ABSTRACT
OBJECTIVES: To evaluate changes in health outcomes between years 2 and 3 after discharge following COVID-19 and to identify risk factors for poor health 3-year post-discharge. DESIGN: This is a multicentre observational cohort study. SETTING: This study was conducted in two centres from Wuhan, China. PARTICIPANTS: Eligibility screening has been performed in 3988 discharged laboratory-confirmed adult COVID-19 patients. Exclusion criteria were refusal to participate, inability to contact and death before follow-up. The WHO COVID-19 guidelines on defining disease severity were adopted. RESULTS: 1594 patients participated in the 1-year, 2-year and 3-year follow-ups, including 796 (49.9%) male patients, and 422 (26.5%) patients were classified in the severe disease group. 3 years after discharge, 182 (11.4%) patients still complained of at least one symptom. The most common symptoms were fatigue, myalgia, chest tightness, cough, anxiety, shortness of breath and expectoration. Fatigue or myalgia, the most common symptom cluster, frequently coexisted with chest symptoms and anxiety. Symptom persistence between years 2 and 3 was reported in 70 patients (4.4%) for which intensive care unit (ICU) admission was a risk factor (p=0.038). Of the 1586 patients who completed the chronic obstructive pulmonary disease assessment test (CAT), 97 (6.1%) scored ≥10, with older age being associated with CAT ≥10 (p=0.007). CONCLUSIONS: Between years 2 and 3 after SARS-CoV-2 infection, most patients returned to an asymptomatic state, and only a few were still symptomatic. ICU admission was a risk factor for symptom persistence.
Subject(s)
COVID-19 , Patient Discharge , SARS-CoV-2 , Humans , COVID-19/epidemiology , Male , Female , China/epidemiology , Middle Aged , Patient Discharge/statistics & numerical data , Adult , Aged , Risk Factors , Cohort Studies , Severity of Illness Index , Intensive Care Units/statistics & numerical dataABSTRACT
The excited-state proton transfer (ESPT) reaction between anthracen-2-yl-3-phenylurea (PUA) derivatives and tetrabutylammonium acetate (TBAAc) in dimethyl sulfoxide (DMSO) solvent was theoretically investigated using time-dependent density functional theory. The electron-donating methoxy group (OMe) and electron-withdrawing trifluoromethyl group (CF3) were bonded to 2PUA to form OMe-2PUA and CF3-2PUA, respectively. Two hydrogen bonds formed in the 1 : 1 hydrogen-bonded complexes between the 2PUA derivative and acetate ion (AcO-), namely N1-H1â¯O1 and N2-H2â¯O2. Strong charge transfer (CT) due to the electron-donating OMe group led to H1 transfer in the S1 state for the OMe-2PUA:AcO- hydrogen-bonded complex. On the contrary, weak CT due to the electron-withdrawing CF3 group led to H2 transfer in the S1 state for CF3-2PUA. After the ESPT reaction, the binding energies of the hydrogen-bonded complexes strongly decreased in both cases, and this promoted the separation of contact-ion pairs (CIPs*) and formed different types of anionic species. CF3-2PUA- could keep its nearly planar structure in the S1 state and emit "abnormal" fluorescence. On the other hand, the anionic OMe-2PUA- underwent a twisting motion to form a twisted structure in the S1 state with very low energy, and this led to a rapid internal conversion (IC) to quench long-wave fluorescence in the emission spectra.
ABSTRACT
Emerging evidence suggests that neurological and other post-acute sequelae of COVID-19 can persist beyond or develop following SARS-CoV-2 infection. However, the long-term trajectories of cognitive change after a COVID-19 infection remain unclear. Here we investigated cognitive changes over a period of 2.5 years among 1,245 individuals aged 60 years or older who survived infection with the original SARS-CoV-2 strain in Wuhan, China, and 358 uninfected spouses. We show that the overall incidence of cognitive impairment among older COVID-19 survivors was 19.1% at 2.5 years after infection and hospitalization, evaluated using the Telephone Interview for Cognitive Status-40. Cognitive decline primarily manifested in individuals with severe COVID-19 during the initial year of infection, after which the rate of decline decelerated. Severe COVID-19, cognitive impairment at 6 months and hypertension were associated with long-term cognitive decline. These findings reveal the long-term cognitive trajectory of the disease and underscore the importance of post-infection cognitive care for COVID-19 survivors.
ABSTRACT
Immunosenescence contributes to systematic aging and plays a role in the pathogenesis of Alzheimer's disease (AD). Therefore, the objective of this study was to investigate the potential of immune rejuvenation as a therapeutic strategy for AD. To achieve this, the immune systems of aged APP/PS1 mice were rejuvenated through young bone marrow transplantation (BMT). Single-cell RNA sequencing revealed that young BMT restored the expression of aging- and AD-related genes in multiple cell types within blood immune cells. The level of circulating senescence-associated secretory phenotype proteins was decreased following young BMT. Notably, young BMT resulted in a significant reduction in cerebral Aß plaque burden, neuronal degeneration, neuroinflammation, and improvement of behavioral deficits in aged APP/PS1 mice. The ameliorated cerebral amyloidosis was associated with an enhanced Aß clearance of peripheral monocytes. In conclusion, our study provides evidence that immune system rejuvenation represents a promising therapeutic approach for AD.
Subject(s)
Alzheimer Disease , Disease Models, Animal , Rejuvenation , Animals , Alzheimer Disease/therapy , Alzheimer Disease/metabolism , Alzheimer Disease/immunology , Mice , Mice, Transgenic , Bone Marrow Transplantation , Behavior, Animal , Amyloid beta-Peptides/metabolism , Monocytes/immunology , Monocytes/metabolism , Plaque, Amyloid/pathology , Plaque, Amyloid/metabolism , Aging/immunology , HumansABSTRACT
OBJECTIVES: This study was conducted to develop nomograms for predicting repeat intrahepatic recurrence (rIHR) and overall survival (OS), after radiofrequency ablation (RFA), treatment in patients with recurrent colorectal liver metastases (CLMs) after hepatectomy based on clinicopathologic features. METHODS: A total of 160 consecutive patients with recurrent CLMs after hepatectomy who were treated with ultrasound-guided percutaneous RFA from 2012 to 2022 were retrospectively included. Patients were randomly divided into a training cohort and a validation cohort, with a ratio of 8:2. Potential prognostic factors associated with rIHR and OS, after RFA, were identified by using the competing-risks and Cox proportional hazard models, respectively, and were used to construct the nomogram. The nomogram was evaluated by Harrell's C-index and a calibration curve. RESULTS: The 1-, 2-, and 3-year rIHR rates after RFA were 58.8%, 70.2%, and 74.2%, respectively. The 1-, 3- and 5-year OS rates were 96.3%, 60.4%, and 38.5%, respectively. In the multivariate analysis, mutant RAS, interval from hepatectomy to intrahepatic recurrence ≤ 12 months, CEA level >5 ng/ml, and ablation margin <5 mm were the independent predictive factors for rIHR. Mutant RAS, largest CLM at hepatectomy >3 cm, CEA level >5 ng/ml, and extrahepatic disease were independent predictors of poor OS. Two nomograms for rIHR and OS were constructed using the respective significant variables. In both cohorts, the nomogram demonstrated good discrimination and calibration. CONCLUSIONS: The established nomograms can predict individual risk of rIHR and OS after RFA for recurrent CLMs and contribute to improving individualized management.
Subject(s)
Catheter Ablation , Colorectal Neoplasms , Liver Neoplasms , Radiofrequency Ablation , Humans , Colorectal Neoplasms/pathology , Liver Neoplasms/pathology , Neoplasm Recurrence, Local/surgery , Nomograms , Prognosis , Retrospective StudiesABSTRACT
Purpose: To explore the association between type 2 diabetes mellitus (T2DM) and body composition based on magnetic resonance fat fraction (FF) mapping. Methods: A total of 341 subjects, who underwent abdominal MRI examination with FF mapping were enrolled in this study, including 68 T2DM patients and 273 non-T2DM patients. The FFs and areas of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and abdominal muscle (AM) were measured at the level of the L1-L2 vertebral. The FF of bone marrow adipose tissue (BMAT) was determined by the averaged FF values measured at the level of T12 and L1 vertebral, respectively. The whole hepatic fat fraction (HFF) and pancreatic fat fraction (PFF) were measured based on 3D semi-automatic segmentation on the FF mapping. All data were analyzed by GraphPad Prism and MedCalc. Results: VAT area, VAT FF, HFF, PFF of T2DM group were higher than those of non-T2DM group after adjusting for age and sex (P < 0.05). However, there was no differences in SAT area, SAT FF, BMAT FF, AM area and AM FF between the two groups (P > 0.05). VAT area and PFF were independent risk factors of T2DM (all P < 0.05). The area under the curve (AUC) of the receiver operating characteristic (ROC) for VAT area and PFF in differentiating between T2DM and non-T2DM were 0.685 and 0.787, respectively, and the AUC of PFF was higher than VAT area (P < 0.05). Additionally, in seemingly healthy individuals, the SAT area, VAT area, and AM area were found to be significantly associated with being overweight and/or obese (BMI ≥ 25) (all P < 0.05). Conclusions: In this study, it was found that there were significant associations between T2DM and VAT area, VAT FF, HFF and PFF. In addition, VAT area and PFF were the independent risk factors of T2DM. Especially, PFF showed a high diagnostic performance in discrimination between T2DM and non-T2DM. These findings may highlight the crucial role of PFF in the pathophysiology of T2DM, and it might be served as a potential imaging biomarker of the prevention and treatment of T2DM. Additionally, in individuals without diabetes, focusing on SAT area, VAT area and AM area may help identify potential health risks and provide a basis for targeted weight management and prevention measures.
Subject(s)
Diabetes Mellitus, Type 2 , Humans , Diabetes Mellitus, Type 2/metabolism , Obesity/metabolism , Pancreas/metabolism , Pancreas/pathology , Body Composition , Magnetic Resonance Imaging/methodsABSTRACT
The emission of volatile organic compounds (VOCs) significantly contributes to air pollution and poses a serious threat to human health. Benzene, one of the most toxic VOCs, is difficult for the human body to metabolize and is classified as a Group 1 carcinogen. The development of efficient adsorbents for removing trace amounts of benzene from ambient air is thus of great importance. In this work, we studied the benzene adsorption properties of four Zr-based metal-organic frameworks (Zr-MOFs) through static volumetric and dynamic breakthrough experiments. Two previously reported Zr-MOFs, BUT-12 and STA-26, were prepared with a tritopic carboxylic acid ligand (H3L1) functionalized with three methyl groups, and STA-26 is a 2-fold interpenetrated network of BUT-12. Two new isoreticular Zr-MOFs, BUT-12-Et and STA-26-Et, were synthesized using a similar ligand, H3L2, where the methyl groups are replaced with ethyl groups. There are mesopores in BUT-12 and BUT-12-Et and micropores in STA-26 and STA-26-Et. The four Zr-MOFs all showed high stability in liquid water and acidic aqueous solutions. The microporous STA-26 and STA-26-Et showed much higher benzene uptakes than mesoporous BUT-12 and BUT-12-Et at room temperature under low pressures. Particularly, the benzene adsorption capacity of STA-26-Et was high up to 2.21 mmol/g at P/P0 = 0.001 (P0 = 12.78 kPa), higher than those of the other three Zr-MOFs and most reported solid adsorbents. Breakthrough experiments confirmed that STA-26-Et could effectively capture trace benzene (10 ppm) from dry air; however, its benzene capture capacity was reduced by 90% under humid conditions (RH = 50%). Coating of the crystals of STA-26-Et with polydimethylsiloxane (PDMS) increased the hydrophobicity of the exterior MOF surfaces, leading to a more than 2-fold improvement in its benzene capture capacity in the breakthrough experiment under humid condition. PDMS coating of STA-26-Et likely slowed down the water adsorption process, and thus, the adsorbent afforded more efficient capture of benzene. This work demonstrates that modifying both the interior and exterior surfaces of MOFs can effectively enhance their performance in capturing trace benzene from ambient air, even under humid conditions. This finding is meaningful for the development of new adsorbents for effective air purification applications.
ABSTRACT
OBJECTIVE: The aim of the work described here was to explore a potential method for improving the diagnostic detection of hepatocellular carcinoma (HCC) based on the contrast-enhanced ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS) Version 2017. METHODS: We retrospectively evaluated 585 liver nodules in 427 patients at risk for HCC from December 2020 to March 2023. The nodules were categorized as LR-1 to LR-M based on CEUS LI-RADS Version 2017 and were randomly subclassified into a developmental cohort (DC) and a validation cohort (VC) at 3:1. In the DC, the cutoff value of the time difference (∆T) for differentiating HCC from other malignancies by LR-M was calculated and used to reclassify nodules in the VC. The diagnostic effect on HCC detection before and after reclassification was further assessed. RESULTS: According to the current CEUS LI-RADS, 140 of 426 (32.9%) confirmed HCC nodules were misclassified as LR-M. In the DC (439 nodules), the receiver operating characteristic (ROC) curve revealed that the cutoff value of ∆T (wash-out onset time minus contrast arrival time) recommended for HCC diagnosis was greater than 21 s. In the VC (146 nodules), 34 HCCs were correctly categorized as LR-5 according to the cutoff value, and after reclassification, LR-5 had higher accuracy (67.1% vs. 89.0%, p < 0.001) and sensitivity (56.0% vs. 87.2%, p < 0.001) for HCC diagnosis with high specificity (100% vs. 94.6%, p = 0.500). CONCLUSION: Using the time difference method could identify HCC nodules misdiagnosed as LR-M and improve the diagnostic performance of current CEUS LI-RADS.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/pathology , Retrospective Studies , Contrast Media , Reproducibility of Results , Magnetic Resonance Imaging/methods , Sensitivity and SpecificityABSTRACT
This study aimed to examine the effect and underlying mechanism of Puerariae Lobatae Radix on insulin resistance in db/db mice with type 2 diabetes mellitus(T2DM) based on the analysis of intestinal flora. Fifty db/db mice were randomly divided into a model group(M group), a metformin group(YX group), a high-dose Puerariae Lobatae Radix group(YGG group), a medium-dose Puerariae Lobatae Radix group(YGZ group), and a low-dose Puerariae Lobatae Radix group(YGD group). Another 10 db/m mice were assigned to the normal group(K group). After continuous administration for eight weeks, body weight and blood sugar of mice were measured. Enzyme linked immunosorbent assay(ELISA) was used to detect glycosylated serum protein(GSP) and fasting serum insulin(FINS), and insulin resistance index(HOMA-IR) was calculated. The histopathological changes in the pancreas were observed by HE staining. Tumor necrosis factor(TNF)-α expression in the pancreas was detected using immunohistochemistry. The structural changes in fecal intestinal flora in the K, M, and YGZ groups were detected by 16S rRNA. Western blot was used to detect the expression of farnesoid X receptor(FXR) and takeda G protein-coupled receptor 5(TGR5) in the ileum, cholesterol 7α-hydroxylase(CYP7A1) and sterol 27α-hydroxylase(CYP27A1) in the liver, and G protein-coupled receptors 41(GPR41) and 43(GPR43) in the colon. Compared with the K group, the M group showed increased body weight, blood sugar, serum GSP, fasting blood glucose(FBG), and FINS, increased HOMA-IR, inflammatory infiltration of islet cells, necrosis and degeneration of massive acinar cells, unclear boundary between islet cells and acinar cells, disturbed intestinal flora, and down-regulated FXR, TGR5, CYP7A1, CYP27A1, GPR41, and GPR43. Compared with the M group, the YX, YGG, YGZ, and YGD groups showed decreased body weight, blood sugar, serum GSP, FBG, and FINS, islet cells with intact and clumpy morphology and clear boundary, necrosis of a few acinar cells, and more visible islet cells. The intestinal flora in the YGZ group changed from phylum to genus levels, and the relative abundance of intestinal flora affecting the metabolites of intestinal flora increased. The protein expression of FXR, TGR5, CYP7A1, CYP27A1, GPR41, and GPR43 increased. The results show that Puerariae Lobatae Radix can improve the inflammatory damage of pancreatic islet cells and reduce insulin resistance in db/db mice with T2DM. The mechanism of action may be related to the increase in the abundance of Actinobacteria, Bifidobacterium, and Bacteroides in the intestinal tract and the protein expression related to metabolites of intestinal flora.
Subject(s)
Diabetes Mellitus, Type 2 , Gastrointestinal Microbiome , Insulin Resistance , Pueraria , Mice , Animals , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/genetics , Pueraria/chemistry , RNA, Ribosomal, 16S , Body Weight , NecrosisABSTRACT
Propyne/propylene separation is important in the petrochemical industry but challenging due to their similar physical properties and close molecular sizes. Metal-organic frameworks (MOFs) are a class of promising adsorbents for light hydrocarbon separations. Among them, the so-called "flexible-robust" MOFs combine the advantages of flexibility and rigidity in structure and could show enhanced gas separation selectivity as well as improved gas uptake at low pressure. Interpenetrated MOFs offer a platform to explore the "flexible-robust" feature of MOFs based on their subnetwork displacement in the process of gas adsorption. Herein, we present two hydrolytically stable MOFs (BUT-308 and BUT-309) with interpenetrated structures and fascinating propyne/propylene separation performance. BUT-308 is composed of interpenetrated 2D Cu(BDC-NH2)BPB layers (H2BDC-NH2 = 2-aminobenzene-1,4-dicarboxylic acid; BPB = 1,4-bis(4-pyridyl)benzene), while BUT-309 consists of twofold interpenetrated 3D pillared-layer Cu2(BDC-NH2)2(BPB-CF3) nets (BPB-CF3 = 2-trifluoromethyl-1,4-bis(4-pyridyl)benzene). Gas adsorption measurements showed that BUT-309 was a "flexible-robust" adsorbent with multistep adsorption isotherms for C3H4 rather than C3H6 at a wide temperature range. The guest-dependent pore-opening behavior endows BUT-309 with high potential in the C3H4/C3H6 separation. The C3H4 adsorption measurements of BUT-309 at 273-323 K showed that the lowering of the temperature induced the pore-opening action at lower pressure. Column breakthrough experiments further confirmed the capability of BUT-309 for the efficient removal of C3H4 from a C3H4/C3H6 binary gas, and the C3H6 processing capacity at 273 K (15.7 cm3 g-1) was higher than that at 298 K (35.2 cm3 g-1). This work shows a rare example of "flexible-robust" MOFs and demonstrated its high potential for C3H4/C3H6 separation.
ABSTRACT
BACKGROUND: The profile of naturally occurring antibodies to amyloid-ß (NAbs-Aß) is altered in patients with Alzheimer's disease (AD). However, the diagnostic potential of NAbs-Aß for AD is not clear yet. OBJECTIVE: This study aims to investigate the diagnostic capacities of NAbs-Aß for AD. METHODS: A total of 40 AD patients and 40 cognitively normal (CN) controls were enrolled in this study. Levels of NAbs-Aß were detected by ELISA. The correlations of NAbs-Aß levels with cognitive function and AD-associated biomarkers were examined by Spearman correlation analysis. Diagnostic abilities of NAbs-Aß were evaluated by the receiver operating characteristic (ROC) curve analyses. The integrative diagnostic models were established by logistic regression models. RESULTS: We found that NAbs-Aß7-18 had the highest diagnostic capability (AUCâ=â0.72) among all single NAbs-Aß. The combined model (NAbs-Aß7-18, NAbs-Aß19-30, and NAbs-Aß25-36) had a noticeable improvement (AUCâ=â0.84) in the diagnostic capacity compared with each single NAbs-Aß. CONCLUSION: NAbs-Aßs are promising in the diagnosis of AD. Further investigations are needed to confirm the translational potential of this diagnostic strategy.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Humans , Alzheimer Disease/diagnosis , Autoantibodies , Amyloid beta-Peptides , Cognition , Enzyme-Linked Immunosorbent Assay , BiomarkersABSTRACT
Amyloid ß (Aß) and tau play pivotal roles in the pathogenesis of Alzheimer's disease (AD). Previous studies have shown that brain-derived Aß and tau can be cleared through transport into the periphery, and the kidneys may be vital organs involved in the clearance of Aß and tau. However, the effects of deficiency in the clearance of Aß and tau by the kidneys on brain AD-type pathologies in humans remain largely unknown. In this study, we first recruited 41 patients with chronic kidney disease (CKD) and 40 age- and sex-matched controls with normal renal function to analyze the associations of the estimated glomerular filtration rate (eGFR) with plasma Aß and tau levels. To analyze the associations of eGFR with cerebrospinal fluid (CSF) AD biomarkers, we recruited 42 cognitively normal CKD patients and 150 cognitively normal controls with CSF samples. Compared with controls with normal renal function, CKD patients had higher plasma levels of Aß40, Aß42 and total tau (T-tau), lower CSF levels of Aß40 and Aß42 and higher levels of CSF T-tau/Aß42 and phosphorylated tau (P-tau)/Aß42. Plasma Aß40, Aß42, and T-tau levels were negatively correlated with eGFR. In addition, eGFR was negatively correlated with CSF levels of T-tau, T-tau/Aß42, and P-tau/Aß42 but positively correlated with Mini-Mental State Examination (MMSE) scores. Thus, this study showed that the decline in renal function was correlated with abnormal AD biomarkers and cognitive decline, which provides human evidence that renal function may be involved in the pathogenesis of AD.
Subject(s)
Alzheimer Disease , Renal Insufficiency, Chronic , Humans , Amyloid beta-Peptides , Alzheimer Disease/pathology , tau Proteins/cerebrospinal fluid , Biomarkers , Peptide Fragments , Kidney/physiology , Kidney/pathologyABSTRACT
The extracellular domain (p75ECD) of p75 neurotrophin receptor (p75NTR) antagonizes Aß neurotoxicity and promotes Aß clearance in Alzheimer's disease (AD). The impaired shedding of p75ECD is a key pathological process in AD, but its regulatory mechanism is largely unknown. This study was designed to investigate the presence and alterations of naturally-occurring autoantibodies against p75ECD (p75ECD-NAbs) in AD patients and their effects on AD pathology. We found that the cerebrospinal fluid (CSF) level of p75ECD-NAbs was increased in AD, and negatively associated with the CSF levels of p75ECD. Transgenic AD mice actively immunized with p75ECD showed a lower level of p75ECD and more severe AD pathology in the brain, as well as worse cognitive functions than the control groups, which were immunized with Re-p75ECD (the reverse sequence of p75ECD) and phosphate-buffered saline, respectively. These findings demonstrate the impact of p75ECD-NAbs on p75NTR/p75ECD imbalance, providing a novel insight into the role of autoimmunity and p75NTR in AD.
Subject(s)
Alzheimer Disease , Mice , Animals , Alzheimer Disease/pathology , Receptor, Nerve Growth Factor , Amyloid beta-Peptides , Autoantibodies , Mice, TransgenicABSTRACT
Noise pollution has become one of the important social hazards that endanger the auditory system of residents, causing noise-induced hearing loss (NIHL). Oxidative stress has a significant role in the pathogenesis of NIHL, in which the silent information regulator 1(SIRT1)/proliferator-activated receptor-gamma coactivator 1α (PGC-1α) signaling pathway is closely engaged. Ginsenoside Rd (GSRd), a main monomer extract from ginseng plants, has been confirmed to suppress oxidative stress. Therefore, the hypothesis that GSRd may attenuate noise-induced cochlear hair cell loss seemed promising. Forty-eight male guinea pigs were randomly divided into four groups: control, noise exposure, GSRd treatment (30 mg/kg Rd for 10d + noise), and experimental control (30 mg/kg glycerol + noise). The experimental groups received military helicopter noise exposure at 115 dB (A) for 4 h daily for five consecutive days. Hair cell damage was evaluated by using inner ear basilar membrane preparation and scanning electron microscopy. Terminal dUTP nick end labeling (TUNEL) and immunofluorescence staining were conducted. Changes in the SIRT1/PGC-1α signaling pathway and other apoptosis-related markers in the cochleae, as well as oxidative stress parameters, were used as readouts. Loss of outer hair cells, more disordered cilia, prominent apoptosis, and elevated free radical levels were observed in the experimental groups. GSRd treatment markedly mitigated hearing threshold shifts, ameliorated outer hair cell loss and lodging or loss of cilia, and improved apoptosis through decreasing Bcl-2 associated X protein (Bax) expression and increasing Bcl-2 expression. In addition, GSRd alleviated the noise-induced cochlear redox injury by upregulating superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels, decreasing malondialdehyde (MDA) levels, and enhancing the activity of SIRT1 and PGC-1α messenger ribonucleic acid (mRNA) and protein expression. In conclusion, GSRd can improve structural and oxidative damage to the cochleae caused by noise. The underlying mechanisms may be associated with the SIRT1/PGC-1α signaling pathway.
Subject(s)
Aviation , Hearing Loss, Noise-Induced , Animals , Guinea Pigs , Hair Cells, Auditory/metabolism , Hair Cells, Auditory/pathology , Noise , Oxidative Stress , Proto-Oncogene Proteins c-bcl-2/metabolism , Sirtuin 1/metabolismABSTRACT
The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease (AD) and associated socioeconomic burdens. Abnormal metabolism of amyloid-ß (Aß) has been proposed as a significant pathomechanism in AD, supported by results of recent clinical trials using anti-Aß antibodies. Nonetheless, the cognitive benefits of the current treatments are limited. The etiology of AD is multifactorial, encompassing Aß and tau accumulation, neuroinflammation, demyelination, vascular dysfunction, and comorbidities, which collectively lead to widespread neurodegeneration in the brain and cognitive impairment. Hence, solely removing Aß from the brain may be insufficient to combat neurodegeneration and preserve cognition. To attain effective treatment for AD, it is necessary to (1) conduct extensive research on various mechanisms that cause neurodegeneration, including advances in neuroimaging techniques for earlier detection and a more precise characterization of molecular events at scales ranging from cellular to the full system level; (2) identify neuroprotective intervention targets against different neurodegeneration mechanisms; and (3) discover novel and optimal combinations of neuroprotective intervention strategies to maintain cognitive function in AD patients. The Alzheimer's Disease Neuroprotection Research Initiative's objective is to facilitate coordinated, multidisciplinary efforts to develop systemic neuroprotective strategies to combat AD. The aim is to achieve mitigation of the full spectrum of pathological processes underlying AD, with the goal of halting or even reversing cognitive decline.
ABSTRACT
This study deciphered the mechanism of Shenling Baizhu Powder in treatment of mouse model of ulcerative colitis(UC) via NOD-like receptor thermoprotein domain 3(NLRP3) signaling pathway. After three days of adaptive feeding, 70 SPF-grade BALB/c mice were randomized into 7 groups: normal group, model group(dextran sodium sulfate, DSS), mesalazine group(DSS + 5-aminosalicylic acid, 5-ASA), NLRP3 inhibitor group(DSS + MCC950), and high-, medium-, and low-dose Shenling Baizhu Powder groups(DSS + high-, medium-, and low-dose Shenling Baizhu Powder), with 10 mice per group. The normal group had free access to double distilled water, and the remaining groups had free access to DSS-containing water to establish the acute UC model. Intragastric administration was started at the same time as modeling for one week. During the experiment, the general mental state and disease activity of each group of mice were recorded and scored. After the experiment, colon and serum samples were collected. The pathological changes in colon tissue were observed through hematoxylin-eosin(HE) staining. Enzyme-linked immunosorbent assay(ELISA) was employed to determine the levels of interleukin-18(IL-18) and myeloperoxidase(MPO) in colon tissue and interleukin-1ß(IL-1ß) in serum. Immunofluorescence(IF) and immunohistochemistry(IHC) methods were employed to examine the expression of NLRP3 and IL-18 in colon tissue. Western blot was employed to measure the protein levels of NLRP3, apoptosis-associated speck-like protein(ASC), cystein-aspartate protease 1(caspase-1), and downstream inflammatory cytokines in colon tissue. Compared with the normal group, the modeling of UC increased the disease activity index(DAI), colon pathological injury score, IL-1ß level in serum, and IL-18 and MPO levels in colon tissue(P<0.05, P<0.01). Furthermore, the modeling caused obvious pathological changes and up-regulated the expression of NLRP3, caspase-1, ASC, pro-IL-1ß, cleaved-IL-1ß, pro-IL-18, and cleaved-IL-18 in the colon(P<0.01). Compared with the model group, the administration of corresponding drugs decreased the DAI, pathological injury score, IL-1ß level in serum, and IL-18 and MPO levels in colon tissue, and down-regulated the protein levels of NLRP3, caspase-1, ASC, pro-IL-1ß, cleaved-IL-1ß, pro-IL-18, and cleaved-IL-18 in the colon(P<0.05, P<0.01). According to the results of previous study and this study, we concluded that Shenling Baizhu Powder can alleviate the inflammatory response and intestinal damage of DSS-induced UC by regulating the expression of the proteins and inflammatory cytokines associated with NLRP3 signaling pathway.
Subject(s)
Colitis, Ulcerative , Colitis , Mice , Animals , Colitis, Ulcerative/chemically induced , Colitis, Ulcerative/drug therapy , Dextran Sulfate/adverse effects , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Interleukin-18/genetics , Powders , Colon/metabolism , Caspase 1 , Mesalamine/adverse effects , Mice, Inbred BALB C , Disease Models, Animal , Cytokines/metabolism , Water , Colitis/chemically induced , Colitis/drug therapy , Colitis/pathologyABSTRACT
BACKGROUND: Imbalance between the production and clearance of amyloid-ß (Aß) promotes the development of Alzheimer's disease (AD). Presenilin-1 (PS1) is the catalytic subunit of γ-secretase, which is involved in the process of Aß production. The profiles of autoantibodies are dysregulated in AD patients. OBJECTIVE: This study aims to investigate the relative levels and clinical relevance of naturally occurring antibodies to PS1 (NAbs-PS1) in AD. METHODS: A total of 55 subjects with AD (including both dementia and mild cognitive impairment due to AD), 28 subjects with cognitive impairment (including both dementia and mild cognitive impairment) not due to AD (non-AD CI), and 70 cognitively normal (CN) subjects were recruited. One-site ELISA was utilized to determine the relative levels of NAbs-PS1 in plasma. RESULTS: AD subjects had lower plasma levels of NAbs-PS1 than CN and non-AD CI subjects. Plasma NAbs-PS1 were negatively associated with the brain Aß load, as reflected by PET-PiB SUVR, and were positively associated with cognitive functions of participants. Plasma NAbs-PS1 discriminated AD patients from CN with an area under the curve (AUC) of 0.730, a sensitivity of 69.09%, and a specificity of 67.14%, and they discriminated AD patients from non-AD CI subjects with an AUC of 0.750, a specificity of 70.91%, and a sensitivity of 71.43%. CONCLUSION: This study found an aberrant immunological phenotype in AD patients. Further investigations are needed to determine the pathophysiological functions of NAbs-PS1 in AD.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Humans , Alzheimer Disease/genetics , Amyloid beta-Protein Precursor/genetics , Presenilin-1/genetics , Presenilin-1/metabolism , Amyloid beta-Peptides/metabolism , Amyloid Precursor Protein Secretases/metabolism , Brain/diagnostic imaging , Brain/metabolism , AntibodiesABSTRACT
Cerebrospinal fluid (CSF) biomarkers are essential for the accurate diagnosis of Alzheimer's disease (AD), yet their measurement levels vary widely across centers and regions, leaving no uniform cutoff values to date. Diagnostic cutoff values of CSF biomarkers for AD are lacking for the Chinese population. As a member of the Alzheimer's Association Quality Control program for CSF biomarkers, we aimed to establish diagnostic models based on CSF biomarkers and risk factors for AD in a Chinese cohort. A total of 64 AD dementia patients and 105 age- and sex-matched cognitively normal (CN) controls from the Chongqing Ageing & Dementia Study cohort were included. CSF Aß42, P-tau181, and T-tau levels were measured by ELISA. Combined biomarker models and integrative models with demographic characteristics were established by logistic regression. The cutoff values to distinguish AD from CN were 933 pg/mL for Aß42, 48.7 pg/mL for P-tau181 and 313 pg/mL for T-tau. The AN model, including Aß42 and T-tau, had a higher diagnostic accuracy of 89.9%. Integrating age and APOE ε4 status to AN model (the ANA'E model) increased the diagnostic accuracy to 90.5% and improved the model performance. This study established cutoff values of CSF biomarkers and optimal combined models for AD diagnosis in a Chinese cohort.
Subject(s)
Alzheimer Disease , Aging , Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/diagnosis , Amyloid beta-Peptides/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , China , Humans , Peptide Fragments/cerebrospinal fluid , tau Proteins/cerebrospinal fluidABSTRACT
Objective: To establish an animal model of noise-induced hidden hearing loss (NIHHL), evaluate the dynamic changes in cochlear ribbon synapses and cochlear hair cell morphology, and observe the involvement of the SIRT1/PGC-1α signaling pathway in NIHHL. Methods: Male guinea pigs were randomly divided into three groups: control group, noise exposure group, and resveratrol treatment group. Each group was divided into five subgroups: the control group and 1 day, 1 week, 2 weeks, and 1 month post noise exposure groups. The experimental groups received noise stimulation at 105 dB SPL for 2 h. Hearing levels were examined by auditory brainstem response (ABR). Ribbon synapses were evaluated by inner ear basilar membrane preparation and immunofluorescence. The cochlear morphology was observed using scanning electron microscopy. Western blotting analysis and immunofluorescence was performed to assess the change of SIRT1/PGC-1α signaling. Levels of superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), ATP and SIRT1 activity were measured using commercial testing kits. Results: In the noise exposure group, hearing threshold exhibited a temporary threshold shift (TTS), and amplitude of ABR wave I decreased irreversibly. Ribbon synapse density decreased after noise exposure, and the stereocilia were chaotic and then returned to normal. The expression and activity of SIRT1 and PGC-1α protein was lower than that in the control group. SOD, CAT and ATP were also influenced by noise exposure and were lower than those in the control group, but MDA showed no statistical differences compared with the control group. After resveratrol treatment, SIRT1 expression and activity showed a significant increase after noise exposure, compared with the noise exposure group. In parallel, the PGC-1α and antioxidant proteins were also significantly altered after noise exposure, compared with the noise exposure group. The damage to the ribbon synapses and the stereocilia were attenuated by resveratrol as well. More importantly, the auditory function, especially ABR wave I amplitudes, was also promoted in the resveratrol treatment group. Conclusion: The SIRT1/PGC-1α signaling pathway and oxidative stress are involved in the pathogenesis of NIHHL and could be potential therapeutical targets in the future.