Mitochondrial GRIM19 Loss Induces Liver Fibrosis through NLRP3/IL33 Activation via Reactive Oxygen Species/NF-кB Signaling.

Background and Aims: Hepatic fibrosis (HF) is a critical step in the progression of hepatocellular carcinoma (HCC). Gene associated with retinoid-IFN-induced mortality 19 (GRIM19), an essential component of mitochondrial respiratory chain complex I, is frequently attenuated in various human cancers, including HCC. Here, we aimed to investigate the potential relationship and underlying mechanism between GRIM19 loss and HF pathogenesis. Methods: GRIM19 expression was evaluated in normal liver tissues, hepatitis, hepatic cirrhosis, and HCC using human liver disease spectrum tissue microarrays. We studied hepatocyte-specific GRIM19 knockout mice and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 (Cas9) lentivirus-mediated GRIM19 gene-editing in murine hepatocyte AML12 cells in vitro and in vivo. We performed flow cytometry, immunofluorescence, immunohistochemistry, western blotting, and pharmacological intervention to uncover the potential mechanisms underlying GRIM19 loss-induced HF. Results: Mitochondrial GRIM19 was progressively downregulated in chronic liver disease tissues, including hepatitis, cirrhosis, and HCC tissues. Hepatocyte-specific GRIM19 heterozygous deletion induced spontaneous hepatitis and subsequent liver fibrogenesis in mice. In addition, GRIM19 loss caused chronic liver injury through reactive oxygen species (ROS)-mediated oxidative stress, resulting in aberrant NF-кB activation via an IKK/IкB partner in hepatocytes. Furthermore, GRIM19 loss activated NLRP3-mediated IL33 signaling via the ROS/NF-кB pathway in hepatocytes. Intraperitoneal administration of the NLRP3 inhibitor MCC950 dramatically alleviated GRIM19 loss-driven HF in vivo. Conclusions: The mitochondrial GRIM19 loss facilitates liver fibrosis through NLRP3/IL33 activation via ROS/NF-кB signaling, providing potential therapeutic approaches for earlier HF prevention.

Choriocapillaris reduction accurately discriminates against early-onset Alzheimer's disease.

INTRODUCTION: This study addresses the urgent need for non-invasive early-onset Alzheimer's disease (EOAD) prediction. Using optical coherence tomography angiography (OCTA), we present a choriocapillaris model sensitive to EOAD, correlating with serum biomarkers. METHODS: Eighty-four EOAD patients and 73 controls were assigned to swept-source OCTA (SS-OCTA) or the spectral domain OCTA (SD-OCTA) cohorts. Our hypothesis on choriocapillaris predictive potential in EOAD was tested and validated in these two cohorts. RESULTS: Both cohorts revealed diminished choriocapillaris signals, demonstrating the highest discriminatory capability (area under the receiver operating characteristic curve: SS-OCTA 0.913, SD-OCTA 0.991; P < 0.001). A sparser SS-OCTA choriocapillaris correlated with increased serum amyloid beta (Aß)42, Aß42/40, and phosphorylated tau (p-tau)181 levels (all P < 0.05). Apolipoprotein E status did not affect choriocapillaris measurement. DISCUSSION: The choriocapillaris, observed in both cohorts, proves sensitive to EOAD diagnosis, and correlates with serum Aß and p-tau181 levels, suggesting its potential as a diagnostic tool for identifying and tracking microvascular changes in EOAD. HIGHLIGHTS: Optical coherence tomography angiography may be applied for non-invasive screening of Alzheimer's disease (AD). Choriocapillaris demonstrates high sensitivity and specificity for early-onset AD diagnosis. Microvascular dynamics abnormalities are associated with AD.

Correlation between serum biomarkers, brain volume, and retinal neuronal loss in early-onset Alzheimer's disease.

PURPOSE: To compare the peripapillary retinal nerve fiber layer (pRNFL), retinal nerve fiber layer (RNFL), and ganglion cell complex (GCC) thickness measurement in early-onset Alzheimer's disease (EOAD) and controls using spectral domain optical coherence tomography (SD-OCT). We also assessed the relationship between SD-OCT measurements and cognitive measures, serum biomarkers for Alzheimer's disease (AD), and cerebral microstructural volume. METHODS: pRNFL, RNFL, and GCC thicknesses were measured in 43 EOAD and 42 controls using SD-OCT. Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) were used to assess cognitive status, magnetic resonance imaging (MRI) tool was used to quantify cerebral microstructural volume, and serum biomarkers were quantified from peripheral blood. RESULTS: EOAD patients had thinner pRNFL (P < 0.001), RNFL (P = 0.008), and GCC (P = 0.018) thicknesses compared to controls after adjusting for multiple factors. pRNFL thickness correlated (P = 0.016) with serum t-tau level. Serum Aß42 (P < 0.05) concentration correlated with RNFL thickness. Importantly, occipital lobe volume (P = 0.010) correlated with GCC thicknesses in EOAD patients. CONCLUSION: Our findings suggest that retinal thickness may be useful markers for assessing neurodegenerative process in EOAD.

CSTB accelerates the progression of hepatocellular carcinoma via the ERK/AKT/mTOR signaling pathway.

Hepatocellular carcinoma (HCC) is a significant contributor to global cancer-related deaths, leading to high mortality rates. However, the pathogenesis of HCC remains unclear. In this research, by the bioinformatics data analysis, we found that elevated CSTB expression correlated with advanced disease and predicted diminished overall survival (OS) in HCC patients. We subsequently verified the oncogenic role of CSTB as well as the potential underlying mechanisms in HCC through a series of in vitro experiments, such as CCK-8 assays, cloning assays, flow cytometry, Transwell assays, and western blotting. Our findings illustrated that the silencing of CSTB effectively suppressed cellular proliferation by inducing cell cycle arrest in the G2 phase and impaired HCC cell invasion and migration by stimulating epithelial-mesenchymal transition (EMT). Additionally, we analyzed the pathways enriched in HCC using RNA sequencing and found that the ERK/AKT/mTOR signaling pathway was related to increased CSTB expression in HCC. Finally, we confirmed the tumorigenic role of CSTB via in vivo experiments. Thus, our findings revealed that silencing CSTB inhibited the HCC progression via the ERK/AKT/mTOR signaling pathway, highlighting new perspectives for investigating the mechanisms of HCC.

Enhanced Gasdermin-E-mediated Pyroptosis in Alzheimer's Disease.

Amyloid ß protein (Aß) is a critical factor in the pathogenesis of Alzheimer's disease (AD). Aß induces apoptosis, and gasdermin-E (GSDME) expression can switch apoptosis to pyroptosis. In this study, we demonstrated that GSDME was highly expressed in the hippocampus of APP23/PS45 mouse models compared to that in age-matched wild-type mice. Aß treatment induced pyroptosis by active caspase-3/GSDME in SH-SY5Y cells. Furthermore, the knockdown of GSDME improved the cognitive impairments of APP23/PS45 mice by alleviating inflammatory response. Our findings reveal that GSDME, as a modulator of Aß and pyroptosis, plays a potential role in Alzheimer's disease pathogenesis and shows that GSDME is a therapeutic target for AD.

APOE ε4 Gene Carriers Demonstrate Reduced Retinal Capillary Densities in Asymptomatic Older Adults.

Early identification of Apolipoprotein E (APOE)-related microvascular pathology will help to study the microangiopathic contribution to Alzheimer's disease and provide a therapeutic target for early intervention. To evaluate the differences in retinal microvasculature parameters between APOE ε4 carriers and non-carriers, asymptomatic older adults aged ≥ 55 years underwent APOE ε4 genotype analysis, neuropsychological examination, and optical coherence tomography angiography (OCTA) imaging. One hundred sixty-three older adults were included in the data analysis. Participants were also defined as cognitively impaired (CI) and non-cognitively impaired (NCI) according to their MoCA scores and educational years. APOE ε4 carriers demonstrated reduced SVC (p = 0.023) compared to APOE ε4 non-carriers. Compared to NCI, CI participants showed reduced SVC density (p = 0.006). In the NCI group, no significant differences (p > 0.05) were observed in the microvascular densities between APOE ε4 carriers and non-carriers. In the CI group, APOE ε4 carriers displayed reduced microvascular densities compared to non-carriers (SVC, p = 0.006; DVC, p = 0.048). We showed that CI and APOE ε4 affect retinal microvasculature in older adults. Quantitative measures of the retinal microvasculature could serve as surrogates for brain microcirculation, providing an opportunity to study microvascular contributions to AD.

PCP4 Promotes Alzheimer's Disease Pathogenesis by Affecting Amyloid-ß Protein Precursor Processing.

BACKGROUND: Down syndrome (DS) is caused by an extra copy of all or part of chromosome 21. The patients with DS develop typical Alzheimer's disease (AD) neuropathology, indicating the role of genes on human chromosome 21 (HSA21) in the pathogenesis of AD. Purkinje cell protein 4 (PCP4), also known as brain-specific protein 19, is a critical gene located on HSA21. However, the role of PCP4 in DS and AD pathogenesis is not clear. OBJECTIVE: To explore the role of PCP4 in amyloid-ß protein precursor (AßPP) processing in AD. METHODS: In this study, we investigated the role of PCP4 in AD progression in vitro and in vivo. In vitro experiments, we overexpressed PCP4 in human Swedish mutant AßPP stable expression or neural cell lines. In vitro experiments, APP23/PS45 double transgenic mice were selected and treated with AAV-PCP4. Multiple topics were detected by western blot, RT-PCR, immunohistochemical and behavioral test. RESULTS: We found that PCP4 expression was altered in AD. PCP4 was overexpressed in APP23/PS45 transgenic mice and PCP4 affected the processing of AßPP. The production of amyloid-ß protein (Aß) was also promoted by PCP4. The upregulation of endogenous AßPP expression and the downregulation of ADAM10 were due to the transcriptional regulation of PCP4. In addition, PCP4 increased Aß deposition and neural plaque formation in the brain, and exuberated learning and memory impairment in transgenic AD model mice. CONCLUSION: Our finding reveals that PCP4 contributes to the pathogenesis of AD by affecting AßPP processing and suggests PCP4 as a novel therapeutic target for AD by targeting Aß pathology.

Synthesis of Azepane Derivatives via Formal 1,3-Migration of Hydroxy and Acyloxy Groups and Selective Annulation.

Formal 1,3-migration of hydroxy and acyloxy groups initiated by α-imino rhodium carbene was achieved, and the following selective annulations of the corresponding zwitterions could efficiently afford azepane derivatives. Benefiting from a time-saving procedure as well as a good functional group tolerance, this unique migration-annulation protocol could provide an efficient tool for synthesizing seven-membered N-heterocycles. The plausible mechanism is discussed.

Synthesis of α-Amino Cyclobutanones via Formal 1,3-Hydroxy Migration Triggered by Formation of α-Imino Rhodium Carbene.

Formal intramolecular 1,3-OH migration of α-imino carbene was achieved producing a unique zwitterion, and the subsequent selective annulation afforded α-amino cyclobutanone. Features such as readily available substrates, mild reaction conditions, a time-saving procedure, excellent functional group compatibility, and valuable transformations of the products qualified this unique protocol as an efficient tool for the synthesis of strained cyclic compounds. Density functional theory calculations were in good agreement with experimental observations, and a plausible mechanism is presented.

A light-enhanced α-FeOOH nanowires/polyaniline anode for improved electricity generation performance in microbial fuel cells.

Low power density and poor anode performance seriously limit the potential of practical application of microbial fuel cell (MFC). Utilizing solar energy by developing photoanode is one of the effective pathways to improve the performance of MFC. Here solar energy harvesting was integrated into MFC to achieved the comprehensive utilization of multiple energy sources. A hybrid MFC photoanode (α-FeOOH-NWs/PANI anode) was constructed by loading polyaniline (PANI) and α-FeOOH nanowires (α-FeOOH-NWs) on carbon paper through electro-polymerization synthesis method. Compared with clean carbon paper, nanowires and PANI increased the surface roughness of the electrode, which facilitated the biofilm formation. The electrochemical and photoelectric analysis demonstrated that PANI introduced new electroactive groups and reduced the charge transfer resistance, exhibiting excellent electrochemical and photoelectric activites. The MFC with the α-FeOOH-NWs/PANI photoanode had higher voltage output and power density under light illumination, with the power density of 1.95 W/m2 under light, which was 1.4 times higher than that without light. The hybrid α-FeOOH-NWs/PANI photoanode enhanced the separation efficiency of photogenerated electron-hole pairs, thereby improving the photoelectric response capability and generating a high photocurrent. Our research provided a new concept for the combination of solar energy harvesting and MFCs, yielding an overall enhancement of electricity eneration performance in MFC.

Gallic acid inhibits neuroinflammation and reduces neonatal hypoxic-ischemic brain damages.

Neuroinflammation is a leading cause of secondary neuronal injury in neonatal hypoxic-ischemic encephalopathy (HIE). Regulation of neuroinflammation may be beneficial for treatment of HIE and its secondary complications. Gallic acid (GA) has been shown to have anti-inflammatory and antioxidant effects. In this report we found that oxygen-glucose deprivation and/reoxygenation (OGD/R)-induced cell death, and the generation of excessive reactive oxygen species (ROS) and inflammatory cytokines by microglia were inhibited by GA treatment. Furthermore, GA treatment reduced neuroinflammation and neuronal loss, and alleviated motor and cognitive impairments in rats with hypoxic-ischemic brain damage (HIBD). Together, our results reveal that GA is an effective regulator of neuroinflammation and has potential as a pharmaceutical intervention for HIE therapy.

The synergy of N-doped and SPR-promoted photocatalytic removal of NO with graphene/Bi nanocomposites.

Nitrogen-doped graphene/bismuth (NG/Bi) nanocomposites with different graphene contents were successfully assembled using a one-pot method. Detailed characterization of the as-synthesized samples, including powder X-ray diffraction (XRD), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), UV-vis diffuse reflectance spectroscopy (DRS), photoluminescence spectra (PL) and photoelectrochemical measurements was conducted. The results showed that nitrogen elements were introduced into the skeleton of graphene and Bi nanoparticles were irregularly distributed on the N-doped graphene nanosheets. The NG/Bi composites performed better photocatalytic NO removal activity than their counterparts under UV light illumination. The removal ratio of NO over 2%-NG/Bi was 49.5%, and the recycling activity after 5 runs was not significantly weakened. The enhanced photocatalytic performance was due to the synergistic effect of N-graphene, which not only elevated the absorption of light, but also accelerated the transfer of hot electrons generated by the SPR effect of Bi.

ZnO/ZnAl2O4 Nanocomposite with 3D Sphere-Like Hierarchical Structure for Photocatalytic Reduction of Aqueous Cr(VI).

Three dimensional (3D) ZnO/ZnAl2O4 nanocomposites (ZnnAl-MMO) were synthesized by a simple urea-assisted hydrothermal process and subsequent high-temperature calcination. The as-prepared samples and their precursors were characterized by X-ray diffraction (XRD), Scanning electron microscopy (SEM), Transmission electron microscopy (TEM), UV-Vis diffuse reflectance spectroscopy (DRS), and Photoluminescence spectra (PL). It was observed that the morphology of ZnnAl-MMO nanocomposites could be tuned from cubic aggregates, hierarchically flower-like spheres to porous microspheres by simply changing the molar ratio of metal cations of the starting reaction mixtures. The photocatalytic performance of ZnO/ZnAl2O4 nanocomposites in the photoreduction of aqueous Cr(VI) indicated that the as-prepared 3D hierarchical sphere-like ZnnAl-MMO nanocomposite showed excellent photocatalytic activity of Cr(VI) reduction under UV light irradiation. The results indicated that the maximum removal percentage of aqueous Cr(VI) was 98% within four hours at 10 mg/L initial concentration of Cr(VI), owing to the effective charge separation and diversion of photogenerated carriers across the heterojunction interface of the composite. Our study put forward a facile method to fabricate hierarchical ZnO/ZnAl2O4 composites with potential applications for wastewater treatment.

Green and Effective Removal of Aqueous Graphene Oxide under UV-Light Irradiation.

The potential extensive application of graphene oxide (GO) in various fields results in the possibility of its release into the natural environment with negative impacts on humans and the ecosystem. The UV-induced removal behavior of aqueous GO was evaluated in this study, and the effect of various parameters (including initial GO concentration, initial solution pH and co-existing ions) on removal rate of GO were investigated in detail. The results showed that UV-light induced a maximum removal rate of GO of 99.1% after 32 h irradiation without any additives, and that the photo-induced removal process in all cases fitted well with pseudo-first-order kinetics. Under optimal conditions, GO was completely removed, with initial GO concentrations of 10 mg/L while adjusting solution pH to 3 or adding Ca2+-containing salt. The GO and photoreduced graphene oxide (prGO) were characterized using High-resolution Transmission Microscopy (HRTEM), X-ray Photoelectron Spectroscopy (XPS), and Fourier-transform Infrared Spectroscopy (FT-IR). The radical species trapping experiments and Electron Spin Resonance (ESR) tests indicated that self-reduction of GO upon UV-light exposure could be achieved via photogenerated electrons from a GO semiconductor. Further mechanism study showed that the high efficiency of UV-induced GO removal came from UV-induced photoreduction, and pH-induced or cation-induced coagulation. This study provided a green and effective method to remove GO from aqueous solutions.

Nutritional Deficiency in Early Life Facilitates Aging-Associated Cognitive Decline.

BACKGROUND: Nutrition is important for the fetal developmental programming. Nutritional deficiency in early life could increase the susceptibility to many aging-related disorders including cognitive decline. OBJECTIVE: Our study aims to investigate the effect of early famine exposure on aging-associated cognitive function. METHODS: We recruited 6790 subjects born between 1956 to 1964 during which the Great Chinese Famine occurred (1959-1961). Cognitive function of these subjects were evaluated using the Mini-Mental State Examination (MMSE), the Activities of Daily Living scale (ADL), the Instrumental Activities of Daily Living scale (IADL) and the Clinical Dementia Rating (CDR). RESULTS: Our study identified that early exposure to the famine significantly increased the risk of cognitive impairments in later life, leading to higher prevalence of Mild Cognitive Impairment (MCI) and dementia. We also found the sex and rural-urban differences in this malnutrition-induced effect. Illiteracy, history of stroke or diabetes mellitus are great risk factors to facilitate the cognitive decline. CONCLUSION: These findings demonstrate that exposure to famine during early life including prenatal period and early childhood facilitates aging-associated cognitive deficits.