Computational insights into the cross-talk between medin and Aß: implications for age-related vascular risk factors in Alzheimer's disease.

The aggregation of medin forming aortic medial amyloid is linked to arterial wall degeneration and cerebrovascular dysfunction. Elevated levels of arteriolar medin are correlated with an increased presence of vascular amyloid-ß (Aß) aggregates, a hallmark of Alzheimer's disease (AD) and vascular dementia. The cross-interaction between medin and Aß results in the formation of heterologous fibrils through co-aggregation and cross-seeding processes both in vitro and in vivo. However, a comprehensive molecular understanding of the cross-interaction between medin and Aß-two intrinsically disordered proteins-is critically lacking. Here, we employed atomistic discrete molecular dynamics simulations to systematically investigate the self-association, co-aggregation and also the phenomenon of cross-seeding between these two proteins. Our results demonstrated that both Aß and medin were aggregation prone and their mixture tended to form ß-sheet-rich hetero-aggregates. The formation of Aß-medin hetero-aggregates did not hinder Aß and medin from recruiting additional Aß and medin peptides to grow into larger ß-sheet-rich aggregates. The ß-barrel oligomer intermediates observed in the self-aggregations of Aß and medin were also present during their co-aggregation. In cross-seeding simulations, preformed Aß fibrils could recruit isolated medin monomers to form elongated ß-sheets. Overall, our comprehensive simulations suggested that the cross-interaction between Aß and medin may contribute to their pathological aggregation, given the inherent amyloidogenic tendencies of both medin and Aß. Targeting medin, therefore, could offer a novel therapeutic approach to preserving brain function during aging and AD by improving vascular health.

Deciphering the influence of Y12L and N17H substitutions on the conformation and oligomerization of human calcitonin.

The abnormal aggregation of human calcitonin (hCT) hormone peptides impairs their physiological function, leading to harmful immune responses and cytotoxicity, which limits their clinical utility. Interestingly, a representative hCT analog incorporating Y12L and N17H substitutions (DM-hCT) has shown reduced aggregation tendencies while maintaining bioactivity. But the molecular mechanism of Y12L and N17H substitutions on the conformational dynamics of hCT remains unclear. Here, we systematically investigated the folding and self-assembly dynamics of hCT and DM-hCT using atomistic discrete molecular dynamics (DMD) simulations. Our findings revealed that hCT monomers predominantly adopted unstructured conformations with dynamic helices. Oligomerization of hCT resulted in the formation of ß-sheet-rich aggregates and ß-barrel intermediates. The Y12L and N17H substitutions enhanced helical conformations and suppressed ß-sheet formation in both monomers and oligomers. These substitutions stabilized the dynamic helices and disrupted aromatic interactions responsible for ß-sheet formation at residue 12. Notably, DM-hCT assemblies still exhibited ß-sheets in phenylalanine-rich and C-terminal hydrophobic regions, suggesting that future optimizations should focus on these areas. Our simulations provide insights into the molecular mechanisms underlying hCT aggregation and the amyloid-resistant effects of Y12L and N17H substitutions. These findings have valuable implications for the development of clinical hCT analogs.

Molecular Insights into the Differential Effects of Acetylation on the Aggregation of Tau Microtubule-Binding Repeats.

Aggregation of tau protein into intracellular fibrillary inclusions is characterized as the hallmark of tauopathies, including Alzheimer's disease and chronic traumatic encephalopathy. The microtubule-binding (MTB) domain of tau, containing either three or four repeats with sequence similarities, plays an important role in determining tau's aggregation. Previous studies have reported that abnormal acetylation of lysine residues displays a distinct effect on the formation of pathological tau aggregates. However, the underlying molecular mechanism remains mostly elusive. In this study, we performed extensive replica exchange molecular dynamics (REMD) simulations of 144 µs in total to systematically investigate the dimerization of four tau MTB repeats and explore the impacts of Lys280 (K280) or Lys321 (K321) acetylation on the conformational ensembles of the R2 or R3 dimer. Our results show that R3 is the most prone to aggregation among the four repeats, followed by R2 and R4, while R1 displays the weakest aggregation propensity with a disordered structure. Acetylation of K280 could promote the aggregation of R2 peptides by increasing the formation of ß-sheet structures and strengthening the interchain interaction. However, K321 acetylation decreases the ß-sheet content of the R3 dimer, reduces the ability of R3 peptides to form long ß-strands, and promotes the stable helix structure formation. The salt bridge and Y310-Y310 π-π stacking interactions of the R3 dimer are greatly weakened by K321 acetylation, resulting in the inhibition of dimerization. This study uncovers the structural ensembles of tau MTB repeats and provides mechanistic insights into the influences of acetylation on tau aggregation, which may deepen the understanding of the pathogenesis of tauopathies.

Molecular Insights into the Effects of F16L and F19L Substitutions on the Conformation and Aggregation Dynamics of Human Calcitonin.

Human calcitonin (hCT) regulates calcium-phosphorus metabolism, but its amyloid aggregation disrupts physiological activity, increases thyroid carcinoma risk, and hampers its clinical use for bone-related diseases like osteoporosis and Paget's disease. Improving hCT with targeted modifications to mitigate amyloid formation while maintaining its function holds promise as a strategy. Understanding how each residue in hCT's amyloidogenic core affects its structure and aggregation dynamics is crucial for designing effective analogues. Mutants F16L-hCT and F19L-hCT, where Phe residues in the core are replaced with Leu as in nonamyloidogenic salmon calcitonin, showed different aggregation kinetics. However, the molecular effects of these substitutions in hCT are still unclear. Here, we systematically investigated the folding and self-assembly conformational dynamics of hCT, F16L-hCT, and F19L-hCT through multiple long-time scale independent atomistic discrete molecular dynamics (DMD) simulations. Our results indicated that the hCT monomer primarily assumed unstructured conformations with dynamic helices around residues 4-12 and 14-21. During self-assembly, the amyloidogenic core of hCT14-21 converted from dynamic helices to ß-sheets. However, substituting F16L did not induce significant conformational changes, as F16L-hCT exhibited characteristics similar to those of wild-type hCT in both monomeric and oligomeric states. In contrast, F19L-hCT exhibited substantially more helices and fewer ß-sheets than did hCT, irrespective of their monomers or oligomers. The substitution of F19L significantly enhanced the stability of the helical conformation for hCT14-21, thereby suppressing the helix-to-ß-sheet conformational conversion. Overall, our findings elucidate the molecular mechanisms underlying hCT aggregation and the effects of F16L and F19L substitutions on the conformational dynamics of hCT, highlighting the critical role of F19 as an important target in the design of amyloid-resistant hCT analogs for future clinical applications.

Computational Investigation of Coaggregation and Cross-Seeding between Aß and hIAPP Underpinning the Cross-Talk in Alzheimer's Disease and Type 2 Diabetes.

The coexistence of amyloid-ß (Aß) and human islet amyloid polypeptide (hIAPP) in the brain and pancreas is associated with an increased risk of Alzheimer's disease (AD) and type 2 diabetes (T2D) due to their coaggregation and cross-seeding. Despite this, the molecular mechanisms underlying their interaction remain elusive. Here, we systematically investigated the cross-talk between Aß and hIAPP using atomistic discrete molecular dynamics (DMD) simulations. Our results revealed that the amyloidogenic core regions of both Aß (Aß10-21 and Aß30-41) and hIAPP (hIAPP8-20 and hIAPP22-29), driving their self-aggregation, also exhibited a strong tendency for cross-interaction. This propensity led to the formation of ß-sheet-rich heterocomplexes, including potentially toxic ß-barrel oligomers. The formation of Aß and hIAPP heteroaggregates did not impede the recruitment of additional peptides to grow into larger aggregates. Our cross-seeding simulations demonstrated that both Aß and hIAPP fibrils could mutually act as seeds, assisting each other's monomers in converting into ß-sheets at the exposed fibril elongation ends. The amyloidogenic core regions of Aß and hIAPP, in both oligomeric and fibrillar states, exhibited the ability to recruit isolated peptides, thereby extending the ß-sheet edges, with limited sensitivity to the amino acid sequence. These findings suggest that targeting these regions by capping them with amyloid-resistant peptide drugs may hold potential as a therapeutic approach for addressing AD, T2D, and their copathologies.

Dissecting the Self-assembly Dynamics of Imperfect Repeats in α-Synuclein.

The pathological aggregation of α-synuclein (αS) into amyloid fibrils is the hallmark of Parkinson's disease (PD). The self-assembly and membrane interactions of αS are mainly governed by the seven imperfect 11-residue repeats of the XKTKEGVXXXX motif around residues 1-95. However, the particular role of each repeat in αS fibrillization remains unclear. To answer this question, we studied the aggregation dynamics of each repeat with up to 10 peptides in silico by conducting multiple independent micro-second atomistic discrete molecular dynamics simulations. Our simulations revealed that only repeats R3 and R6 readily self-assembled into ß-sheet-rich oligomers, while the other repeats remained as unstructured monomers with weak self-assembly and ß-sheet propensities. The self-assembly process of R3 featured frequent conformational changes with ß-sheet formation mainly in the non-conserved hydrophobic tail, whereas R6 spontaneously self-assembled into extended and stable cross-ß structures. These results of seven repeats are consistent with their structures and organization in recently solved αS fibrils. As the primary amyloidogenic core, R6 was buried inside the central cross-ß core of all αS fibrils, attracting the hydrophobic tails of adjacent R4, R5, and R7 repeats forming ß-sheets around R6 in the core. Further away from R6 in the sequence but with a moderate amyloid aggregation propensity, the R3 tail could serve as a secondary amyloidogenic core and form independent ß-sheets in the fibril. Overall, our results demonstrate the critical role of R3 and R6 repeats in αS amyloid aggregation and suggest their potential as targets for the peptide-based and small-molecule amyloid inhibitors.

Unveiling Medin Folding and Dimerization Dynamics and Conformations via Atomistic Discrete Molecular Dynamics Simulations.

Medin is a principal component of localized amyloid found in the vasculature of individuals over 50 years old. Its amyloid aggregation has been linked to endothelial dysfunction and vascular inflammation, contributing to the pathogenesis of various vascular diseases. Despite its significance, the structures of the medin monomer, oligomer, and fibril remain elusive, and the dynamic processes of medin aggregation are not fully understood. In this study, we comprehensively investigated the medin folding and dimerization dynamics and conformations using atomistic discrete molecular dynamics simulations. Our simulation results suggested that the folding initiation of the medin involved the formation of ß-sheets around medin30-41 and medin42-50, with subsequent capping of other segments to their ß-sheet edges. Medin monomers typically consisted of three or four ß-strands, along with a dynamic N-terminal helix. Two isolated medin peptides readily aggregated into a ß-sheet-rich dimer, displaying a strong aggregation propensity. Dimerization of medin not only enhanced the ß-sheet conformations but also led to the formation of ß-barrel oligomers. The aggregation tendencies of medin1-18 and medin19-29 were relatively weak. However, the segments of medin30-41 and medin42-50 played a crucial role as they primarily formed a ß-sheet core and facilitated medin1-18 and medin19-29 to form intra- and interpeptide ß-sheets. The findings highlight the critical role of the medin30-41 and medin42-50 regions in stabilizing the monomer structure and driving the medin amyloid aggregation. These regions could potentially serve as promising targets for designing antiamyloid inhibitors against amyloid aggregation of medin. Additionally, our study provides a full picture of the monomer conformations and dimerization dynamics for medin, which will help better understand the pathology of medin aggregation.

SEVI Inhibits Aß Amyloid Aggregation by Capping the ß-Sheet Elongation Edges.

Inhibiting the aggregation of amyloid peptides with endogenous peptides has broad interest due to their intrinsically high biocompatibility and low immunogenicity. Here, we investigated the inhibition mechanism of the prostatic acidic phosphatase fragment SEVI (semen-derived enhancer of viral infection) against Aß42 fibrillization using atomistic discrete molecular dynamic simulations. Our result revealed that SEVI was intrinsically disordered with dynamic formation of residual helices. With a high positive net charge, the self-aggregation tendency of SEVI was weak. Aß42 had a strong aggregation propensity by readily self-assembling into ß-sheet-rich aggregates. SEVI preferred to interact with Aß42, rather than SEVI themselves. In the heteroaggregates, Aß42 mainly adopted ß-sheets buried inside and capped by SEVI in the outer layer. SEVI could bind to various Aß aggregation species─including monomers, dimers, and proto-fibrils─by capping the exposed ß-sheet elongation edges. The aggregation processes Aß42 from the formation of oligomers to conformational nucleation into fibrils and fibril growth should be inhibited as their ß-sheet elongation edges are being occupied by the highly charged SEVI. Overall, our computational study uncovered the molecular mechanism of experimentally observed inhibition of SEVI against Aß42 aggregation, providing novel insights into the development of therapeutic strategies against Alzheimer's disease.

Co-aggregation of α-synuclein with amyloid-ß stabilizes ß-sheet-rich oligomers and enhances the formation of ß-barrels.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative diseases with markedly different pathological features of ß-amyloid (Aß) plaques and α-synuclein (αS) Lewy bodies (LBs), respectively. However, clinical overlaps in symptoms and pathologies between AD and PD are commonly observed caused by the cross-interaction between Aß and αS. To uncover the molecular mechanisms behind their overlapping symptoms and pathologies, we computationally investigated the impact of αS on an Aß monomer and dimerization using atomistic discrete molecular dynamics simulations (DMD). Our results revealed that αS could directly interact with Aß monomers and dimers, thus forming ß-sheet-rich oligomers, including potentially toxic ß-barrel intermediates. The binding hotspot involved the second half of the N-terminal domain and NAC region in αS, along with residues 10-21 and 31-42 in Aß. In their hetero-complex, the binding hotspot primarily assumed a ß-sheet core buried inside, which was dynamically shielded by the highly charged, amyloid-resistant C-terminus of αS. Because the amyloid prion region was the same as the binding hotspot being buried, their fibrillization may be delayed, causing the toxic oligomers to increase. This study sheds light on the intricate relationship between Aß and αS and provides insights into the overlapping pathology of AD and PD.

IL-4-Producing Dendritic Cells Induced during Schistosoma japonica Infection Promote Th2 Cells via IL-4-Dependent Pathway.

Although dendritic cells (DCs) have been widely demonstrated to play essential roles in initiation of Th2 responses in helminth infections and allergic reactions, the mechanisms remain uncertain largely because DCs do not produce IL-4. In present investigation, we have uncovered a novel subset of DCs from mice infected with Th2-provoking pathogens Schistosoma japonica, which independently promoted Th2 cells via IL-4-dependent pathway. These DCs contained similar levels of IL-4 mRNA and higher levels of IL-12p40 mRNA comparing to basophils, correlating to their Th2-promoting and Th1-promoting dual polarization capacities. Characterized by expression of FcεRI(+), these DCs were induced independent of T cells. Further investigations revealed that Th2-promoting FcεRI(+) DCs were monocyte-derived inflammatory DCs, which were sufficient to induce Th2 cells in vivo. Egg Ags together with GM-CSF or IL-3 alone were able to stimulate the generation of Th2-promoting FcεRI(+) DCs from bone marrow cells in vitro. To our knowledge, our data for the first time demonstrate that IL-4-producing DCs are induced under some Th2-provoking situations, and they should play important roles in initiation of Th2 response.

Interleukin-4- and NACHT, LRR and PYD domains-containing protein 3-independent mechanisms of alum enhanced T helper type 2 responses on basophils.

Aluminium hydroxide (alum), the most widely used adjuvant in human and animal vaccines, has long been known to promote T helper type 2 (Th2) responses and Th2-associated humoral responses, but the mechanisms have remained poorly understood. In this study, we explored whether alum is able to directly modulate antigen-presenting cells to enhance their potency for Th2 polarization. We found that alum treatment of dendritic cells failed to show any Th2-promoting activities. In contrast, alum was able to enhance the capacity of basophils to induce Th2 cells. When basophils from interleukin-4 (IL-4) knockout mice were examined, the intrinsic Th2-promoting activities by basophils were largely abrogated, but the alum-enhanced Th2-promoting activities on basophils were still detectable. More importantly, Th2-promoting adjuvant activities by alum found in IL-4 knockout mice were also largely reduced when basophils were depleted by antibody administration. Therefore, basophils can mediate Th2-promoting activities by alum both in vitro and in vivo through IL-4-independent mechanisms. Further studies revealed that secreted soluble molecules from alum-treated basophils were able to confer the Th2-promoting activities, and neutralization of thymic stromal lymphopoietin or IL-25 attenuated the IL-4-independent development of Th2 cells elicited by alum-treated basophils. Finally, alum was able to activate NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome in murine basophils in the same way as alum in professional antigen-presenting cells, but NLRP3 was not required for Th2-promoting activities on basophils by alum in vitro. These results demonstrated that alum can enhance the capacities of basophils to polarize Th2 cells via IL-4- and NLRP3-independent pathways.

Lentiviral Vector-Mediated FoxO1 Overexpression Inhibits Extracellular Matrix Protein Secretion Under High Glucose Conditions in Mesangial Cells.

Diabetic nephropathy is characterized by inordinate secretion of extracellular matrix (ECM) proteins from mesangial cells (MCs), which is tightly associated with excessive activation of TGF-ß signaling. The forkhead transcription factor O1 (FoxO1) protects mesangial cells from hyperglycemia-induced oxidative stress, which may be involved in ameliorating the redundant secretion of ECM proteins under high glucose conditions. Here, we reported that high glucose elevated the level of p-Akt to attenuate endogenous FoxO1 bioactivities in MCs, accompanied with decreases in the mRNA expressions of catalase (CAT) and superoxide dismutase 2 (SOD2). Meanwhile, the expressions of major ECM proteins-FN and Col I-increased under high glucose conditions, in consistent with the activation of TGF-ß/Smad signaling. By contrast, overexpression of nucleus-localized FoxO1 (insensitive to Akt phosphorylation) directly up-regulated the expressions of anti-oxidative enzymes, accompanied with inactivation of TGF-ß/Smad3 pathway, as well as decreases of extracellular matrix proteins. Moreover, similar to those MCs overexpressed of nucleus-localized FoxO1 in high glucose conditions, MCs with down-regulation of FoxO1 by small interference-RNA under normal glucose conditions showed increased FN level and activated TGF-ß/Smad3 pathway. Our findings link the anti-oxidative activity of FoxO1 and the TGF-ß-induced secretion of ECM proteins, indicating the novel role of FoxO1 in protecting MCs under high glucose conditions.

Vitamin D supplement improved testicular function in diabetic rats.

This study was designed to investigate the role that 1,25(OH)2D3 plays against testicular lesion in diabetic rats and try to find its possible mechanism of the steroidogenesis and the spermatogenesis. In diabetic rats, prolonged hyperglycemia evaluated inflammatory cytokines, damaged sperm production function and redox balance, diminished serum testosterone. After treated with 1,25(OH)2D3 at two different doses respectively for 12 months, all the alternations were effectively normalized. 1,25(OH)2D3 showed inhibitory effect on excessive inflammatory biomarkers and adjusted the expression reproductive genes and testicular androgen synthesis. It also upregulated Bcl-2 expression, decreased Bax and COX-2 expression and inhibited active caspase cascade (caspase 8 and caspase 3), which may preserved the testicular cells under diabetic condition. It revealed that vitamin D supplement may protect the cells through suppressing inflammation factors and alleviating cell apoptotic death, as well as upregulating the expression of genes related to reproductive and testosterone synthesis.

Overexpression of FOXO1 ameliorates the podocyte epithelial-mesenchymal transition induced by high glucose in vitro and in vivo.

Accumulating evidence has suggested that the epithelial-mesenchymal transition (EMT) is a pathway that potentially leads to podocyte depletion and proteinuria in diabetic nephropathy (DN). Therefore, this study was designed to investigate the protective effects of forkhead transcription factor O1 (FOXO1) on podocyte EMT, under high-glucose (HG) conditions in vitro and under diabetic conditions in vivo. The results showed that HG-induced podocyte EMT was associated with FOXO1 inactivation, which was accompanied by activation of the transforming growth factor (TGF)-ß1/SMAD3/integrin-linked kinase (ILK) pathway. Accordingly, constitutive FOXO1 activation suppressed the TGF-ß1/Smad3/ILK pathway and partially reversed EMT, similar to the effects observed after treatment with SIS3 or QLT0267, which are selective inhibitors of TGF-ß1-dependent SMAD3 phosphorylation and ILK, respectively. In addition, lentiviral-mediated FOXO1 overexpression in the kidneys of diabetic mice considerably increased FOXO1 expression and activation, while decreasing proteinuria and renal pathological injury. These data suggested that forced FOXO1 activation inhibited HG-induced podocyte EMT and ameliorated proteinuria and renal injury in diabetic mice. Our findings further highlighted that FOXO1 played a protective role against diabetes in mice and may potentially be used as a novel therapeutic target for treating diabetic nephropathy.

Effects of overexpressing FoxO1 on apoptosis in glomeruli of diabetic mice and in podocytes cultured in high glucose medium.

Podocyte apoptosis induced by high levels of glucose is a key event in the development and prognosis of diabetic nephropathy (DN). Forkhead transcription factor O1 (FoxO1) has been defined as a critical mediator of oxidative stress in animal models of diabetes and is involved in mitophagy. To test the role of FoxO1 in regulating podocyte apoptosis both in vivo and in vitro, we generated FoxO1 overexpression models. High-glucose (HG) induced podocyte apoptosis with decreased mitophagy. These changes were accompanied by mitochondrial dysfunction and more severe podocyte loss in mouse kidney. FoxO1 overexpression prevented the apoptosis induced by HG. Reduction of cell apoptosis and renal damage depended upon the expression of PTEN-induced putative kinase 1 (PINK1). These findings suggest that specific overexpression of renal FoxO1 decreases podocyte apoptosis, which may be explained in part by its regulation of PINK1, and that targeting FoxO1 may represent a novel therapeutic approach for DN.

Valsartan inhibits amylin-induced podocyte damage.

Previous studies have described the deposition of amylin in the kidney of patients with type 2 diabetes mellitus (T2DM). These deposits play a critical role in the pathogenesis of diabetic nephropathy (DN), although the mechanism underlying this effect is unknown. Thus, this study was undertaken to investigate whether amylin aggregation stimulates the local angiotensin II type 1 receptor (AT1R) in podocytes, and to examine its role in podocyte apoptosis. Amylin-induced apoptosis was investigated in vitro in differentiated, conditionally immortalized mouse podocytes and in vivo in KM mice. Expression of genes including nephrin, podocin, AT1R and desmin was measured through quantitative real time PCR, western blot and immunohistochemistry. Apoptosis was determined by flow cytometry, while the cellular distribution of podocin and nephrin was investigated by immunofluorescence. The ultra-structure of glomeruli was examined by transmission electron microscopy (TEM). Amylin enhanced apoptosis in a dose-dependent manner in vitro. The peptide also suppressed podocin and nephrin expression, but enhanced that of AT1R and desmin. Both effects were significantly blocked by valsartan, which inhibits angiotensin II type 1 receptor. These findings suggest that amylin activates a local intracellular RAS in podocytes and induces damage and apoptosis.

Targeting ferroptosis as a prospective therapeutic approach for diabetic nephropathy.

Diabetic nephropathy (DN) is a severe complication of diabetes mellitus, causing a substantive threat to the public, which receives global concern. However, there are limited drugs targeting the treatment of DN. Owing to this, it is highly crucial to investigate the pathogenesis and potential therapeutic targets of DN. The process of ferroptosis is a type of regulated cell death (RCD) involving the presence of iron, distinct from autophagy, apoptosis, and pyroptosis. A primary mechanism of ferroptosis is associated with iron metabolism, lipid metabolism, and the accumulation of ROS. Recently, many studies testified to the significance of ferroptosis in kidney tissue under diabetic conditions and explored the drugs targeting ferroptosis in DN therapy. Our review summarized the most current studies between ferroptosis and DN, along with investigating the significant processes of ferroptosis in different kidney cells, providing a novel target treatment option for DN.

Associations between life's essential 8 and metabolic health among us adults: insights of NHANES from 2005 to 2018.

BACKGROUND: Metabolic unhealth (MUH) is closely associated with cardiovascular disease (CVD). Life's Essential 8 (LE8), a recently updated cardiovascular health (CVH) assessment, has some overlapping indicators with MUH but is more comprehensive and complicated than MUH. Given the close relationship between them, it is important to compare these two measurements. METHODS: This population-based cross-sectional survey included 20- to 80-year-old individuals from 7 National Health and Nutrition Examination Survey (NHANES) cycles between 2005 and 2018. Based on the parameters provided by the American Heart Association, the LE8 score (which ranges from 0 to 100) was used to classify CVH into three categories: low (0-49), moderate (50-79), and high (80-100). The MUH status was evaluated by blood glucose, blood pressure, and blood lipids. The associations were assessed by multivariable regression analysis, subgroup analysis, restricted cubic spline models, and sensitivity analysis. RESULTS: A total of 22,582 participants were enrolled (median of age was 45 years old), among them, 11,127 were female (weighted percentage, 49%) and 16,595 were classified as MUH (weighted percentage, 73.5%). The weighted median LE8 scores of metabolic health (MH) and MUH individuals are 73.75 and 59.38, respectively. Higher LE8 scores were linked to lower risks of MUH (odds ratio [OR] for every 10 scores increase, 0.53; 95% CI 0.51-0.55), and a nonlinear dose-response relationship was seen after the adjustment of potential confounders. This negative correlation between LE8 scores, and MUH was strengthened among elderly population. CONCLUSIONS: Higher LE8 and its subscales scores were inversely and nonlinearly linked with the lower presence of MUH. MUH is consistent with LE8 scores, which can be considered as an alternative indicator when it is difficult to collect the information of health behaviors.

LncRNA H19: a novel player in the regulation of diabetic kidney disease.

Diabetic kidney disease (DKD), one of the most severe complications of diabetes mellitus (DM), has received considerable attention owing to its increasing prevalence and contribution to chronic kidney disease (CKD) and end-stage kidney disease (ESRD). However, the use of drugs targeting DKD remains limited. Recent data suggest that long non-coding RNAs (lncRNAs) play a vital role in the development of DKD. The lncRNA H19 is the first imprinted gene, which is expressed in the embryo and down-regulated at birth, and its role in tumors has long been a subject of controversy, however, in recent years, it has received increasing attention in kidney disease. The LncRNA H19 is engaged in the pathological progression of DKD, including glomerulosclerosis and tubulointerstitial fibrosis via the induction of inflammatory responses, apoptosis, ferroptosis, pyroptosis, autophagy, and oxidative damage. In this review, we highlight the most recent research on the molecular mechanism and regulatory forms of lncRNA H19 in DKD, including epigenetic, post-transcriptional, and post-translational regulation, providing a new predictive marker and therapeutic target for the management of DKD.

Deciphering the Inhibitory Mechanism of Naphthoquinone-Dopamine on the Aggregation of Tau Core Fragments PHF6* and PHF6.

The formation of neurofibrillary tangles by abnormal aggregation of tau protein is considered to be an important pathological characteristic of tauopathies, including Alzheimer's disease and chronic traumatic encephalopathy. Two hexapeptides 275VQIINK280 and 306VQIVYK311 in the microtubule binding region, named PHF6* and PHF6, are known to be aggregation-prone and responsible for tau fibrillization. Previous experiments reported that naphthoquinone-dopamine (NQDA) could effectively inhibit the aggregation of PHF6* and PHF6 and disrupt the fibrillar aggregates into nontoxic species, displaying a dual effect on the amyloid aggregation. However, the underlying molecular mechanism remains mostly elusive. Herein, we performed all-atom molecular dynamics (MD) simulations for 114 µs in total to systematically investigate the impacts of NQDA on the oligomerization of PHF6* and PHF6. The conformational ensembles of PHF6* and PHF6 peptides generated by replica exchange MD simulations show that NQDA could effectively prevent the hydrogen bond formation, reduce the ability of peptides to self-assemble into long ß-strand and large ß-sheets, and induce peptides to form a loosely packed and coil-rich oligomer. The interaction analysis shows that the binding of NQDA to PHF6* is mainly through hydrophobic interactions with residue I277 and hydrogen bonding interactions with Q276; for the PHF6 peptides, NQDA displays a strong π-π stacking interaction with residue Y310, thus impeding the Y310-Y310 π-π stacking and I308-Y310 CH-π interactions. The DA group of NQDA displays a stronger cation-π interaction than the NQ group, while the NQ group exhibits a stronger π-π stacking interaction. MD simulations demonstrate that NQDA prevents the conformational conversion to ß-sheet-rich aggregates and displays an inhibitory effect on the oligomerization dynamics of PHF6* and PHF6. Our results provide a complete picture of inhibitory mechanisms of NQDA on PHF6* and PHF6 oligomerization, which may pave the way for designing drug candidates for the treatment of tauopathies.