PubMed

Eur J Pharmacol. 2024 May 8:176639. doi: 10.1016/j.ejphar.2024.176639. Online ahead of print.ABSTRACTAnlotinib, an orally administered small molecule inhibitor of receptor tyrosine kinases (RTKs), exerts significant anti-angiogenic and vascular normalization effects. However, the mechanisms underlying its involvement in tumor metabolic reprogramming are still unclear. This study aims to investigate the distribution and expression levels of metabolites within tumors after anlotinib treatment using spatial metabolomics analysis. Subsequently, by integrating the transcriptomics and proteomics analyses, we identified that anlotinib treatment primarily modulated four metabolic pathways, including taurine and hypotaurine metabolism, steroid synthesis, pentose phosphate pathway, and lipid biosynthesis. This regulation significantly influenced the metabolic levels of compounds such as sulfonic acids, cholesterol, inositol phosphate pyrophosphate, and palmitoyl-CoA in the tumor, thereby impacting tumor initiation and progression. This study provides potential metabolic biomarkers for anlotinib treatment in tumors.PMID:38729415 | DOI:10.1016/j.ejphar.2024.176639

Environ Res. 2024 May 8:119092. doi: 10.1016/j.envres.2024.119092. Online ahead of print.ABSTRACTWith the acceleration of industrialization, Cd pollution has emerged as a major threat to soil ecosystem health and food safety. Hyperaccumulating plants like Sedum alfredii Hance are considered to be used as part of an effective strategy for the ecological remediation of Cd polluted soils. This study delved deeply into the physiological, transcriptomic, and metabolomic responses of S. alfredii under cadmium (Cd) stress when treated with exogenous salicylic acid (SA). We found that SA notably enhanced the growth of S. alfredii and thereby increased absorption and accumulation of Cd, effectively alleviating the oxidative stress caused by Cd through upregulation of the antioxidant system. Transcriptomic and metabolomic data further unveiled the influence of SA on photosynthesis, antioxidant defensive mechanisms, and metal absorption enrichment pathways. Notably, the interactions between SA and other plant hormones, especially IAA and JA, played a central role in these processes. These findings offer us a comprehensive perspective on understanding how to enhance the growth and heavy metal absorption capabilities of hyperaccumulator plants by regulating plant hormones, providing invaluable strategies for future environmental remediation efforts.PMID:38729407 | DOI:10.1016/j.envres.2024.119092

J Dent. 2024 May 8:105046. doi: 10.1016/j.jdent.2024.105046. Online ahead of print.ABSTRACTOBJECTIVES: The high prevalence of antibiotic-resistant bacteria poses a threat to the global public health. The appropriate use of adjuvants to restore the antimicrobial activity of antibiotics against resistant bacteria could be an effective strategy for combating antibiotic resistance. In this study, we investigated the counteraction of Triton X-100 (TX-100) and the mechanisms underlying the antibiotic resistance of Enterococcus faecalis (E. faecalis).METHODS: Standard, wild-type (WT), and induced antibiotic-resistant E. faecalis strains were used in this study. In vitro antibacterial experiments were conducted to evaluate the antimicrobial activities of gentamicin sulfate and ciprofloxacin hydrochloride in the presence and absence of 0.02% TX-100 against both planktonic and biofilm bacteria. Transcriptomic and untargeted metabolomic analyses were performed to explore the molecular mechanisms of TX-100 as an antibiotic adjuvant. Additionally, membrane permeability, membrane potential, glycolysis-related enzyme activity, intracellular adenosine triphosphate (ATP), and expression levels of virulence genes were assessed. The biocompatibility of different drug combinations was also evaluated.RESULTS: A substantially low TX-100 concentration improved the antimicrobial effects of gentamicin sulfate or ciprofloxacin hydrochloride against antibiotic-resistant E. faecalis. Mechanistic studies demonstrated that TX-100 increased cell membrane permeability and dissipated membrane potential. Moreover, antibiotic resistance and pathogenicity of E. faecalis were attenuated by TX-100 via downregulation of the ABC transporter, phosphotransferase system (PTS), and ATP supply.CONCLUSIONS: TX-100 enhanced the antimicrobial activity of gentamicin sulfate and ciprofloxacin hydrochloride at a low concentration by improving antibiotic susceptibility and attenuating antibiotic resistance and pathogenicity of E. faecalis.CLINICAL SIGNIFICANCE: These findings provide a theoretical basis for developing new root canal disinfectants that can reduce antibiotic resistance.PMID:38729285 | DOI:10.1016/j.jdent.2024.105046

Chem Biol Interact. 2024 May 8:111044. doi: 10.1016/j.cbi.2024.111044. Online ahead of print.ABSTRACTMastitis is an inflammatory disease of the mammary gland with a high incidence in lactating animals, significantly impacting their health and breastfeeding. Moreover, mastitis adversely affects milk quality and yield, resulting in substantial economic losses for the dairy farming industry. Forsythiaside A (FTA), a phenylethanol glycoside analog extracted from Forsythia, exhibits notable anti-inflammatory and antioxidant properties. However, its protective effects and specific mechanisms against mastitis remain unclear. In this study, a lipopolysaccharide (LPS)-induced mouse mastitis model was used to investigate the protective effect of FTA on LPS-induced mastitis and its potential mechanism using histological assays, western blot, qRT-PCR, FITC-albumin permeability test, 16s rRNA gene sequencing analysis and non-targeted metabolomics assays to investigate the protective effect of FTA on LPS-induced mastitis model and its potential mechanism. The results demonstrated that FTA significantly mitigated LPS-induced mouse mastitis by reducing inflammation and apoptosis levels, modulating the PI3K/AKT/mTOR signaling pathways, inducing autophagy, and enhancing antioxidant capacity and the expression of tight junction proteins. Furthermore, FTA increased the abundance of beneficial microbiota while decreasing the levels of harmful microbiota in mice, thus counteracting the gut microbiota disruption induced by LPS stimulation. Intestinal metabolomics analysis revealed that FTA primarily regulated LPS-induced metabolite alterations through key metabolic pathways, such as tryptophan metabolism. This study confirms the anti-inflammatory and antioxidant effects of FTA on mouse mastitis, which are associated with key metabolic pathways, including the restoration of gut microbiota balance and the regulation of tryptophan metabolism. These findings provide a novel foundation for the treatment and prevention of mammalian mastitis using FTA.PMID:38729284 | DOI:10.1016/j.cbi.2024.111044

Biochim Biophys Acta Mol Cell Biol Lipids. 2024 May 8:159505. doi: 10.1016/j.bbalip.2024.159505. Online ahead of print.ABSTRACTTylophora indica (Burm f.) Merrill, belong to family Asclepiadaceae, is considered to be a natural remedy with high medicinal benefits. The objective of this work is to assess the metabolomic profile of T. indica leaves enriched in alkaloids, as well as to evaluate the in vitro cytotoxicity of these leaves using the MTT assay on human breast MCF-7 and liver HepG2 cancer cell lines. Dried leaves of T. indica were extracted by sonication, using methanol containing 2 % (v/v) of acetic acid and obtained fraction was characterized by HPTLC and UPLC-MS. The UPLC-MS study yielded a preliminary identification of 32 metabolites, with tylophorine, tylophorine B, tylophorinine, and tylophorinidine being the predominant metabolites. The cytotoxicity of the extract of T. indica was evaluated on HepG2 and MCF-7 cell lines, yielding inhibitory concentration (IC50) values of 75.71 μg/mL and 69.60 μg/mL, respectively. Data suggested that the phytochemical screening clearly showed presence of numerous secondary metabolites with moderate cytotoxic efficacy. In conclusion, the future prospects of T. indica appear promising for the advancement of phytopharmaceutical-based anticancer medications, as well as for the design of contemporary pharmaceuticals in the field of cancer chemotherapy.PMID:38729236 | DOI:10.1016/j.bbalip.2024.159505

Biomed Pharmacother. 2024 May 9;175:116701. doi: 10.1016/j.biopha.2024.116701. Online ahead of print.ABSTRACTNicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) have received considerable attention as anti-aging and anti-metabolic disease nutraceuticals. However, few studies have focused on their role in ameliorating hepatic metabolic disturbances. In the present study, the effects of NMN and NR on the liver of mice with nonalcoholic fatty liver disease (NAFLD) were investigated via transcriptome and metabolome analyses. NMN and NR reduced body weight gain, improved glucose homeostasis, regulated plasma lipid levels, and ameliorated liver injury, oxidative stress, and lipid accumulation in mice with HFD-induced NAFLD. Integrated transcriptome and metabolome analyses indicated that NMN and NR altered the biosynthesis of unsaturated fatty acids, arachidonic acid metabolism, and linoleic acid metabolism pathways, increased saturated fatty acid (palmitic acid, stearate, and arachidic acid) content, and increased polyunsaturated fatty acid (linoleic acid and eicosapentaenoic acid) content. Quantitative reverse transcription PCR (qRT-PCR) showed that NMN and NR primarily promoted arachidonic acid and linoleic acid catabolism via cytochrome P450 (CYP450) enzymes. This study established a theoretical foundation for the potential use of NMN and NR in future clinical settings.PMID:38729053 | DOI:10.1016/j.biopha.2024.116701

Food Chem. 2024 Apr 28;452:139501. doi: 10.1016/j.foodchem.2024.139501. Online ahead of print.ABSTRACTTo clarify the change mechanism of biological activity and physicochemical characteristics in Lacticaseibacillus paracasei JY025 fortified milk powder (LFMP) during storage, morphological observation, JY025 survival, storage stability, and metabolomics of LFMP were determined during the storage period in this study. The results showed that the LFMP had a higher survival rate of JY025 compared with the bacterial powder of JY025 (LBP) during storage, which suggested that milk powder matrix could reduce strain JY025 mortality under prolonged storage in the LFMP samples. The fortification of strain JY025 also affected the stability of milk powder during the storage period. There was lower water activity and higher glass transition temperature in LFMP samples compared with blank control milk powder (BCMP) during storage. Moreover, the metabolomics results of LFMP indicated that vitamin degradation, Maillard reaction, lipid oxidation, tricarboxylic acid cycle, and lactobacilli metabolism are interrelated and influence each other to create complicated metabolism networks.PMID:38728887 | DOI:10.1016/j.foodchem.2024.139501

J Hazard Mater. 2024 Apr 27;472:134448. doi: 10.1016/j.jhazmat.2024.134448. Online ahead of print.ABSTRACTMicroplastics (MPs) are a major concern in marine ecosystem because MPs are persistent and ubiquitous in oceans and are easily consumed by marine biota. Although many studies have reported the toxicity of MPs to marine biota, the toxicity of environmentally relevant types of MPs is little understood. We investigated the toxic effects of fragmented polyethylene terephthalate (PET) MP, one of the most abundant MPs in the ocean, on the marine rotifer Brachionus koreanus at the individual and molecular level. No significant rotifer mortality was observed after exposure to PET MPs for 24 and 48 h. The ingestion and egestion assays showed that rotifers readily ingested PET MPs in the absence of food but not when food was supplied; thus, there were also no chronic effects of PET MPs. In contrast, intracellular reactive oxygen species levels and glutathione S-transferase activity in rotifers were significantly increased by PET MPs. Transcriptomic and metabolomic analyses revealed that genes and metabolites related to energy metabolism and immune processes were significantly affected by PET MPs in a concentration-dependent manner. Although acute toxicity of PET MPs was not observed, PET MPs are potentially toxic to the antioxidant system, immune system, and energy metabolism in rotifers.PMID:38728862 | DOI:10.1016/j.jhazmat.2024.134448

Plant Physiol Biochem. 2024 May 3;211:108704. doi: 10.1016/j.plaphy.2024.108704. Online ahead of print.ABSTRACTNanomaterials (NMs) have proven to be a game-changer in agriculture, showcasing their potential to boost plant growth and safeguarding crops. The agricultural sector has widely adopted NMs, benefiting from their small size, high surface area, and optical properties to augment crop productivity and provide protection against various stressors. This is attributed to their unique characteristics, contributing to their widespread use in agriculture. Human exposure from various components of agro-environmental sectors (soil, crops) NMs residues are likely to upsurge with exposure paths may stimulates bioaccumulation in food chain. With the aim to achieve sustainability, nanotechnology (NTs) do exhibit its potentials in various domains of agriculture also have its flip side too. In this review article we have opted a fusion approach using bibliometric based analysis of global research trend followed by a holistic assessment of pros and cons i.e. toxicological aspect too. Moreover, we have also tried to analyse the current scenario of policy associated with the application of NMs in agro-environment.PMID:38728836 | DOI:10.1016/j.plaphy.2024.108704

Curr Opin Biotechnol. 2024 May 8;87:103135. doi: 10.1016/j.copbio.2024.103135. Online ahead of print.ABSTRACTPlant bioactives hold immense potential in the medicine and food industry. The recent advancements in omics applied in deciphering specialized metabolic pathways underscore the importance of high-quality genome releases and the wealth of data in metabolomics and transcriptomics. While harnessing data, whether integrated or standalone, has proven successful in unveiling plant natural product (PNP) biosynthetic pathways, the democratization of machine learning in biology opens exciting new opportunities for enhancing the exploration of these pathways. This review highlights the recent breakthroughs in disrupting plant-specialized biosynthetic pathways through the utilization of omics data harnessing and machine learning techniques.PMID:38728826 | DOI:10.1016/j.copbio.2024.103135

Environ Sci Technol. 2024 May 10. doi: 10.1021/acs.est.3c09148. Online ahead of print.ABSTRACTThis randomized crossover study investigated the metabolic and mRNA alterations associated with exposure to high and low traffic-related air pollution (TRAP) in 50 participants who were either healthy or were diagnosed with chronic pulmonary obstructive disease (COPD) or ischemic heart disease (IHD). For the first time, this study combined transcriptomics and serum metabolomics measured in the same participants over multiple time points (2 h before, and 2 and 24 h after exposure) and over two contrasted exposure regimes to identify potential multiomic modifications linked to TRAP exposure. With a multivariate normal model, we identified 78 metabolic features and 53 mRNA features associated with at least one TRAP exposure. Nitrogen dioxide (NO2) emerged as the dominant pollutant, with 67 unique associated metabolomic features. Pathway analysis and annotation of metabolic features consistently indicated perturbations in the tryptophan metabolism associated with NO2 exposure, particularly in the gut-microbiome-associated indole pathway. Conditional multiomics networks revealed complex and intricate mechanisms associated with TRAP exposure, with some effects persisting 24 h after exposure. Our findings indicate that exposure to TRAP can alter important physiological mechanisms even after a short-term exposure of a 2 h walk. We describe for the first time a potential link between NO2 exposure and perturbation of the microbiome-related pathways.PMID:38728551 | DOI:10.1021/acs.est.3c09148

Angew Chem Int Ed Engl. 2024 May 10:e202405165. doi: 10.1002/anie.202405165. Online ahead of print.ABSTRACTVarious nonribosomal peptide synthetases (NRPS) create structural and functional diversity by incorporating a-hydroxy acids into peptide backbones. Trigonic acid, an unusual cyclopropanol-substituted hydroxy acid, is the source of the molecular warhead of malleicyprol, a critical virulence factor of human and animal pathogens of the Burkholderia pseudomallei (BP) group. The process of selecting and loading this building block remained enigmatic as the NRPS module designated for this task is noncanonical. Using a combination of bioinformatics, mutational analyses, targeted metabolomics, and in vitro biochemical assays, we show that two trans-acting enzymes are required to load this central building block onto the modular assembly line. An adenylation-thiolation didomain enzyme (BurJ) activates trigonic acid, followed by the translocation of the enzyme-bound α-hydroxy acid thioester by an FkbH-like protein with a mutated phosphatase domain (BurH). This specialized gateway is the first reported direct loading of a hydroxy acid onto a bona fide NRPS module in bacteria and expands the synthetic biology toolbox for the site-specific incorporation of non-canonical building blocks. Moreover, insight into the biochemical basis of virulence factor biosynthesis can provide a foundation for developing enzyme inhibitors as anti-virulence therapeutics against BP pathogen infections.PMID:38728443 | DOI:10.1002/anie.202405165

Tree Physiol. 2024 May 10:tpae051. doi: 10.1093/treephys/tpae051. Online ahead of print.ABSTRACTFlavonoids are crucial medicinal active ingredients in Ginkgo biloba. However, the effect of protein post-translational modifications (PTMs) on flavonoid biosynthesis remains poorly explored. Lysine acetylation, a reversible PTM, plays a crucial role in metabolic regulation. This study aims to investigate the potential role of acetylation in G. biloba flavonoid biosynthesis. Through comprehensive analysis of transcriptomes, metabolomes, proteomes, and acetylated proteins in different tissues, a total of 11,788 lysine acetylation sites were identified on 4324 acetylated proteins, including 89 acetylation sites on 23 proteins. Additionally, 128 types of differentially accumulated flavonoids were identified among tissues, and a dataset of differentially expressed genes related to the flavonoid biosynthesis pathway was constructed. Twelve (CHI, C3H1, ANR, DFR, CCoAOMT1, F3H1, F3H2, CCoAOMT2, C3H2, HCT, F3'5'H, and FG2) acetylated proteins that might be involved in flavonoid biosynthesis were identified. Specifically, we found that the modification levels of CCoAOMT1 and F3'5'H sites correlated with the catalytic production of homoeriodictyol and dihydromyricetin, respectively. Inhibitors of lysine deacetylase (trichostatin A, TSA) impacted total flavonoid content in different tissues and increased flavonoid levels in G. biloba roots. Treatment with TSA revealed that expression levels of GbF3'5'H and GbCCoAOMT1 in stems and leaves aligned with total flavonoid content variations, while in roots, expression levels of GbC3H2 and GbFG2 corresponded to total flavonoid content changes. Collectively, these findings reveal for the first time the important role of acetylation in flavonoid biosynthesis.PMID:38728368 | DOI:10.1093/treephys/tpae051

PLoS One. 2024 May 10;19(5):e0292978. doi: 10.1371/journal.pone.0292978. eCollection 2024.ABSTRACTEndosalpingiosis (ES) and endometriosis (EM) refer to the growth of tubal and endometrial epithelium respectively, outside of their site of origin. We hypothesize that uterine secretome factors drive ectopic growth. To test this, we developed a mouse model of ES and EM using tdTomato (tdT) transgenic fluorescent mice as donors. To block implantation factors, progesterone knockout (PKO) tdT mice were created. Fluorescent lesions were present after oviduct implantation with and without WT endometrium. Implantation was increased (p<0.05) when tdt oviductal tissue was implanted with endometrium compared to oviductal tissue alone. Implantation was reduced (p<0.0005) in animals implanted with minced tdT oviductal tissue with PKO tdT endometrium compared to WT endometrium. Finally, oviductal tissues was incubated with and without a known implantation factor, leukemia inhibitory factor (LIF) prior to and during implantation. LIF promoted lesion implantation. In conclusion, endometrial derived implantation factors, such as LIF, are necessary to initiate ectopic tissue growth. We have developed an animal model of ectopic growth of gynecologic tissues in a WT mouse which will potentially allow for development of new prevention and treatment modalities.PMID:38728307 | DOI:10.1371/journal.pone.0292978

Arch Microbiol. 2024 May 10;206(6):254. doi: 10.1007/s00203-024-03977-7.ABSTRACTPhthalic acid esters (PAEs) are human made chemicals widely used as plasticizers to enhance the flexibility of plastic products. Due to the lack of chemical bonding between phthalates and plastics, these materials can easily enter the environment. Deleterious effects caused by this chemo-pollutant have drawn the attention of the scientific community to remediate them from different ecosystem. In this context, many bacterial strains have been reported across different habitats and Sphingobium yanoikuyae strain P4 is among the few psychrotolerant bacterial species reported to biodegrade simple and complex phthalates. In the present study, biodegradation of three structurally different PAEs viz., diethyl phthalate (DEP), di-isobutyl phthalate (DIBP), and butyl benzyl phthalate (BBP) have been investigated by the strain P4. Quantitative analyses through High-performance liquid chromatography (HPLC) revealed that the bacterium completely degraded 1 g/L of DEP, DIBP, and BBP supplemented individually in minimal media pH 7.0 within 72, 54, and 120 h of incubation, respectively, at 28 °C and under shake culture condition (180 rpm). In addition, the strain could grow in minimal media supplemented individually with up to 3 g/L of DEP and 10.0 g/L of DIBP and BBP at 28 °C and pH 7.0. The strain also could grow in metabolites resulting from biodegradation of DEP, DIBP, and BBP, viz. n-butanol, isobutanol, butyric acid, ethanol, benzyl alcohol, benzoic acid, phthalic acid, and protocatechuic acid. Furthermore, phthalic acid and protocatechuic acid were also detected as degradation pathway metabolites of DEP and DIBP by HPLC, which gave an initial idea about the biodegradation pathway(s) of these phthalates.PMID:38727835 | DOI:10.1007/s00203-024-03977-7

Anal Chem. 2024 May 10. doi: 10.1021/acs.analchem.3c05574. Online ahead of print.ABSTRACTThe exploration of metabolomics and targeted segments of proteins stands as a pivotal facet of Nuclear Magnetic Resonance (NMR) analysis, furnishing valuable insights into molecular architectures and potential therapeutic applications. The issue of spectral congestion frequently presents challenges in ascribing distinct peaks within the confines of both one-dimensional (1D) and two-dimensional (2D) NMR spectra. Numerous strategies have been proposed to resolve specific resonances in NMR spectra differentially. Among these approaches, relaxation editing emerges as a viable solution. In the realm of relaxation phenomena within NMR, Long-Lived States (LLS) and Long-Lived Coherences (LLC) manifest as promising phenomena, offering enhanced relaxation lifetimes in comparison to the traditional longitudinal (T1) and transverse (T2) relaxation times for coupled nuclear spins. Notably, LLC presents a pathway to attenuate uncoupled high-intensity peaks, effectively diminishing their impact. The foundation of this technique rests upon the premise that the relaxation lifetime in the rotating frame (T1ρ) remains smaller than TLLC. In pursuit of refining spectral assignments within complex mixtures, we introduce a new pulse sequence tailored for LLC Total Correlation Spectroscopy (LLC-TOCSY). This demonstrates efficacy in extracting LLC signals within configurations involving multiple coupled spins, thereby decluttering the spectrum and enhancing the accuracy of peak assignments. To validate the effectiveness of this method, a collection of samples was subjected to scrutiny, yielding compelling results.PMID:38727639 | DOI:10.1021/acs.analchem.3c05574

Pediatr Allergy Immunol. 2024 May;35(5):e14133. doi: 10.1111/pai.14133.ABSTRACTFood allergy (FA) is a widespread issue, affecting as many as 10% of the population. Over the past two to three decades, the prevalence of FA has been on the rise, particularly in industrialized and westernized countries. FA is a complex, multifactorial disease mediated by type 2 immune responses and involving environmental and genetic factors. However, the precise mechanisms remain inadequately understood. Metabolomics has the potential to identify disease endotypes, which could beneficially promote personalized prevention and treatment. A metabolome approach would facilitate the identification of surrogate metabolite markers reflecting the disease activity and prognosis. Here, we present a literature overview of recent metabolomic studies conducted on children with FA.PMID:38727629 | DOI:10.1111/pai.14133

ACS Nano. 2024 May 10. doi: 10.1021/acsnano.4c01835. Online ahead of print.ABSTRACTIn the current work, the foliar application of selenium nanomaterials (Se0 NMs) suppressed sheath blight in rice (Oryza sativa). The beneficial effects were nanoscale specific and concentration dependent. Specifically, foliar amendment of 5 mg/L Se0 NMs decreased the disease severity by 68.8% in Rhizoctonia solani-infected rice; this level of control was 1.57- and 2.20-fold greater than that of the Se ions with equivalent Se mass and a commercially available pesticide (Thifluzamide). Mechanistically, (1) the controlled release ability of Se0 NMs enabled a wider safe concentration range and greater bioavailability to Se0 NMs, and (2) transcriptomic and metabolomic analyses demonstrated that Se0 NMs simultaneously promoted the salicylic acid- and jasmonic-acid-dependent acquired disease resistance pathways, antioxidative system, and flavonoid biosynthesis. Additionally, Se0 NMs improved rice yield by 31.1%, increased the nutritional quality by 6.4-7.2%, enhanced organic Se content by 44.8%, and decreased arsenic and cadmium contents by 38.7 and 42.1%, respectively, in grains as compared with infected controls. Human simulated gastrointestinal tract model results showed that the application of Se0 NMs enhanced the bioaccessibility of Se in grains by 22.0% and decreased the bioaccessibility of As and Cd in grains by 20.3 and 13.4%, respectively. These findings demonstrate that Se0 NMs can serve as an effective and sustainable strategy to increase food quality and security.PMID:38727520 | DOI:10.1021/acsnano.4c01835

Cells. 2024 Apr 29;13(9):760. doi: 10.3390/cells13090760.ABSTRACTDerangement of the epidermal barrier lipids and dysregulated immune responses are key pathogenic features of atopic dermatitis (AD). The Th2-type cytokines interleukin IL-4 and IL-13 play a prominent role in AD by activating the Janus Kinase/Signal Transduction and Activator of Transcription (JAK/STAT) intracellular signaling axis. This study aimed to investigate the role of JAK/STAT in the lipid perturbations induced by Th2 signaling in 3D epidermal equivalents. Tofacitinib, a low-molecular-mass JAK inhibitor, was used to screen for JAK/STAT-mediated deregulation of lipid metabolism. Th2 cytokines decreased the expression of elongases 1, 3, and 4 and serine-palmitoyl-transferase and increased that of sphingolipid delta(4)-desaturase and carbonic anhydrase 2. Th2 cytokines inhibited the synthesis of palmitoleic acid and caused depletion of triglycerides, in association with altered phosphatidylcholine profiles and fatty acid (FA) metabolism. Overall, the ceramide profiles were minimally affected. Except for most sphingolipids and very-long-chain FAs, the effects of Th2 on lipid pathways were reversed by co-treatment with tofacitinib. An increase in the mRNA levels of CPT1A and ACAT1, reduced by tofacitinib, suggests that Th2 cytokines promote FA beta-oxidation. In conclusion, pharmacological inhibition of JAK/STAT activation prevents the lipid disruption caused by the halted homeostasis of FA metabolism.PMID:38727296 | DOI:10.3390/cells13090760

Cells. 2024 Apr 23;13(9):734. doi: 10.3390/cells13090734.ABSTRACTThe histone deacetylase inhibitor (HDACi) valproic acid (VPA) has neuroprotective and anti-inflammatory effects in experimental traumatic brain injury (TBI), which have been partially attributed to the epigenetic disinhibition of the transcription repressor RE1-Silencing Transcription Factor/Neuron-Restrictive Silencer Factor (REST/NRSF). Additionally, VPA changes post-traumatic brain injury (TBI) brain metabolism to create a neuroprotective environment. To address the interconnection of neuroprotection, metabolism, inflammation and REST/NRSF after TBI, we subjected C57BL/6N mice to experimental TBI and intraperitoneal VPA administration or vehicle solution at 15 min, 1, 2, and 3 days post-injury (dpi). At 7 dpi, TBI-induced an up-regulation of REST/NRSF gene expression and HDACi function of VPA on histone H3 acetylation were confirmed. Neurological deficits, brain lesion size, blood-brain barrier permeability, or astrogliosis were not affected, and REST/NRSF target genes were only marginally influenced by VPA. However, VPA attenuated structural damage in the hippocampus, microgliosis and expression of the pro-inflammatory marker genes. Analyses of plasma lipidomic and polar metabolomic patterns revealed that VPA treatment increased lysophosphatidylcholines (LPCs), which were inversely associated with interleukin 1 beta (Il1b) and tumor necrosis factor (Tnf) gene expression in the brain. The results show that VPA has mild neuroprotective and anti-inflammatory effects likely originating from favorable systemic metabolic changes resulting in increased plasma LPCs that are known to be actively taken up by the brain and function as carriers for neuroprotective polyunsaturated fatty acids.PMID:38727269 | DOI:10.3390/cells13090734