4-Hydroxybenzoic acid restrains Nlrp3 inflammasome priming and activation via disrupting PU.1 DNA binding activity and direct antioxidation.

Reactive oxygen species (ROS) production is considered central to triggering the nucleotide-binding domain-like receptor family pyrin domain containing 3 (Nlrp3) inflammasome activation and the subsequent inflammatory responses. Coenzyme Q10 (CoQ10) plays a critical role in maintaining intracellular ROS homeostasis and inhibiting excessive Nlrp3 inflammasome activation. However, direct supplementation of CoQ10 showed unsatisfactory clinical improvement due to its limited absorption and bioavailability. Therefore, stimulating endogenous CoQ10 biosynthesis by supplementing CoQ10 precursors may provide a more promising therapeutic approach. In this study, we described the role of 4-hydroxybenzoic acid (4-HBA), a precursor of CoQ10, in attenuating excessive inflammatory responses. We found that while supplementation of 4-HBA inhibited the priming and activation of Nlrp3 inflammasome, this effect was independent of its metabolic transformation into CoQ10. 4-HBA itself exhibits antioxidative activities. Furthermore, 4-HBA can disrupt the binding activity of PU.1 on the promoters of Tlr4 and Md2, thereby directly suppressing Nlrp3 inflammasome priming during LPS-induced inflammatory responses. Therefore, strategically utilizing 4-HBA or increasing 4-HBA intake may represent a potential strategy for reducing excessive inflammation.

A mouse protozoan boosts antigen-specific mucosal IgA responses in a specific lipid metabolism- and signaling-dependent manner.

IgA antibodies play an important role in mucosal immunity. However, there is still no effective way to consistently boost mucosal IgA responses, and the factors influencing these responses are not fully understood. We observed that colonization with the murine intestinal symbiotic protozoan Tritrichomonas musculis (T.mu) boosted antigen-specific mucosal IgA responses in wild-type C57BL/6 mice. This enhancement was attributed to the accumulation of free arachidonic acid (ARA) in the intestinal lumen, which served as a signal to stimulate the production of antigen-specific mucosal IgA. When ARA was prevented from undergoing its downstream metabolic transformation using the 5-lipoxygenase inhibitor zileuton or by blocking its downstream biological signaling through genetic deletion of the Leukotriene B4 receptor 1 (Blt1), the T.mu-mediated enhancement of antigen-specific mucosal IgA production was suppressed. Moreover, both T.mu transfer and dietary supplementation of ARA augmented the efficacy of an oral vaccine against Salmonella infection, with this effect being dependent on Blt1. Our findings elucidate a tripartite circuit linking nutrients from the diet or intestinal microbiota, host lipid metabolism, and the mucosal humoral immune response.

Association of lifestyle with valvular heart disease progression and life expectancy among elderly people from different socioeconomic backgrounds.

BACKGROUND: Current cardiovascular prevention strategies are based on studies that seldom include valvular heart disease (VHD). The role of modifiable lifestyle factors on VHD progression and life expectancy among the elderly with different socioeconomic statuses (SES) remains unknown. METHODS: This cohort study included 164,775 UK Biobank participants aged 60 years and older. Lifestyle was determined using a five-factor scoring system covering smoking status, obesity, physical activity, diet, and sleep patterns. Based on this score, participants were then classified into "poor," "moderate," or "ideal" lifestyle groups. SES was classified as high or low based on the Townsend Deprivation Index. The association of lifestyle with major VHD progression was evaluated using a multistate mode. The life table method was employed to determine life expectancy with VHD and without VHD. RESULTS: The UK Biobank documented 5132 incident VHD cases with a mean follow-up of 12.3 years and 1418 deaths following VHD with a mean follow-up of 6.0 years. Compared to those with a poor lifestyle, women and men followed an ideal lifestyle had lower hazard ratios for incident VHD (0.66 with 95% CI, 0.59-0.73 for women and 0.77 with 95% CI, 0.71-0.83 for men) and for post-VHD mortality (0.58 for women, 95% CI 0.46-0.74 and 0.62 for men, 95% CI 0.54-0.73). When lifestyle and SES were combined, the lower risk of incident VHD and mortality were observed among participants with an ideal lifestyle and high SES compared to participants with an unhealthy lifestyle and low SES. There was no significant interaction between lifestyle and SES in their correlation with the incidence and subsequent mortality of VHD. Among low SES populations, 60-year-old women and men with VHD who followed ideal lifestyles lived 4.2 years (95% CI, 3.8-4.7) and 5.1 years (95% CI, 4.5-5.6) longer, respectively, compared to those with poor lifestyles. In contrast, the life expectancy gain for those without VHD was 4.4 years (95% CI, 4.0-4.8) for women and 5.3 years (95% CI, 4.8-5.7) for men when adhering to an ideal lifestyle versus a poor one. CONCLUSIONS: Adopting a healthier lifestyle can significantly slow down the progression from free of VHD to incident VHD and further to death and increase life expectancy for both individuals with and without VHD within diverse socioeconomic elderly populations.

Microbial succession in different years of pit mud from a distillery in Sichuan for Nong-xiang Baijiu fermentation.

Microbial community and succession of 5-, 20-, and 50-year pit mud (PM) were uncovered in this study. The results showed that Bacteroidetes, Firmicutes and Ascomycota were dominant phyla in these PM samples. Interestingly, most sequences could not be classified into fungal taxa at the genus level by UNITE Database, the diversity and richness of bacteria in these PMs were higher than that of fungi. It was noteworthy that both 20-year and 50-year PMs exhibited higher abundances of Caproiciproducens and Petrimonas when compared with 5-year PM. While higher proportions of Lactobacillus and Acinetobacter were observed in the 5-year PM. Furfermore, these PMs microbiota mainly involved biosynthesis, degradation, and generation of precursor metabolites, which contributed to carbon cycling of Nong-xiang Baijiu anaerobic fermentation. Taken together, lactic acid bacteria depletion and caproic acid bacteria accumulation might be an important succession trend of PM microbiota during the long-term fermentation of Chinese Nong-xiang Baijiu. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-024-01558-4.

Assembly of protein-directed fluorescent gold nanoclusters for high-sensitivity detection of uranyl ions.

Uranium is a key element in the nuclear industry, whose accidental release causes health and environmental problems. In this paper, a protein-directed fluorescent sensor with aggregation-induced emission characteristics (gold nanoclusters@ovalbumin, AuNCs@OVA) was synthesized for the detection of UO22+ with high sensitivity and selectivity. The sensor exhibited good fluorescence stability, and its fluorescence intensity could be selectively enhanced by UO22+. Based on FT-IR and XPS analyses, the increase in fluorescence intensity of AuNCs@OVA after the addition of UO22+ was attributed to aggregation induced by the complexation between UO22+ and the amino, carboxyl, hydroxyl, and phosphate groups of ovalbumin. The detection limit was determined to be 34.4 nM, and the sensor showed excellent ion selectivity for UO22+. In combination with a smartphone program, the sensor could realize the real-time detection of UO22+ in a quantitative and portable way.

Desaminotyrosine is a redox-active microbial metabolite that bolsters macrophage antimicrobial functions while attenuating IL-6 production.

Intestinal microbiota contributes to host defense against pathogens while avoiding the induction of inflammation in homeostatic conditions, but the mechanism is not fully understood. To investigate the potential role of the bacterial metabolite desaminotyrosine (DAT) in regulating host defense and inflammation, we pretreated mouse bone marrow-derived macrophages (BMDMs) with DAT for 12 hours and then challenged with bacterial lipopolysaccharide (LPS). We found that DAT priming-enhanced type I interferon response while selectively inhibiting proinflammatory interleukin (IL)-6 production after exposure to LPS. This is related to the fact that DAT is a natural antioxidant determined by radical scavenging assay in a cell-free system. DAT-primed cells had increased levels of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) upon LPS stimulation. Countering the increased NADPH by supplementing extra oxidized NADP+ to cells reversed DAT's effect on LPS-induced Il-6 and interferon-stimulated gene expressions. DAT-primed cells also were more resistant to oxidative stress-induced generation of reactive oxygen species and cell death. DAT promoted the production of antimicrobial effector nitric oxide in a cellular redox-dependent manner, leading to enhanced macrophage antimicrobial activity during Salmonella enterica infection. Our data suggest that DAT acts as a host-microbiota crosstalk signal in shaping host immune defense and inflammatory response.

Improved calculation method for dry modal analysis of four-stage centrifugal-pump rotor system based on concentrated-mass method.

To improve the accuracy of modal analysis for a four-stage centrifugal-pump rotor system with a balancing disc based on the concentrated-mass analytical method, a simplified concentrated mass mathematical model and an ANSYS simulation model are established. The results from these two models are compared to determine factors that cause significant differences in the mode shapes. Subsequently, an optimized mathematical model based on the corrected mass moment of an inertia matrix and stiffness correction coefficients is proposed, and the effectiveness of this optimized mathematical model is validated using a four-stage centrifugal pump with back blades. The results show that the natural frequencies obtained from the ANSYS simulations are consistently higher than those obtained using the analytical method. The simplification of the moment of inertia at the impeller and balancing disc contributes primarily to the calculated errors. The optimized mathematical model reduces the errors in the natural frequencies from 12.96%, 12.13%, 9.96%, 5.85%, and 8.74% to 2.45%, 1.56%, 0.65%, 5.34%, and 2.28%, respectively. The optimization of natural frequencies offers better performance at lower-order modes, whereas its effects on higher-order modes are less significant. The optimization method is applicable to centrifugal pumps with back blades and reduces the error in theoretical calculations, based on reductions in the concentrated mass from 13.11%, 12.85%, 9.91%, and 7.2% to 3.7%, 3.86%, 0.57%, and 2.87%, respectively, thus further confirming the feasibility of the optimized model design.

Sulfonated cottonseed hydrolysates with adjustable amphiphilicity as environmental -Stress stable emulsifiers.

Cottonseed protein isolate (CPI) is a valuable agro-industrial waste with potential biotechnological applications. However, inadequate stability in water due to its characteristic hinders its widespread use. Therefore, a new sulfonation modification approach was developed to improve the amphiphilicity and structural flexibility of CPI. Structural characterizations confirmed the successful incorporation of sulfonate groups with structural and conformational changes. This significantly unfolded molecular-chain, and improved amphiphilicity, flexibility, and surface-hydrophobicity while reducing pI (5.1-1.7), and molecular-weight (5745-2089 g/mol). The modified samples exhibited improved emulsification with higher amounts of absorbed proteins on the droplet interface, smaller droplet size, and a higher zeta-potential. Additionally, they possessed good emulsification ability under acidic conditions. The nano-emulsions exhibited long-term stability (≥70 days) under different environmental conditions, with excellent fluidity. This study contributes to understanding sulfonation as a viable approach for improving protein properties, thus, opening up new possibilities for their application and maximizing their economic benefits.

Fam96a is essential for the host control of Toxoplasma gondii infection by fine-tuning macrophage polarization via an iron-dependent mechanism.

BACKGROUND: Toxoplasmosis affects a quarter of the world's population. Toxoplasma gondii (T.gondii) is an intracellular parasitic protozoa. Macrophages are necessary for proliferation and spread of T.gondii by regulating immunity and metabolism. Family with sequence similarity 96A (Fam96a; formally named Ciao2a) is an evolutionarily conserved protein that is highly expressed in macrophages, but whether it play a role in control of T. gondii infection is unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we utilized myeloid cell-specific knockout mice to test its role in anti-T. gondii immunity. The results showed that myeloid cell-specific deletion of Fam96a led to exacerbate both acute and chronic toxoplasmosis after exposure to T. gondii. This was related to a defectively reprogrammed polarization in Fam96a-deficient macrophages inhibited the induction of immune effector molecules, including iNOS, by suppressing interferon/STAT1 signaling. Fam96a regulated macrophage polarization process was in part dependent on its ability to fine-tuning intracellular iron (Fe) homeostasis in response to inflammatory stimuli. In addition, Fam96a regulated the mitochondrial oxidative phosphorylation or related events that involved in control of T. gondii. CONCLUSIONS/SIGNIFICANCE: All these findings suggest that Fam96a ablation in macrophages disrupts iron homeostasis and inhibits immune effector molecules, which may aggravate both acute and chronic toxoplasmosis. It highlights that Fam96a may autonomously act as a critical gatekeeper of T. gondii control in macrophages.

Plant polyphenol surfactant construction with strong surface activity and chelation properties as efficient decontamination of UO22+ on cotton fabric.

Chemically synthesized surfactants have promising applications in the treatment of uranium, however, their hazardous environmental effects, non-biodegradability, and numerous drawbacks prevent them from being widely used in practice. Herein, we successfully synthesized a green chelating and foaming integrated surfactant (BTBS) by Mannich reaction and acylation of bayberry tannin for the effective removal of UO22+ from aqueous environments or solid surfaces. The as-prepared surfactant was systematically characterized by FT-IR, showing that the hydrophobic groups were successfully grafted onto tannin. The modified material showed better foaming and emulsifying properties, which proved this method could improve the amphiphilicity of tannin. Moreover, for the first time, a foam fractionation method in conjunction with a tannin-based surfactant was applied for UO22+ removal from water. This surfactant was used as a co-surfactant and could readily remove 90 % of UO22+ (20 mg L-1) from water. The removal of UO22+ could be completed in a short time (30 min), and the maximum adsorption capacity was determined as 175.9 mg g-1. This surfactant can also be used for efficient decontamination of uranium-contaminated cotton cloth with a high removal rate of 94.55 %. In addition, the mechanism studies show that the adsorption of BTBS for UO22+ can be mainly attributed to a chelating mechanism between UO22+ and the adjacent phenolic hydroxyls. The novel biomass-derived BTBS with advantages such as high capture capacity, environmental friendliness, and cost-effectiveness suggests that it plays an important role in the remediation of radionuclide pollution.

Anterior and Posterior Basolateral Amygdala Projections of Cell Type-Specific D1-Expressing Neurons From the Medial Prefrontal Cortex Differentially Control Alcohol-Seeking Behavior.

BACKGROUND: Alcohol use disorder is characterized by compulsive alcohol-seeking behavior, which is associated with dysregulation of afferent projections from the medial prefrontal cortex to the basolateral amygdala (BLA). However, the contribution of the cell type-specific mechanism in this neuronal circuit to alcohol-seeking behavior remains unclear. METHODS: Mice were trained with 2-bottle choice and operant alcohol self-administration procedures. Anterograde and retrograde viral methods traced the connection between dopamine type 1 receptor (D1R) neurons and BLA neurons. Electrophysiology and in vivo optogenetic techniques were used to test the function of neural circuits in alcohol-seeking behavior. RESULTS: Chronic alcohol consumption preferentially changed the activity of posterior BLA (pBLA) neurons but not anterior BLA (aBLA) neurons and overexcited D1R neurons in the medial prefrontal cortex. Interestingly, we found that 2 populations of D1R neurons, anterior and posterior (pD1R) neurons, separately targeted the aBLA and pBLA, respectively, and only a few D1R neurons innervated both aBLA and pBLA neurons. Furthermore, pD1R neurons exhibited more excitability than anterior D1R neurons in alcohol-drinking mice. Moreover, we observed enhanced glutamatergic transmission and an increased NMDA/AMPA receptor ratio in the medial prefrontal cortex inputs from pD1R neurons to the pBLA. Optogenetic long-term depression induction of the pD1R-pBLA circuit reduced alcohol-seeking behavior, while optogenetic long-term depression or long-term potentiation induction of the anterior D1R-aBLA circuit produced no change in alcohol intake. CONCLUSIONS: The pD1R-pBLA circuit mediates chronic alcohol consumption, which may suggest a cell type-specific neuronal mechanism underlying reward-seeking behavior in alcohol use disorder.

Improvement of amphipathic properties with molecular structure unfolding and activation of cottonseed protein as ultra stable and safe emulsifier by deamidation.

By-product cottonseed proteins are excellent options for numerous applications due to their superior properties and lower cost. However, its complex folded structure and large molecular weight lead to lower reactivity and insufficient amphiphilicity. Cottonseed protein isolate (CPI) is less-soluble in water. Therefore, we improved the amphiphilicity of CPI with associated hydrolysis, molecular structure unfolding, and activation by alkaline-induced deamidation (at 24, 36, and 72 h) and produced three cottonseed protein hydrolysates CPH 24, 36, and 72. FTIR/UV-CD measurements confirmed the conformational changes and conversion of the structural content. Particle size decreased 2503.4-771.8 nm, while surface hydrophobicity (133.5-326.7), carboxyl content (1.13 × 10Ö¾3-2.09 × 10Ö¾3), and flexibility increased, signifying hydrolysis, unfolding, and amphiphilicity improvement. Longer deamidation (CPH 72) exhibited the best properties, its prepared emulsions were long-term stable under all the environmental stresses without visible phase separation after at least 40 days of storage except at pH 4. Compared to CPI, it had smaller droplets (939.3-264.9 nm) and larger absolute ζ-potential (-26.5 to -58.0 mV). From the in-vitro cytotoxicity test, deamidated CPI is extremely safer than commonly used synthetic surfactants. This research provides a new method for producing multifunctional emulsifiers from CPI, which could be utilized in the development of functional foods/non-foods.

Characterization of an EPS-producing bifidobacterial strain based on integration of phenotypic and complete genome sequencing data.

Bifidobacterium and Lactobacillus are known to be common members of the human intestinal microbiota, which play important roles in maintaining the homeostasis of host gut microenvironment. Several bifidobacterial and lactobacilli strains have been used as probiotics for health benefits. The exopolysaccharides (EPSs) produced by strains from Bifidobacterium and Lactobacillus are considered as beneficial traits mediating these beneficial effects. In this study, 21 strains belonging to Bifidobacterium and Lactobacillus were isolated from healthy infants' stool and were screened for EPS-producing ability. Among these strains, Bifidobacterium longum XZM1 showed the highest EPS productivity, which was further confirmed and characterized. The complete genome of strain XZM1 was sequenced, which revealed the presence of a gene cluster for EPS production. Furthermore, comparative genome analysis was performed among XZM1 and other strains from B. longum species. Following purification, the molecular weight (Mw) of EPS from XZM1 was determined as 4023 Da (Mw) through gel permeation chromatography. Analysis of the EPS hydrolysates revealed that the EPS was composed of mannose, glucose, galactose, arabinose, and fucose. Additionally, the EPS exhibited higher scavenging abilities toward hydroxyl than 1,1-diphenyl-2-picrylhydrazyl free radical. Overall, these results suggest that XZM1 from B. longum species may be a promising probiotic candidate.

Secondary bond interface assembly of polyethyleneimine on zein microparticles for rapid adsorption of Reactive Black 5.

Textile dye wastewater has the characteristics of high concentration, complex composition and changeable color degree and pH, which is difficult to be effectively and completely treated, and easy to cause environmental pollution. Here, a strategy of secondary bond interface assembly of polyethyleneimine on zein microparticles (PEI) (PEI@zein) was constructed to achieve rapid and efficient removal of Reactive Black 5 (RB5), which is one of the most widely used reactive dyes in the textile industry. Structural analysis indicated that the as-prepared PEI layer immobilized on zein microparticles was constructed based on the interface assembly dominated by hydrophobic interactions and electrostatic attraction between PEI molecules and zein chains. The novel interface showed excellent absorption performance for RB5 with an absorption capacity of 631.0 mg·g-1, rapid adsorption in 2 min, wide pH range of 4-10. Mechanism analysis suggested the effective adsorption of RB5 by PEI@zein microparticles was mainly attributed to secondary bond interface such as electrostatic interaction and hydrogen bond between RB5 and PEI immobilized on the surface of zein microparticles. Moreover, due to the presence of secondary bond interface, RB5 adsorbed on microparticles can be easily desorbed by using 0.01 M NaOH. Therefore, the strategy of secondary bond interface assembly with polyethyleneimine on zein microparticles has high potential for practical application in the treatment of dye-containing wastewater.

Dietary ingredient change induces a transient MyD88-dependent mucosal enteric glial cell response and promotes obesity.

OBJECTIVE: Consumption of a modern Western-type high-fat low-fiber diet increases the risk of obesity. However, how a host responds to such a diet, especially during the early period of dietary transition from a previous low-fat and fiber-rich diet, remains poorly explored. METHODS: Wild-type C57BL/6 mice were fed a normal chow diet or a high-fat diet. Enteric glial cell (EGC) activation was detected through quantitative real-time PCR (qRT-PCR), immunoblotting and immunohistology analysis. Fluorocitrate or genetic deletion of glial fibrillary acidic protein (GFAP)-positive glial-intrinsic myeloid differentiation factor 88 (Myd88) was used to inhibit EGC activation, and the effect of a high-fat diet on obesity was further investigated. The role of MYD88-dependent sensing of commensal products in adipocyte was observed to analyze the effect of obesity. RESULTS: A dietary shift from a normal chow diet to a high-fat diet in mice induced a transient early-phase emergence of a GFAP-positive EGC network in the lamina propria of the ileum, accompanied with an increase in glial-derived neurotrophic factor production. Inhibition of glial cell activity blocked this response. GFAP-positive glial Myd88 knockout mice gained less body weight after high-fat diet (HFD) feeding than littermate controls. In contrast, adipocyte deletion of Myd88 in mice had no effect on weight gain but instead exacerbated glucose intolerance. Furthermore, short-term fluorocitrate intervention during HFD feeding attenuated body weight gain. CONCLUSIONS: Our findings indicate that EGCs are early responders to intestinal ecosystem changes and the GFAP-positive glial Myd88 signaling participates in regulating obesity.

Remimazolam versus propofol for deep sedation/anaesthesia in upper gastrointestinal endoscopy in elderly patients: A multicenter, randomized controlled trial.

BACKGROUND AND OBJECTIVE: Propofol is the most commonly used sedative in gastrointestinal endoscopic procedures, but is associated with cardiorespiratory suppression, particularly in elderly patients. Remimazolam is a new short-acting GABA(A) receptor agonist with minimal impact on cardiorespiratory suppression, and may be a viable alternative in elderly patients undergoing endoscopic procedures. METHODS: This multicenter, randomized controlled trial was conducted between September 2020 and September 2021. Elderly patients (65-85 years of age) scheduled to undergo upper gastrointestinal endoscopy were randomized in 1:1 ratio to receive remimazolam tosilate (300 mg/h) or propofol (3 g/h) in addition to 50-µg fentanyl, until the Modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S) reached ≤1. MOAA/S was maintained at 0 or 1 throughout the procedure using 2.5 mg remimazolam or 0.5 mg/kg propofol boluses in the two groups, respectively. The primary outcome was the rate of hypotension (defined as systolic blood pressure at ≤90 mmHg or > 30% decline vs. the baseline). Bradycardia was defined as heart rate ≤50 per minute; respiratory depression was defined as respiratory rate <8 per minute and/or SpO2 < 90%. RESULTS: A total of 400 patients (161 men and 239 women; 70.4 ± 4.6 years of age) were enrolled (200 patients per group). Average body mass index was 22.2 ± 2.4 kg/m2 . The rate of hypotension was 36.5% in the remimazolam group and 69.6% in the propofol group (p < 0.001). The remimazolam group also had a lower rate of bradycardia (1.5% vs. 8.5%, p < 0.001), respiratory depression (4.5% vs. 10.0%, p < 0.05) and pain at the injection site (0% vs. 12.0%, p < 0.001). CONCLUSION: Remimazolam was associated with a lower rate of hypotension in elderly patients undergoing upper gastrointestinal endoscopy under deep sedation/anaesthesia than propofol.

Cerebral Ischemic Lesions after Transcatheter Aortic Valve Implantation in Patients with Non-Calcific Aortic Stenosis.

Evidence for transcatheter aortic valve implantation (TAVI) is scarce among patients with non-calcific aortic stenosis, and it is not known whether aortic valve calcification is associated with new cerebral ischemic lesions (CILs) that are detected by diffusion-weighted magnetic resonance imaging. So, our study enrolled 328 patients who underwent transfemoral TAVI using a self-expanding valve between December 2016 and June 2021 from the TORCH registry (NCT02803294). A total of 34 patients were finally confirmed as non-calcific AS and the remaining 294 patients were included in the calcific AS group. Incidence of new CILs (70.6% vs. 85.7%, p = 0.022), number of lesions (2.0 vs. 3.0, p = 0.010), and lesions volume (105.0 mm3 vs. 200.0 mm3, p = 0.047) was significantly lower in the non-calcific AS group. However, the maximum and average lesion volumes were comparable between two groups. Non-calcific AS was associated with lower risk for developing new CILs by univariate logistic regression analysis [Odds ratio (OR): 0.040, 95% confident interval (CI): 0.18-0.90, p = 0.026] and multivariate analysis (OR: 0.031, 95% CI: 0.13-0.76, p = 0.010). In summary, non-calcific AS patients had a lower risk of developing new cerebral ischemic infarction after TAVI compared to calcific AS patients. However, new ischemic lesions were still found in over 70% of patients.

Aryl hydrocarbon receptor activation drives polymorphonuclear myeloid-derived suppressor cell response and efficiently attenuates experimental Sjögren's syndrome.

Myeloid-derived suppressor cells (MDSCs) comprise heterogeneous myeloid cell populations with immunosuppressive capacity that contribute to immune regulation and tolerance induction. We previously reported impaired MDSC function in patients with primary Sjögren's syndrome (pSS) and mice with experimental SS (ESS). However, the molecular mechanisms underlying MDSC dysfunction remain largely unclear. In this study, we first found that aryl hydrocarbon receptor (AhR) was highly expressed by human and murine polymorphonuclear MDSCs (PMN-MDSCs). Indole-3-propionic acid (IPA), a natural AhR ligand produced from dietary tryptophan, significantly promoted PMN-MDSC differentiation and suppressive function on CD4+ T cells. In contrast, feeding a tryptophan-free diet resulted in a decreased PMN-MDSC response, a phenotype that could be reversed by IPA supplementation. The functional importance of PMN-MDSCs was demonstrated in ESS mice by using a cell-depletion approach. Notably, AhR expression was reduced in PMN-MDSCs during ESS development, while AhR antagonism resulted in exacerbated ESS pathology and dysregulated T effector cells, which could be phenocopied by a tryptophan-free diet. Interferon regulatory factor 4 (IRF4), a repressive transcription factor, was upregulated in PMN-MDSCs during ESS progression. Chromatin immunoprecipitation analysis revealed that IRF4 could bind to the promoter region of AhR, while IRF4 deficiency markedly enhanced AhR-mediated PMN-MDSC responses. Furthermore, dietary supplementation with IPA markedly ameliorated salivary glandular pathology in ESS mice with restored MDSC immunosuppressive function. Together, our results identify a novel function of AhR in modulating the PMN-MDSC response and demonstrate the therapeutic potential of targeting AhR for the treatment of pSS.

FAM96A is essential for maintaining organismal energy balance and adipose tissue homeostasis in mice.

The iron (Fe) metabolism plays important role in regulating systemic metabolism and obesity development. The Fe inside cells can form iron-sulfur (Fe-S) clusters, which are usually assembled into target proteins with the help of a conserved cluster assembly machinery. Family with sequence similarity 96A (FAM96A; also designated CIAO2A) is a cytosolic Fe-S assembly protein involved in the regulation of cellular Fe homeostasis. However, the biological function of FAM96A in vivo is still incompletely defined. Here, we tested the role of FAM96A in regulating organismal Fe metabolism, which is relevant to obesity and adipose tissue homeostasis. We found that in mice genetically lacking FAM96A globally, intracellular Fe homeostasis was interrupted in both white and brown adipocytes, but the systemic Fe level was normal. FAM96A deficiency led to adipocyte hypertrophy and organismal energy expenditure reduction even under nonobesogenic normal chow diet-fed conditions. Mechanistically, FAM96A deficiency promoted mechanistic target of rapamycin (mTOR) signaling in adipocytes, leading to an elevation of de novo lipogenesis and, therefore, fat mass accumulation. Furthermore, it also caused mitochondrial defects, including defects in mitochondrial number, ultrastructure, redox activity, and metabolic function in brown adipocytes, which are known to be critical for the control of energy balance. Moreover, adipocyte-selective FAM96A knockout partially phenocopied global FAM96A deficiency with adipocyte hypertrophy and organismal energy expenditure defects but the mice were resistant to high-fat diet-induced weight gain. Thus, FAM96A in adipocytes may autonomously act as a critical gatekeeper of organismal energy balance by coupling Fe metabolism to adipose tissue homeostasis.

A tyrosine catabolic intermediate 4-hydroxyphenylpyruate attenuates murine endotoxic shock by blocking NLRP3 inflammasome activation.

The metabolic alterations of amino acid metabolism are closely associated with inflammatory response. However, relatively little is known about the roles of phenylalanine (Phe)/tyrosine (Tyr) catabolites during inflammation. Nitisinone (NTBC) is an orphan drug used to treat hereditary tyrosinemia type I potentially by changing Phe/Tyr metabolic flow. In this study, we used NTBC as a tool to investigate the potential role of the Phe/Tyr catabolic pathway in inflammatory responses. We found that NTBC was effective in tempering the bacterial endotoxin lipopolysaccharide (LPS)-induced septic shock in mice. Mechanistically, the protective effect was related to the accumulation of a Phe/Tyr catabolic intermediate, 4-hydroxyphenylpyruvate (4-HPP), induced by the NTBC treatment. 4-HPP could inhibit NLRP3 inflammasome priming and activation processes and therefore reduce IL-1ß release and pyroptosis. Like NTBC, 4-HPP was also effective in attenuating endotoxic shock in mice. Our results suggest the Phe/Tyr catabolic pathway as a potential immunoregulatory hub that may be exploited therapeutically to alleviate inflammation.