Identifying individual brain development using multimodality brain network.

The cortical development of our brains is in a hierarchical manner and promotes the emergence of large-scale functional hierarchy. However, under interindividual heterogenicity, how the spatiotemporal features of brain networks reflect brain development and mental health remains unclear. Here we collect both resting-state electroencephalography and functional magnetic resonance imaging data from the Child Mind Institute Biobank to demonstrate that during brain growth, the global dynamic patterns of brain states become more active and the dominant networks shift from sensory to higher-level networks; the individual functional network patterns become more similar to that of adults and their spatial coupling tends to be invariable. Furthermore, the properties of multimodality brain networks are sufficiently robust to identify healthy brain age and mental disorders at specific ages. Therefore, multimodality brain networks provide new insights into the functional development of the brain and a more reliable and reasonable approach for age prediction and individual diagnosis.

Exploring the Missing link between vitamin D and autism spectrum disorder: Scientific evidence and new perspectives.

Aim: This study aims to address the key question of the causal relationship between serum levels of 25-hydroxyvitamin D (vitamin D) and autism spectrum disorders (ASD). Methods: Publicly available Genome-Wide Association Study (GWAS) datasets were used to conduct the bidirectional Two-sample MR analyses using methods including inverse-variance weighted (IVW), weighted median, MR-Egger regression, simple mode, MR-PRESSO test, Steiger filtering, and weighted mode, followed by BWMR for validation. Results: The MR analysis indicated that there was no causal relationship between Vitamin D as the exposure and ASD as the outcome in the positive direction of the MR analysis (IVW: OR = 0.984, 95 % CI: 0.821-1.18, P = 0.866). The subsequent BWMR validation stage yielded consistent results (OR = 0.984, 95 % CI 0.829-1.20, P = 0.994). Notably, in the reverse MR analysis with ASD as the exposure and Vitamin D as the outcome, the results suggested that the occurrence of ASD could lead to decreased Vitamin D levels (IVW: OR = 0.976, 95 % CI: 0.961-0.990, P = 0.000855), with BWMR findings in the validation stage confirming the discovery phase (OR = 0.975, 95 % CI: 0.958-0.991, P = 0.00297). For the positive MR analysis, no pleiotropy was detected in the instrumental variables. Similarly, no pleiotropy or heterogeneity was detected in the instrumental variables for the reverse MR analysis. Sensitivity analysis using the leave-one-out approach for both positive and reverse instrumental variables suggested that the MR analysis results were robust. Conclusion: Through the discovery and validation analysis process, we can confidently assert that there is no causative link between Vitamin D and ASD, and that supplementing Vitamin D is not expected to provide effective improvement for patients with ASD. Our study significantly advances a new perspective in ASD research and has a positive impact on medication guidance for patients with ASD.

Cxcr4 regulates a pool of adipocyte progenitors and contributes to adiposity in a sex-dependent manner.

Sex steroids modulate the distribution of mammalian white adipose tissues. Moreover, WAT remodeling requires adipocyte progenitor cells. Nevertheless, the sex-dependent mechanisms regulating adipocyte progenitors remain undetermined. Here, we uncover Cxcr4 acting in a sexually dimorphic manner to affect a pool of proliferating cells leading to restriction of female fat mass. We find that deletion of Cxcr4 in Pparγ-expressing cells results in female, not male, lipodystrophy, which cannot be restored by high-fat diet consumption. Additionally, Cxcr4 deletion is associated with a loss of a pool of proliferating adipocyte progenitors. Cxcr4 loss is accompanied by the upregulation of estrogen receptor alpha in adipose-derived PPARγ-labelled cells related to estradiol hypersensitivity and stalled adipogenesis. Estrogen removal or administration of antiestrogens restores WAT accumulation and dynamics of adipose-derived cells in Cxcr4-deficient mice. These findings implicate Cxcr4 as a female adipogenic rheostat, which may inform strategies to target female adiposity.

Xiaoke Bitong capsule alleviates inflammatory impairment via inhibition of the TNF signaling pathway to against diabetic peripheral neuropathy.

BACKGROUND: Xiaoke Bitong capsule (XBC) is a crude herbal compound believed to tonify qi, improve blood circulation, and alleviate blood stasis. It has been used as an herbal formula for the prevention and treatment of diabetic peripheral neuropathy (DPN) under the guidance of traditional Chinese medicine (TCM). However, the pharmacological mechanisms by which XBC ameliorates DPN remain poorly understood. The interaction between pro-inflammatory factors and the activation of tumor necrosis factor (TNF) plays a critical role in the underlying mechanisms of DPN. XBC may protect against DPN through the regulation of the TNF pathway. PURPOSE: Many studies show the association between DPN and nerve dysfunction, however, treatment options are limited. To identify specific therapeutic targets and active components of XBC that contribute to its anti-DPN effects, our study aimed to investigate the potential mechanism of action of XBC during the progression of DPN using a system pharmacology approach. METHODS: An approach involving UPLC-Q-TOF/MS and network pharmacology was used to analyze the compositions, potential targets, and active pathways of XBC. Further, models of streptozocin (STZ) induced mouse and glucose induced RSC96 cells were established to explore the therapeutic effects of XBC. High glucose induced RSC96 cells were pretreated with small interfering RNA (siRNA) to identify potential therapeutic targets of DPN. RESULTS: Seventy-one active compositions of XBC and five potential targets, including mitogen-activated protein kinase 8 (MAPK), interleukin-6 (IL-6), poly-ADP-ribose polymerase-1 (PARP1), vascular endothelial growth factor A (VEGFA), and transcription factor p65 (NF-κB), were considered as the potential regulators of DPN. In addition, the results revealed that the TNF signaling pathway was closely related to DPN. Moreover, DPN contributed to the decreased expressions of PI3K and AKT, increased TNF-α and IL-1ß in RSC96 cells, which were both reversed by XBC or TNF-α siRNA. CONCLUSION: XBC could protect against DPN by inhibiting the release of pro-inflammatory cytokines and regulating the activation of the TNF signaling pathway, further accelerating neurogenesis, and alleviating peripheral nerve lesions. Therefore, this study highlights the therapeutic value of XBC for DPN.

27-Hydroxycholesterol acts on estrogen receptor α expressed by POMC neurons in the arcuate nucleus to modulate feeding behavior.

Oxysterols are metabolites of cholesterol that regulate cholesterol homeostasis. Among these, the most abundant oxysterol is 27-hydroxycholesterol (27HC), which can cross the blood-brain barrier. Because 27HC functions as an endogenous selective estrogen receptor modulator, we hypothesize that 27HC binds to the estrogen receptor α (ERα) in the brain to regulate energy balance. Supporting this view, we found that delivering 27HC to the brain reduced food intake and activated proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (POMCARH) in an ERα-dependent manner. In addition, we observed that inhibiting brain ERα, deleting ERα in POMC neurons, or chemogenetic inhibition of POMCARH neurons blocked the anorexigenic effects of 27HC. Mechanistically, we further revealed that 27HC stimulates POMCARH neurons by inhibiting the small conductance of the calcium-activated potassium (SK) channel. Together, our findings suggest that 27HC, through its interaction with ERα and modulation of the SK channel, inhibits food intake as a negative feedback mechanism against a surge in circulating cholesterol.

Xiezhuo Tiaozhi formula inhibits macrophage pyroptosis in the non-alcoholic fatty liver disease by targeting the SIRT1 pathway.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a challenging disease to interfere with and represents a potential long-term risk factor for hepatic fibrosis and liver cancer. The Xiezhuo Tiaozhi (XZTZ) formula, a water extract from crude herbs, has been widely used as an anti-NAFLD agent through clinical observation. However, the underlying pharmacological mechanisms of the XZTZ formula and its impact on the potential pathways against NAFLD have not been elucidated. PURPOSE: Our study aims to investigate the pharmacological effects and underlying regulatory mechanisms of the XZTZ formula to treat NAFLD. METHODS: The possible active components and pharmacological mechanisms of the XZTZ formula against NAFLD were identified using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) and molecular docking. To further explore the potential mechanisms, forty-eight 6-week-old male C57BL/6 J mice were given individual attention with high-fat and high-sugar diet (HFHSD) or relevant control (Ctrl) diets for 16 weeks to successfully construct a NAFLD mouse model. Subsequently, the levels of serum biochemicals, pathological changes in the liver, and pyroptosis levels were assessed in mice to investigate the therapeutic effects of the XZTZ formula. Further, LPS-induced RAW264.7 cells and Immortalized Mouse Kupffer cells (ImKC) were used to verify the potential mechanisms of the XZTZ formula against NAFLD in vitro. RESULTS: We identified 7 chemical compounds and 2 potential therapeutic targets as plausible therapeutic points for the treatment of NAFLD using the XZTZ formula. Subsequent histopathological analysis revealed marked hepatic steatosis and lipid accumulation in the HFHSD mice liver, while conditions were effectively ameliorated by administration of the XZTZ formula. Additionally, our work demonstrated that the XZTZ formula could attenuate M1 polarization, promote M2 polarization, and suppress pyroptosis via the SIRT1 pathway in tissue samples. Moreover, validation performed through LPS-induced RAW264.7 and ImKC cells by showing that silencing SIRT1 weaken the effects of the XZTZ formula on relative pyroptosis affirmed that its role was associated with the SIRT1 pathway in macrophage. CONCLUSION: These findings suggest that the XZTZ formula alleviated hepatic steatosis and lipid accumulation in NAFLD mice. These ameliorations are associated with mechanisms involving the attenuation of M1 polarization, promotion of M2 polarization, and anti-pyroptosis effects through the SIRT1 pathway.

Macrophage-derived chemokine CCL22 establishes local LN-mediated adaptive thermogenesis and energy expenditure.

There is a regional preference around lymph nodes (LNs) for adipose beiging. Here, we show that local LN removal within inguinal white adipose tissue (iWAT) greatly impairs cold-induced beiging, and this impairment can be restored by injecting M2 macrophages or macrophage-derived C-C motif chemokine (CCL22) into iWAT. CCL22 injection into iWAT effectively promotes iWAT beiging, while blocking CCL22 with antibodies can prevent it. Mechanistically, the CCL22 receptor, C-C motif chemokine receptor 4 (CCR4), within eosinophils and its downstream focal adhesion kinase/p65/interleukin-4 signaling are essential for CCL22-mediated beige adipocyte formation. Moreover, CCL22 levels are inversely correlated with body weight and fat mass in mice and humans. Acute elevation of CCL22 levels effectively prevents diet-induced body weight and fat gain by enhancing adipose beiging. Together, our data identify the CCL22-CCR4 axis as an essential mediator for LN-controlled adaptive thermogenesis and highlight its potential to combat obesity and its associated complications.

Lack of T04C9.1, the Homologue of Mammalian APPL2, Leads to Premature Ageing and Shortens Lifespan in Caenorhabditis elegans.

Ageing has been identified as an independent risk factor for various diseases; however, the physiological basis and molecular changes related to ageing are still largely unknown. Here, we show that the level of APPL2, an adaptor protein, is significantly reduced in the major organs of aged mice. Knocking down APPL2 causes premature ageing of human umbilical vein endothelial cells (HUVECs). We find that a lack of T04C9.1, the homologue of mammalian APPL2, leads to premature ageing, slow movements, lipid deposition, decreased resistance to stresses, and shortened lifespan in Caenorhabditis elegans (C. elegans), which are associated with decreased autophagy. Activating autophagy by rapamycin or inhibition of let-363 suppresses the age-related alternations, impaired motility, and shortened lifespan of C. elegans, which are reversed by knocking down autophagy-related genes. Our work provides evidence that APPL2 and its C. elegans homologue T04C9.1 decrease with age and reveals that a lack of T04C9.1 bridges autophagy decline and ageing in C. elegans.

Estrogen counteracts age-related decline in beige adipogenesis through the NAMPT-regulated ER stress response.

Thermogenic beige adipocytes are recognized as potential therapeutic targets for combating metabolic diseases. However, the metabolic advantages that they offer are compromised with aging. Here we show that treating mice with estrogen (E2), a hormone that decreases with age, can counteract the age-related decline in beige adipogenesis when exposed to cold temperature while concurrently enhancing energy expenditure and improving glucose tolerance in mice. Mechanistically, we found that nicotinamide phosphoribosyl transferase (NAMPT) plays a pivotal role in facilitating the formation of E2-induced beige adipocytes, which subsequently suppresses the onset of age-related endoplasmic reticulum (ER) stress. Furthermore, we found that targeting NAMPT signaling, either genetically or pharmacologically, can restore the formation of beige adipocytes by increasing the number of perivascular adipocyte progenitor cells. Conversely, the absence of NAMPT signaling prevents this process. Together, our findings shed light on the mechanisms regulating the age-dependent impairment of beige adipocyte formation and underscore the E2-NAMPT-controlled ER stress pathway as a key regulator of this process.

Preparation, Characterization, and Antioxidant Properties of Self-Assembled Nanomicelles of Curcumin-Loaded Amphiphilic Modified Chitosan.

Curcumin (Cur) is a phytochemical with various beneficial properties, including antioxidant, anti-inflammatory, and anticancer activities. However, its hydrophobicity, poor bioavailability, and stability limit its application in many biological approaches. In this study, a novel amphiphilic chitosan wall material was synthesized. The process was carried out via grafting chitosan with succinic anhydride (SA) as a hydrophilic group and deoxycholic acid (DA) as a hydrophobic group; 1H-NMR, FTIR, and XRD were employed to characterize the amphiphilic chitosan (CS-SA-DA). Using a low-cost, inorganic solvent-based procedure, CS-SA-DA was self-assembled to load Cur nanomicelles. This amphiphilic polymer formed self-assembled micelles with a core-shell structure and a critical micelle concentration (CMC) of 0.093 mg·mL-1. Cur-loaded nanomicelles were prepared by self-assembly and characterized by the Nano Particle Size Potential Analyzer and transmission electron microscopy (TEM). The mean particle size of the spherical Cur-loaded micelles was 770 nm. The drug entrapment efficiency and loading capacities were up to 80.80 ± 0.99% and 19.02 ± 0.46%, respectively. The in vitro release profiles of curcumin from micelles showed a constant release of the active drug molecule. Cytotoxicity studies and toxicity tests for zebrafish exhibited the comparable efficacy and safety of this delivery system. Moreover, the results showed that the entrapment of curcumin in micelles improves its stability, antioxidant, and anti-inflammatory activity.

Smooth muscle cell-derived Cxcl12 directs macrophage accrual and sympathetic innervation to control thermogenic adipose tissue.

Sympathetic innervation of brown adipose tissue (BAT) controls mammalian adaptative thermogenesis. However, the cellular and molecular underpinnings contributing to BAT innervation remain poorly defined. Here, we show that smooth muscle cells (SMCs) support BAT growth, lipid utilization, and thermogenic plasticity. Moreover, we find that BAT SMCs express and control the bioavailability of Cxcl12. SMC deletion of Cxcl12 fosters brown adipocyte lipid accumulation, reduces energy expenditure, and increases susceptibility to diet-induced metabolic dysfunction. Mechanistically, we find that Cxcl12 stimulates CD301+ macrophage recruitment and supports sympathetic neuronal maintenance. Administering recombinant Cxcl12 to obese mice or leptin-deficient (Ob/Ob) mice is sufficient to boost macrophage presence and drive sympathetic innervation to restore BAT morphology and thermogenic responses. Altogether, our data reveal an SMC chemokine-dependent pathway linking immunological infiltration and sympathetic innervation as a rheostat for BAT maintenance and thermogenesis.

The Notch-PDGFRß axis suppresses brown adipocyte progenitor differentiation in early post-natal mice.

De novo brown adipogenesis holds potential in combating the epidemics of obesity and diabetes. However, the identity of brown adipocyte progenitor cells (APCs) and their regulation have not been extensively explored. Here, through in vivo lineage tracing and mouse modeling, we observed that platelet-derived growth factor receptor beta (PDGFRß)+ pericytes give rise to developmental brown adipocytes but not to those in adult homeostasis. By contrast, T-box 18 (TBX18)+ pericytes contribute to brown adipogenesis throughout both developmental and adult stages, though in a depot-specific manner. Mechanistically, Notch inhibition in PDGFRß+ pericytes promotes brown adipogenesis by downregulating PDGFRß. Furthermore, inhibition of Notch signaling in PDGFRß+ pericytes mitigates high-fat, high-sucrose (HFHS)-induced glucose and metabolic impairment in mice during their development and juvenile phases. Collectively, these findings show that the Notch/PDGFRß axis negatively regulates developmental brown adipogenesis, and its repression promotes brown adipose tissue expansion and improves metabolic health.

P21-activated kinase-1 signaling is required to preserve adipose tissue homeostasis and cardiac function.

While P21-activated kinase-1 (PAK1) has been extensively studied in relation to cardiovascular health and glucose metabolism, its roles within adipose tissue and cardiometabolic diseases are less understood. In this study, we explored the effects of PAK1 deletion on energy balance, adipose tissue homeostasis, and cardiac function utilizing a whole-body PAK1 knockout (PAK1-/-) mouse model. Our findings revealed that body weight differences between PAK1-/- and WT mice emerged at 9 weeks of age, with further increases observed at 12 weeks. Furthermore, PAK1-/- mice displayed increased fat mass and decreased lean mass at 12 weeks, indicating a shift towards adiposity. In conjunction with the increased body weight, PAK1-/- mice had increased food intake and reduced energy expenditure. At a mechanistic level, PAK1 deletion boosted the expression of lipogenic markers while diminishing thermogenic markers expression in adipose tissues, contributing to reduced energy expenditure and the overall obesogenic phenotype. Moreover, our findings highlighted a significant impact on cardiac function following PAK1 deletion, including alterations in calcium kinetics and compromised systolic and lusitropy functions. In summary, our study emphasizes the significant role of PAK1 in weight regulation and cardiac function, enriching our comprehension of heart health and metabolism. These findings could potentially facilitate the identification of novel therapeutic targets in cardiometabolic diseases.

Jiawei Yanghe Decoction attenuate allergic airway inflammation by suppressing group 2 innate lymphoid cells responses.

ETHNOPHARMACOLOGICAL RELEVANCE: Jiawei Yanghe Decoction (JWYHD) is modified Yanghe Decoction (YHD). YHD historically utilized as a potent medicinal solution for addressing chronic inflammatory conditions, holds promising therapeutic potential in the treatment of asthma. However, the mechanisms underlying JWYHD's effects on allergic asthma remain unclear. AIM OF THE STUDY: To investigate the therapeutic effect as well as the underlying mechanisms of JWYHD on asthmatic mice. MATERIALS AND METHODS: The ovalbumin (OVA)-induced mouse model was utilized, followed by the administration of JWYHD to allergic asthmatic mice. Subsequently, inflammatory cells in the bronchoalveolar lavage fluid (BALF) and lung tissues were conducted. The levels of various cytokines including interleukin (IL)-4, IL-5, IL-13, IL-33, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ in BALF, as well as the total immunoglobulin E (IgE) content in serum, were assessed. Lung function and tissue pathology examinations were performed to assess the protective impacts of JWYHD. The chemical components of JWYHD and its lung prototype compounds (referred to the chemical components present in JWYHD that were observed in the lung) were explored by ultra-high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). RNA-seq analysis revealed the regulation mechanisms of JWYHD treating asthma. Furthermore, the effect of JWYHD on type 2 innate lymphoid cells (ILC2s) in asthmatic mice was detected by flow cytometry and Smart-RNA-seq analysis. Then molecular docking analysis was used to show the interaction between identified compounds and key targets. RESULTS: JWYHD significantly attenuated the airway inflammation of asthmatic mice, reduced the levels of inflammatory cells in BALF, as well the levels of the cytokines IL-4, IL-5, IL-13, IL-33, and TNF-α in BALF and IgE in serum. Airway hyperresponsiveness (AHR) and lung inflammation infiltration were also alleviated by JWYHD. Moreover, RNA-seq analysis revealed that JWYHD attenuated airway inflammation in asthmatic mice via regulating immunity. Flow cytometry confirmed that JWYHD could inhibit ILC2 responses. ILC2 Smart-RNA-seq analysis showed that JWYHD impaired the inflammation reaction-related signaling pathways in ILC2s, and neuropilin-1 (Nrp1), endothelial transcription factor 3 (GATA3) and interleukin 1 receptor like protein 1 (ST2) might be the key targets. The molecular docking analysis investigating the connection between the primary targets and JWYHD's prototype compounds in the lung demonstrated that liquiritin apioside, icariin, glycyrrhizic acid, and uralsaponin B, identified through UPLC-Q-TOF/MS, exhibited significant affinity in binding to the mentioned key targets. CONCLUSION: Our results suggested that the mechanism of JWYHD in treating asthma might be related to limiting ILC2 responses. Our findings provided some pharmacological evidence for the clinical application of JWYHD in the treatment of asthma.

Platelet-derived growth factor receptor beta is required for embryonic specification and confinement of the adult white adipose lineage.

White adipose tissue (WAT) development and adult homeostasis rely on distinct adipocyte progenitor cells (APCs). While adult APCs are defined early during embryogenesis and generate adipocytes after WAT organogenesis, the mechanisms underlying adult adipose lineage determination and preservation remain undefined. Here, we uncover a critical role for platelet-derived growth factor receptor beta (Pdgfrß) in identifying the adult APC lineage. Without Pdgfrß, APCs lose their adipogenic competency to incite fibrotic tissue replacement and inflammation. Through lineage tracing analysis, we reveal that the adult APC lineage is lost and develops into macrophages when Pdgfrß is deleted embryonically. Moreover, to maintain the APC lineage, Pdgfrß activation stimulates p38/MAPK phosphorylation to promote APC proliferation and maintains the APC state by phosphorylating peroxisome proliferator activated receptor gamma (Pparγ) at serine 112. Together, our findings identify a role for Pdgfrß acting as a rheostat for adult adipose lineage confinement to prevent unintended lineage switches.

Risk of papillary thyroid carcinoma and nodular goiter associated with exposure to semi-volatile organic compounds: A multi-pollutant assessment based on machine learning algorithms.

BACKGROUND: Exposure to semi-volatile organic compounds (SVOCs) may link to thyroid nodule risk, but studies of mixed-SVOCs exposure effects are lacking. Traditional analytical methods are inadequate for dealing with mixed exposures, while machine learning (ML) seems to be a good way to fill the gaps in the field of environmental epidemiology research. OBJECTIVES: Different ML algorithms were used to explore the relationship between mixed-SVOCs exposure and thyroid nodule. METHODS: A 1:1:1 age- and gender-matched case-control study was conducted in which 96 serum SVOCs were measured in 50 papillary thyroid carcinoma (PTC), 50 nodular goiters (NG), and 50 controls. Different ML techniques such as Random Forest, AdaBoost were selected based on their predictive power, and variables were selected based on their weights in the models. Weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) were used to assess the mixed effects of the SVOCs exposure on thyroid nodule. RESULTS: Forty-three of 96 SVOCs with detection rate >80 % were included in the analysis. ML algorithms showed a consistent selection of SVOCs associated with thyroid nodule. Fluazifop-butyl and fenpropathrin are positively associated with PTC and NG in single compound models (all P < 0.05). WQS model shows that exposure to mixed-SVOCs was associated with an increased risk of PTC and NG, with the mixture dominated by fenpropathrin, followed by fluazifop-butyl and propham. In the BKMR model, mixtures showed a significant positive association with thyroid nodule risk at high exposure levels, and fluazifop-butyl showed positive effects associated with PTC and NG. CONCLUSION: This study confirms the feasibility of ML methods for variable selection in high-dimensional complex data and showed that mixed exposure to SVOCs was associated with increased risk of PTC and NG. The observed association was primarily driven by fluazifop-butyl and fenpropathrin. The findings warranted further investigation.

Evolutionary diversity of the control of the azole response by Tra1 across yeast species.

Tra1 is an essential coactivator protein of the yeast SAGA and NuA4 acetyltransferase complexes that regulate gene expression through multiple mechanisms including the acetylation of histone proteins. Tra1 is a pseudokinase of the PIKK family characterized by a C-terminal PI3K domain with no known kinase activity. However, mutations of specific arginine residues to glutamine in the PI3K domains (an allele termed tra1Q3) result in reduced growth and increased sensitivity to multiple stresses. In the opportunistic fungal pathogen Candida albicans, the tra1Q3 allele reduces pathogenicity and increases sensitivity to the echinocandin antifungal drug caspofungin, which disrupts the fungal cell wall. Here, we found that compromised Tra1 function, in contrast to what is seen with caspofungin, increases tolerance to the azole class of antifungal drugs, which inhibits ergosterol synthesis. In C. albicans, tra1Q3 increases the expression of genes linked to azole resistance, such as ERG11 and CDR1. CDR1 encodes a multidrug ABC transporter associated with efflux of multiple xenobiotics, including azoles. Consequently, cells carrying tra1Q3 show reduced intracellular accumulation of fluconazole. In contrast, a tra1Q3 Saccharomyces cerevisiae strain displayed opposite phenotypes: decreased tolerance to azole, decreased expression of the efflux pump PDR5, and increased intracellular accumulation of fluconazole. Therefore, our data provide evidence that Tra1 differentially regulates the antifungal response across yeast species.

Gut-derived ammonia contributes to alcohol-related fatty liver development via facilitating ethanol metabolism and provoking ATF4-dependent de novo lipogenesis activation.

BACKGROUND & AIMS: Dysbiosis contributes to alcohol-associated liver disease (ALD); however, the precise mechanisms remain elusive. Given the critical role of the gut microbiota in ammonia production, we herein aim to investigate whether and how gut-derived ammonia contributes to ALD. METHODS: Blood samples were collected from human subjects with/without alcohol drinking. Mice were exposed to the Lieber-DeCarli isocaloric control or ethanol-containing diets with and without rifaximin (a nonabsorbable antibiotic clinically used for lowering gut ammonia production) supplementation for five weeks. Both in vitro (NH4Cl exposure of AML12 hepatocytes) and in vivo (urease administration for 5 days in mice) hyperammonemia models were employed. RNA sequencing and fecal amplicon sequencing were performed. Ammonia and triglyceride concentrations were measured. The gene and protein expression of enzymes involved in multiple pathways were measured. RESULTS: Chronic alcohol consumption causes hyperammonemia in both mice and human subjects. In healthy livers and hepatocytes, ammonia exposure upregulates the expression of urea cycle genes, elevates hepatic de novo lipogenesis (DNL), and increases fat accumulation. Intriguingly, ammonia promotes ethanol catabolism and acetyl-CoA formation, which, together with ammonia, synergistically facilitates intracellular fat accumulation in hepatocytes. Mechanistic investigations uncovered that ATF4 activation, as a result of ER stress induction and general control nonderepressible 2 activation, plays a central role in ammonia-provoked DNL elevation. Rifaximin ameliorates ALD pathologies in mice, concomitant with blunted hepatic ER stress induction, ATF4 activation, and DNL activation. CONCLUSIONS: An overproduction of ammonia by gut microbiota, synergistically interacting with ethanol, is a significant contributor to ALD pathologies.

Self-Assembled Amphiphilic Chitosan Nanomicelles: Synthesis, Characterization and Antibacterial Activity.

Although amphiphilic chitosan has been widely studied as a drug carrier for drug delivery, fewer studies have been conducted on the antimicrobial activity of amphiphilic chitosan. In this study, we successfully synthesized deoxycholic acid-modified chitosan (CS-DA) by grafting deoxycholic acid (DA) onto chitosan C2-NH2, followed by grafting succinic anhydride, to prepare a novel amphiphilic chitosan (CS-DA-SA). The substitution degree was 23.93% for deoxycholic acid and 29.25% for succinic anhydride. Both CS-DA and CS-DA-SA showed good blood compatibility. Notably, the synthesized CS-DA-SA can self-assemble to form nanomicelles at low concentrations in an aqueous environment. The results of CS, CS-DA, and CS-DA-SA against Escherichia coli and Staphylococcus aureus showed that CS-DA and CS-DA-SA exhibited stronger antimicrobial effects than CS. CS-DA-SA may exert its antimicrobial effect by disrupting cell membranes or forming a membrane on the cell surface. Overall, the novel CS-DA-SA biomaterials have a promising future in antibacterial therapy.

Simple model systems reveal conserved mechanisms of Alzheimer's disease and related tauopathies.

The lack of effective therapies that slow the progression of Alzheimer's disease (AD) and related tauopathies highlights the need for a more comprehensive understanding of the fundamental cellular mechanisms underlying these diseases. Model organisms, including yeast, worms, and flies, provide simple systems with which to investigate the mechanisms of disease. The evolutionary conservation of cellular pathways regulating proteostasis and stress response in these organisms facilitates the study of genetic factors that contribute to, or protect against, neurodegeneration. Here, we review genetic modifiers of neurodegeneration and related cellular pathways identified in the budding yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans, and the fruit fly Drosophila melanogaster, focusing on models of AD and related tauopathies. We further address the potential of simple model systems to better understand the fundamental mechanisms that lead to AD and other neurodegenerative disorders.