterations may aid in the development of new targets for the intervention and management of disorders associated with inflammation and infections.

Ammonia is highly toxic to aquatic organisms and has become a consistent pollutant in intensive fish farming conditions. Dihydroartemisinin (DhA) has potential value in the treatment of ammonia poisoning in aquaculture. However, the application investigation of DhA is insufficient in the field of aquaculture. In the present study, 540 zebrafish with an average body weight of (1.00 ± 0.01) g were randomly assigned into 9 groups. The zebrafish were fed a basal diet supplemented with or without 0.25% or 0.5% DhA for 1 week. The zebrafish were then exposed to water supplemented with or without 40 or 80 mg/L ammonium acetate (NH4AC) for 4 days. The results showed that dietary supplementation with 0.5% DhA attenuated mortality and ammonia accumulation in zebrafish exposed to 80 mg/L NH4AC. In addition, the alleviative effects of 0.5% DhA were associated with enhanced mRNA levels for ammonia transporter (Rhesus-associated glycoprotein, Rh family C glycoprotein 1, Na+/K+-ATPase, carbonic anhydrase), anti-inflammatory cytokines (transforming growth factor β), as well as the down-regulation of mRNA expression of inflammatory factors (interleukin 1β), hypoxia-inducible factors (hypoxia-inducible factor 1 αb, hypoxia-inducible factor 2α), and protein abundances of autophagy (autophagy-related gene 5, BCL-2-interacting myosin-like coiled-coil protein-1, microtubule-associated protein 1 light chain 3 Ⅱ, cathepsin B, cathepsin L). Taken together, DhA has great potential in aquaculture as a defence against ammonia toxicity.

The objective of this research is to investigate the characteristics of the deformation response in adjacent subway tunnels caused by deep foundation excavation of reclaimed land. Focusing on a deep foundation excavation project situated in proximity to Line 11 of the subway in Shenzhen, this study employs theoretical analysis, numerical simulation, and on-site measurements to thoroughly investigate the deformation issues induced by the unloading of the excavation. The research results are as follows: using the energy method to calculate the uneven deformation of adjacent subway tunnels caused by the excavation can overcome the limitations of traditional algorithms, which treat the subway tunnel as a uniformly elastic foundation beam, resulting in more reasonable calculation results. Increasing the self-stiffness (EI)eq of the tunnel can effectively reduce the maximum displacement (wmax) of the tunnel, and as (EI)eq increases, its “weakening effect” on wmax gradually diminishes. Underground continuous walls can effectively control tunnel deformation, with tunnel displacement decreasing as the thickness and concrete strength of the continuous walls increase. “Long excavation” deep foundation excavations can impact the displacement and uplift range of the tunnel, with the maximum tunnel displacement showing a nonlinear decrease with increasing excavation depth. Tunnel displacement decreases as geotechnical parameters (elastic modulus E, internal friction angle φ, and cohesion C) increase, with the elastic modulus being the most sensitive parameter. The research findings can be applied to tunnel construction, maintenance, and safety evaluations, providing valuable references for similar engineering projects in the future.

ABSTRACTPancreatic cancer (PC) is featured with low survival rate and poor outcomes. Herein, we found that the expression of caspase-recruitment domain-containing protein 9 (CARD9), predominantly expressed in innate immune cells, was positively related to the prognosis of PC patients. CARD9-deficient PC mice exhibited rapider cancer progression and poorer survival rate. CARD9 knockout decreased dendritic cell (DC) maturation and impaired DC ability to activate T cells in vivo and in vitro. Adoptive DC transfer confirmed that the role of CARD9 deficiency in PC relied on DCs. Creatine was identified as the most significant differential metabolite between WT DCs and CARD9−/− DCs wherein it played an essential role in maintaining DC maturation and function. CARD9 deficiency led to decreased creatine levels in DCs by inhibiting the transcription of the creatine-specific transporter, solute carrier family 6 member 8 (SLC6A8). Furtherly, CARD9 deletion blocked p65 activation by abolishing the formation of CARD9-BCL10-MALT1 complex, which prevented the binding between p65 and SLC6A8 promoter. These events decreased the creatine transport into DCs, and led to DC immaturity and impairment in antitumor immunity, consequently promoting PC progression.

Abstract The treatment outcome of hepatocellular carcinoma (HCC) is severely hampered due to its etiology, and thus in depth understanding of the genetic mechanisms underlying response of HCC to various anticancer agents is needed. Here, we have identified Phosphotyrosine interaction domain-containing protein 1 (PID1) as a novel regulator involved in modulation of apoptosis induced by anticancer agents in a context-dependent manner. PID1 relieved chemotherapy-induced ROS production, mitochondrial outer membrane permeability and mitochondrial respiratory depression. In addition, PID1 restricted AKT-mediated inhibition on Raf-1 through interacting with PDPK1 at phosphorylated tyrosine sites, thus enhancing Raf-1-mediated BAD inhibition. Interestingly, AKT, Bcl2 inhibition or Raf-1 silencing abolished PID1-mediated anti-apoptotic effects. However, PID1 altered the rhythmicity of pharmacological activity of Sorafenib on various survival-related kinases, thus resulting in AKT blockade via Raf-1/BRAF/ERK/MEK pathway. BRAF inhibition or Raf-1 depletion disrupted PID1-mediated barrier in AKT activation in response to Sorafenib. Moreover, in vivo study indicated that PID1 deficiency led to increased survival rate upon Doxorubicin treatment but reduced efficacy of Sorafenib. Overall, we propose that PID1 can function as an underlying biomarker of resistance to conventional chemotherapeutic agents but sensitivity towards Sorafenib.

Platinum-based chemotherapy resistance is a key factor of poor prognosis and recurrence in hepatocellular carcinoma (HCC). Herein, RNAseq analysis revealed that elevated tubulin folding cofactor E (TBCE) expression is associated with platinum-based chemotherapy resistance. High expression of TBCE contributes to worse prognoses and earlier recurrence among liver cancer patients. Mechanistically, TBCE silencing significantly affects cytoskeleton rearrangement, which in turn increases cisplatin-induced cycle arrest and apoptosis. To develop these findings into potential therapeutic drugs, endosomal pH-responsive nanoparticles (NPs) were developed to simultaneously encapsulate TBCE siRNA and cisplatin (DDP) to reverse this phenomena. NPs (siTBCE + DDP) concurrently silenced TBCE expression, increased cell sensitivity to platinum treatment, and subsequently resulted in superior anti-tumor effects both in vitro and in vivo in orthotopic and patient-derived xenograft (PDX) models. Taken together, NP-mediated delivery and the co-treatment of siTBCE + DDP proved to be effective in reversing chemotherapy resistance of DDP in multiple tumor models.

Monoclonal antibody-based therapy has achieved great success and is now one of the most crucial therapeutic modalities for cancer therapy. The first monoclonal antibody authorized for treating human epidermal growth receptor 2 (HER2)-positive breast cancer is trastuzumab. However, resistance to trastuzumab therapy is frequently encountered and thus significantly restricts the therapeutic outcomes. To address this issue, tumor microenvironment (TME) pH-responsive nanoparticles (NPs) were herein developed for systemic mRNA delivery to reverse the trastuzumab resistance of breast cancer (BCa). This nanoplatform is comprised of a methoxyl-poly (ethylene glycol)-b-poly (lactic-co-glycolic acid) copolymer with a TME pH-liable linker (Meo-PEG-Dlinkm-PLGA) and an amphiphilic cationic lipid that can complex PTEN mRNA via electrostatic interaction. When the long-circulating mRNA-loaded NPs build up in the tumor after being delivered intravenously, they could be efficiently internalized by tumor cells due to the TME pH-triggered PEG detachment from the NP surface. With the intracellular mRNA release to up-regulate PTEN expression, the constantly activated PI3K/Akt signaling pathway could be blocked in the trastuzumab-resistant BCa cells, thereby resulting in the reversal of trastuzumab resistance and effectively suppress the development of BCa.

Abstract Tyrosine kinase inhibitors represented by sorafenib are the first‐line treatment for hepatocellular carcinoma (HCC), but the low response rate of HCC patient has become a clinical pain‐point. Emerging evidences have revealed that metabolic reprogramming plays an important role in regulating the sensitivity of tumor cells to various chemotherapeutics including sorafenib. However, the underlying mechanisms are very complex and are not fully elucidated. By comparing the transcriptome sequencing data of sorafenib‐sensitive and ‐insensitive HCC patients, it is revealed that cofilin 1 (CFL1) is highly expressed in the tumor tissues of sorafenib‐insensitive HCC patients and closely correlated with their poor prognosis. Mechanically, CFL1 can promote phosphoglycerate dehydrogenase transcription and enhance serine synthesis and metabolism to accelerate the production of antioxidants for scavenging the excessive reactive oxygen species induced by sorafenib, thereby impairing the sorafenib sensitivity of HCC. To translate this finding and consider the severe side effects of sorafenib, a reduction‐responsive nanoplatform for systemic co‐delivery of CFL1 siRNA (siCFL1) and sorafenib is further developed, and its high efficacy in inhibiting HCC tumor growth without apparent toxicity is demonstrated. These results indicate that nanoparticles‐mediated co‐delivery of siCFL1 and sorafenib can be a new strategy for the treatment of advanced HCC.

ObjectivesThis retrospective study aimed to describe our institutional experience with cytoreductive cystectomy (Cx) in patients with pathological T4 (pT4) bladder cancer (BCa) and to investigate the clinicopathologic factors that can predict patient survival outcomes.MethodsWe reviewed the baseline demographics, clinicopathologic features, perioperative complications, and follow-up data of 44 patients who underwent Cx for pT4 BCa at our institution between 2013 and 2021. The Kaplan–Meier curve and the log-rank test were used to analyze progression-free survival (PFS) and overall survival (OS). Univariate and multivariate analyses were performed using the Cox regression model.ResultsThe median age of the patients was 68 years [95% confidence interval (CI) 49–81]. Overall, 21 patients (47.7%) were estimated to have a high age-adjusted Charlson comorbidity index (ACCI) score (>4), and nine patients (20.5%) had pT4b substage BCa. None of the patients died of complications within 30–90 days after surgery. Severe complications occurred in 16% (n = 7) of patients within 30–90 days. During a median follow-up of 51 months, disease progression was detected in 25 patients (56.8%), and 29 patients (65.9%) died of any cause. The median PFS and OS were 15.0 and 21.0 months, respectively. The Kaplan–Meier analysis indicated that patients with high ACCI scores or pT4b BCa had worse PFS (P = 0.003 and P = 0.002, respectively) and OS (P = 0.016 and P = 0.034, respectively) than those with low ACCI scores or pT4a BCa. On multivariate analysis, pT4b substage [hazard ratio (HR), 4.166; 95% CI, 1.549–11.206; P = 0.005] and ACCI score >4 (HR, 2.329; 95% CI, 1.105–4.908; P = 0.026) remained independent risk factors for PFS and OS, respectively.ConclusionOur study revealed that the pT4b substage is associated with a poor prognosis and that the ACCI score is a relevant and practical method to evaluate survival outcomes in patients with pT4 BCa after Cx.

The AlGaInP window layers with different growth modes of Al in (AlxGa1−x)0.5In0.5P were prepared to investigate the effect of different growth modes of Al on the photoelectric properties of red LEDs. The experimental results show that the forward voltage of (AlxGa1−x)0.5In0.5P LEDs n-window layer with the ridge gradient Al content was 30 mV (x = 0.15) and 190 mV (x = 0.45), respectively, which are lower than that of the n-window layer without ridge gradient Al content samples. Meanwhile, the light output power of the ridge gradient Al content LED is 12.3% (x = 0.15) and 3.6% (x = 0.45) higher than that of the other two samples, respectively. Compared with the Al composition ridge gradient sample, the photoelectric efficiency is 2.45% (x = 0.15) and 5.68% (x = 0.45), respectively, due to the reduction in the voltage and the increase in the light output power.

With the development of urbanization, the demand for bricks continues to increase. However, traditional brick production methods result in significant energy consumption and environmental pollution. In Hebei Province, China, historical mineral extraction activities have left behind substantial iron ore tailings (IOT). With the objective of recycling IOT resources and promoting ecological restoration and sustainable development, the feasibility of producing alkali-activated bricks using iron ore tailings was explored. This study primarily utilized IOT supplemented with ground granulated blast-furnace slag (GGBS) to successfully synthesize sustainable eco-friendly alkali-activated high-content IOT bricks. Experimental investigations were conducted to explore the effects of the raw material mixing ratio, content, and modulus of the alkaline activator, molding pressure, and grain size distribution on the strength. The research demonstrated that the IOT: GGBS ratio of 85:15 met the requirements of the Chinese JC/T422-2007 MU25 standard, resulting in compressive and flexural strengths of 31.72 MPa and 2.83 MPa, respectively. Increasing the alkali activator content enhanced the brick strength, with an optimal alkali activator modulus of 1 M. Moreover, the molding pressure significantly improved brick strength and also enhanced the particle-to-particle contact density. Bricks prepared using finer particle size IOT exhibited higher compressive strength, whereas flexural strength remained relatively unaffected by particle size distribution. Furthermore, a comprehensive analysis of the microstructure and alkali activation mechanism of IOT-GGBS bricks was performed using XRD, SEM, FTIR, and AFM techniques. The results indicated that IOT primarily acted as an aggregate and partially participated in the reaction, whereas GGBS reacted extensively, generating C-S-H gel and C-A-H, providing robust bonding strength. Additionally, the increase in GGBS content led to the partial disintegration of some IOT particles, forming more stable aggregates under the influence of the C-S-H gel. This study offers theoretical guidance for the efficient utilization of IOT in construction materials, thereby contributing to the promotion of sustainable development and environmental conservation.

Aqueous zinc ion batteries (AZIBs) are a promising energy storage technology due to their cost-effectiveness and safety. Organic materials with sustainable and designable structures are of great interest as AZIBs cathodes. However, small molecules in organic cathode materials face dissolution problems and suboptimal cycle life, whereas large molecules suffer from a low theoretical capacity due to their inert carbon skeletons. Here, we designed two covalent organic framework (COF) materials (benzoquinoxaline benzoquinone-based COF (BB-COF) and triquinoxalinylene benzoquinone-based COF (TB-COF)) with the same structure and number of energy storage groups to investigate the correlation between the densities of active sites and electrochemical performance. We conclude that the electrochemical behavior of organic conjugate-based energy storage materials lacks a linear correlation with active site quantity. Adjusting active site densities is crucial for material advancement. BB-COF and TB-COF with dual active sites (C=O and C=N) exhibit distinct characteristics. TB-COF, which has dense active groups, shows a high initial capacity (222 mAh g−1). Conversely, BB-COF, which features a large conjugated ring diameter, presents superior rate performance and enduring cycle stability. It even maintains stable cycling for 2000 cycles at −40 ℃. In-situ electrochemical quartz crystal microbalance tests reveal the energy storage mechanism of BB-COF, in which H+ storage is followed by Zn2+ storage.

Abstract Background The isolated superior mesenteric artery dissection (SMAD) is a rare and sporadic cause of acute abdominal pain. It most frequently affects male patients in their fifth to sixth decades, while our patient was a young woman who delivered a baby before the onset of abdominal pain. Possible risk factors for SMAD include hypertension, arteriosclerosis, abnormalities in elastic fibres, trauma, and pregnancy. In our case, delivery was suggested as a risk factor, which has not been reported previously. Case presentation A 27-year-old woman complained of acute severe upper abdominal pain and vomiting for 2 days after delivery. The patient had no significant medical history. Physical examination revealed epigastric mild tenderness. All routine blood tests, blood coagulation analysis, liver function tests and abdomen computed tomography showed no remarkable findings. Computed tomography angiography revealed a marked dissection 3.5 cm below the superior mesenteric artery ostium. Since distal blood flow existed and the patient was in a puerperal state with no evidences of mesenteric ischemia, she was managed conservatively, including intestinal rest by fasting, parenteral nutritional support and antibioticis, without anticoagulants or antiplatelet agents. Fortunately, she recovered smoothly and had no recurrence. Conclusions SMAD is a rare and sporadic cause of acute abdominal pain that occurs in young women after delivery.

Ultra-high-performance concrete (UHPC) is a kind of building material with ultra-high strength, toughness, and durability. However, under the conditions of ordinary molding technology, most of the fibers cannot play a bridging role in the direction of force. In this study, UHPC specimens with different steel fiber contents (0%, 2%, 4%, and 6% by volume) and directional reinforced fiber were prepared. Based on the split-Hopkinson pressure bar (SHPB), the influence of directional distributed steel fiber on the dynamic impact mechanical properties of the UHPC specimen were systematically investigated. The stress–strain curves, stress peaks, dynamic increase factor (DIF), and ductile energy absorption properties of the specimens at different strain rates were obtained. The results showed that oriented steel fiber significantly increases the dynamic property of UHPC. The dynamic impact peak strain, peak stress, and DIF of the UHPC specimen with 2% oriented steel fiber were 35.78%, 8.8%, and 12.6% higher than that prepared by normal molding technology, respectively. Moreover, with the increase of fiber content, the peak stress, energy absorption, and multiple-impact compression resistance of the specimen were greatly improved. When the fiber content was 6%, the dynamic impact peak strain, dynamic impact compressive strength ratio, and energy absorption capacity of the specimen were 3.09, 1.45, and 4.1 times the reference group, respectively.

Kinsenoside (KD) exhibits anti-inflammatory and immunosuppressive effects. Dendritic cells (DCs) are critical regulators of the pathologic inflammatory milieu in liver fibrosis (LF). Herein, we explored whether and how KD repressed development of LF via DC regulation and verified the pathway involved in the process. Given our analysis, both KD and adoptive transfer of KD-conditioned DCs conspicuously reduced hepatic histopathological damage, proinflammatory cytokine release and extracellular matrix deposition in CCl4-induced LF mice. Of note, KD restrained the LF-driven rise in CD86, MHC-II, and CCR7 levels and, simultaneously, upregulated PD-L1 expression on DCs specifically, which blocked CD8+T cell activation. Additionally, KD reduced DC glycolysis, maintained DCs immature, accompanied by IL-12 decrease in DCs. Inhibiting DC function by KD disturbed the communication of DCs and HSCs with the expression or secretion of α-SMA and Col-I declined in the liver. Mechanistically, KD suppressed the phosphorylation of PI3K-AKT driven by LF or PI3K agonist, followed by enhanced nuclear transport of FoxO1 and upregulated interaction of FoxO1 with the PD-L1 promoter in DCs. PI3K inhibitor or si-IL-12 acting on DC could relieve LF, HSC activation and diminish the effect of KD. In conclusion, KD suppressed DC maturation with promoted PD-L1 expression via PI3K-AKT-FoxO1 and decreased IL-12 secretion, which blocked activation of CD8+T cells and HSCs, thereby alleviating liver injury and fibro-inflammation in LF.

Abstract Background Excessive white fat accumulation in humans and other animals is associated with the development of multiple metabolic diseases. It is unknown whether dietary L-arginine supplementation reduces lipid deposition in high fat diet-fed Nile tilapia (Oreochromis niloticus). Results In the present study, we found that dietary supplementation with 1% or 2% arginine decreased the deposition and concentration of fats in the liver; the concentrations of triglycerides, low-density lipoprotein, total cholesterol, and high-density lipoprotein in the serum; and the diameter of adipocytes in intraperitoneal adipose tissue. Compared with the un-supplementation control group, the hepatic activities of alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, and hepatic concentration of malondialdehyde were reduced but these for catalase and superoxide dismutase were enhanced by dietary supplementation with 2% arginine. Arginine supplementation reduced the total amounts of monounsaturated fatty acids, while increasing the total amounts of n-3 and n-6 polyunsaturated fatty acids in the liver. These effects of arginine were associated with reductions in mRNA levels for genes related to lipogenesis (sterol regulatory element-binding protein-1, acetyl-CoA carboxylase α, stearoyl-CoA desaturase, and fatty acid synthase) but increases in mRNA levels for genes involved in fatty acid β-oxidation (carnitine palmitoyltransferase 1α and peroxisome proliferator-activated receptor α). In addition, hepatic mRNA levels for Δ4 fatty acyl desaturase 2 and elongase 5 of very long-chain fatty acids were enhanced by arginine supplementation. Conclusion These results revealed that dietary L-arginine supplementation to tilapia reduced high fat diet-induced fat deposition and fatty acid composition in the liver by regulating the expression of genes for lipid metabolism.

Glial cell-line-derived neurotrophic factor (GDNF) is a potent neuroprotective agent in cellular and animal models of Parkinson’s disease (PD). However, CNS delivery of GDNF in clinical trials has proven challenging due to blood-brain barrier (BBB) impermeability, poor diffusion within brain tissue, and large brain size. We report that using non-toxic mobilization-enabled preconditioning, hematopoietic stem cell (HSC) transplantation-based macrophage-mediated gene delivery may provide a solution to overcome these obstacles. Syngeneic bone marrow HSCs were transduced ex vivo with a lentiviral vector expressing macrophage promoter-driven GDNF and transplanted into 14-week-old MitoPark mice exhibiting PD-like impairments. Transplant preconditioning with granulocyte colony-stimulating factor (G-CSF) and AMD3100 was used to vacate bone marrow stem cell niches. Chimerism reached ∼80% after seven transplantation cycles. Transgene-expressing macrophages infiltrated degenerating CNS regions of MitoPark mice (not wild-type littermate controls), resulting in increased GDNF levels in the midbrain. Macrophage GDNF delivery not only markedly improved motor and non-motor dysfunction, but also dramatically mitigated the loss of dopaminergic neurons in both substantia nigra and the ventral tegmental area and preserved axonal terminals in the striatum. Striatal dopamine levels were almost completely restored. Our data support further development of mobilization-enabled HSC transplantation (HSCT)-based macrophage-mediated GDNF gene delivery as a disease-modifying therapy for PD.

Aqueous zinc-ion hybrid supercapacitors (AZHSs) are promising candidates for powering mobile devices due to their intrinsically high safety, the high theoretical capacity of zinc anodes, and the wide range of sources of raw materials for activated carbon (AC) cathodes. Here, we report that there is a synergistic effect between the anions of an AZHS electrolyte, which can significantly improve the specific capacity and rate capability of an AC cathode. The results showed that the specific capacities of the AC cathode//2 M ZnSO4(aq)//Zn anode energy storage system were 115 and 41 mAh g−1 at 0.1 and 5 A g−1 current densities, respectively. The specific capacity at a 0.1 A g−1 current density was enhanced to 136 mAh g−1 by doping 0.5% ZnCl2 and 0.5% Zn(CF3SO3)2 in the 2 M ZnSO4 electrolyte. The specific capacity at a 5 Ag−1 current density was enhanced to 69 mAh g−1 by doping 1% ZnCl2 and 0.5% Zn(CF3SO3)2 in the 2 M ZnSO4 electrolyte. In addition, the co-doped electrolyte increased the energy consumption of the binding of the AC surface groups with H+ and inhibited the precipitation of Zn4SO4(OH)6·5H2O. This provides an important perspective for improving the performance of AZHSs.

Heat stress due to global warming exerts deleterious effects on both humans and animals. However, nutritional strategies to reduce heat stress-induced intestinal mucosal barrier dysfunction and the underlying mechanisms remain largely unknown. In the present study, 240 tilapia were distributed into four treatment groups that were fed a basal diet supplemented with or without 0.1% Yucca schidigera extract under normal (28 °C) temperature or heat stress (36 °C) conditions for 2 weeks. Our results showed that tilapia exposed to heat stress resulted in growth arrest, intestinal dysfunction, oxidative damage, endoplasmic reticulum stress, and pro-inflammatory response, which were significantly relieved by yucca supplementation. The alleviative effect of Yucca schidigera extract was related to the down-regulation of mRNA expression of ubiquitin-proteasome system (Polyubiquitin, Proteasome 26S, Proteasome α5, Proteasome β3, and Ubiquitin-like 3) and inflammatory factors (tumor necrosis factor α, interleukin 1β, and interleukin 8), as well as the improved histological structure and activation of Hsp70, nuclear factor erythroid 2-related factor 2 signaling, interleukin 10, lysozyme, complement 3, and acid phosphatase in the intestine of tilapia. Collectively, these results indicated that heat stress-induced growth arrest, intestinal dysfunction, and oxidative damage were alleviated by dietary supplementation with Yucca schidigera extract. This offers a nutritional way of improving the growth and intestinal health of tilapia exposed to a hot environment.

Tea contains high levels of the compound epigallocatechin gallate (EGCG). It is considered an important functional component in tea and has anti-cancer, antioxidant, and anti-inflammatory effects. The eight phenolic hydroxyl groups in EGCG’s chemical structure are the basis for EGCG’s multiple biological effects. At the same time, it also leads to poor chemical stability, rendering EGCG prone to oxidation and isomerization reactions that change its original structure and biological activity. Learning how to maintain the activity of EGCG has become an important goal in understanding the biological activity of EGCG and the research and development of tea-related products. Metal–organic frameworks (MOFs) are porous materials with a three-dimensional network structure that are composed of inorganic metals or metal clusters together with organic complexes. MOFs exploit the porous nature of the material itself. When a drug is an appropriate size, it can be wrapped into the pores by physical or chemical methods; this allows the drug to be released slowly, and MOFs can also reduce drug toxicity. In this study, we used MOF Zn(BTC)4 materials to load EGCG and investigated the sustained release effect of EGCG@MOF Zn(BTC)4 and the biological effects on wound healing in a diabetic mouse model.

Forkhead box transcription factor M1 (FOXM1) is a proliferation‐associated transcription factor involved in tumorigenesis through transcriptional regulation of its target genes in various cells, including dendritic cells (DCs). Although previous work has shown that FOXM1 enhances DC maturation in response to house dust mite allergens, it is not known whether FOXM1 affects DC maturation in the context of tumor‐specific immunity. In this study, we examined the central role of FOXM1 in regulating bone marrow‐derived dendritic cell (BMDC) maturation phenotypes and function in pancreatic cancer and colon cancer. FOXM1 retarded maturation phenotypes of BMDCs, inhibited promotion of T‐cell proliferation, and decreased interleukin‐12 (IL‐12) p70 in tumor‐bearing mice (TBM). Notably, FOXM1 expression was epigenetically regulated by dimethylation on H3 lysine 79 (H3K79me2), a modification present in both tumor cells and BMDCs. Increased H3K79me2 enrichment was observed at the FOXM1 promoter in both BMDCs from TBM, and in BMDCs from wild‐type mice cultured with tumor‐conditioned medium that mimics the tumor microenvironment (TME). Furthermore, inhibition of the H3K79 methyltransferase DOT1L not only decreased enrichment of H3K79me2, but also downregulated expression of FOXM1 and partially reversed its immunosuppressive effects on BMDCs. Furthermore, we found that FOXM1 upregulated transcription of Wnt family number 5A (Wnt5a) in BMDCs in vitro; we also observed that exogenous Wnt5a expression abrogated BMDC maturation phenotypes by inhibiting FOXM1 and H3K79me2 modification. Therefore, our results reveal that upregulation of FOXM1 by H3K79me2 in pancreatic cancer and colon cancer significantly inhibits maturation phenotypes and function of BMDCs through the Wnt5a signaling pathway, and thus provide novel insights into FOXM1‐based antitumor immunotherapy.

A simple and efficient method based on ultrafiltration liquid chromatography–mass spectrometry was applied to rapidly screen and identify ligands for lactate dehydrogenase (LDH) from the extracts of black soybeans (Glycine max L. Merrill), and the compounds were further assessed for ant-stroke activity using a PC12 cell model. Six major isoflavones including daidzin, glycitin, genistin, 6″-O-acetyl daidzin, 6″-O-acetyl glycitin and malonyl genistin were identified as potent LDH inhibitors. A continuous online method consisted of a microwave-assisted extraction, online solvent concentration tank and countercurrent chromatography (MAE-SCT-CCC) was newly developed for scaled up production of these compounds with high purity and efficiency. This novel approach using ultrafiltration LC–MS coupled with MAE-SCT-CCC and a PC12 cell model, provides not only a powerful tool for screening, extracting, and separating lactate dehydrogenase inhibitors from complex samples, but also a useful platform for large scale production of functional food and nutraceutical ingredients.

Summary: cGAS-STING signaling is essential for innate immunity. Its misregulation promotes cancer or autoimmune and autoinflammatory diseases, and it is imperative to identify effective lead compounds that specifically downregulate the pathway. We report here that astin C, a cyclopeptide isolated from the medicinal plant Aster tataricus, inhibits cGAS-STING signaling and the innate inflammatory responses triggered by cytosolic DNAs. Moreover, mice treated with astin C are more susceptible to HSV-1 infection. Consistently, astin C markedly attenuates the autoinflammatory responses in Trex1−/− BMDM cells and in Trex1−/− mouse autoimmune disease model. Mechanistically, astin C specifically blocks the recruitment of IRF3 onto the STING signalosome. Collectively, this study characterizes a STING-specific small-molecular inhibitor that may be applied for potentially manipulating the STING-mediated clinical diseases. : Li et al. have characterized a small-molecule cyclopeptide, astin C, which specifically inhibits cGAS-STING signaling as well as the innate inflammatory responses. This finding provides a way to potentially manipulate STING-mediated clinical diseases. Keywords: cGAS, STING, IRF3, TBK1, HSV-1, cyclopeptide, astin C, therapeutic target, innate immunity, autoimmune diseases

Stimulator of interferon genes (STING) is critical for cytosolic DNA-triggered innate immunity. STING is modified by several types of polyubiquitin chains. Here, we report that the deubiquitinase CYLD sustains STING signaling by stabilizing the STING protein. CYLD deficiency promoted the K48-linked polyubiquitination and degradation of STING, attenuating the induction of IRF3-responsive genes after HSV-1 infection or the transfection of DNA ligands. Additionally, CYLD knockout mice were more susceptible to HSV-1 infection than their wild-type (WT) littermates. Mechanistically, STING translocated from the ER to the Golgi upon HSV-1 stimulation; CYLD partially accumulated with STING and interacted selectively with K48-linked polyubiquitin chains on STING, specifically removing the K48-linked polyubiquitin chains from STING and ultimately boosting the innate antiviral response. Our study reveals that CYLD is a novel checkpoint in the cGAS-STING signaling pathway and sheds new light on the dynamic regulation of STING activity by ubiquitination.

Salmonella typhimurium infection is associated with gastrointestinal disorder and cellular injury in the liver of both humans and animals. Cinnamaldehyde, the main component of essential oil from cinnamon, has been reported to have anti-inflammatory, anti-oxidative, and anti-apoptotic effects. However, it remains unknown whether cinnamaldehyde can alleviate Salmonella typhimurium infection-induced liver injury in mice. In the present study, we found that cinnamaldehyde attenuated Salmonella typhimurium-induced body weight loss, the increase of organ (liver and spleen) indexes, hepatocyte apoptosis, and the mortality rate in mice. Further study showed that cinnamaldehyde significantly alleviated Salmonella typhimurium-induced liver injury as shown by activities of alanine transaminase, aspartate transaminase, and myeloperoxidase, as well as malondialdehyde. The increased mRNA level of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, and IFN-γ) and chemokines (CCL2 and CCL3) induced by Salmonella typhimurium were significantly abolished by cinnamaldehyde supplementation. These alterations were associated with a regulatory effect of cinnamaldehyde on TLR2, TLR4, and MyD88. 16S rDNA sequence analysis showed that Salmonella typhimurium infection led to upregulation of the abundances of genera Akkermansia, Bacteroides, Alistipes, Muribaculum, and Prevotellaceae UCG-001, and downregulation of the abundances of genera Lactobacillus, Enterorhabdus, and Eggerthellaceae (unclassified). These alterations were reversed by cinnamaldehyde supplementation. In conclusion, cinnamaldehyde attenuated the inflammatory response, oxidative stress, and apoptosis in the liver of Salmonella typhimurium-infected mice. Supplementation of cinnamaldehyde might be a preventive strategy to alleviate liver injury caused by Salmonella typhimurium infection in humans and animals.

Dangguiliuhuang decoction (DGLHD) has been demonstrated to be effective in treating inflammatory, hepatic steatosis, and insulin resistance. In the study, we tried to elucidate the pharmacological efficacy and mechanism of DGLHD against liver fibrosis and predicate potential active ingredients and targets via network analysis and experimental validation. In the formula, we totally discovered 76 potential active ingredients like baicalein, berberine, and wogonin, and 286 corresponding targets including PTGS (prostaglandin-endoperoxide synthase) 2, PPAR (peroxisome proliferator-activated receptors) -γ, and NF-κB (nuclear factor-κB). Pathway and functional enrichment analysis of these putative targets indicated that DGLHD obviously influenced NF-κB and PPAR signaling pathway. Consistently, DGLHD downregulated levels of ALT (alanine transaminase) and AST (aspartate transaminase), reduced production of proinflammatory cytokines-TNF (tumor necrosis factor) -α and IL (Interleukin) -1β in serum and liver from mice with hepatic fibrosis, and inhibited hepatic stellate cell (HSC)-T6 cells proliferation. DGLHD decreased TGF (transforming growth factor) -β1 and α-SMA (smooth muscle actin) expression as well, maintained MMP (matrix metalloprotein) 13-TIMP (tissue inhibitor of metalloproteinases) 1 balance, leading to mitigated ECM (extracellular matrix) deposition in vivo and in vitro. Moreover, our experimental data confirmed that the alleviated inflammation and ECM accumulation were pertinent to NF-κB inhibition and PPAR-γ activation. Overall, our results suggest that DGLHD aims at multiply targets and impedes the progression of hepatic fibrosis by ameliorating abnormal inflammation and ECM deposition, thereby serving as a novel regimen for treating hepatic fibrosis in clinic.

The cyclic GMP-AMP synthase (cGAS), upon cytosolic DNA stimulation, catalyzes the formation of the second messenger 2'3'-cGAMP, which then binds to stimulator of interferon genes (STING) and activates downstream signaling. It remains to be elucidated how the cGAS enzymatic activity is modulated dynamically. Here, we reported that the ER ubiquitin ligase RNF185 interacted with cGAS during HSV-1 infection. Ectopic-expression or knockdown of RNF185 respectively enhanced or impaired the IRF3-responsive gene expression. Mechanistically, RNF185 specifically catalyzed the K27-linked poly-ubiquitination of cGAS, which promoted its enzymatic activity. Additionally, Systemic Lupus Erythematosus (SLE) patients displayed elevated expression of RNF185 mRNA. Collectively, this study uncovers RNF185 as the first E3 ubiquitin ligase of cGAS, shedding light on the regulation of cGAS activity in innate immune responses.

Stimulator of interferon genes (STING, also known as MITA, ERIS or MPYS) induces the activation of TBK1 kinase and IRF3 transcription factor, upon sensing of microbial DNAs. How IRF3 is recruited onto the STING signalosome remains unknown. We report here that silencing of the ER adaptor SCAP markedly impairs the IRF3-responsive gene expression induced by STING. Scap knockdown mice are more susceptible to HSV-1 infection. Interestingly, SCAP translocates from ER, via Golgi, to perinuclear microsome in a STING-dependent manner. Mechanistically, the N-terminal transmembrane domain of SCAP interacts with STING, and the C-terminal cytosolic domain of SCAP binds to IRF3, thus recruiting IRF3 onto STING signalosome. Mis-localization of SCAP abolishes its antiviral function. Collectively, this study characterizes SCAP as an essential adaptor in the STING signaling pathway, uncovering a critical missing link in DNAs-triggered host antiviral responses.

Recently, an increasing number of human and animal studies have reported that exposure to benzo(a)pyrene (BaP) induces neurological abnormalities and is also associated with adverse effects, such as tumor formation, immunosuppression, teratogenicity, and hormonal disorders. However, the exact mechanisms underlying BaP-induced impairment of neurological function remain unclear. The aim of this study was to examine the regulating mechanisms underlying the impact of chronic BaP exposure on neurobehavioral performance.C57BL mice received either BaP in different doses (1.0, 2.5, 6.25 mg/kg) or olive oil twice a week for 90 days. Memory and emotional behaviors were evaluated using Y-maze and open-field tests, respectively. Furthermore, levels of mRNA expression were measured by using qPCR, and DNA methylation of NMDA receptor 2B subunit (NR2B) was examined using bisulfate pyrosequencing in the prefrontal cortex and hippocampus.Compared to controls, mice that received BaP (2.5, 6.25 mg/kg) showed deficits in short-term memory and an anxiety-like behavior. These behavioral alterations were associated with a down-regulation of the NR2B gene and a concomitant increase in the level of DNA methylation in the NR2B promoter in the two brain regions.Chronic BaP exposure induces an increase in DNA methylation in the NR2B gene promoter and down-regulates NR2B expression, which may contribute to its neurotoxic effects on behavioral performance. The results suggest that NR2B vulnerability represents a target for environmental toxicants in the brain.

The MitoPark mouse, a relatively new genetic model of Parkinson's disease (PD), has a dopaminergic neuron-specific knock-out that inactivates the mitochondrial transcription factor A (Tfam), a protein essential for mitochondrial DNA expression and maintenance. This study used multimodal MRI to characterize the neuroanatomical correlates of PD-related deficits in MitoPark mice, along with functional behavioral tests. Compared with age-matched wild-type animals, MitoPark mice at 30 weeks showed: i) reduced whole-brain volume and increased ventricular volume, indicative of brain atrophy, ii) reduced transverse relaxation time (T2*) of the substantia nigra and striatum, suggestive of abnormal iron accumulation, iii) reduced apparent diffusion coefficient in the substantia nigra, suggestive of neuronal loss, iv) reduced fractional anisotropy in the corpus callosum and substantia nigra, indicative of white-matter damages, v) cerebral blood flow was not significantly affected, and vi) reduced motor activity in open-field tests, reduced memory in novel object recognition tests, as well as decreased mobility in tail suspension tests, an indication of depression. In sum, MitoPark mice recapitulate changes in many MRI parameters reported in PD patients. Multimodal MRI may prove useful for evaluating neuroanatomical correlates of PD pathophysiology in MitoPark mice, and for longitudinally monitoring disease progression and therapeutic interventions for PD.

Etomidate is a rapid hypnotic intravenous anesthetic agent. The major side effect of etomidate is the reduced plasma concentration of corticosteroids, leading to the abnormal reaction of adrenals. Cortisol and testosterone biosynthesis has similar biosynthetic pathway, and shares several common steroidogenic enzymes, such as P450 side chain cleavage enzyme (CYP11A1) and 3β-hydroxysteroid dehydrogenase 1 (HSD3B1). The effect of etomidate on Leydig cell steroidogenesis during the cell maturation process is not well established.Immature Leydig cells isolated from 35 day-old rats were cultured with 30 μM etomidate for 3 hours in combination with LH, 8Br-cAMP, 25R-OH-cholesterol, pregnenolone, progesterone, androstenedione, testosterone and dihydrotestosterone, respectively. The concentrations of 5α-androstanediol and testosterone in the media were measured by radioimmunoassay. Leydig cells were cultured with various concentrations of etomidate (0.3-30 μM) for 3 hours, and total RNAs were extracted. Q-PCR was used to measure the mRNA levels of following genes: Lhcgr, Scarb1, Star, Cyp11a1, Hsd3b1, Cyp17a1, Hsd17b3, Srd5a1, and Akr1c14. The testis mitochondria and microsomes from 35-day-old rat testes were prepared and used to detect the direct action of etomidate on CYP11A1 and HSD3B1 activity.In intact Leydig cells, 30 μM etomidate significantly inhibited androgen synthesis. Further studies showed that etomidate also inhibited the LH- stimulated androgen production. On purified testicular mitochondria and ER fractions, etomidate competitively inhibited both CYP11A1 and HSD3B1 activities, with the half maximal inhibitory concentration (IC50) values of 12.62 and 2.75 μM, respectively. In addition, etomidate inhibited steroidogenesis-related gene expression. At about 0.3 μM, etomidate significantly inhibited the expression of Akr1C14. At the higher concentration (30 μM), it also reduced the expression levels of Cyp11a1, Hsd17b3 and Srd5a1. In conclusion, etomidate directly inhibits the activities of CYP11A1 and HSD3B1, and the expression levels of Cyp11a1 and Hsd17b3, leading to the lower production of androgen by Leydig cells.

We have previously identified 8 SNPs in Han Chinese HBV carriers that are associated with disease progression. Although not well studied, genetic factors may also play a significant role in developing chronic HBV disease after exposure. We extend the effect of these eight SNPs on persistent HBV infection in this study. A total of 875 unrelated Han Chinese, 493 chronic hepatitis B subjects (CHB) and 382 HBV clearance individuals (Clear), were recruited from Hubei Province from September 2007 to March 2010. SNPs were verified by using TaqMan 7900HT Sequence Detection System. By using multiple logistic regression analysis, each of the 8 SNP associations was tested using 3 different genetic models (Dominant, Recessive and Additive model), in 4 types of analyses (full sample, men, women, age stratified). A Bonferroni correction was used to account for multiple statistical tests for each SNP association (P

Viral infection induces innate immunity and apoptosis. Apoptosis is an effective means to sacrifice virus-infected host cells and therefore restrict the spread of pathogens. However, the underlying mechanisms of this process are still poorly understood. Here, we show that the mitochondrial antiviral signaling protein (MAVS/VISA/Cardif/IPS-1) is critical for SeV (Sendai virus)-induced apoptosis. MAVS specifically activates c-Jun N-terminal kinase 2 (JNK2) but not other MAP kinases. Jnk2-/- cells, but not Jnk1-/- cells, are unable to initiate virus-induced apoptosis and SeV further fails to trigger apoptosis in MAPK kinase 7 (MKK7) knockout (Mkk7-/-) cells. Mechanistically, MAVS recruits MKK7 onto mitochondria via its 3D domain, which subsequently phosphorylates JNK2 and thus activates the apoptosis pathway. Consistently, Jnk2-/- mice, but not Jnk1-/- mice, display marked inflammatory injury in lung and liver after viral challenge. Collectively, we have identified a novel signaling pathway, involving MAVS-MKK7-JNK2, which mediates virus-induced apoptosis and highlights the indispensable role of mitochondrial outer membrane in host defenses.

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase catalyzes the transfer of electrons from NADPH to O2, which is the main source of reactive oxygen species (ROS) in nonphagocytic cells. Excess ROS are toxic; therefore, keeping ROS in homeostasis in cells can protect cells from oxidative damage. It is meaningful to further understand the molecular mechanism by which ROS homeostasis is mediated. Human protein HSCARG is a newly identified oxidative sensor and a negative regulator of NF-κB. Here, we find that HSCARG represses the cellular ROS generation through inhibiting mRNA and protein expression of p47phox, a subunit of NADPH oxidase. In contrast, shRNA-mediated HSCARG knockdown increases endogenous p47phox expression level. And HSCARG has no obvious effect on ROS production in p47phox-depleted cells. Furthermore, HSCARG regulates p47phox through inhibition of NF-κB activity. Our findings identify HSCARG as a novel regulator in regulation of the activity of NADPH oxidase and ROS homeostasis.

Experimental evidence suggests that oxidative and nitrative mechanisms account for much of the dopaminergic neuronal injury in Parkinson's disease (PD). The ubiquitously expressed non-receptor tyrosine kinase c-Abl is activated by oxidative stress and thus, may play a role in redox-mediated neurodegeneration. Recently, we reported that c-Abl is activated in PD and that a c-Abl inhibitor mitigated neuronal damage in a PD animal model, suggesting a novel neuroprotective therapeutic approach. In the studies presented here, we evaluated the efficacy of a potent and clinically relevant second-generation irreversible Abl kinase inhibitor, INNO-406, as a therapeutic agent for PD. Our studies reveal that INNO-406 is capable of preventing the progression of dopaminergic neuronal damage in a toxin-induced C57 mouse model of PD. Using bovine brain microvessel endothelium as an in vitro blood-brain barrier (BBB) model, we detected rapid and significant transfer of INNO-406. Additionally, pharmacokinetic analyses demonstrated significant nanomolar concentrations of INNO-406 in brain in the presence or absence of MPTP administration, however, INNO-406 did not alter the brain levels of MPP+ in MPTP-treated mice. Finally, we showed that 10 mg/kg of INNO-406 given to C57 mice for one week before MPTP treatment (4×20 mg/kg i.p., every 2 h) and then for one week after MPTP treatment decreased the loss of dopamine in the striatum by 45% and the loss of TH+ neurons in substantia nigra pars compacts by 40%. This treatment regimen also abrogated activation of c-Abl, tyrosine phosphorylation of the Abl substrate and E3-ubiquitin ligase parkin, and accumulation of the toxic parkin substrate AIMP2. We propose that compounds of the INNO-406 class of Abl inhibitors will be useful new neuroprotective drugs for the treatment of PD-like pathology in preclinical systems that should be easily translated to the clinic.

Parkinson's disease (PD) is a neurodegenerative disorder primarily characterized by progressive loss of dopamine neurons, leading to loss of motor coordination. However, PD is associated with a high rate of non-motor neuropsychiatric comorbities that often develop before the onset of movement symptoms. The MitoPark transgenic mouse model is the first to recapitulate the cardinal clinical features, namely progressive neurodegeneration and death of neurons, loss of motor function and therapeutic response to L-DOPA. To investigate whether MitoPark mice exhibit early onset of cognitive impairment, a non-motor neuropsychiatric comorbidity, we measured performance on a spatial learning and memory task before (∼8 weeks) or after (∼20 weeks) the onset of locomotor decline in MitoPark mice or in littermate controls. Consistent with previous studies, we established that a progressive loss of spontaneous locomotor activity began at 12 weeks of age, which was followed by progressive loss of body weight beginning at 16-20 weeks. Spatial learning and memory was measured using the Barnes Maze. By 20 weeks of age, MitoPark mice displayed a substantial reduction in overall locomotor activity that impaired their ability to perform the task. However, in the 8-week-old mice, locomotor activity was no different between genotypes, yet MitoPark mice took longer, traveled further and committed more errors than same age control mice, while learning to successfully navigate the maze. The modest between-day learning deficit of MitoPark mice was characterized by impaired within-day learning during the first two days of testing. No difference was observed between genotypes during probe trials conducted one or twelve days after the final acquisition test. Additionally, 8-week-old MitoPark mice exhibited impaired novel object recognition when compared to control mice. Together, these data establish that mild cognitive impairment precedes the loss of motor function in a novel rodent model of PD, which may provide unique opportunities for therapeutic development.