Biology subjects

Xie, L.

Publications and source records attributed to Xie, L..

At least 109 records · Page 6Linked to original sources

bioRxiv2024

Virtual Growing Child (VGC): A general normative comparative system via quantitative dynamic MRI for quantifying pediatric regional respiratory anomalies with application in thoracic insufficiency syndrome (TIS)

BackgroundA normative database of regional respiratory structure and function in healthy children does not exist. MethodsVGC provides a database with four categories of regional respiratory measurement parameters including morphological, architectural, dynamic, and developmental. The database has 3,820 3D segmentations (around 100,000 2D slices with segmentations). Age and gender group analysis and comparisons for healthy children were performed using those parameters via two-sided t-testing to compare mean measurements, for left and right sides at end-inspiration (EI) and end-expiration (EE), for different age and gender specific groups. We also apply VGC measurements for comparison with TIS patients via an extrapolation approach to estimate the association between measurement and age via a linear model and to predict measurements for TIS patients. Furthermore, we check the Mahalanobis distance between TIS patients and healthy children of corresponding age. FindingsThe difference between male and female groups (10-12 years) behave differently from that in other age groups which is consistent with physiology/natural growth behavior related to adolescence with higher right lung and right diaphragm tidal volumes for females(p<0.05). The comparison of TIS patients before and after surgery show that the right and left components are not symmetrical, and the left side diaphragm height and tidal volume has been significantly improved after surgery (p <0.05). The left lung volume at EE, and left diaphragm height at EI of TIS patients after surgery are closer to the normal children with a significant smaller Mahalanobis distance (MD) after surgery (p<0.05). InterpretationThe VGC system can serve as a reference standard to quantify regional respiratory abnormalities on dMRI in young patients with various respiratory conditions and facilitate treatment planning and response assessment. FundingThe grant R01HL150147 from the National Institutes of Health (PI Udupa).

bioengineering↗

bioRxiv2024

Rules of engagement for condensins and cohesins guide mitotic chromosome formation

During mitosis, interphase chromatin is rapidly converted into rod-shaped mitotic chromosomes. Using Hi-C, imaging, proteomics and polymer modeling, we determine how the activity and interplay between loop-extruding SMC motors accomplishes this dramatic transition. Our work reveals rules of engagement for SMC complexes that are critical for allowing cells to refold interphase chromatin into mitotic chromosomes. We find that condensin disassembles interphase chromatin loop organization by evicting or displacing extrusive cohesin. In contrast, condensin bypasses cohesive cohesins, thereby maintaining sister chromatid cohesion while separating the sisters. Studies of mitotic chromosomes formed by cohesin, condensin II and condensin I alone or in combination allow us to develop new models of mitotic chromosome conformation. In these models, loops are consecutive and not overlapping, implying that condensins do not freely pass one another but stall upon encountering each other. The dynamics of Hi-C interactions and chromosome morphology reveal that during prophase loops are extruded in vivo at [~]1-3 kb/sec by condensins as they form a disordered discontinuous helical scaffold within individual chromatids.

molecular biology↗

bioRxiv2024

Beyond enumeration: Phenotype independent "labeling-capture-release" process enabling precise detection of circulating tumour cells and downstream applications

Although strategies for circulating tumor cells (CTCs) enrichment have been proposed, the practical effects of clinical CTCs detection are far from satisfactory. Generally, the methodologies for CTCs detection aim at naturally occurring targets, but misdetection/interferences are prevalent due to the diverse phenotypes and subpopulations of CTCs with high heterogeneity. Herein, a CTCs isolation system based on the "labeling-capture-release" process is demonstrated for precise and high-efficient enrichment of CTCs from clinical blood samples. The mechanism which is based on abnormal glyco-metabolism of tumor cells including CTCs can be utilized for the surface decoration of CTCs with artificial azido groups. With the aid of bio-orthogonal plates designed with DBCO- and disulfide groups and exploiting the anti-fouling effects, the cells labeled with azido groups can be captured via a copper-free click reaction and released in a non-destructive manner during subsequent disulfide reduction. The technique is demonstrated to label multiple different types of tumor cells with the EpCAM+/- phenotypes and adherent/suspended status, and all the epithelial/interstitial/hybrid phenotypes of CTCs can be separated from clinical blood samples from 25 patients with 10 different cancer types. Moreover, our strategy is superior to the clinically approved CTCs detection system from the perspective of broad-spectrum and accurate recognition of heterogeneous CTCs. The capturing efficiency of this isolation system is over 80% and the release efficiency exceeds 90%. Most of the released CTCs survive with maintained glycolytic activity thus boding well for downstream applications such as drug susceptibility tests using viable CTCs.

bioengineering↗

bioRxiv2024

Assessing the impact of Brd2 depletion on chromatin compartmentalization

Recent insights into genome organization have emphasized the importance of A/B chromatin compartments. While our previous research showed that Brd2 depletion weakens compartment boundaries and promotes A/B mixing 1, Hinojosa-Gonzalez et al.2 were unable to replicate the findings. In response, we revisited our Micro-C data and successfully replicated the original results using the default parameters in the cooltools software package. We show that, after correcting inconsistencies with the selection and phasing of the compartment profiles, the decrease in B compartment strength persists but the change in compartment identity is to a much lesser extent than originally reported. To further assess the regulatory role of Brd2, we used saddle plots to determine the strength of compartmentalization and observed a consistent decrease of compartment strength especially at B compartments upon Brd2 depletion. This study highlights the importance of selecting appropriate parameters and analytical tools for compartment analysis and carefully interpreting the results.

genomics↗

bioRxiv2024

Targeting G9a translational mechanism of SARS-CoV-2 pathogenesis for multifaceted therapeutics of COVID-19 and its sequalae

By largely unknown mechanism(s), SARS-CoV-2 hijacks the host translation apparatus to promote COVID-19 pathogenesis. We report that the histone methyltransferase G9a noncanonically regulates viral hijacking of the translation machinery to bring about COVID-19 symptoms of hyperinflammation, lymphopenia, and blood coagulation. Chemoproteomic analysis of COVID-19 patient peripheral mononuclear blood cells (PBMC) identified enhanced interactions between SARS-CoV-2-upregulated G9a and distinct translation regulators, particularly the N6-methyladenosine (m6A) RNA methylase METTL3. These interactions with translation regulators implicated G9a in translational regulation of COVID-19. Inhibition of G9a activity suppressed SARS-CoV-2 replication in human alveolar epithelial cells. Accordingly, multi-omics analysis of the same alveolar cells identified SARS-CoV-2-induced changes at the transcriptional, m6A-epitranscriptional, translational, and post-translational (phosphorylation or secretion) levels that were reversed by inhibitor treatment. As suggested by the aforesaid chemoproteomic analysis, these multi-omics-correlated changes revealed a G9a-regulated translational mechanism of COVID-19 pathogenesis in which G9a directs translation of viral and host proteins associated with SARS-CoV-2 replication and with dysregulation of host response. Comparison of proteomic analyses of G9a inhibitor-treated, SARS-CoV-2 infected cells, or ex vivo culture of patient PBMCs, with COVID-19 patient data revealed that G9a inhibition reversed the patient proteomic landscape that correlated with COVID-19 pathology/symptoms. These data also indicated that the G9a-regulated, inhibitor-reversed, translational mechanism outperformed G9a-transcriptional suppression to ultimately determine COVID-19 pathogenesis and to define the inhibitor action, from which biomarkers of serve symptom vulnerability were mechanistically derived. This cell line-to-patient conservation of G9a-translated, COVID-19 proteome suggests that G9a inhibitors can be used to treat patients with COVID-19, particularly patients with long-lasting COVID-19 sequelae.

immunology↗

bioRxiv2024

Circular RNA HMGCS1 sponges miR-4521 to aggravate type 2 diabetes-induced vascular endothelial dysfunction

Noncoding RNA plays a pivotal role as novel regulators of endothelial cell function. Type 2 diabetes, acknowledged as a primary contributor to cardiovascular diseases, plays a vital role in vascular endothelial cell dysfunction due to induced abnormalities of glucolipid metabolism and oxidative stress. In this study, aberrant expression levels of circHMGCS1 and MIR4521 were observed in diabetes-induced human umbilical vein endothelial cell dysfunction. Persistent inhibition of MIR4521 accelerated development and exacerbated vascular endothelial dysfunction in diabetic mice. Mechanistically, circHMGCS1 upregulated arginase 1 by sponging MIR4521, leading to decrease in vascular nitric oxide secretion and inhibition of endothelial nitric oxide synthase activity, and an increase in the expression of adhesion molecules and generation of cellular reactive oxygen species, reduced vasodilation and accelerated the impairment of vascular endothelial function. Collectively, these findings illuminate the physiological role and interacting mechanisms of circHMGCS1 and MIR4521 in diabetes-induced cardiovascular diseases, suggesting that modulating the expression of circHMGCS1 and MIR4521 could serve as a potential strategy to prevent diabetes-associated cardiovascular diseases. Furthermore, our findings provide a novel technical avenue for unraveling ncRNAs regulatory roles of ncRNAs in diabetes and its associated complications.

cell biology↗

bioRxiv2024

Quantitative profiling of human translation initiation reveals regulatory elements that potently affect endogenous and therapeutically modified mRNAs

mRNA therapeutics offer a potentially universal strategy for the efficient development and delivery of therapeutic proteins. Current mRNA vaccines include chemically modified nucleotides to reduce cellular immunogenicity. Here, we develop an efficient, high-throughput method to measure human translation initiation on therapeutically modified as well as endogenous RNAs. Using systems-level biochemistry, we quantify ribosome recruitment to tens of thousands of human 5' untranslated regions and identify sequences that mediate 250-fold effects. We observe widespread effects of coding sequences on translation initiation and identify small regulatory elements of 3-6 nucleotides that are sufficient to potently affect translational output. Incorporation of N1-methylpseudouridine (m1{Psi}) selectively enhances translation by specific 5' UTRs that we demonstrate surpass those of current mRNA vaccines. Our approach is broadly applicable to dissect mechanisms of human translation initiation and engineer more potent therapeutic mRNAs. HighlightsO_LIMeasurement of >30,000 human 5' UTRs reveals a 250-fold range of translation output C_LIO_LISystematic mutagenesis demonstrates the causality of short (3-6nt) regulatory elements C_LIO_LIN1-methylpseudouridine alters translation initiation in a sequence-specific manner C_LIO_LIOptimal modified 5' UTRs outperform those in the current class of mRNA vaccines C_LI

systems biology↗

bioRxiv2024

A series of spontaneously blinking dyes for super-resolution microscopy

Spontaneously blinking fluorophores permit the detection and localization of individual molecules without reducing buffers or caging groups, thus simplifying single-molecule localization microscopy (SMLM). The intrinsic blinking properties of such dyes are dictated by molecular structure and modulated by environment, which can limit utility. We report a series of tuned spontaneously blinking dyes with duty cycles that span two orders of magnitude, allowing facile SMLM in cells and dense biomolecular structures.

cell biology↗

bioRxiv2024

Decoding cell identity with multi-scale explainable deep learning

Cells are the fundamental structural and functional units of life. Studying the definition and composition of different cell types can help us understand the complex mechanisms underlying biological diversity and functionality. The increasing volume of extensive single-cell omics data makes it possible to provide detailed characterisations of cell types. Recently, there has been a rise in deep learning-based approaches that generate cell type labels solely through mapping query data to reference data. However, these approaches lack multi-scale descriptions and interpretations of identified cell types. Here, we propose Cell Decoder, a biological prior knowledge informed model to achieve multi-scale representation of cells. We implemented automated machine learning and post-hoc analysis techniques to decode cell identity. We have shown that Cell Decoder compares favourably to existing methods, offering multi-view interpretability for decoding cell identity and data integration. Furthermore, we have showcased its applicability in uncovering novel cell types and states in both human bone and mouse embryonic contexts, thereby revealing the multi-scale heterogeneity inherent in cell identities.

bioinformatics↗

bioRxiv2024

TrustAffinity: accurate, reliable and scalable out-of-distribution protein-ligand binding affinity prediction using trustworthy deep learning

Polypharmacology has emerged as a new paradigm to discover novel therapeutics for unmet medical needs. Accurate, reliable and scalable predictions of protein-ligand binding affinity across multiple proteins are essential for polypharmacology. Machine learning is a promising tool for multi-target binding affinity predictions, often formulated as a multi-modal regression problem. Despite considerable efforts, three challenges remain: out-of-distribution (OOD) generalizations for compounds with new chemical scaffolds, uncertainty quantification of OOD predictions, and scalability to billions of compounds, which structure-based methods fail to achieve. To address aforementioned challenges, we propose a new model-agnostic anomaly detection-based uncertainty quantification method, embedding Mahalanobis Outlier Scoring and Anomaly Identification via Clustering (eMOSAIC). eMOSAIC uniquely quantifies distribution similarities or differences between the multi-modal representation of known cases and that of a new unseen one. We apply eMOSAIC to a multi-modal deep neural network model for multi-target ligand binding affinity predictions, leveraging a pre-trained strucrture-informed large protein language model. We extensively validate eMOSAIC in OOD settings, showing that it significantly outperforms state-of-the-art sequence-based deep learning and structure-based protein-ligand docking (PLD) methods by a large margin as well as existing uncertainty quantification methods. This finding highlights eMOSAICs potential for real-world polypharmacology and other applications.

bioinformatics↗

bioRxiv2024

TDP-43 pathology links innate and adaptive immunity in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is the most common fatal motor neuron disease. Approximately 90% of ALS patients exhibit pathology of the master RNA regulator, Transactive Response DNA Binding protein (TDP-43). Despite the prevalence TDP-43 pathology in ALS motor neurons, recent findings suggest immune dysfunction is a determinant of disease progression in patients. Whether TDP-43 pathology elicits disease-modifying immune responses in ALS remains underexplored. In this study, we demonstrate that TDP-43 pathology is internalized by antigen presenting cells, causes vesicle rupture, and leads to innate and adaptive immune cell activation. Using a multiplex imaging platform, we observed interactions between innate and adaptive immune cells near TDP-43 pathological lesions in ALS brain. We used a mass cytometry-based whole-blood stimulation assay to provide evidence that ALS patient peripheral immune cells exhibit responses to TDP-43 aggregates. Taken together, this study provides a novel link between TDP-43 pathology and ALS immune dysfunction, and further highlights the translational and diagnostic implications of monitoring and manipulating the ALS immune response.

cell biology↗

bioRxiv2023

Histone deacetylase inhibitor RG2833 has therapeutic potential for Alzheimer's disease in females

Nearly two-thirds of patients with Alzheimers are women. Identifying therapeutics specific for women is critical to lowering their elevated risk for developing this major cause of adult dementia. Moreover, targeting epigenetic processes that regulate multiple cellular pathways is advantageous given Alzheimers multifactorial nature. Histone acetylation is an epigenetic process heavily involved in memory consolidation. Its disruption is linked to Alzheimers. Through our computational studies, we predicted that the investigational drug RG2833 (N-[6-(2-aminoanilino)-6-oxohexyl]-4-methylbenzamide) has repurposing potential for Alzheimers. RG2833 is a histone deacetylase HDAC1/3 inhibitor that is orally bioavailable and permeates the blood-brain-barrier. We investigated the RG2833 therapeutic potential in TgF344-AD rats, which are a model of Alzheimers that exhibits age-dependent progression, thus mimicking this aspect of Alzheimers patients that is difficult to establish in animal models. We investigated the RG2833 effects on cognitive performance, gene expression, and AD-like pathology in 11-month TgF344-AD female and male rats. A total of 89 rats were used: wild type n = 45 (17 females, 28 males), and TgF344-AD n = 44 (24 females, 20 males)] across multiple cohorts. No obvious toxicity was detected in the TgF344-AD rats up to 6 months of RG2833-treatment starting at 5 months of age administering the drug in rodent chow at [~]30mg/kg of body weight. We started treatment early in the course of pathology when therapeutic intervention is predicted to be more effective than in later stages of the disease. The drug-treatment significantly mitigated hippocampal-dependent spatial memory deficits in 11-month TgF344-AD females but not in males, compared to wild type littermates. This female sex-specific drug effect has not been previously reported. RG2833-treatment failed to ameliorate amyloid beta accumulation and microgliosis in female and male TgF344-AD rats. However, RNAseq analysis of hippocampal tissue from TgF344-AD rats showed that drug-treatment in females upregulated the expression of immediate early genes, such as Arc, Egr1 and c-Fos, and other genes involved in synaptic plasticity and memory consolidation. Remarkably, out of 17,168 genes analyzed for each sex, no significant changes in gene expression were detected in males at P < 0.05, false discovery rate < 0.05, and fold-change [≥] 1.5. Our data suggest that histone modifying therapeutics such as RG2833 improve cognitive behavior by modulating the expression of immediate early, neuroprotective and synaptic plasticity genes. Our preclinical study supports that RG2833 has therapeutic potential specifically for female Alzheimers patients. RG2833 evaluations using other AD-related models is necessary to confirm our findings.

neuroscience↗

bioRxiv2023

Integrated Transcriptomic and Metabolomic Profiling of Sheep Ovarian Tissues Confer their association in Fecundity associated Pathways

BackgroundLow fertility is considered the major constraint in sheep rearing industry depending on several factors like, estrus cycle, ovulation rate and litter size but fecundity of ewe plays a key role in sheep reproduction, influenced by several intrinsic and extrinsic factors. However, genetic improvements of traits associated with reproduction through conventional breeding is a very complex and slow process. In current study, we went through a comprehensive integration of high throughput transcriptomic and metabolomics approaches to understand the role of key regulatory genes and metabolites in fecundity of two different and widely raised sheep breeds (Small Tail Han & Dolang) in different regions of China. ResultUPLC/MS/MS system based metabolomic profiling of ovarian tissue from both breeds results into the identification of 1,423 metabolites, including 542 DEMs (379 upregulated and 163 downregulated). Integration of metabolomics and transcriptomics data identified 48 pathways contributed by 37 genes and 85 metabolites through regulatory network analysis. Functional enrichment analysis showed significantly enriched pathways associated with fecundity including Riboflavin metabolism, xenobiotics, bile acid biosynthesis, and Drug metabolism, which produces hormones for regulation of ovarian function, ovulation, and establishment of pregnancy. Further, analyzed two restrictive constrained plots analyzed via multivariate statistical analysis. In one plot complement component C3 associated with Leukotriene D4, and Uridine 5-diphosphate involved in the processes of Neuroactive legend receptor interaction pathway and in second plot IFNGR1 associated with Progesterone, Fumaric acid, and Cortisone involved in the processes of cancer pathway and any disruptions in hormonal balance may induce cancer, which can affect fertility, menstrual cycles, and overall reproductive health. ConclusionExpression profiling, functional enrichments, co-expression network analysis and integrated transcriptomemetabolome data showed gene-metabolite association in energy metabolism, Inflammation, and drug metabolism, all of which play a role in ovarian physiology and ovarian metabolic disorders. Identification and validation of genes, metabolites, and gene-metabolite interactions will help to elucidate the regulatory mechanisms and pathways underlying sheep fecundity and could be leveraged to improve reproductive traits. Graphical Abstract: Scheme of Study O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/572136v1_ufig1.gif" ALT="Figure 1"> View larger version (119K): org.highwire.dtl.DTLVardef@12a42b7org.highwire.dtl.DTLVardef@182169forg.highwire.dtl.DTLVardef@19b2ed4org.highwire.dtl.DTLVardef@11f9eab_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2023

Camel milk affects serum metabolites by modulating the intestinal microflora

Gut microbes play a vital role in human health and are influenced by numerous factors including diet, genetics, and environment. (Fermented) Camel milk, which is abundant in nutrients and lacks allergenic proteins, has been consumed for its edible and medicinal properties for centuries. Research on camel milks impact on gut microbiota and host metabolism is still limited. The results found that sour camel milk contained various beneficial bacteria such as Lactobacillus helveticus, Acinetobacter lwoffii, Eubacterium coprostanoligenes group, Lachnospiraceae, which could be transported to the recipients intestines by diet. This study specified that the transportation of microbiome happened both intra- and inter-species and played a principal role in the formation of progeny gut microflora. An investigation on type 2 diabetic rats revealed that the composition of gut microflora and serum metabolites of those fed with high-dose camel whey was closer to that of the normal. Eubacterium limnetica, which can reduce the risk of diseases by producing MtcB protein, was found in the gut microflora of the ones taking camel milk. These results evidenced the high potential of camel milk as a functional food.

microbiology↗

bioRxiv2023

Monocytes reprogrammed by 4-PBA potently contribute to the resolution of inflammation and atherosclerosis

BackgroundChronic inflammation initiated by inflammatory monocytes underlies the pathogenesis of atherosclerosis. However, approaches that can effectively resolve chronic low-grade inflammation targeting monocytes are not readily available. The small chemical compound 4-phenylbutyric acid (4-PBA) exhibits broad anti-inflammatory effects in reducing atherosclerosis. Selective delivery of 4-PBA reprogrammed monocytes may hold novel potential in providing targeted and precision therapeutics for the treatment of atherosclerosis. MethodsSystems analyses integrating single-cell RNA-sequencing and complementary immunological approaches characterized key resolving characteristics as well as defining markers of reprogrammed monocytes trained by 4-PBA. Molecular mechanisms responsible for monocyte reprogramming was assessed by integrated biochemical and genetic approaches. The inter-cellular propagation of homeostasis resolution was evaluated by co-culture assays with donor monocytes trained by 4-PBA and recipient naive monocytes. The in vivo effects of monocyte resolution and atherosclerosis prevention by 4-PBA were assessed with the high fat diet-fed ApoE-/- mouse model with i.p. 4-PBA administration. Furthermore, the selective efficacy of 4-PBA trained monocytes were examined by i.v. transfusion of ex vivo trained monocytes by 4-PBA into recipient high fat diet-fed ApoE-/- mice. ResultsIn this study, we found that monocytes can be potently reprogrammed by 4-PBA into an immune-resolving state characterized by reduced adhesion and enhanced expression of anti-inflammatory mediator CD24. Mechanistically, 4-PBA reduced the expression of ICAM-1 via reducing peroxisome stress and attenuating SYK-mTOR signaling. Concurrently, 4-PBA enhanced the expression of resolving mediator CD24 through promoting PPAR{gamma} neddylation mediated by TOLLIP. 4-PBA trained monocytes can effectively propagate anti-inflammation activity to neighboring monocytes through CD24. Our data further demonstrated that 4-PBA trained monocytes effectively reduce atherosclerosis pathogenesis when administered in vivo. ConclusionOur study describes a robust and effective approach to generate resolving monocytes, characterizes novel mechanisms for targeted monocyte reprogramming, and offers a precision-therapeutics for atherosclerosis based on delivering reprogrammed resolving monocytes.

immunology↗

bioRxiv2023

A quantitative genetics framework for understanding the selection response of microbial communities

Heritability, a quantity that reflects the degree of resemblance between parent and offspring traits, is measured during plant and animal breeding because it predicts selection success during artificial selection of individuals. However, when whole microbial communities are under artificial selection to improve their traits, high heritability of the community trait does not necessarily predict selection success. To better understand the relationship between heritability and success during community selection, we establish a quantitative genetics framework, and in doing so, we obtain practical recommendations. Specifically, we decompose a community trait into "trait determinants": genotype compositions and species compositions that impact the community trait and that vary among communities. This allows us to interpret heritability of a community trait in terms of the heritability of its determinants. We then use the Price equation to partition the selection response of a community trait into three phenomena: inter-community selection (heritability multiplied by selection intensity), transmission infidelity (the change in community trait from parent to offspring), and nonlinearity (due to a nonlinear relationship between parent and offspring traits). We illustrate that evolution within a community can cause the three terms to covary: in addition to the known effect of worsening transmission infidelity, intra-community evolution can lead to inflated heritability values greater than one (through an effect whereby "the poor get poorer"), and simultaneously magnify nonlinearity. As a consequence of these effects, heritability no longer predicts the selection response of a community trait. We propose effective selection strategies that improve heritability without accelerating intra-community evolution.

evolutionary biology↗

bioRxiv2023

A muscle hypertrophy-derived myokine reprograms the stromal vascular fractions differentiation towards thermogenic adipocytes in subcutaneous adipose tissue

Skeletal muscle plays a significant role in both local and systemic energy metabolism; however, the cross-talk between skeletal muscle and adipose tissue remains largely unexplored. In this study, we identify the HIF2-Bambi-Thbs4 axis as a critical driver of muscle hypertrophy and metabolic improvement. Deletion of Bambi induces muscle hypertrophy and oxidative switching, thereby enhancing local and systemic metabolism under conditions of rodent chow and high-fat diets (HFD). Other than the metabolic regulation of skeletal muscle hypertrophy, we hypothesize that a portion of this improvement may be attributed to the metabolic reprogramming of the stromal vascular fraction (SVFs) of iWAT, promoting the development of beige adipocytes. Leveraging multi-omics approaches, we establish Thbs4 as a newly identified, muscle hypertrophy-derived myokine that serves as an essential regulator of this metabolic reprogramming. Thbs4 is upregulated in skeletal muscle during hypertrophy and aerobic exercise, localizes to the iWAT membrane, and facilitates the transformation of white adipocytes into beige adipocytes under conditions such as cold exposure, muscle hypertrophy, or aerobic exercise. Moreover, overexpression of Thbs4 elevates its plasma levels and leads to the transformation of white to beige adipocytes, therefore offering long-term protection against HFD-induced metabolic disorders. Conversely, Thbs4 knockout (Thbs4-KO) disrupts the metabolic reprogramming of SVFs and exacerbates metabolic syndromes induced by an HFD, mirroring the observed decline in Thbs4 levels in aged mice. Therefore, our findings underscore Thbs4s potential as both a long-term metabolic protective factor and a therapeutic target for the treatment of metabolic disorders. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/558627v1_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@1178e6org.highwire.dtl.DTLVardef@1184d4eorg.highwire.dtl.DTLVardef@7b592aorg.highwire.dtl.DTLVardef@1b0b03_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIBambi, a direct target gene of HIF2 in skeletal muscle, when deleted, triggers muscle hypertrophy and the transformation of white into beige adipocytes, improving systemic energy metabolism. C_LIO_LIThe metabolic reprogramming of stromal vascular fractions (SVFs) contributes to the observed improvements in energy metabolism and adipocyte hyperplasia. C_LIO_LIThbs4, a novel myokine produced in skeletal muscle during hypertrophy and aerobic exercise, plays a key role in the transformation of white into beige adipocytes. C_LIO_LIOverexpression of Thbs4 provides enduring protection against high-fat diet (HFD)-induced metabolic disorders, demonstrating its potential as a therapeutic target. C_LIO_LIThbs4 deletion abrogates the beneficial metabolic reprogramming of SVFs and exacerbates HFD-induced metabolic syndromes, further underlining its crucial role in metabolic regulation. C_LI

physiology↗

bioRxiv2023

Diazoxide/dibenozylmethane treatment mitigates spatial memory deficits and pathology and up regulates protective genes in an Alzheimer's transgenic rat model

INTRODUCTIONAlzheimers disease (AD) is a multifactorial disease for which therapeutic efficacy should benefit from a multi-target approach. Thus, we evaluated a combined chronic treatment with diazoxide (DZ) and dibenzoylmethane (DIB). DZ is a potassium channel activator. DIB counteract eIF2-P-driven stress responses. The individual therapeutic benefits of each drug on attenuating neurodegeneration and apoptosis were previously examined, but not as a combined treatment. METHODSWe evaluated the efficacy of chronic DZ/DIB treatment on TgF344-AD rats (Tg-AD) at 4- and 11-months of age and wild-type littermates. Spatial working memory was assessed with the radial 8-arm maze, and AD pathology by immunohistochemistry. We used RNA sequencing for transcriptome analysis. RESULTSDZ/DIB-treatment mitigated the spatial memory deficits as well as the buildup of hippocampal A{beta} plaques and tau PHF exhibited by 11-month Tg-AD rats. The DZ/DIB-treatment had no effect on wild-type littermates. We did not detect AD-related deficits in untreated 4-month Tg-AD rats, but DZ/DIB-treatment altered their transcriptome. DZ/DIB-treatment of 4-month Tg-AD rats upregulated several genes normally downregulated in AD and/or aging. Expression of two potential early biomarkers for AD, EGR2 (early growth response 2) and HISIT1H2AA (histone H2AA), were also altered by the DZ/DIB treatment in 4-month Tg-AD rats. The treatment reduced levels of eIF2, a protein involved in abnormal translational repression and a contributing factor to neuronal loss. DISCUSSIONThis preclinical study represents the first report on the combined DZ/DIB-treatment. Besides the benefits of this treatment on spatial memory and AD pathology, we identified two potential early AD biomarkers. Furthermore, the DZ/DIB-treatment prevented downregulation of genes associated with AD and/or aging. Overall, our results strongly support that the combination DZ/DIB-treatment mitigates AD pathology. Evaluations across multiple AD-related models are warranted to further corroborate that the DZ/DIB combination is a candidate treatment for AD. HighlightsO_LIDZ/DIB treatment improves cognitive deficits and AD pathology in TgF344-AD rats C_LIO_LIEGR2 and HISIT1H2AA genes are potential early AD biomarkers in TgF344-AD rats C_LIO_LIDZ/DIB treatment of 4-month TgF344-AD rats blocks downregulation of AD/aging genes C_LI RESEARCH IN CONTEXT1. Systematic Review: We reviewed the literature using traditional sources (e.g., PubMed) to assess the status of DZ and DIB treatment individually in preclinical studies in animal models. To our knowledge there is no data with this chronic combined treatment. 2. Interpretation: Treatment takes advantage of a polypharmacological approach to AD therapeutics, considering the multifactorial nature of AD. DZ and DIB individually have been successful in mitigating hippocampal AD pathology but their combined effects were unknown, particularly in a rodent model that shows a more complete disease progression that incorporates aging as a risk factor. The effects of the treatment go beyond previous data in individual DZ and DIB treatment, supporting the need for combination drug treatments to treat a multifactorial disorder. 3. Future Directions: Investigate the potential of DZ/DIB treatment to stop the progression or ameliorate AD pathology when administered at a later age, when pathology is first detected. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=138 HEIGHT=200 SRC="FIGDIR/small/555966v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@7cc6a0org.highwire.dtl.DTLVardef@1d468feorg.highwire.dtl.DTLVardef@390f19org.highwire.dtl.DTLVardef@e40c8_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗