Search Results (95)

Background/Objectives: Diatomaceous earth (DE), a natural substance rich in amorphous silica and recognized as a food additive, is gaining attention as a dietary silicon supplement. However, its bioavailability and impact on lipid digestion and absorption remain poorly characterized. This study aimed to investigate silicon bioavailability after short-term DE supplementation and its effects on postprandial glycemia and triglyceridemia, the expression of lipid metabolism-related proteins, and the modulation of the intestinal mucosal barrier. Methods: Female Wistar rats received daily oral supplementation of DE (equivalent to 2 or 4 mg silicon/kg body weight) for one week. Silicon digestibility, excretion, and hepatic accumulation were quantified. Postprandial glycemia and triglyceridemia were monitored. Lipid profile was analyzed by HPSEC in gastric and intestinal contents. Jejunal morphology and mucin-secreting cells were assessed histologically. Lipid metabolism markers were evaluated by immunohistochemistry and Western blot in both intestinal and hepatic tissues. Results: DE supplementation enhanced silicon absorption and increased hepatic levels. Fecal output and moisture content were also elevated, especially at the higher dose. DE significantly reduced postprandial triglyceridemia and consequently increased luminal triglyceride retention. These changes were associated with decreased jejunal levels of IFABP, ACAT2, and MTP, as well as reduced hepatic levels of MTP and LDLr, alongside increased levels of ABCG5/G8 and LXRα/β, indicating a partial blockage of lipid absorption and enhanced cholesterol efflux. The effects on the intestinal barrier were evidenced by villi shortening and an increase in mucin-producing cells. Conclusion: Food-grade DE is a bioavailable source of silicon with hypolipidemic potential, mainly by reducing intestinal lipid absorption. This is supported by lower postprandial triglycerides, increased luminal lipid retention, and decreased expression of lipid transport proteins. The study in healthy female rats underscores the importance of sex-specific responses and supports DE as a dietary strategy to improve lipid metabolism. Full article

Fertilization management constitutes a critical determinant of agroecosystem productivity. Reasonable fertilization can increase the organic matter content in soil; however, the potential mechanism of how different fertilization regimes impact soil carbon sequestration is unclear. We hypothesized that the combined application of biochar and organic fertilizer would enhance soil carbon sequestration by improving soil physicochemical conditions, increasing microbial activity, and promoting the accumulation of stable forms of carbon. This study systematically investigated different regimes, including the application of chemical fertilizer alone (SCN), chemical fertilizer with biochar (SCB), chemical fertilizer with organic fertilizer (SCO), and chemical fertilizer with both biochar and organic fertilizer (SCBO), on soil physiochemical properties, enzyme activities, labile organic carbon fractions, microbial carbon fixation gene expression, and community composition. The results demonstrated that (1) the application of organic materials significantly enhanced soil nutrient levels and enzyme activities, with the best performance from SCBO; (2) the organic materials increased the labile soil organic carbon (SOC) content and the carbon pool management index, with SCO showing the highest at 69.82%; (3) SCB and SCBO improved the stability of soil carbon components by increasing the proportion of Aromatic C; and (4) the carbon fixation genes ACAT and sdhA exhibited the highest abundance in SCBO. In parallel, the relative abundance of Actinomycetota increased with the application of organic materials, reaching its peak in SCBO. Mantel testing revealed a strong correlation between microbial community composition and SOC, emphasizing the importance of SOC in microbial growth and metabolism. Moreover, the strong correlation between carbon fixation genes and aromatic carbon suggested that specific carbon forms, particularly aromatic structures, played a critical role in driving microbial carbon fixation processes. Full article

Common and rare variation in CACNA1C gene expression has been consistently associated with neuropsychiatric disorders such as schizophrenia, bipolar disorder, and major depression. However, the underlying biological pathways that cause this association have yet to be fully determined. In this study, we present evidence that rats with a reduced gene dosage of Cacna1c have increased basal corticosterone levels in the periphery and reduced the expression of Nr3c1 encoding the glucocorticoid receptor in the hippocampus and hypothalamus. These results are consistent, with an effect of Cacna1c dosage on hypothalamus–pituitary–adrenal (HPA) axis function. Heterozygous Cacna1c rats had lower levels of the histone markers H3K4me3 and H3K27acat exon 1₇ of the Nr3c1 gene. These histone modifications are typically linked to increased gene expression, but here were not associated with changes in the expression of exon 1₇ variants under non-stress conditions. Heterozygous Cacna1c rats additionally show increased anxiety behaviours. These results support an association of Cacna1c heterozygosity with the altered activity of the HPA axis and function in the resting state, and this may be a predisposing mechanism that contributes to the increased risk of psychiatric disorders with stress. Full article

Intramuscular fat (IMF) content in beef cattle is a critical determinant of beef meat quality, as it positively influences juiciness, tenderness, and palatability. In China, the crossbreeding of Wagyu and Angus is a prevalent method for achieving a better marbling level. However, the molecular mechanisms governing IMF regulation in these crossbreeds remain poorly understood. To elucidate the mechanism of IMF deposition in these crossbred cattle, we conducted a comparative transcriptomic analysis of longissimus dorsi muscles and livers from cattle with divergent IMF content. RNA-seq revealed 940 and 429 differentially expressed genes (DEGs) in the liver and muscle, respectively, with 60 genes co-differentially expressed (co-DEGs) in both tissues. Functional enrichment highlighted lipid metabolism pathways including fatty acid β-oxidation, PPAR signaling, and glycerolipid metabolism. A total of eleven genes including ACAA2, ACADL, ACOX2, CPT1B, CPT2, LPL, SLC27A1, ACAT1, GK, ACOX3, and ACSM5, were screened as key candidate genes for IMF deposition. A “liver–muscle” regulatory network of IMF deposition was built to illustrate the tissues’ interaction. The reliability of the transcriptomic data was verified by quantitative reverse real-time PCR (qRT-PCR). Our findings provide novel molecular markers for increasing the IMF content and accelerating the genetic improvement of beef quality traits in crossbred cattle. Full article

Diosgenin, a crucial precursor for steroidal drug production, has poorly understood regulatory pathways. Diosgenin is the primary active component of Dioscorea zingiberensis. Notably, D. zingiberensis also possesses the highest diosgenin content among Dioscorea species, reaching up to 16.15% of dry weight. This study identified DZHDZ32 as a potential regulator of diosgenin biosynthesis in D. zingiberensis through transient overexpression. To validate its function, we developed an optimized genetic transformation method for D. zingiberensis and generated two DZHDZ32-overexpressing lines. The DZHDZ32 transcription factor belongs to the HD-ZIP I subfamily and is localized to the nucleus. Notably, overexpression of DZHDZ32 resulted in a significant increase in its transcript levels in leaves (264.59- and 666.93-fold), leading to elevated levels of diosgenin and its biosynthetic intermediates, including cholesterol and β-sitosterol. Specifically, diosgenin content increased by 41.68% and 68.07%, cholesterol by 10.29% and 16.03%, and β-sitosterol by 12.33% and 19.49% in leaves compared to wild-type plants. Yeast one-hybrid and dual-luciferase assays demonstrated that DZHDZ32 directly binds to the promoters of ACAT and GPPS1, consistent with the significant upregulation of ACAT and GPPS1 expression (3.69- and 4.87-fold and 4.75- and 6.53-fold, respectively) in the overexpressing lines. This study established an optimized genetic transformation method for D. zingiberensis and identified DZHDZ32 as a key regulator of diosgenin biosynthesis. The discovery of DZHDZ32 has significant implications for enhancing diosgenin production and advancing steroidal drug development. Full article

The Nanjiang Yellow Goat (NJYG), Jintang Black Goat (JTBG), and Jianzhou Da’er Goat (JZDEG) are representative local goat breeds for meat production in Sichuan Province, China. This study conducted a comprehensive evaluation of the meat quality of the longissimus dorsi muscle of three goat breeds. Variations in meat quality were observed in terms of meat pH, color, ash and fat content, water activity, and muscle fiber structure. Quantitative proteomics analysis was employed to identify biomarkers for goat meat quality, revealing hundreds of differentially expressed proteins among three goat breeds. KEGG enrichment analysis revealed enriched pathways including oxidative phosphorylation, thermogenesis, citrate cycle (TCA cycle), fatty acid degradation and metabolism, as well as valine, leucine, and isoleucine degradation. Moreover, weighted protein co-expression network analysis and protein–protein interaction analysis uncovered valuable biomarkers, including GSTM3, NDUFS, OGDH, ACO2, HADH, ACAT1, ACADS, ACAA2, HSPG2, ITGA7, PARVB, ALDH9A1, ADH5, and LOC102190016, for assessing goat meat quality. This investigation highlighted the disparities in meat quality among local goat breeds in Sichuan, China, and provided insights into underlying biological pathways and valuable biomarkers for goat meat quality. Full article

Butterfly larvae display intricate cognitive capacities and behaviors, but relatively little is known about how those behaviors alter their brains at the molecular level. Here, we optimized a hybridization chain reaction 3.0 (HCR v3.0) protocol to visualize the expression of multiple RNA molecules in fixed larval brains of the African butterfly Bicyclus anynana. We optimized the polyacrylamide gel mounting, fixation, and sample permeabilization steps, and mapped the expression domains of ten genes in whole larval brain tissue at single-cell resolution. The genes included optomotor blind (omb), yellow-like, zinc finger protein SNAI2-like (SNAI2), weary (wry), extradenticle (exd), Synapsin, Distal-less (Dll), bric-à-brac 1 (bab1), dachshund (dac), and acetyl coenzyme A acetyltransferase B (AcatB). This method can be used alongside single-cell sequencing to visualize the spatial location of brain cells that change in gene expression or splicing patterns in response to specific behaviors or cognitive experiences. Full article

The cholesterol biosynthesis pathway is upregulated during breast cancer development and progression. Inhibition of the aberrantly upregulated cholesterol pathway by statins reduces breast tumor incidence and burden by 50% in SV40 C3(1) TAg mice, a mouse model of triple negative breast cancer. We hypothesized that fluvastatin’s preventive efficacy could be further enhanced by co-targeting the statin-induced restorative feedback pathways that tightly control the cholesterol pathway and are involved in resistance to statins. Acyl-coenzyme A: cholesterol acyltransferase (ACAT)2 is a cholesterol esterification gene that is upregulated in statin-resistant MCF10.DCIS cells, and in mammary tumors of statin-non-responsive SV40 C3(1) TAg mice. In support of this hypothesis, a combination of fluvastatin and avasimibe effectively inhibited the cell growth of statin-resistant MCF10.DCIS cells. However, this combination failed to prevent breast tumor formation in SV40 C3(1) TAg mice. Although avasimibe inhibited fluvastatin-induced ACAT2 mRNA expression in the breast tissue of the combination-treated mice, confirming that avasimibe effectively hit its target, the fluvastatin and avasimibe combination was completely ineffective in preventing breast cancer in vivo, with approximately 90% of mice developing tumors by 22 weeks, similar to the vehicle control group animals. These findings, along with avasimibe’ s known interactions with CYP450 gene family members, suggest that AVA abrogates the efficacy of fluvastatin through enhanced metabolism of fluvastatin in vivo. The findings reported in this brief communication provide a cautionary note for studies proposing the use of avasimibe in combination therapy for cancer prevention and treatment. Full article

In the present work, nine ‘defect’ perovskites with the chemical formula A₂ZrX₆ have been studied, where the A-site cations are a methylammonium cation, formamidinium cation, and trimethyl-sulfonium cation and the X-site anions are halogen, X = Cl, Br, and I. We employ periodic DFT calculations using GGA-PBE, MBJ, HSEsol, and HSE06 functionals. All studied compounds exhibit a wide-bandgap energy that ranges from 5.22 eV to 2.11 eV, while for some cases, geometry optimization led to significant structural modification. It was found that the increase in the halogen size resulted in a decrease in the bandgap energy. The choice of the organic A-site cation affects the bandgap as well, which is minimal for the methylammonium cation. Such semiconductors with organic cations may be utilized in optoelectronic devices, given the substantial benefit of solution processability and thin film formation compared to purely inorganic analogs, such as Cs₂ZrX₆. Full article

Colorectal cancer (CRC) is recognized as the third most lethal cancer worldwide. While existing treatment options demonstrate considerable efficacy, they are often constrained by non-selectivity and substantial side effects. Recent studies indicate that lipid metabolism significantly influences carcinogenesis, highlighting it as a promising avenue for developing targeted anticancer therapies. The purpose of the study was to see if acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), and stearoyl-CoA 9-desaturase (SCD1) are good metabolic targets and whether the use of inhibitors of these enzymes together with 5-fluorouracil (5-FU) would have a synergistic effect on CRC cell viability. To confirm that the correct lipid targets were chosen, the expression levels of ACAT1, HMGCR, and SCD1 were examined in CRC patients and cell models. At first, each compound (Avasimibe, Lovastatin, MF-438, and 5-FU was tested separately, and then each inhibitor was paired with 5-FU to assess the synergistic effect on cell viability. Gene expression of selected enzymes significantly increased in tissue samples obtained from CRC patients and cancer cell lines (HT-29). Inhibition of any of the selected enzymes reduced CRC cell growth in a dose-dependent manner. More importantly, the combination of 5-FU + Avasimibe (an ACAT1 inhibitor) and 5-FU + MF-438 (an SCD1 inhibitor) produced a stronger antiproliferative effect than the inhibitors alone. 5-FU combined either with Avasimibe or MF-438 showed a synergistic effect with an HSA score of 47.00 at a dose of 0.3 + 30 µM, respectively (2.66% viability rate vs. 46%; p < 0.001), and 39.34 at a dose of 0.3 + 0.06 µM (46% vs. 10.33%; p < 0.001), respectively. The association of 5-FU with Lovastatin (HMGCR inhibitor) did not significantly impact CRC cell viability in a synergistic manner. Inhibition of lipid metabolism combined with standard chemotherapy is a promising strategy that reduces CRC cell viability and allows for the use of a lower drug dose. The combination of 5-FU and Avasimibe has the greatest therapeutic potential among studied compounds. Full article

Aging and apolipoprotein E4 (APOE4) are the two most significant risk factors for late-onset Alzheimer’s disease (LOAD). Compared to APOE3, APOE4 disrupts cholesterol homeostasis, increases cholesteryl esters (CEs), and exacerbates neuroinflammation in brain cells, including microglia. Targeting CEs and neuroinflammation could be a novel strategy to ameliorate APOE4-dependent phenotypes. Toll-like receptor 4 (TLR4) is a key macromolecule in inflammation, and its regulation is associated with the cholesterol content of lipid rafts in cell membranes. We previously demonstrated that in normal microglia expressing APOE3, inhibiting the cholesterol storage enzyme acyl-CoA:cholesterol acyltransferase 1 (ACAT1/SOAT1) reduces CEs, dampened neuroinflammation via modulating the fate of TLR4. We also showed that treating myelin debris-loaded normal microglia with ACAT inhibitor F12511 reduced cellular CEs and activated ABC transporter 1 (ABCA1) for cholesterol efflux. This study found that treating primary microglia expressing APOE4 with F12511 also reduces CEs, activates ABCA1, and dampens LPS-dependent NFκB activation. In vivo, two-week injections of nanoparticle F12511, which consists of DSPE-PEG₂₀₀₀, phosphatidylcholine, and F12511, to aged female APOE4 mice reduced TLR4 protein content and decreased proinflammatory cytokines, including IL-1β in mice brains. Overall, our work suggests nanoparticle F12511 is a novel agent to ameliorate LOAD. Full article

Eco-friendly waterborne coatings frequently exhibit poor corrosion resistance, high solvent content, and extended curing times, attributed to the excessive employment of hydrophilic groups and petroleum-derived polyols. In this work, aniline trimer (ACAT) and polyethylene glycol (PEG) were used as chain extenders. E-44 epoxy resin was subsequently utilized to modify the system and an aniline trimer-modified waterborne polyurethane (AT-WPU) dispersion was prepared and characterized. The chemical structure of the synthesized ACAT was characterized employing 1H NMR, ESI-MS, and FTIR spectroscopy. The structure and coating performance of the AT-WPU dispersion were investigated utilizing FTIR, particle size analysis, thermogravimetric analysis, DSC, TEM, SEM, and electrochemical corrosion testing. The results demonstrate that the aniline trimer-modified waterborne polyurethane dispersion was successfully synthesized. Additionally, the DSC analysis results and thermogravimetric graphs indicate that the glass transition temperature and thermal stability of the coatings increased with the addition of aniline trimer. As the aniline trimer content increased, the hardness and adhesion of the coatings were significantly enhanced. In the electrochemical corrosion assessment, the corrosion current density of AT-WPU-3 attained 7.245 × 10⁻⁹ A·cm⁻², and the corrosion rate was as low as 0.08 μm·Y⁻¹, indicating excellent corrosion resistance. The present study provides promising practical applications in the domain of metal material protection. Full article

Aging is the major risk factor for Alzheimer’s disease (AD). In the aged brain, myelin debris accumulates and is cleared by microglia. Phagocytosed myelin debris increases neutral lipid droplet content in microglia. Neutral lipids include cholesteryl esters (CE) and triacylglycerol (TAG). To examine the effects of myelin debris on neutral lipid content in microglia, we added myelin debris to human HMC3 and mouse N9 cells. The results obtained when using ³H-oleate as a precursor in intact cells reveal that myelin debris significantly increases the biosynthesis of CE but not TAG. Mass analyses have shown that myelin debris increases both CE and TAG. The increase in CE biosynthesis was abolished using inhibitors of the cholesterol storage enzyme acyl-CoA:cholesterol acyltransferase 1 (ACAT1/SOAT1). ACAT1 inhibitors are promising drug candidates for AD treatment. In myelin debris-loaded microglia, treatment with two different ACAT1 inhibitors, K604 and F12511, increased the mRNA and protein content of ATP-binding cassette subfamily A1 (ABCA1), a protein that is located at the plasma membrane and which controls cellular cholesterol disposal. The effect of the ACAT1 inhibitor on ABCA1 was abolished by preincubating cells with the liver X receptor (LXR) antagonist GSK2033. We conclude that ACAT1 inhibitors prevent the accumulation of cholesterol and CE in myelin debris-treated microglia by activating ABCA1 gene expression via the LXR pathway. Full article

The use of C-type natriuretic peptide (CNP) in the interaction with the oocyte and in the temporary postponement of spontaneous meiosis resumption has already been well described. However, its action in pre-implantation developmental-stage embryos is yet to be understood. Thus, our study aimed to detect the presence of the canonical CNP receptor (natriuretic peptide receptor, NPR2) in germinal vesicle (GV)-, metaphase II (MII)-, presumptive zygote (PZ)-, morula (MO)-, and blastocyst (BL)-stage embryos and, later, to observe possible modulations on the embryos when co-cultured with CNP. In Experiment I, we detected and quantified NPR2 on the abovementioned embryo stages. Further, in Experiment II, we intended to test different concentrations (100, 200, or 400 nM of CNP) at different times of inclusion in the in vitro culture (IVC; inclusion from the beginning, i.e., day 1, or from day 5). In Experiment III, 400 nM of CNP was used on day 1 (D1) in the IVC, which was not demonstrated to be embryotoxic, and it showed potentially promising results in the blastocyst production rate when compared to the control. Thus, we analyzed the embryonic development rates of bovine embryos (D7) and hatching kinetics (D7, D8, and D9). Subsequently, morula and blastocyst were collected and evaluated for transcript abundance of their competence and quality (apoptosis, oxidative stress, proliferation, and differentiation) and lipid metabolism. Differences with probabilities less than p < 0.05, and/or fold change (FC) > 1.5, were considered significant. We demonstrate the presence of NPR2 until the blastocyst development stage, when there was a significant decrease in membrane receptors. There was no statistical difference in the production rate after co-culture with 400 nM CNP. However, when we evaluated the abundance of morula transcripts, there was an upregulated transcription in ADCY6 (p = 0.057) and downregulated transcripts in BMP15 (p = 0.013), ACAT1 (p = 0.040), and CASP3 (p = 0.082). In addition, there was a total of 12 transcriptions in morula that presented variation FC > 1.5. In blastocysts, the treatment with CNP induced upregulation in BID, CASP3, SOX2, and HSPA5 transcripts and downregulation in BDNF, NLRP5, ELOVL1, ELOVL4, IGFBP4, and FDX1 transcripts (FC > 1.5). Thus, our study identified and quantified the presence of NPR2 in bovine pre-implantation embryos. Furthermore, 400 nM of CNP in IVC, a concentration not previously described in the literature, modulated some transcripts related to embryonic metabolism, and this was not embryotoxic morphologically. Full article

Cholesterol homeostasis is pivotal for cellular function. Acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1), also abbreviated as SOAT1, is an enzyme responsible for catalyzing the storage of excess cholesterol to cholesteryl esters. ACAT1 is an emerging target to treat diverse diseases including atherosclerosis, cancer, and neurodegenerative diseases. F12511 is a high-affinity ACAT1 inhibitor. Previously, we developed a stealth liposome-based nanoparticle to encapsulate F12511 to enhance its delivery to the brain and showed its efficacy in treating a mouse model for Alzheimer’s disease (AD). In this study, we introduce F26, a close derivative of F12511 metabolite in rats. F26 was encapsulated in the same DSPE-PEG₂₀₀₀/phosphatidylcholine (PC) liposome-based nanoparticle system. We employed various in vitro and in vivo methodologies to assess F26’s efficacy and toxicity compared to F12511. The results demonstrate that F26 is more effective and durable than F12511 in inhibiting ACAT1, in both mouse embryonic fibroblasts (MEFs), and in multiple mouse tissues including the brain tissues, without exhibiting any overt systemic or neurotoxic effects. This study demonstrates the superior pharmacokinetic and safety profile of F26 in wild-type mice, and suggests its therapeutic potential against various neurodegenerative diseases including AD. Full article