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The concept of "type 3 diabetes" has emerged to define alterations in glucose metabolism that predispose individuals to the development of Alzheimer's disease (AD). Novel evidence suggests that changes in the insulin/insulin-like growth factor 1 (IGF-1)/growth hormone (GH) axis, which are characteristic of Diabetes Mellitus, are one of the major factors contributing to excessive amyloid-beta (Aβ) production and neurodegenerative processes in AD. Moreover, molecular findings suggest that insulin resistance and dysregulated IGF-1 signaling promote atherosclerosis via endothelial dysfunction and a pro-inflammatory state. As the pathophysiological role of Aβ1-40 in patients with cardiovascular disease has attracted attention due to its involvement in plaque formation and destabilization, it is of great interest to explore whether a paradigm similar to that in AD exists in the cardiovascular field. Therefore, this review aims to elucidate the intricate interplay between insulin resistance, IGF-1, and Aβ1-40 in the cardiovascular system and assess the applicability of the type 3 diabetes concept. Understanding these relationships may offer novel therapeutic targets and diagnostic strategies to mitigate cardiovascular risk in patients with insulin resistance and dysregulated IGF-1 signaling., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Developing multitargeted ligands as promising therapeutics for Alzheimer's disease (AD) has been considered important. Herein, a novel class of cinnamamide/ester-triazole hybrids with multifaceted effects on AD was developed based on the multitarget-directed ligands strategy. Thirty-seven cinnamamide/ester-triazole hybrids were synthesized, with most exhibiting significant inhibitory activity against Aβ-induced toxicity at a single concentration in vitro. The most optimal hybrid compound 4j inhibited copper-induced Aβ toxicity in AD cells. its action was superior to that of donepezil and memantine. It also moderately inhibited intracellular AChE activity and presented favorable bioavailability and blood-brain barrier penetration with low toxicity in vivo. Of note, it ameliorated cognitive impairment, neuronal degeneration, and Aβ deposition in Aβ 1-42 -injured mice. Mechanistically, the compound regulated APP processing by promoting the ADAM10-associated nonamyloidogenic signaling and inhibiting the BACE1-mediated amyloidogenic pathway. Moreover, it suppressed intracellular AChE activity and tau phosphorylation. Therefore, compound 4j may be a promising multitargeted active molecule against AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Positron emission tomography/computed tomography (PET/CT) with 18 F-florbetapir, a novel amyloid-targeting radiotracer, can quantify left ventricular (LV) amyloid burden in systemic light-chain (AL) amyloidosis. However, its prognostic value is not known., Objectives: The authors' aim was to evaluate the prognostic value of LV amyloid burden quantified by 18 F-florbetapir PET/CT, and to identify mechanistic pathways mediating its association with outcomes., Methods: A total of 81 participants with newly diagnosed AL amyloidosis underwent 18 F-florbetapir PET/CT imaging. Amyloid burden was quantified using 18 F-florbetapir LV uptake as percent injected dose. The Mayo stage for AL amyloidosis was determined using troponin T, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and free light chain levels. Major adverse cardiac events (MACE) were defined as all-cause death, heart failure hospitalization, or cardiac transplantation within 12 months., Results: Among participants (median age, 61 years; 57% males), 36% experienced MACE, increasing from 7% to 63% across tertiles of LV amyloid burden (P < 0.001). LV amyloid burden was associated with MACE (HR: 1.46; 95% CI: 1.16-1.83; P = 0.001). However, this association became nonsignificant when adjusted for Mayo stage. In mediation analysis, the association between LV amyloid burden and MACE was mediated by NT-proBNP (P < 0.001), a marker of cardiomyocyte stretch and heart failure, and a component of Mayo stage., Conclusions: In this first study to link cardiac 18 F-florbetapir uptake to subsequent outcomes, LV amyloid burden estimated by percent injected dose predicted MACE in AL amyloidosis. This effect was not independent of Mayo stage and was mediated primarily through NT-proBNP. These findings provide novel insights into the mechanism linking myocardial amyloid deposits to MACE., Competing Interests: Funding Support and Author Disclosures This work was supported by the National Institutes of Health. Dr Dorbala was supported by grants R01 HL 130563; K24 HL 157648; AHA16 CSA 2888 0004; AHA19SRG34950011. Dr Falk was supported by a grant R01 HL 130563. Dr Liao was supported by grants AHA16 CSA 2888 0004; AHA19SRG34950011. Dr Ruberg was supported by grants R01 HL 130563; R01 HL 093148. Dr Bianchi was partially supported by a grant K08 CA245100; and has received consulting fees from Prothena. Dr Clerc has received a research fellowship from the International Society of Amyloidosis and Pfizer. Dr Cuddy was supported by grants NIH 1K23HL166686-01 and AHA 23CDA857664NIH; and has received an investigator-initiated research grant from Pfizer; and has received consulting fees from BridgeBio, Ionis, AstraZeneca, and Novo Nordisk. Dr DiCarli has received a research grant from Gilead and Alnylam Pharmaceuticals; in-kind research support from Amgen; and consulting fees from Sanofi, MedTrace Pharma, and Valo Health. Dr Kwong has received grant funding from Alynlam Pharmaceuticals. Dr Falk has received consulting fees from Ionis Pharmaceuticals, Alnylam Pharmaceuticals, Caelum Biosciences; and research funding from GlaxoSmithKline and Akcea. Dr Ruberg has received consulting fees from AstraZeneca, and Attralus; and has received research support from Pfizer, Alnylam, Anumana, and Ionis/Akcea. Dr Dorbala has received consulting fees from Pfizer, GE Health Care, and Novo Nordisk; and investigator-initiated grants from Pfizer, GE Healthcare, Attralus, Siemens, and Philips. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Protein aggregation in the form of amyloid fibrils has long been associated with the onset and development of various amyloidoses, including Alzheimer's, Parkinson's or prion diseases. Recent studies of their fibril formation process have revealed that amyloidogenic protein cross-interactions may impact aggregation pathways and kinetic parameters, as well as the structure of the resulting aggregates. Despite a growing number of reports exploring this type of interaction, they only cover just a small number of possible amyloidogenic protein pairings. One such pair is between two neurodegeneration-associated proteins: the pro-inflammatory S100A9 and prion protein, which are known to co-localize in vivo. In this study, we examined their cross-interaction in vitro and discovered that the fibrillar form of S100A9 modulated the aggregation pathway of mouse prion protein 89-230 fragment, while non-aggregated S100A9 also significantly inhibited its primary nucleation process. These results complement previous observations of the pro-inflammatory protein's role in amyloid aggregation and highlight its potential role against neurodegenerative disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abrupt aggregation of amyloid β 1 - 42 (Aβ 1 - 42 ) peptide in the frontal lobe is the expected underlying cause of Alzheimer's disease (AD). β-Sheet-rich oligomers and fibrils formed by Aβ 1 - 42 exert high cell toxicity. A growing body of evidence indicates that lipids can uniquely alter the secondary structure and toxicity of Aβ 1 - 42 aggregates. At the same time, underlying molecular mechanisms that determine this difference in toxicity of amyloid aggregates remain unclear. Using a set of molecular and biophysical assays to determine the molecular mechanism by which Aβ 1 - 42 aggregates formed in the presence of cholesterol, cardiolipin, and phosphatidylcholine exert cell toxicity. Our findings demonstrate that rat neuronal cells exposed to Aβ 1 - 42 fibrils formed in the presence of lipids with different chemical structure exert drastically different magnitude and dynamic of unfolded protein response (UPR) in the endoplasmic reticulum (ER) and mitochondria (MT). We found that the opposite dynamics of UPR in MT and ER in the cells exposed to Aβ 1 - 42 : cardiolipin fibrils and Aβ 1 - 42 aggregates formed in a lipid-free environment. We also found that Aβ 1 - 42 : phosphatidylcholine fibrils upregulated ER UPR simultaneously downregulating the UPR response of MT, whereas Aβ 1 - 42 : cholesterol fibrils suppressed the UPR response of ER and upregulated UPR response of MT. We also observed progressively increasing ROS production that damages mitochondrial membranes and other cell organelles, ultimately leading to cell death., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dmitry Kurouski reports financial support was provided by Texas A&M University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Renin-Angiotensin System (RAS) is a peptidergic system, canonically known for its role in blood pressure regulation. Furthermore, a non-canonical RAS regulates pathophysiological phenomena, such as inflammation since it consists of two main axes: the pro-inflammatory renin/(pro)renin receptor ((P)RR) axis, and the anti-inflammatory angiotensin-converting enzyme 2 (ACE2)/Angiotensin-(1-7) (Ang-(1-7))/Mas Receptor (MasR) axis. Few phytochemicals have shown to exert angiotensinergic and anti-inflammatory effects through some of these axes; nevertheless, anti-inflammatory drugs, such as phytocannabinoids have not been studied regarding this subject. Among phytocannabinoids, β-Caryophyllene stands out as a dietary phytocannabinoid with antiphlogistic activity that possess a unique sesquiterpenoid structure. Although its cannabinergic effect has been studied, its angiotensinergic effect reminds underexplored. This study aims to explore the angiotensinergic effect of β-Caryophyllene on inflammation and stress at a systemic level. After intranasal Lipopolysaccharide (LPS) installation and oral treatment with β-Caryophyllene, the concentration and activity of key RAS elements in the serum, such as Renin, ACE2 and Ang-(1-7), along with the stress hormone corticosterone and pro/anti-inflammatory cytokines, were measured in mice serum. The results show that β-Caryophyllene treatment modified RAS levels by increasing Renin and Ang-(1-7), alongside the reduction of pro-inflammatory cytokines and corticosterone levels. These results indicate that β-Caryophyllene exhibits angiotensinergic activity in favor of anti-inflammation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A series of scutellarein 7- l -amino acid carbamate-4'-cycloalkylamine propyl ether conjugates were designed and synthesized for the first time as multifunctional agents for Alzheimer's disease (AD) therapy. The designed compounds exhibited more balanced and effective multi-target potency. Among them, compound 11l, l -Valine carbamate derivative of scutellarein cycloheptylamine ether, exhibited the most potent inhibition of electric eel AChE enzymes and human AChE enzymes, with an IC 50 values of 7.04 μM and 9.73 μM, respectively. Moreover, 11l exhibited more potent H 3 R antagonistic activities than clobenpropit, with an IC 50 value of 1.09 nM. Compound 11l not only displayed excellent inhibition of self- and Cu 2+ -induced Aβ 1-42 aggregation (95.48 % and 88.63 % inhibition, respectively) but also induced the disassembly of self- and Cu 2+ -induced Aβ fibrils (80.16 % and 89.30 % disaggregation, respectively). Moreover, 11l significantly reduced tau protein hyperphosphorylation induced by Aβ 25-35 . It exhibited effective antioxidant activity and neuroprotective potency, and inhibited RSL3-induced PC12 cell ferroptosis. Assays of hCMEC/D3 and hPepT1-MDCK cell line permeability indicated that 11l would have optimal blood-brain barrier permeability and intestinal absorption characteristics. In addition, in vivo studies revealed that compound 11l significantly attenuated learning and memory impairment in an AD mouse model. Finally, a pharmacokinetic characterization of 11l indicated favorable druggability and pharmacokinetic properties. Taken together, our results suggest that 11l is a potential candidate for AD treatment and merits further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Histidine (His) plays a key role in mediating protein interactions and its unique side chain determines pH responsive self-assembling processes and thus in the formation of nanostructures. In this study, To identify novel self-assembling bioinspired sequences, we analyzed a series of peptide sequences obtained through the point mutation of aromatic residues of 264-277 fragment of nucleophosmin 1 (NPM1) with single and double histidines. Through several orthogonal biophysical techniques and under different pH and ionic strength conditions we evaluated the effects of these substitutions in the amyloidogenic features of derived peptides. The results clearly indicate that both the type of aromatic mutated residue and its position can have different effect on amyloid-like behaviors. They corroborate the crucial role exerted by Tyr 271 in the self-assembling process of CTD of NPM1 in AML mutated form and add novel insights in the accurate investigation of how side chain orientations can determine successful design of innovative bioinspired materials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Although sodium glucose co-transporter 2 inhibitors (SGLT2is) improve heart failure (HF)-related symptoms and outcomes in HF with preserved ejection fraction (HFpEF), underlying mechanisms remain unclear. In HF with reduced EF, dapagliflozin altered ketone and fatty acid metabolites vs placebo; however, metabolite signatures of SGLT2is have not been well elucidated in HFpEF., Objectives: The goal of this study was to assess whether SGLT2i treatment altered systemic metabolic pathways and their relationship to outcomes in HFpEF., Methods: Targeted profiling of 64 metabolites was performed from 293 participants in PRESERVED-HF (Dapagliflozin in PRESERVED Ejection Fraction Heart Failure), a 12-week, placebo-controlled trial of dapagliflozin. Linear regression assessed changes in metabolite factors defined by principal components analysis (PCA) with dapagliflozin vs placebo. The relationship between changes in metabolite factors with changes in study endpoints was also assessed., Results: The mean age was 70 ± 11 years, 58% were female, and 29% were Black. There were no significant differences in 12 PCA-derived metabolite factors between treatment arms, including metabolites reflecting ketone, fatty acid, or branched-chain amino acid (BCAA) pathways. Combining treatment arms, changes in BCAAs and branched-chain ketoacids were negatively associated with changes in N-terminal pro-B-type natriuretic peptide; changes in medium-/long-chain acylcarnitines were positively associated with changes in N-terminal pro-B-type natriuretic peptide and negatively associated with changes in 6-minute walk test distance; and changes in ketones were negatively associated with changes in weight, without treatment interaction., Conclusions: Leveraging targeted metabolomics in a placebo-controlled SGLT2i trial of HFpEF, dapagliflozin did not alter systemic metabolic as reflected by circulating metabolites, in contrast with reported effects in HF with reduced ejection fraction. Metabolite biomarkers reflecting BCAA, ketone, and fatty acid metabolism were associated with markers of disease severity, suggesting a role for potential novel treatment targets. (Dapagliflozin in PRESERVED Ejection Fraction Heart Failure [PRESERVED-HF]; NCT03030235)., Competing Interests: Funding Support and Author Disclosures PRESERVED-HF was an investigator-initiated trial funded by AstraZeneca and conducted by Saint Luke’s Mid America Heart Institute independent of the funding source. The PRESERVED-HF metabolomics substudy was funded by the Edna and Fred L. Mandel Jr Foundation seed grant (to Dr Selvaraj) and support from National Institutes of Health grants K23HL161348 (to Dr Selvaraj), R01HL160689 (to Dr McGarrah), and P30DK124723 (to Dr Newgard). Dr Borlaug was supported in part by R01 HL128526, R01 HL162828, and U01 HL160226, from the National Institutes of Health, and W81XWH2210245, from the United States Department of Defense. Dr Kitzman was supported in part by National Institutes of Health grants U01AG076928, R01AG078153, R01AG045551, R01AG18915, P30AG021332, U24AG059624, and U01HL160272. Dr Selvaraj has received research support from the National Heart, Lung, and Blood Institute (K23HL161348), the Doris Duke Charitable Foundation (#2020061), the American Heart Association (#935275), the Mandel Foundation, the Duke Heart Center Leadership Council, the Institute for Translational Medicine and Therapeutics, and the Foundation for Sarcoidosis Research; and has served on advisory boards for AstraZeneca. Dr Sauer has performed consulting, advising, or has received research funding from Abbott, Boston Scientific, Biotronik, Bayer, Amgen, CSK Vifor, Acorai, Story Health, General Prognostics, Impulse Dynamics, and Edwards Lifesciences. Dr McGarrah has been a consultant for AstraZeneca and M3; and has received research funding from Eli Lilly. Dr Newgard is a member of the Eli Lilly Global Diabetes Advisory Board. Dr Borlaug has received research support from the National Institutes of Health and the United States Department of Defense, as well as research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Janssen, Merck, and Novo Nordisk; and is a named inventor (US Patent No. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. Dr Kitzman has been a consultant for AstraZeneca, Pfizer, Corvia Medical, Bayer, Boehringer Ingelheim, Novo Nordisk, Rivus, and St. Luke’s Medical Center; has received grant support from Novartis, AstraZeneca, Bayer, Pfizer, Novo Nordisk, Rivus, and St. Luke’s Medical Center; and owns stock in Gilead Sciences. Dr S.J. Shah has received support from research grants from the National Institutes of Health (U54 HL160273, R01 HL140731, and R01 HL149423), Pfizer, and AstraZeneca; and consulting fees from Abbott, Alleviant, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Corvia, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, Metabolic Flux, MyoKardia, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, Ultromics, and United Therapeutics. Dr S.H. Shah has received research funding through a sponsored Research Agreement to Duke University from AstraZeneca, Lilly, Verily, and nference; and is co-inventor on unlicensed patents held by Duke University. Dr Kosiborod has received research grant support from AstraZeneca, Boehringer Ingelheim, and Pfizer; is a consultant for and/or on the advisory board of 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received other research support from AstraZeneca; has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and has stock options from Artera Health and Saghmos Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Preterm delivery is associated with cardiovascular remodeling and dysfunction in children and adults. However, it is unknown whether these effects are caused by the neonatal consequences of preterm birth or if these are already present in utero., Objective: We evaluated fetal cardiac morphology and function in fetuses of mothers admitted for preterm labor or preterm prelabor rupture of membranes and the association of these changes with the presence of intra-amniotic infection and/or inflammation., Study Design: In this prospective cohort study, fetal echocardiography and amniocentesis were performed at admission in singleton pregnant women with preterm labor and/or preterm prelabor rupture of membranes between 24.0 and 34.0 weeks' gestation with (intra-amniotic infection and/or inflammation group, n=41) and without intra-amniotic infection and/or inflammation (non-intra-amniotic infection and/or inflammation, n=54). Controls (n=48) were outpatient pregnant women without preterm labor or preterm prelabor rupture of membranes. Intra-amniotic infection was defined by a positive amniotic fluid culture or positive 16S ribosomal RNA gene. Intra-amniotic inflammation was defined by using the amniotic fluid interleukin-6 cutoff levels previously reported by our group being >1.43 ng/mL in preterm prelabor rupture of membranes and >13.4 ng/mL in preterm labor. Fetal cardiac morphology and function was evaluated using echocardiography, and troponin-I and N-terminal pro-brain natriuretic peptide concentrations were measured in amniotic fluid from women with preterm labor or preterm prelabor rupture of membranes and compared with 20 amniotic fluid Biobank samples obtained for reasons other than preterm labor or preterm prelabor rupture of membranes or cardiac pathology. The data were adjusted for the estimated fetal weight below the 10th percentile and for preterm prelabor rupture of membranes at admission and also for gestational age at amniocentesis when amniotic fluid biomarkers were compared., Results: From 2018 to 2021, 143 fetuses were included; 95 fetuses were from mothers admitted with a diagnosis of preterm labor or preterm prelabor rupture of membranes, and among those, 41 (28.7%) were in the intra-amniotic infection and/or inflammation group and 54 (37.8%) were in the non-intra-amniotic infection and/or inflammation group. A total of 48 (33.6%) fetuses were included in the control group. Fetuses with preterm labor and/or preterm prelabor rupture of membranes had signs of subclinical cardiac concentric hypertrophy (median left wall thickness of 0.93 [interquartile range, 0.72-1.16] in the intra-amniotic infection and/or inflammation group; 0.79 [0.66-0.92] in the non-intra-amniotic infection and/or inflammation group; and 0.69 [0.56-0.83] in controls; P<.001) and diastolic dysfunction (tricuspid A duration 0.23 seconds [0.21-0.25], 0.24 [0.22-0.25], and 0.21 [0.2-0.23]; P=.007). Systolic function was similar among groups. Higher values of amniotic fluid troponin I (1413 pg/mL [927-2334], 1190 [829-1636], and 841 [671-959]; P<.001) and N-terminal pro-brain natriuretic peptide were detected (35.0%, 17%, and 0%; P=.005) in fetuses with preterm labor or preterm prelabor rupture of membranes when compared with the control group. The highest N-terminal pro-brain natriuretic peptide concentrations were found in the intra-amniotic infection and/or inflammation group., Conclusion: Fetuses with preterm labor or preterm prelabor rupture of membranes showed signs of cardiac remodeling and subclinical dysfunction, which were more pronounced in those exposed to intra-amniotic infection and/or inflammation. These findings support that the cardiovascular effects observed in children and adults born preterm have, at least in part, a prenatal origin., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) protein aggregates, leading to synaptic dysfunction and neuronal cell death. In this study, we used a comprehensive approach encompassing in vitro assays, computational analyses, and an in vivo Caenorhabditis elegans model to evaluate the inhibitory effects of various xanthones, focusing on Garcinone D (GD), on Aβ42 oligomer formation. Dot blot analysis revealed concentration-dependent responses among xanthones, with GD consistently inhibiting Aβ42 oligomer formation at low concentrations (0.1 and 0.5 μM, inhibitions of 84.66 ± 2.25% and 85.06 ± 6.57%, respectively). Molecular docking and dynamics simulations provided insights into the molecular interactions between xanthones and Aβ42, highlighting the disruption of key residues involved in Aβ42 aggregation. The neuroprotective potential of GD was established using transgenic C. elegans GMC101, with substantial delays in paralysis reported at higher concentrations. Our findings show that GD is a potent suppressor of Aβ42 oligomer formation, suggesting its potential as a therapeutic candidate for AD. The concentration-dependent effects observed in both in vitro and in vivo models underscore the need for nuanced dose-response assessments. These findings contribute novel insights into the therapeutic landscape of xanthones against AD, emphasizing the multifaceted potential of GD for further translational endeavors in neurodegenerative disorder research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The binding and molecular recognition between α-chain of human complement C3b (α-chain of C3b) and human plasminogen Kringle 5 (Kringle 5) were studied and explored by frontal chromatography and dynamics simulation in the combination of bio-specific technologies. The specific interaction between the α-chain of C3b and Kringle 5 was initially confirmed by ligand blot and ELISA (K d = 4.243×10 -6 L/mol). Furthermore, the binding determination conducted via frontal chromatography showed that the presence of a single binding site between them, with the binding constant of 2.98 × 10 5 L/mol. Then the molecular recognition by dynamics simulation and molecular docking showed that there were 9 and 13 amino acid residues respective in the Kringle 5 and α-chain of C3b directly implicated in the binding and the main stabilizing forces were electrostatic force (-55.99 ± 11.82 kcal/mol) and Van der Waals forces (-42.70 ± 3.45 kcal/mol). Additionally, a loop structure (65-71) in Kringle 5 underwent a conformational change from a random structure to an α-helix and a loop structure (417-425) in α-chain of C3b was closer to the molecular center, both of them were more conducive to the binding between them. Meanwhile, the involvement of the lysine binding site of Kringle 5 played an important role in the binding process. In addition, the erythrocyte-antibody complement rosette assay substantiated that the presence of Kringle 5 hindered the transportation of α-chain of C3b to antigen-antibody complex in a dose-dependent manner. These findings collectively indicated that the α-chain of C3b is very likely a receptor protein for Kringle 5, which provides a methodology for other similar investigations and valuable insights into expansion of the pharmacological effects and potential application of Kringle 5 in immune-related diseases., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Liujiao Bian reports financial support was provided by National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Nanoplastics, widely existing in the environment and organisms, have been proven to cross the blood-brain barrier, increasing the incidence of neurodegenerative diseases like Alzheimer's disease (AD). However, current studies mainly focus on the neurotoxicity of nanoplastics themselves, neglecting their synergistic effects with other biomolecules and the resulting neurotoxicity. Amyloid β peptide (Aβ), which triggers neurotoxicity through its self-aggregation, is the paramount pathogenic protein in AD. Here, employing polystyrene nanoparticles (PS) as a model for nanoplastics, we reveal that 100 pM PS nanoparticles significantly accelerate the nucleation rate of two Aβ subtypes (Aβ 40 and Aβ 42 ) at low concentrations, promoting the formation of more Aβ oligomers and leading to evident neurotoxicity. The hydrophobic surface of PS facilitates the interaction of hydrophobic fragments between Aβ monomers, responsible for the augmented neurotoxicity. This work provides consequential insights into the modulatory impact of low-dose PS on Aβ aggregation and the ensuing neurotoxicity, presenting a valuable foundation for future research on the intricate interplay between environmental toxins and brain diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Along the conventional pathways, Renin-angiotensin system (RAS) plays a key role in the physiology of the CNS and pathogenesis of psychiatric diseases. RAS is a complex regulatory pathway which is composed of several peptides and receptors and comprises two counter-regulatory axes. The classical (ACE1/AngII/AT1 receptor) axis and the contemporary (ACE2/Ang (1-7)/Mas receptor) axis. The genes coding for elements of both axes have been broadly studied. Numerous functional polymorphisms on components of RAS have been identified to serve as informative disease and treatment markers. This review summarizes the role of each peptide and receptor in the pathophysiology of psychiatric disorders (depression, bipolar disorders and schizophrenia), followed by a concise look at the role of genetic polymorphism of the RAS in the pathophysiology of these disorders., (Copyright © 2023. Published by Elsevier Inc.)

Cardiovascular diseases (CVD) are the main causes of death in hemodialysis patients, representing a public health challenge. We investigated the effect of different antihypertensive treatments on circulating levels of renin-angiotensin system (RAS) components in end-stage renal disease (ESRD) patients on hemodialysis. ESRD patients were grouped following the prescribed antihypertensive drugs: ß-blocker, ß-blocker+ACEi and ß-blocker+AT 1 R blocker. ESDR patients under no antihypertensive drug treatment were used as controls. Blood samples were collected before hemodialysis sessions. Enzymatic activities of the angiotensin-converting enzymes ACE and ACE2 were measured through fluorescence assays and plasma concentrations of the peptides Angiotensin II (Ang II) and Angiotensin-(1-7) [Ang-(1-7)] were quantified using mass spectrometry (LC-MS/MS). ACE activity was decreased only in the ß-blocker+ACEi group compared to the ß-blocker+AT 1 R, while ACE2 activity did not change according to the antihypertensive treatment. Both Ang II and Ang-(1-7) levels also did not change according to the antihypertensive treatment. We concluded that the treatment of ESRD patients on hemodialysis with different antihypertensive drugs do not alter the circulating levels of RAS components., Competing Interests: Conflict of Interests All authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Aims: Evidence indicates accumulating Aβ peptides in brain activates immune responses in neuronal and peripheral system, which may collaboratively influence pathogenesis of Alzheimer's disease (AD). We aim to investigate whether regulating intestinal innate immune signaling ameliorates Aβ-induced impairments in Drosophila melanogaster., Main Methods: Quantitative polymerase chain reaction (qPCR) was used to observe expression changes of innate immune responses related genes in brain and in gut under the circumstance of Aβ overexpressing in nerve system. Aversive olfactory conditioning and survival assay were used to investigate effects of modulating Attacin-A (AttA) and Dpitercin-A (DptA). Fluorometric assays of respiratory burst activity was introduced to explore whether reducing oxidative stress enables overexpressing intestinal AttA and DptA to reverse Aβ-induced deficits., Key Findings: In vivo genetic analysis revealed that accumulating Aβ42 in neurons modulates innate immune signaling of the IMD pathway both in the brain and in the gut. Increased expression levels of the intestinal AttA and DptA improved learning performance and extended the lifespan of Aβ42 flies. The administration of apramycin led to alleviations of Aβ-induced behavioral changes, indicating that gram-negative bacteria are associated with the development of Aβ-induced pathologies. Further analysis showed that the neural expression of Aβ42 increased oxidative stress in the gut, which disrupted intestinal integrity and decreased learning performance. In addition, increased levels of AMPs targeting gram-negative bacteria and antioxidants reduced oxidative stress in the gut and reversed Aβ-induced behavioral damage., Significance: These findings suggest that innate immune responses in the gut play a pivotal role in modulating Aβ-induced pathologies., Competing Interests: Declaration of competing interest All authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background & Aims: Fatty acid translocase CD36 (CD36/FAT) is a widely expressed membrane protein with multiple immuno-metabolic functions. Genetic CD36 deficiency is associated with increased risk of metabolic dysfunction-associated fatty liver disease (MAFLD) in patients. Liver fibrosis severity mainly affects the prognosis in patients with MAFLD, but the role of hepatocyte CD36 in liver fibrosis of MAFLD remains unclear., Methods: A high-fat high-cholesterol diet and a high-fat diet with high-fructose drinking water were used to induce nonalcoholic steatohepatitis (NASH) in hepatocyte-specific CD36 knockout (CD36LKO) and CD36flox/flox (LWT) mice. Human hepG2 cell line was used to investigate the role of CD36 in regulating Notch pathway in vitro., Results: Compared to LWT mice, CD36LKO mice were susceptible to NASH diet-induced liver injury and fibrosis. The analysis of RNA-sequencing data revealed that Notch pathway was activated in CD36LKO mice. LY3039478, an inhibitor of γ-secretase, inhibited Notch1 protein S3 cleavage and Notch1 intracellular domain (N1ICD) production, alleviating liver injury and fibrosis in CD36LKO mice livers. Likewise, both LY3039478 and knockdown of Notch1 inhibited the CD36KO-induced increase of N1ICD production, causing the decrease of fibrogenic markers in CD36KO HepG2 cells. Mechanistically, CD36 formed a complex with Notch1 and γ-secretase in lipid rafts, and hence CD36 anchored Notch1 in lipid rafts domains and blocked Notch1/γ-secretase interaction, inhibiting γ-secretase-mediated cleavage of Notch1 and the production of N1ICD., Conclusions: Hepatocyte CD36 plays a key role in protecting mice from diet-induced liver injury and fibrosis, which may provide a potential therapeutic strategy for preventing liver fibrogenesis in MAFLD., Competing Interests: Declaration of competing interest The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is the most prevalent acute neurodegenerative disease described by memory loss and other cognitive functions. Benzenesulfonamide, a novel, potent, and small organic molecule, was synthesized to investigate its effects on the levels of oxidative biomarkers (GPx, ROS, and MDA) and expression of beta-amyloid peptides (Aβ40 and Aβ42) in the pathology of AD. The results were compared with the rivastigmine drug. Applying benzenesulfonamide to Alzheimer's-induced Wistar rats showed a significant increase in the level of oxidative biomarkers (GPx, ROS, and MDA) in both the brain and blood serum as well as amyloid-β40 and 42 gene expressions. Therefore, benzenesulfonamide could be considered a novel therapeutic agent against AD., Competing Interests: Declaration of competing interest The authors declare that they have no declaration of interest to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Chronic kidney disease is one of the leading causes of morbidity and mortality especially among the aged population. A decline in kidney function with ageing comparable to ageing-related processes in human kidneys has also been described in Sprague-Dawley (SD) rats. The renin-angiotensin-system (RAS) plays a pivotal role in the pathophysiology of cardiovascular and kidney disease and is a successful therapeutic target. The discovery of angiotensin-(1-7) (Ang(1-7)), mainly produced by angiotensin-converting enzyme 2 (ACE2), and its receptor MAS offered a new view on the RAS. This ACE2/Ang(1-7)/MAS axis counteracts most deleterious actions of the RAS in the kidney. In order to evaluate if activation of this axis has a protective effect in ageing-induced kidney disease we generated a transgenic rat model (TGR(SM22hACE2)) overexpressing human ACE2 in vascular smooth muscle cells. These animals showed a specific transgene expression pattern and increased ACE2 activity in the kidney. Telemetric recording of cardiovascular parameters and evaluation of kidney function by histology and urine analysis revealed no alterations in blood pressure regulation and basal kidney function in young transgenic rats when compared to young SD rats. However, with ageing, SD rats developed a decline in kidney function characterized by severe albuminuria which was significantly less pronounced in TGR(SM22hACE2) rats. Concomitantly, we detected lower mRNA expression levels of kidney damage markers in aged transgenic animals. Thus, our results indicate that vascular ACE2-overexpression protects the kidney against ageing-induced decline in kidney function, supporting the kidney-protective role of the ACE2/Ang(1-7)/MAS axis., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease is a neurologic disorder characterized by the accumulation of extracellular deposits of amyloid-β (Aβ) fibrils in the brain of patients. The key etiologic agent in Alzheimer's disease is not known; however oligomeric Aβ appears detrimental to neuronal functions and increases Aβ fibrils deposition. Previous research has shown that curcumin, a phenolic pigment of turmeric, has an effect on Aβ assemblies, although the mechanism remains unclear. In this study, we demonstrate that curcumin disassembles pentameric oligomers made from synthetic Aβ42 peptides (pentameric oAβ42), using atomic force microscopy imaging followed by Gaussian analysis. Since curcumin shows keto-enol structural isomerism (tautomerism), the effect of keto-enol tautomerism on its disassembly was investigated. We have found that curcumin derivatives capable of keto-enol tautomerization also disassemble pentameric oAβ42, while, a curcumin derivative incapable of tautomerization did not affect the integrity of pentameric oAβ42. These experimental findings indicate that keto-enol tautomerism plays an essential role in the disassembly. We propose a mechanism for oAβ42 disassembly by curcumin based on molecular dynamics calculations of the tautomerism. When curcumin and its derivatives bind to the hydrophobic regions of oAβ42, the keto-form changes predominantly to the enol-form; this transition is associated with structural (twisting, planarization and rigidification) and potential energy changes that give curcumin enough force to act as a torsion molecular-spring that eventually disassembles pentameric oAβ42. This proposed mechanism sheds new light on keto-enol tautomerism as a relevant chemical feature for designing such novel therapeutic drugs that target protein aggregation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nobuyasu Naruse reports financial support was provided by Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (KAKENHI) Grant Number 19K05207. Nobuyasu Naruse reports a relationship with the Japan Society for the Promotion of Science that includes: funding grants. Nobuyasu Naruse has patent pending to Nobuyasu Naruse. The authors declare no competing interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Although the APOE ε4 allele is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), the relationship between apolipoprotein (apoE) and AD pathophysiology is not yet fully understood. Relatively little is known about the apoE protein species, including post-translational modifications, that exist in the human periphery and CNS. To better understand these apoE species, we developed a LC-MS/MS assay that simultaneously quantifies both unmodified and O-glycosylated apoE peptides. The study cohort included 47 older individuals (age 75.6 ± 5.7 years [mean ± standard deviation]), including 23 individuals (49%) with cognitive impairment. Paired plasma and cerebrospinal fluid samples underwent analysis. We quantified O-glycosylation of two apoE protein residues - one in the hinge region and one in the C-terminal region - and found that glycosylation occupancy of the hinge region in the plasma was significantly correlated with plasma total apoE levels, APOE genotype and amyloid status as determined by CSF Aβ42/Aβ40. A model with plasma glycosylation occupancy, plasma total apoE concentration, and APOE genotype distinguished amyloid status with an AUROC of 0.89. These results suggest that plasma apoE glycosylation levels could be a marker of brain amyloidosis, and that apoE glycosylation may play a role in the pathophysiology of AD., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Peroxynitric acid (PNA), a reactive oxygen nitrogen species, has attracted attention in life science because of its unique properties such as high bacteriacidal activity. Since the bactericidal activity of PNA could be related to its reaction with amino acid residues, we speculate that PNA can be used for protein modifications. In this study, PNA was applied to inhibit aggregation of amyloid β1-42 (Aβ42), which is thought to cause Alzheimer's disease (AD). We demonstrated for the first time that PNA could inhibit the aggregation and cytotoxicity of Aβ42. Since PNA could inhibit aggregation of other amyloidogenic proteins such as amylin and insulin, our study shed a light on a novel strategy for the prevention of various diseases caused by amyloids., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The renin-angiotensin system (RAS) is an important fluid regulation system in the body, and excessive activation of the circulatory or local RAS can increase blood pressure (BP). Excess fluoride can increase BP, although the underlying mechanism related to activation of the RAS remains unclear. Thus, the aim of this study was to elucidate the role of the RAS in fluoride-induced hypertension. Markers of the circulating and local RASs related to pathological changes to the kidneys, myocardium, and aorta were measured. Fluoride reduced serum levels of renin, angiotensin II (Ang II), and angiotensin (1-7) [Ang (1-7)], and dysregulated plasma levels of aldosterone and potassium levels. Excess fluoride can damage the kidneys, myocardium, and aorta, overactivate the renal angiotensin converting enzyme (ACE)-Ang II-angiotensin type 1 receptor axis, and inhibit activation of the ACE2-Ang (1-7)-Mas axis, leading to dysregulation of alpha epithelial sodium channels and significantly increased expression of Ang II in the myocardium and aorta. Hence, excess fluoride can cause low-renin hypertension via an imbalance between the circulatory and local RASs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is the most common neurodegenerative disorder in the world. The aggregation of both amyloid beta (Aβ) peptides extracellularly and Tau proteins intracellularly plays key roles in the pathological consequences of AD, which lead to cholinergic neurodegeneration and eventually death. Currently, there are no effective methods to stop the progression of AD. Using ex vivo, in vivo and clinical approaches, we investigated the functional effects of plasminogen on the widely used FAD, Aβ42 oligomer or Tau intracranial injection-induced AD mouse model and explored its therapeutic effects on patients with AD. The results show that intravenously injected plasminogen rapidly crosses the blood‒brain barrier (BBB); increases plasmin activity in the brain; colocalizes with and effectively promotes the clearance of Aβ42 peptide and Tau protein deposits ex vivo and in vivo; increases the choline acetyltransferase (ChAT) level and decreases the acetylcholinesterase (AChE) activity; and improves the memory functions. Clinically, when GMP-level plasminogen was administered to 6 AD patients for 1-2 weeks, their average scores on the Minimum Mental State Examination (MMSE), which is a standard scoring system used to measure the memory loss and cognitive deficits, were extremely significantly improved by 4.2 ± 2.23 points, e.g., an average increase from 15.5 ± 8.22 before treatment to 19.7 ± 7.09 after treatment. The preclinical study and pilot clinical study suggest that plasminogen is effective in treating AD and may be a promising drug candidate., Competing Interests: Declaration of competing interest J.L. founded Talengen Institute of Life Sciences. The institute has applied patents on the use of plasminogen and is developing natural and recombinant plasminogen as a drug candidate to treat Alzheimer's disease and other neurological diseases. Other authors have declared no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The tumor stroma of most solid malignancies is characterized by a pathological accumulation of pro-angiogenic and pro-tumorigenic hyaluronan driving tumorigenesis and metastatic potential. Of all three hyaluronan synthase isoforms, HAS2 is the primary enzyme that promotes the build-up of tumorigenic HA in breast cancer. Previously, we discovered that endorepellin, the angiostatic C-terminal fragment of perlecan, evokes a catabolic mechanism targeting endothelial HAS2 and hyaluronan via autophagic induction. To explore the translational implications of endorepellin in breast cancer, we created a double transgenic, inducible Tie2Cre ERT2 ;endorepellin(ER) Ki mouse line that expresses recombinant endorepellin specifically from the endothelium. We investigated the therapeutic effects of recombinant endorepellin overexpression in an orthotopic, syngeneic breast cancer allograft mouse model. First, adenoviral delivery of Cre evoking intratumor expression of endorepellin in ER Ki mice suppressed breast cancer growth, peritumor hyaluronan and angiogenesis. Moreover, tamoxifen-induced expression of recombinant endorepellin specifically from the endothelium in Tie2Cre ERT2 ;ER Ki mice markedly suppressed breast cancer allograft growth, hyaluronan deposition in the tumor proper and perivascular tissues, and tumor angiogenesis. These results provide insight into the tumor suppressing activity of endorepellin at the molecular level and implicate endorepellin as a promising cancer protein therapy that targets hyaluronan in the tumor microenvironment., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The purpose of this study was to construct a transmembrane peptide-chondroitin sulphate‑gold nanoparticle (TAT-CS@Au) delivery system and investigate its activity as an anti-Alzheimer's disease (AD) drug. We successfully prepared TAT-CS@Au nanoparticles, investigated their anti-AD effects, and explored the possible mechanisms in in vitro models. TAT-CS@Au exhibited excellent cellular uptake and transport capacity, effectively inhibited the accumulation of Aβ 1 - 40, and significantly reduced Aβ 1 - 40 -induced apoptosis in SH-SY5Y cells. Furthermore, TAT-CS@Au significantly reduced oxidative stress damage and cholinergic injury induced by Aβ 1 - 40 by regulating intracellular concentrations of reactive oxygen species (ROS), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), and acetylcholine (ACh). Western blotting results demonstrated that TAT-CS@Au inhibited aberrant tau phosphorylation (Ser199, Thr205, Ser404, and Ser396) through GSK3β inactivation. TAT-CS@Au decreased the levels of inflammatory factors, specifically TNF-α, IL-6, and IL-1β, by inhibiting NF-κB nuclear translocation by activating MAPK signalling pathways. Overall, these results indicate that TAT-CS@Au exhibits excellent transmembrane ability, inhibits Aβ 1 - 40 accumulation, antagonises oxidative stress, reduces aberrant tau phosphorylation, and suppresses the expression of inflammatory factors. TAT-CS@Au may be a multi-target anti-AD drug with good cell permeability, providing new insights into the design and research of anti-AD therapeutics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Amyloid-β (Aβ) peptide, the main pathogenic peptide in Alzheimer's disease, has been shown to induce an increase in cytoplasmic calcium concentration (CCC). In the current study, we explored the cytotoxic signal transduction pathway in 42-amino-acid Aβ (Aβ42)-treated HeLa cells in relation to the increase in CCC. The increase in CCC was prominent in cells treated twice with oligomeric Aβ42. We previously showed that double treatment also promoted Aβ-induced lamin fragmentation (AILF), which appears to be mediated by cathepsin L. Apoptotic caspase activation was a downstream event of AILF. The Ca 2+ chelator BAPTA-AM suppressed cell death, cathepsin L activation, AILF, and caspase activation in Aβ-treated cells. These results indicate that Aβ42 induces an increase in CCC, which is an event upstream of the cytotoxic processes. The products of AILF are different from those produced by other cell death-inducing agents, such as staurosporine, which induces caspase-6-mediated lamin fragmentation (CMLF). CMLF was unaffected by BAPTA-AM and was not detected in cells treated with Aβ42, indicating that Aβ42 peptide induced a specific cytotoxic pathway involving AILF via increased CCC. We confirmed that the same processes (except caspase activation) operated in Aβ42-treated neuroblastoma SH-SY5Y cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD), a common neurodegenerative disease, is characterised by the deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles. An increasing number of studies have demonstrated that Aβ causes neuronal damage and mitochondrial dysfunction. Herein, we evaluated the neuroprotective effect of sodium butyrate (NaB) against Aβ induced neurotoxicity in PC12 cells. The results revealed that 3 mM of NaB promoted the expression of angiotensin-converting enzyme and brain-derived neurotrophic factor, which exert a neuroprotective effect by activating G protein-coupled receptors. Moreover, NaB could significantly improve mitochondrial dysfunction caused by Aβ. In conclusion, NaB protected PC12 cells from Aβ-induced cell damage, highlighting the potential of NaB in AD treatment., Competing Interests: Declaration of competing interest There is no conflict of interest in this manuscript., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is a progressive disease with a long duration and complicated pathogenesis. Thymidine (Thy) and 2'-deoxyuridine (2'-De) are pyrimidines nucleotides that are associated with nervous system diseases. However, it remains unclear whether Thy and 2'-De exert neuroprotective effects in AD. Therefore, this study was conducted to explore the interventional effects and mechanisms of Thy and 2'-De on the Aβ 25-35 -induced brain injury. Donepezil (Do, 10 mg/kg/d), Thy (20 mg/kg/d), and 2'-De (20 mg/kg/d) were administered for 4 weeks after the injection of Aβ 25-35 peptides (200 μM, i.c.v.) to mice. UPLC-MS/MS method was performed to quantify Thy and 2'-De in the hippocampus of mice brain. The cognition ability, neuronal and mitochondria damage, and levels of Aβ 1-42 /Aβ 1-40 , p-Tau, Na + K + -ATPase, apoptosis, oxidative stress, immune cells, and Iba 1 + were measured in Aβ 25-35 -induced mice. The oxygen consumption (OCR) and extracellular acidification rate (ECAR) were measured using a seahorse analyzer in Aβ 25-35 -induced N9 cells. Moreover, 2-Deoxy-D-glucose (2-DG), a glycolysis inhibitor, was added to explore the mechanisms underlying the effects of Thy and 2'-De on Aβ 25-35 -induced N9 cells. The expression of Iba 1 + and levels of CD11b + and reactive oxygen species (ROS) were measured after treatment with Thy (5 μM) and 2'-De (10 μM) against 2-DG (5 mM) in Aβ 25-35 -induced N9 cells. The results suggested that Do, Thy, and 2'-De improved the cognition ability, attenuated the damage to hippocampus and mitochondria, downregulated the levels of Aβ 1-42 /Aβ 1-40 , p-Tau, Na + K + -ATPase, apoptosis, oxidative stress, and Iba 1 + , and regulated the immune response induced by Aβ 25-35 against the brain injury. Furthermore, Do, Thy, and 2'-De increased ATP production and inhibited glycolysis in Aβ 25-35 -induced N9 cells. Moreover, 2-DG enhanced the effects of drugs, reduced microglial activation, and attenuated oxidative stress to interfere with Aβ 25-35 -induced N9 cells. In conclusion, Thy and 2'-De reduced microglial activation and improved oxidative stress damage by modulating glycolytic metabolism on the Aβ 25-35 -induced brain injury., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The renin-angiotensin system (RAS) is a key hormonal system. In recent years, the functional analysis of the novel axis of the RAS (ACE2/Ang-(1-7)/Mas receptor) revealed that its activation can become protective against several pathologies, including cardiovascular diseases. Mas knockout mice (Mas-KO) represent an important tool for new investigations. Indeed, extensive biological research has focused on investigating the functional implications of Mas receptor deletion. However, although the Mas receptor was identified in neonatal cardiomyocytes and also in adult ventricular myocytes, only few reports have explored the Ang-(1-7)/Mas signaling directly in cardiomyocytes to date. This study investigated the implication of Mas receptor knockout to the cytokine profile, energy metabolism, and electrical properties of mice-isolated cardiomyocytes. Here, we demonstrated that Mas-KO mice have modulation in some cytokines, such as G-CSF, IL-6, IL-10, and VEGF in the left ventricle. This model also presents increased mitochondrial number in cardiomyocytes and a reduction in the myocyte diameter. Finally, Mas-KO cardiomyocytes have altered action potential modulation after diazoxide challenge. Such electrical finding was different from the data showed for the TGR(A1-7)3292 (TGR) model, which overexpresses Ang-(1-7) in the plasma by 4.5, used by us as a control. Collectively, our findings exemplify the importance of understanding the ACE2/Ang-(1-7)/Mas pathway in cardiomyocytes and heart tissue. The Mas-KO mice model can be considered an important tool for new RAS investigations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: Rhabdomyolysis (RM) is a critical condition with a high mortality rate, but effective management is still deficient. Till date, there are no studies that have addressed the effect of angiotensin 1-7 in this condition, hence, the rationale of this study was to evaluate the potential protective effect of Angiotensin 1-7 (Ang1-7), on rhabdomyolysis (RM) induced kidney injury in rats and detecting the underlying mechanistic insights., Main Methods: Forty adult male albino rats were divided into groups; the control group, RM group, RM+Ang1-7 group, and RM+Ang1-7+ A779 group. Sera and urine samples were collected for analysis of renal and muscle injury markers. Kidney tissues were taken for estimation of oxidative, inflammatory, and apoptotic markers as well as angiotensin-II (Ang II) and Ang1-7. Renal histology and expression of inducible nitric oxide synthase-1 (iNOS), real-time PCR for angiotensin-converting enzyme-2 (ACE-2), nuclear erythroid factor-2 (Nrf-2), Toll like receptor 4 (TLR-4) and NF-kB in kidney tissues were also measured., Key Findings: Induction of RM caused renal oxidative stress injury, inflammation, apoptosis and marked deterioration in kidney functions as well as reduction of Ang1-7 and raised Angiotensin-II level in kidney tissues. Administration of Ang1-7 to the RM group reversed all the affected parameters which were blocked by A779 administration (Mas receptor blocker)., Significance: We concluded that Ang1-7 could be a potential therapeutic agent that could mitigate RM-induced renal injury. The underlying mechanisms may involve Stimulation of the ACE-2/Ang1-7/MasR axis and modulation of TLR-4/NF-kB/iNOS and Nrf-2/heme‑oxygenase -1 pathways., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Protein aggregating is known as a leading pathogenic characteristic of a wide range of neurodegenerative diseases (NDs). Preventing amyloid-β (Aβ) aggregation and uncovering the associated mechanism through the application of small bioactive compounds can be considered as a useful strategy in hampering the onset of ND. In this study, we analyzed the inhibitory effects of cirsiliol, a trihydroxy-dimethoxyflavone, against human Αβ 42 fibrillization. Also, we explored the probable neurotoxicity of Αβ 42 oligomers grown with cirsiliol at different molar ratios on PC-12 cells after 24 h. The results showed that significant changes in ThT and ANS fluorescence intensities, Congo red absorbance, and ellipticity changes were modulated by co-incubation of cirsiliol with Αβ 42 , in a concentration-dependent manner. The spectroscopy outcomes were also supported by imaging analysis, where a few Αβ 42 fibrillar conformations were detected with cirsiliol. In addition, cellular assays demonstrated that co-incubated Αβ 42 samples with cirsiliol regulated the cell mortality, LDH release, and caspase-3 activation relative to the PC-12 exposed to Aβ 42 oligomers alone. In conclusion, it can suggest that cirsiliol can be used as a potential candidate in the development of small molecules-based drugs for the advancement of therapeutic platforms against ND., (Copyright © 2022. Published by Elsevier B.V.)

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the extracellular amyloid plaques in the brain. Recent studies have shown that ferroptosis, a recently identified cell death pathway associated with the accumulation of lipid hydroperoxides, is closely related to the occurrence and exacerbation of AD. The application of ferroptosis inhibitors can alleviate the development of AD in both cellular and animal models. Herein, a series of dual-functional hydroxylated chalcone derivatives by integrating the heterocyclic dimethylaminopyrimidine in the core structure were designed and synthesized beyond our previous research to optimize their inhibition activities towards Aβ protein aggregation and ferroptosis simultaneously. The inhibitory ability of the novel synthesized chalcone derivatives were greatly improved. The results indicated that the introduction of the dimethylaminopyrimidine structure provided improved effect on Aβ protein aggregation inhibitory activity in both solution and cellular models. Trihydroxy chalcone derivative A-N-5 provided the best inhibition activities against Aβ protein aggregation in cellular models. The trihydroxy compound A-N-5 did not show cytotoxicity at the concentration lower than 100 µM (with IC 50  > 1 mM), but had a significant effect on promoting cell proliferation. Results indicated that compound A-N-5 could potentially promote neuronal cell growth in the damaged brain tissue. The compound could also inhibit ferroptosis induced by RSL or erastin and reduce the lipid peroxidation levels induced by Aβ 1-42 protein aggregation. Molecular docking was also conducted to explain the better inhibitory effect of novel compounds to inhibit Aβ protein aggregation compared to the previous designed molecules without incorporation of the dimethylaminopyrimidine. In summary, the trihydroxy compound A-N-5 showed the best inhibition activities against Aβ aggregation as well as ferroptosis with low cytotoxicity as a promising molecular skeleton candidate for further development of lead compound for in vivo test to treat AD., (Copyright © 2022. Published by Elsevier Inc.)

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders, characterized by aggregation of amyloid polypeptides, β-amyloid (Aβ) and α-synuclein (αS), respectively. Aβ and αS follow similar aggregation pathways, starting from monomers, to soluble toxic oligomeric assemblies, and to insoluble fibrils. Various studies have suggested overlaps in the pathologies of AD and PD, and have shown Aβ-αS interactions. Unfortunately, whether these protein-protein interactions lead to self- and co-assembly of Aβ and αS into oligomers - a potentially toxic synergistic mechanism - is poorly understood. Among the various Aβ isoforms, interactions of Aβ containing 42 amino acids (Aβ (1-42), referred to as Aβ42) with αS are of most direct relevance due to the high aggregation propensity and the strong toxic effect of this Aβ isoform. In this study, we carefully determined molecular consequences of interactions between Aβ42 and αS in their respective monomeric, oligomeric, and fibrillar forms using a comprehensive set of experimental tools. We show that the three αS conformers, namely, monomers, oligomers and fibrils interfered with fibrillization of Aβ42. Specifically, αS monomers and oligomers promoted oligomerization and stabilization of soluble Aβ42, possibly via direct binding or co-assembly, while αS fibrils hindered soluble Aβ42 species from converting into insoluble aggregates by the formation of large oligomers. We also provide evidence that the interactions with αS were mediated by various parts of Aβ42, depending on Aβ42 and αS conformers. Furthermore, we compared similarities and dissimilarities between Aβ42-αS and Aβ40-αS interactions. Overall, the present study provides a comprehensive depiction of the molecular interplay between Aβ42 and αS, providing insight into its synergistic toxic mechanism., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: Angiotensin-converting enzyme (ACE) 2 is the receptor for severe acute respiratory syndrome coronavirus 2 which causes coronavirus disease 2019 (COVID-19). Viral cellular entry requires ACE2 and transmembrane protease serine 2 (TMPRSS2). ACE inhibitors (ACEIs) or angiotensin (Ang) receptor blockers (ARBs) influence ACE2 in animals, though evidence in human lungs is lacking. We investigated ACE2 and TMPRSS2 in type II pneumocytes, the key cells that maintain lung homeostasis, in lung parenchymal of ACEI/ARB-treated subjects compared to untreated control subjects., Main Methods: Ang II and Ang-(1-7) levels and ACE2 and TMPRSS2 protein expression were measured by radioimmunoassay and immunohistochemistry, respectively., Key Findings: We found that the ratio Ang-(1-7)/Ang II, a surrogate marker of ACE2 activity, as well as the amount of ACE2-expressing type II pneumocytes were not different between ACEI/ARB-treated and untreated subjects. ACE2 protein content correlated positively with smoking habit and age. The percentage of TMPRSS2-expressing type II pneumocytes was higher in males than females and in subjects under 60 years of age but it was not different between ACEI/ARB-treated and untreated subjects. However, there was a positive association of TMPRSS2 protein content with age and smoking in ACEI/ARB-treated subjects, with high TMPRSS2 protein levels most evident in ACEI/ARB-treated older adults and smokers., Significance: ACEI/ARB treatment influences human lung TMPRSS2 but not ACE2 protein content and this effect is dependent on age and smoking habit. This finding may help explain the increased susceptibility to COVID-19 seen in smokers and older patients with treated cardiovascular-related pathologies., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The apolipoprotein E gene ε4 allele (APOE ε4) and higher circulating level of C-reactive protein (CRP) have been extensively investigated as risk factors for Alzheimer's disease (AD). Paradoxically, APOE ε4 has been associated with lower levels of blood CRP in middle-aged and older populations. However, few studies have investigated this intriguing relation and its impact on neurological markers for AD in younger ages, nor across the whole lifespan. Here, we examine associations of blood CRP levels, APOE ε4, and biomarkers for AD in a cognitively healthy lifespan cohort (N up to 749; 20-81 years of age) and replicate the findings in UK Biobank (N = 304 322; 37-72 years of age), the developmental ABCD study (N = 10 283; 9-11 years of age), and a middle-aged sample (N = 339; 40-65 years of age). Hippocampal volume, brain amyloid-β (Aβ) plaque levels, cerebrospinal fluid (CSF) levels of Aβ and tau species, and neurofilament protein light protein (NFL) were used as AD biomarkers in subsamples. In addition, we examined the genetic contribution to the variation of CRP levels over different CRP ranges using polygenic scores for CRP (PGS-CRP). Our results show APOE ε4 consistently associates with low blood CRP levels across all age groups (p < 0.05). Strikingly, both ε4 and PGS-CRP associated mainly with blood CRP levels within the low range (<5mg/L). We then show both APOE ε4 and high CRP levels associate with smaller hippocampus volumes across the lifespan (p < 0.025). APOE ε4 was associated with high Aβ plaque levels in the brain (FDR-corrected p = 8.69x10 -4 ), low levels of CSF Aβ42 (FDR-corrected p = 6.9x10 -2 ), and lower ratios of Aβ42 to Aβ40 (FDR-corrected p = 5.08x10 -5 ). Blood CRP levels were weakly correlated with higher ratio of CSF Aβ42 to Aβ40 (p = 0.03, FDR-corrected p = 0.4). APOE ε4 did not correlate with blood concentrations of another 9 inflammatory cytokines, and none of these cytokines correlated with AD biomarkers. CONCLUSION: The inverse correlation between APOEε 4 and blood CRP levels existed before any pathological AD biomarker was observed, and only in the low CRP level range. Thus, we suggest to investigate whether APOEε 4 can confer risk by being associated with a lower inflammatory response to daily exposures, possibly leading to greater accumulation of low-grade inflammatory stress throughout life. A lifespan perspective is needed to understand this relationship concerning risk of developing AD., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The assembly of amyloidogenic proteins into highly-structured fibrillar aggregates is related to the onset and progression of several amyloidoses, including neurodegenerative Alzheimer's or Parkinson's diseases. Despite years of research and a general understanding of the process of such aggregate formation, there are currently still very few drugs and treatment modalities available. One of the factors that is relatively insufficiently understood is the cross-interaction between different amyloid-forming proteins. In recent years, it has been shown that several of these proteins or their aggregates can alter each other's fibrillization properties, however, there are still many unknowns in the amyloid interactome. In this work, we examine the interaction between amyloid disease-related prion protein and superoxide dismutase-1. We show that not only does superoxide dismutase-1 increase the lag time of prion protein fibril formation, but it also changes the conformation of the resulting aggregates., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Activated mitophagy and mitochondrial unfolded protein response (UPR mt ) has been reported to protect against mitochondrial dysfunction, which is closely related to the onset of Alzheimer's disease (AD). Honokiol (HKL, C 18 H 18 O 2 ) is a kind of natural extraction from bark of Magnolia officinalis with anti-AD effect, and our study aims to explore the effect of HKL on mitophagy and UPR mt in AD. Briefly, male APP/PS1 mice and Aβ oligmer (AβO)-treated primary hippocampal neurons were respectively used to mimic AD in vivo and in vitro. It was determined that HKL significantly ameliorated cognitive impairment and synaptic damages in APP/PS1 mice. Besides, the activated mitophagy and UPR mt together with inhibited oxidative stress and improved mitochondrial dynamic disorder were further validated in hippocampus of HKL-treated APP/PS1 mice. Meanwhile, HKL-treated mice displayed much higher hippocampal expression and activity of mitochondrial sirtuin 3 (SIRT3). Therefore, SIRT3 knockdown was further achieved in primary hippocampal neurons by effective shRNA, and we determined that HKL improved synaptic damage, mitochondrial dysfunction, mitophagy and UPR mt in AβO-treated primary hippocampal neurons in a SIRT3-dependent manner. In summary, our study validates the protective effect of HKL on AD, and highlights that HKL exerts anti-AD effect by activating mitophagy and UPR mt ., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is a common neurodegenerative disease that mainly affects elderly people. However, the translational research of AD is frustrating, suggesting that the development of new AD animal models is crucial. By gavage administration of acrolein, we constructed a simple sporadic AD animal model which showed classic pathologies of AD in 1 month. The AD-like phenotypes and pathological changes were as followed. 1) olfactory dysfunctions, cognitive impairments and psychological symptoms in C57BL/6 mice; 2) increased levels of Aβ1-42 and Tau phosphorylation (S396/T231) in cortex and hippocampus; 3) astrocytes and microglia proliferation; 4) reduced levels of postsynaptic density 95(PSD95) and Synapsin1, as well as the density of dendritic spines in the CA1 and DG neurons of the hippocampus; 5) high-frequency stimulation failed to induce the long-term potentiation (LTP) in the hippocampus after exposure to acrolein for 4 weeks; 6) decreased blood oxygen level-dependent (BOLD) signal in the olfactory bulb and induced high T2 signals in the hippocampus, which matched to the clinical observation in the brain of AD patients, and 7) activated RhoA/ROCK2/ p-cofilin-associated pathway in hippocampus of acrolein-treated mice, which may be the causes of synaptic damage and neuroinflammation in acrolein mice model. Taken together, the acrolein-induced sporadic AD mouse model closely reflects the pathological features of AD, which will be useful for the research on the mechanism of AD onset and the development of anti-AD drugs., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Drug resistance of cancer cells is a significant impediment to effective chemotherapy. One primary reason for this is copper exporters - ATPase copper transporting alpha (ATP7A) and ATPase copper transporting beta (ATP7B). These molecular pumps belong to P-type ATPases and dispose off the Platinum (Pt) based anticancer drugs from cancer cells, causing resistance in them. For the disposal of Pt-drugs, copper exporters require phosphorylation mediated by protein kinase D (PKD) for their activation and trafficking. Even though various research works are underway to overcome resistance to anticancer drugs, the role of PKD is mainly ignored. In this study, we have found a significant upregulation of ATP7A and ATP7B in cervical cancer cells (HeLa) and Liver Hepatocellular Carcinoma cells (HepG2) in the presence of Cisplatin or Carboplatin; both at transcriptional as well as translational levels. Interestingly, the expression of ATP7A and ATP7B were significantly downregulated in the presence of a PKD inhibitor (CID2011756), resulting in the reduction of PKD mediated phosphorylation of ATP7A/7B. This causes enhancement of proteasome-mediated degradation of ATP7A/7B and thereby sensitizes the cells towards Cisplatin and Carboplatin. Similarly, the treatment of Cisplatin resistant HepG2 cells with PKD inhibitor causes enhanced sensitivity towards Cisplatin drug. However, the presence of proteasome inhibitor (MG132) reversed the effect of the PKD inhibitor on the expression level of ATP7A/7B, indicating the necessity of phosphorylation for its stability. Hence, we conclude that the combinatorial usage of Cisplatin with drugs targeting PKD can be developed as an effective chemotherapeutic approach to overcome drug resistance., (Copyright © 2022. Published by Elsevier Ltd.)

The recombinant carboxyl-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) exerts neuroprotective and neurorestorative effects on the dopaminergic system of animal models of Parkinson's disease (PD). The present study aimed to determine the effect of the Hc-TeTx fragment on the markers of oxidative stress and nitrosative stress generated by the acute toxicity of 1-methyl-4-phenylpyridinium (MPP + ). For this purpose, the Hc-TeTx fragment was administered once a day in three 20 μg/kg consecutive injections into the grastrocnemius muscle of the rats, with an intra-striatal unilateral injection of 1 μL of MPP + [10 μg/mL] then administered in order to cause a dopaminergic lesion. The results obtained show that the rats treated with Hc-TeTx plus MPP + presented an increase in the expression of tyrosine hydroxylase (TH), a significantly greater decrease in the levels of the markers of oxidative stress, nitrosative stress, and neurodegeneration than that observed for the group injured with only MPP + . Moreover, it was observed that total superoxide dismutase (SOD) and copper/zinc SOD activity increased with the administration of Hc-TeTx. Finally, immunoreactivity levels were observed to decrease for the levels of 3-nitrotyrosine and the glial fibrillary acidic protein in the ipsilateral striatum of the rats treated with Hc-TeTx plus MPP + , in contrast with those lesioned with MPP + alone. Our results demonstrate that the recombinant Hc-TeTx fragment may be a potent antioxidant and, therefore, could be suggested as a therapeutic tool against the dopaminergic neuronal impairment observed in the early stages of PD., (Copyright © 2021 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.)

In Alzheimer disease, Tau pathology is thought to propagate from cell to cell throughout interconnected brain areas. However, the forms of Tau released into the brain interstitial fluid (ISF) in vivo during the development of Tauopathy and their pathological relevance remain unclear. Combining in vivo microdialysis and biochemical analysis, we find that in Tau transgenic mice, human Tau (hTau) present in brain ISF is truncated and comprises at least 10 distinct fragments spanning the entire Tau protein. The fragmentation pattern is similar across different Tau transgenic models, pathological stages and brain areas. ISF hTau concentration decreases during Tauopathy progression, while its phosphorylation increases. ISF from mice with established Tauopathy induces Tau aggregation in HEK293-Tau biosensor cells. Notably, immunodepletion of ISF phosphorylated Tau, but not Tau fragments, significantly reduces its ability to seed Tau aggregation and only a fraction of Tau, separated by ultracentrifugation, is seeding-competent. These results indicate that ISF seeding competence is driven by a small subset of Tau, which potentially contribute to the propagation of Tau pathology., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: We aimed to determine whether resistance training (RT) regulates renal renin-angiotensin system (RAS) components and inflammatory mediators in diabetic rats., Main Methods: Male Wistar rats (3 months old) were randomly assigned into four groups: non-trained (NT), trained (T), non-trained + diabetes (NTD) and trained +diabetes (TD). Diabetes was induced by streptozotocin (50 mg/kg, Sigma Chemical Co., St. Louis, MO, USA), before RT protocol. Trained rats performed RT protocol on a 110-cm ladder (8 ladder climbs, once/day, 5 days/week, 8 weeks), carrying a load corresponding to 50-80% of maximum carrying capacity. Blood glucose, albuminuria and urinary volume were measured. Renal levels of angiotensin peptides (angiotensin I, II and 1-7), inflammatory markers, and also the activities of angiotensin-converting enzyme (ACE) and ACE2 were determined., Key Findings: Blood glucose and urinary volume were elevated in diabetic animals, and RT decreased albuminuria, renal Ang I and Ang II levels in diabetic rats. RT shifted the balance of renal RAS toward ACE2/Ang 1-7 axis in TD group, and mitigated the high levels of interleukin (IL)-10, IL-1β and cytokine-induced neutrophil chemoattractant 1 (CINC) in the context of diabetes. Strong positive correlations were found between albuminuria and Ang II, IL-10 and IL-1β. On the other hand, intrarenal Ang 1-7 levels were negatively correlated with IL-10 and IL-1β levels., Significance: RT improved kidney function by modulating intrarenal RAS toward ACE2/Ang 1-7 axis and inflammatory cytokines. RT represents a reasonable strategy to improve the renal complications induced by diabetes, counteracting nephropathy-associated maladaptive responses., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Investigating the drug-AChE binding mechanism is vital in understanding its cogent use in medical practice against Alzheimer's disease (AD). The production and accumulation of oligomers of β-amyloid is a central event in the neuropathology of AD. Beside the inhibition of assembly process, modulation of the aggregation process of these proteins towards minimally toxic pathways may be a possible therapeutic strategy for AD. Hence, the present study aims to examine the effect of multifunctional fused tricyclic 7-hydroxy 4-methyl coumarin analogs (HMC 1 - 5 ) on the self-induced aggregation of β-amyloid using Thioflavin T (ThT) assay, scanning electron microscopic study, AlamarBlue and immune blotting assays and also the binding mechanism with AChE by fluorescence emission, conformational, molecular docking and molecular dynamic simulation studies under physiological pH 7.4. The ThT assay, FE-SEM study, cell line and western blots establish that the HMC 1 - 5 molecules could irreversibly disrupt preformed Aβ 42 fibrils, accelerate the aggregates into micro size co-assembled structures, and effectively eliminate the cytotoxicity of Aβ 1 - 42 . Fluorescence emission studies indicating a strong binding affinity between HMC 1 - 5 and AChE with the binding constants of 1.04 × 10 5 , 3.57 × 10 4 , 1.97 × 10 4 , 3.07 × 10 4 and 2.95 × 10 4 M -1 , respectively and binding sites number found to be 1. CD studies disclosed a partial unfolding in the secondary structure of AChE upon binding with HMC 1 - 5 . Docking analysis inferred that the HMC 1 - 5 were bound through hydrophobic and hydrophilic interactions to the AChE active site. Molecular dynamics simulations emphasized the stability of AChE-HMC 1 - 5 complexes throughout the 100 ns simulations, and the local conformational changes of the residues of AChE validate the stability of complexes. These results provide new and unique complementary approach for modulating the biological effects of the Aβ aggregates by coumarin analogs and new insights for further in vivo investigations as novel anti AD agents., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aims: Enterovirus A71 (EV-A71) is an etiological agent of hand foot and mouth disease (HFMD) and has the potential to cause severe neurological infections in children. L-SP40 peptide was previously known to inhibit EV-A71 by prophylactic action. This study aimed to identify the mechanism of inhibition in Rhabdomyosarcoma (RD) cells and in vivo therapeutic potential of L-SP40 peptide in a murine model., Main Methods: A pull-down assay was performed to identify the binding partner of the L-SP40 peptide. Co-immunoprecipitation and co-localization assays with the L-SP40 peptide were employed to confirm the receptor partner in RD cells. The outcomes were validated using receptor knockdown and antibody blocking assays. The L-SP40 peptide was further evaluated for the protection of neonatal mice against lethal challenge by mouse-adapted EV-A71., Key Findings: The L-SP40 peptide was found to interact and co-localize with nucleolin, the key attachment receptor of Enteroviruses A species, as demonstrated in the pull-down, co-immunoprecipitation and co-localization assays. Knockdown of nucleolin from RD cells led to a significant reduction of 3.5 logs of viral titer of EV-A71. The L-SP40 peptide demonstrated 80% protection of neonatal mice against lethal challenge by the mouse-adapted virus with a drastic reduction in the viral loads in the blood (~4.5 logs), skeletal muscles (1.5 logs) and brain stem (1.5 logs)., Significance: L-SP40 peptide prevented severe hind limb paralysis and death in suckling mice and could serve as a potential broad-spectrum antiviral candidate to be further evaluated for safety and potency in future clinical trials against EV-A71., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: Insulin-like growth factor-1 (IGF-1) and bone morphogenetic protein 2 (BMP-2) both promote osteogenesis of bone marrow mesenchymal stem cells (BMSCs). IGF-1C, the C domain peptide of IGF-1, and P24, a BMP-2-derived peptide, both have similar biological activities as their parent growth factors. This study aimed to investigate the effects and mechanisms of polypeptides IGF-1C and P24 on the osteogenic differentiation of BMSCs., Methods: The optimum concentrations of IGF-IC and P24 were explored. The effects of the two polypeptides on BMSC proliferation and osteogenic differentiation were examined using a CCK-8 assay, flow cytometry, alkaline phosphatase (ALP) staining, ALP activity assay, alizarin red S staining, qPCR, and Western blotting. In addition, specific pathway inhibitors were utilized to explore whether the p38 and JNK pathways were involved in this process., Results: The optimal concentration of both polypeptides was 50 μg/ml. IGF-1C and P24 synergistically promoted BMSC proliferation, increased ALP activity and calcified nodule formation, upregulated the mRNA and protein levels of Osx, Runx2, Ocn, Opn, and Col1a1, and improved the phosphorylation levels of p38 and JNK proteins. Inhibition of the pathways significantly reduced p38 and JNK activation and blocked Runx2 expression while inhibiting ALP activity and calcified nodule formation., Conclusions: These findings suggest that IGF-1C and P24 synergistically promote the osteogenesis of BMSCs through activation of the p38 and JNK signaling pathways., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Pulmonary fibrosis is a devastating lung disease with multifactorial etiology characterized by alveolar injury, fibroblast proliferation and excessive deposition of extracellular matrix proteins, which progressively results in respiratory failure and death. Accumulating evidence from experimental and clinical studies supports a central role of the renin angiotensin aldosterone system (RAAS) in the pathogenesis and progression of idiopathic pulmonary fibrosis. Angiotensin II (Ang II), a key vasoactive peptide of the RAAS mediates pro-inflammatory and pro-fibrotic effects on the lungs, adversely affecting organ function. Recent years have witnessed seminal discoveries in the field of RAAS. Identification of new enzymes, peptides and receptors has led to the development of several novel concepts. Of particular interest is the establishment of a protective axis of the RAAS comprising of Angiotensin converting enzyme 2 (ACE2), Angiotensin-(1-7) [Ang-(1-7)], and the Mas receptor (the ACE2/Ang-(1-7)/Mas axis), and the discovery of a functional role for the Angiotensin type 2 (AT 2 ) receptor. Herein, we will review our current understanding of the role of RAAS in lung fibrogenesis, provide evidence on the anti-fibrotic actions of the newly recognized RAAS components (the ACE2/Ang-(1-7)/Mas axis and AT 2 receptor), discuss potential strategies and translational efforts to convert this new knowledge into effective therapeutics for PF., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The interaction of calmodulin (CaM) with the receptor for retinol uptake, STRA6, involves an α-helix termed BP2 that is located on the intracellular side of this homodimeric transporter (Chen et al., 2016 [1]). In the absence of Ca 2+ , NMR data showed that a peptide derived from BP2 bound to the C-terminal lobe (C-lobe) of Mg 2+ -bound CaM ( Mg CaM). Upon titration of Ca 2+ into Mg CaM-BP2, NMR chemical shift perturbations (CSPs) were observed for residues in the C-lobe, including those in the EF-hand Ca 2+ -binding domains, EF3 and EF4 ( Ca K D  = 60 ± 7 nM). As higher concentrations of free Ca 2+ were achieved, CSPs occurred for residues in the N-terminal lobe (N-lobe) including those in EF1 and EF2 ( Ca K D  = 1000 ± 160 nM). Thermodynamic and kinetic Ca 2+ binding studies showed that BP2 addition increased the Ca 2+ -binding affinity of CaM and slowed its Ca 2+ dissociation rates (k off ) in both the C- and N-lobe EF-hand domains, respectively. These data are consistent with BP2 binding to the C-lobe of CaM at low free Ca 2+ concentrations (<100 nM) like those found at resting intracellular levels. As free Ca 2+ levels approach 1000 nM, which is typical inside a cell upon an intracellular Ca 2+ -signaling event, BP2 is shown here to interact with both the N- and C-lobes of Ca 2+ -loaded CaM ( Ca CaM-BP2). Because this structural rearrangement observed for the Ca CaM-BP2 complex occurs as intracellular free Ca 2+ concentrations approach those typical of a Ca 2+ -signaling event ( Ca K D  = 1000 ± 160 nM), this conformational change could be relevant to vitamin A transport by full-length Ca CaM-STRA6., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Neuronostatin is a peptide hormone encoded by the somatostatin gene. Biological effects of neuronostatin are mediated through activation of GPR107. There is evidence indicating that neuronostatin modulates energy homeostasis by suppressing food intake and insulin secretion, while stimulating glucagon secretion. While it was found that neuronostatin receptor is expressed in white adipose tissue, the role of neuronostatin in controlling adipose tissue formation is unknown. The aim of this study is to investigate the effects of neuronostatin on proliferation and differentiation of rat primary preadipocytes and 3T3-L1 cells. We found that neuronostatin receptor GPR107 is expressed in rat preadipocytes and 3T3-L1 cells. Neuronostatin promotes proliferation of preadipocytes via AKT activation. Downregulation of GPR107 mRNA expression and protein production results in an attenuation of neuronostatin-induced stimulation of preadipocyte proliferation. Moreover, neuronostatin reduces intracellular lipid content and the expression of adipogenesis-modulating genes C/ebpα, C/ebpβ, Pparγ, and Fabp4. In summary, these results show that neuronostatin, AKT-dependently, stimulates the proliferation of preadipocytes via GPR107. In contrast, neuronostatin inhibits the differentiation of preadipocytes into mature adipocytes., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Cortical atrophy is an early feature of Alzheimer´s disease (AD). The biological processes associated with variability in cortical thickness remain largely unknown. We studied 220 cerebrospinal fluid (CSF) proteins to evaluate biological pathways associated with cortical thickness in 34 brain regions in 79 cognitively normal older individuals with normal (>192 ng/L, n = 47), and abnormal (≤192 ng/L, n = 32) CSF beta-amyloid 1-42 (Aβ 42 ). Interactions for Aβ 42 status were tested. Panther GeneOntology and Cytoscape ClueGO analyses were used to evaluate biological processes associated with regional cortical thickness. 170 (77.3 %) proteins related with cortical thickness in at least 1 brain region across the total group, and 171 (77.7 %) proteins showed Aβ 42 specific associations. Higher levels of proteins related to axonal and synaptic integrity, amyloid accumulation, and inflammation were associated with thinner cortex in lateral temporal regions, the rostral anterior cingulum, the lateral occipital cortex and the pars opercularis only in the abnormal Aβ 42 group. Alterations in CSF proteomics are associated with a regional cortical atrophy in the earliest stages of AD., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)