ABSTRACT
Photocatalysis represents a sustainable strategy for addressing energy shortages and global warming. The main challenges in the photocatalytic process include limited light absorption, rapid recombination of photo-induced carriers, and poor surface catalytic activity for reactant molecules. Defect engineering in photocatalysts has been proven to be an efficient approach for improving solar-to-chemical energy conversion. Sulfur vacancies can adjust the electron structure, act as electron reservoirs, and provide abundant adsorption and activate sites, leading to enhanced photocatalytic activity. In this work, we aim to elucidate the role of sulfur vacancies in photocatalytic reactions and provide valuable insights for engineering high-efficiency photocatalysts with abundant sulfur vacancies in the future. First, we delve into the fundamental understanding of photocatalysis. Subsequently, various strategies for fabricating sulfur vacancies in photocatalysts are summarized, along with the corresponding characterization techniques. More importantly, the enhanced photocatalytic mechanism, focusing on three key factors, including electron structure, charge transfer, and the surface catalytic reaction, is discussed in detail. Finally, the future opportunities and challenges in sulfur vacancy engineering for photocatalysis are identified.
ABSTRACT
Cardiac hypertrophy, worldwide known as an adaptive functional compensatory state of myocardial stress, is mainly believed to proceed to severe heart diseases, even to sudden death. Emerging studies have explored the microRNA alteration during hypertrophy. However, the mechanisms of microRNAs involved in cardiac hypertrophy are still uncertain. We studied young rats to establish abdominal aorta coarctation (AAC) for 4 weeks. With the significant downregulated cardiac function and upregulated hypertrophic biomarkers, AAC-induced rats showed enlarged myocardiocytes and alterations in microRNAs, especially downregulated miR-31-5p. miR-31-5p targets the 3'UTR of Nfatc2ip and inhibits myocardial hypertrophy in vitro and in vivo. Furthermore, we verified that Nfatc2ip is necessary and sufficient for cardiac hypertrophy in neonatal rat cardiomyocytes. Moreover, we found miR-31-5p inhibited the colocalization of Nfatc2ip and hypertrophic gene ß-Mhc. Luciferase assay and ChiP-qPCR test demonstrated that Nfatc2ip binded to the core-promoter of ß-Mhc and enhanced its transcriptional activity. Above all, our study found a new pathway, mir-31-5p/Nfatc2ip/ß-Mhc, which is involved in cardiac hypertrophy, suggesting a potential target for intervention of cardiac hypertrophy.
Subject(s)
Cardiomegaly , MicroRNAs , Myocytes, Cardiac , NFATC Transcription Factors , MicroRNAs/genetics , MicroRNAs/metabolism , Animals , Cardiomegaly/genetics , Cardiomegaly/metabolism , Cardiomegaly/pathology , NFATC Transcription Factors/metabolism , NFATC Transcription Factors/genetics , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Rats , Male , Rats, Sprague-Dawley , Gene Expression Regulation , 3' Untranslated Regions , Disease Models, AnimalABSTRACT
The quality of aerial remote sensing imaging is heavily impacted by the thermal distortions in optical cameras caused by temperature fluctuations. This paper introduces a lumped parameter thermal network (LPTN) model for the optical system of aerial cameras, aiming to serve as a guideline for their thermal design. By optimizing the thermal resistances associated with convection and radiation while considering the camera's unique internal architecture, this model endeavors to improve the accuracy of temperature predictions. Additionally, the proposed LPTN framework enables the establishment of a heat leakage network, which offers a detailed examination of heat leakage paths and rates. This analysis offers valuable insights into the thermal performance of the camera, thereby guiding the refinement of heating zones and the development of effective active control strategies. Operating at a total power consumption of 26 W, the thermal system adheres to the low-power limit. Experimental data from thermal tests indicate that the temperatures within the optical system are maintained consistently between 19 °C and 22 °C throughout the flight, with temperature gradients remaining below 3 °C, satisfying the temperature requirements. The proposed LPTN model exhibits swiftness and efficacy in determining thermal characteristics, significantly facilitating the thermal design process and ensuring optimal power allocation for aerial cameras.
ABSTRACT
Cognitive impairment in the elderly is associated with alterations in bile acid (BA) metabolism. In this study, we observe elevated levels of serum conjugated primary bile acids (CPBAs) and ammonia in elderly individuals, mild cognitive impairment, Alzheimer's disease, and aging rodents, with a more pronounced change in females. These changes are correlated with increased expression of the ileal apical sodium-bile acid transporter (ASBT), hippocampal synapse loss, and elevated brain CPBA and ammonia levels in rodents. In vitro experiments confirm that a CPBA, taurocholic acid, and ammonia induced synaptic loss. Manipulating intestinal BA transport using ASBT activators or inhibitors demonstrates the impact on brain CPBA and ammonia levels as well as cognitive decline in rodents. Additionally, administration of an intestinal BA sequestrant, cholestyramine, alleviates cognitive impairment, normalizing CPBAs and ammonia in aging mice. These findings highlight the potential of targeting intestinal BA absorption as a therapeutic strategy for age-related cognitive impairment.
Subject(s)
Aging , Ammonia , Bile Acids and Salts , Cognitive Dysfunction , Intestinal Absorption , Animals , Bile Acids and Salts/metabolism , Cognitive Dysfunction/metabolism , Cognitive Dysfunction/pathology , Intestinal Absorption/drug effects , Male , Female , Humans , Mice , Aging/metabolism , Ammonia/metabolism , Aged , Mice, Inbred C57BL , Cholestyramine Resin/pharmacology , Symporters/metabolism , Organic Anion Transporters, Sodium-Dependent/metabolism , Organic Anion Transporters, Sodium-Dependent/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Hippocampus/metabolism , Hippocampus/pathology , Rats , Aged, 80 and overABSTRACT
The metabolic implications in Alzheimer's disease (AD) remain poorly understood. Here, we conducted a metabolomics study on a moderately aging Chinese Han cohort (n = 1397; mean age 66 years). Conjugated bile acids, branch-chain amino acids (BCAAs), and glutamate-related features exhibited strong correlations with cognitive impairment, clinical stage, and brain amyloid-ß deposition (n = 421). These features demonstrated synergistic performances across clinical stages and subpopulations and enhanced the differentiation of AD stages beyond demographics and Apolipoprotein E ε4 allele (APOE-ε4). We validated their performances in eight data sets (total n = 7685) obtained from Alzheimer's Disease Neuroimaging Initiative (ADNI) and Religious Orders Study and Memory and Aging Project (ROSMAP). Importantly, identified features are linked to blood ammonia homeostasis. We further confirmed the elevated ammonia level through AD development (n = 1060). Our findings highlight AD as a metabolic disease and emphasize the metabolite-mediated ammonia disturbance in AD and its potential as a signature and therapeutic target for AD.
Subject(s)
Alzheimer Disease , Ammonia , Metabolomics , Phenotype , Humans , Alzheimer Disease/metabolism , Alzheimer Disease/genetics , Ammonia/metabolism , Aged , Female , Male , Middle Aged , Brain/metabolism , Brain/diagnostic imaging , Cognitive Dysfunction/metabolism , Cognitive Dysfunction/genetics , Amyloid beta-Peptides/metabolism , Apolipoprotein E4/genetics , Apolipoprotein E4/metabolism , Bile Acids and Salts/metabolism , Aged, 80 and over , Cohort StudiesABSTRACT
The gut-brain axis is implicated in depression development, yet its underlying mechanism remains unclear. We observed depleted gut bacterial species, including Bifidobacterium longum and Roseburia intestinalis, and the neurotransmitter homovanillic acid (HVA) in individuals with depression and mouse depression models. Although R. intestinalis does not directly produce HVA, it enhances B. longum abundance, leading to HVA generation. This highlights a synergistic interaction among gut microbiota in regulating intestinal neurotransmitter production. Administering HVA, B. longum, or R. intestinalis to mouse models with chronic unpredictable mild stress (CUMS) and corticosterone (CORT)-induced depression significantly improved depressive symptoms. Mechanistically, HVA inhibited synaptic autophagic death by preventing excessive degradation of microtubule-associated protein 1 light chain 3 (LC3) and SQSTM1/p62 proteins, protecting hippocampal neurons' presynaptic membrane. These findings underscore the role of the gut microbial metabolism in modulating synaptic integrity and provide insights into potential novel treatment strategies for depression.
Subject(s)
Depression , Gastrointestinal Microbiome , Homovanillic Acid , Mice, Inbred C57BL , Animals , Gastrointestinal Microbiome/drug effects , Mice , Depression/drug therapy , Depression/metabolism , Male , Humans , Homovanillic Acid/metabolism , Synapses/metabolism , Synapses/drug effects , Hippocampus/metabolism , Hippocampus/drug effects , Neurons/metabolism , Neurons/drug effects , FemaleABSTRACT
Liver Stagnation and Spleen Deficiency (LSSD) is a Chinese Medicine (CM) pattern commonly observed in gastrointestinal (GI) diseases, yet its biological nature remains unknown. This limits the global use of CM medications for treating GI diseases. Recent studies emphasize the role of gut microbiota and their metabolites in the pathogenesis and treatment of LSSD-associated GI diseases. There is increasing evidence supporting that an altered gut microbiome in LSSD patients or animals contributes to GI and extra-intestinal symptoms and affects the effectiveness of CM therapies. The gut microbiota is considered to be an essential component of the biological basis of LSSD. This study aims to provide an overview of existing research findings and gaps for the pathophysiological study of LSSD from the gut microbiota perspective in order to understand the relationship between the CM pattern and disease progression and to optimize CM-based diagnosis, prevention, and therapy.
Subject(s)
Gastrointestinal Diseases , Gastrointestinal Microbiome , Animals , Humans , Medicine, Chinese TraditionalABSTRACT
Sex disparities in serum bile acid (BA) levels and Alzheimer's disease (AD) prevalence have been established. However, the precise link between changes in serum BAs and AD development remains elusive. Here, authors quantitatively determined 33 serum BAs and 58 BA features in 4 219 samples collected from 1 180 participants from the Alzheimer's Disease Neuroimaging Initiative. The findings revealed that these BA features exhibited significant correlations with clinical stages, encompassing cognitively normal (CN), early and late mild cognitive impairment, and AD, as well as cognitive performance. Importantly, these associations are more pronounced in men than women. Among participants with progressive disease stages (n = 660), BAs underwent early changes in men, occurring before AD. By incorporating BA features into diagnostic and predictive models, positive enhancements are achieved for all models. The area under the receiver operating characteristic curve improved from 0.78 to 0.91 for men and from 0.76 to 0.83 for women for the differentiation of CN and AD. Additionally, the key findings are validated in a subset of participants (n = 578) with cerebrospinal fluid amyloid-beta and tau levels. These findings underscore the role of BAs in AD progression, offering potential improvements in the accuracy of AD prediction.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Male , Humans , Female , Alzheimer Disease/diagnosis , Amyloid beta-Peptides/cerebrospinal fluid , Bile Acids and SaltsABSTRACT
Mesophilic, anaerobic, and cellulolytic Ruminiclostridium-type bacterial species can secrete an extracellular, multi-enzyme machinery cellulosome, which efficiently degrades cellulose. In this study, we first reported the complete genome of Ruminiclostridium papyrosolvens DSM2782, a single circular 5,027,861-bp chromosome with 37.1% G + C content, and compared it with other Ruminiclostridium-type species. Pan-genome analysis showed that Ruminiclostridium-type species share a large number of core genes to conserve basic functions, although they have a high level of intraspecific genetic diversity. Especially, KEGG mapping revealed that Ruminiclostridium-type species mainly use ABC transporters regulated by two-component systems (TCSs) to absorb extracellular sugars but not phosphotransferase systems (PTSs) that are employed by solventogenic clostridia, such as Clostridium acetobutylicum. Furthermore, we performed comparative analyses of the species-specific repertoire of CAZymes for each of the Ruminiclostridium-type species. The high similarity of their cohesins suggests a common ancestor and potential cross-species recognition. Additionally, both differences between the C-terminal cohesins and other cohesins of scaffoldins and between the dockerins linking with cellulases and other catalytic domains indicate a preference for the location of cellulosomal catalytic subunits at scaffoldins. The information gained in this study may be utilized directly or developed further by genetic engineering and optimizing enzyme systems or cell factories for enhanced biotechnological biomass deconstruction and biofuel production.
ABSTRACT
Diabetic cardiomyopathy (DCM) is a cardiovascular disease which has been reported as a major cause of mortality worldwide for several years. Berberine (BBR) is a natural compound extracted from a Chinese herb, with a clinically reported antiDCM effect; however, its molecular mechanisms have not yet been fully elucidated. The present study indicated that BBR markedly alleviated DCM by inhibiting IL1ß secretion and the expression of gasdermin D (Gsdmd) at the posttranscriptional level. Considering the importance of microRNAs (miRNAs/miRs) in the regulation of the posttranscriptional process of specific genes, the ability of BBR to upregulate the expression levels of miR18a3p by activating its promoter (1,000/500) was examined. Notably, miR18a3p targeted Gsdmd and abated pyroptosis in high glucosetreated H9C2 cells. Moreover, miR18a3p overexpression inhibited Gsdmd expression and improved biomarkers of cardiac function in a rat model of DCM. On the whole, the findings of the present study indicate that BBR alleviates DCM by inhibiting miR18a3pmediated Gsdmd activation; thus, BBR may be considered a potential therapeutic agent for the treatment of DCM.
Subject(s)
Berberine , Diabetes Mellitus , Diabetic Cardiomyopathies , MicroRNAs , Animals , Rats , Berberine/pharmacology , Berberine/therapeutic use , Diabetic Cardiomyopathies/drug therapy , Diabetic Cardiomyopathies/genetics , Diabetic Cardiomyopathies/metabolism , Inflammasomes/metabolism , MicroRNAs/genetics , MicroRNAs/pharmacology , PyroptosisABSTRACT
We report on the synthesis of a cage-type calix[4]pyrrole (1) bearing an additional basic pyridinebisthiazolamine group on the strap. The receptor in its protonated form shows strong affinity and selectivity for sulfate over a wide range of inorganic anions. With receptor 1 as a liquid-liquid extractant, H+/SO42- in the form of H2SO4 is almost quantitatively extracted from an aqueous solution containing HNO3 at a high concentration to CH2Cl2 in a recyclable manner.
ABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is prevalent worldwide, while no pharmaceutical treatment has been approved. Natural herbs are promising for their amelioration effect on lipid metabolism. Theabrownin (TB) and Poria cocos polysaccharide (PCP) have been reported to have effect on hyperlipidemia and diabetes. Here, we compared the effect of individual TB or PCP and the combination of TB and PCP (TB + PCP) on NAFLD phenotypes and the alteration of metabolism in the mice with high-fat diet. The results showed that TB, PCP, and TB + PCP reduced serum and hepatic lipid levels, among which TB + PCP was the most effective. Serum metabolomic profile and liver mRNA analyses revealed that the treatments altered metabolic pathways involved in fatty acid metabolism, bile acid metabolism, and tricarboxylic acid cycle, which was also most significant in the TB + PCP group. This study demonstrated that TB, PCP, especially the combination of TB and PCP could be potential therapeutic formula for NAFLD that promoted lipid utilization and inhibited lipid synthesis and absorption.
ABSTRACT
Near-infrared (NIR) fluorophores are widely used as fluorescent probes for bioimaging because of their minimal photodamage to biological samples, deep penetration, and low interference from background autofluorescence. Here, we employed a NIR fluorescent cyanine dye Cy5.5 to label DNA probes for nucleic acid blot hybridization. The specificity and sensitivity of fluorescent DNA probes were proven by both Southern blot and Northern blot using cellulolytic bacterium Ruminiclostridium cellulolyticum as a model. Furthermore, employing the method, we successfully identified the gene disruption of ClosTron to rule out off-target, analyzed the differential transcription of genes under different conditions, and confirmed RNA cleavage. Compared to other nonradioactive probes, the preparation and detection of Cy5.5-labeled probes are more simple, more economical, and versatile, suggesting that the Cy5.5-labeled probes are suitable for nucleic acid blot hybridization in addition to bioimaging.
Subject(s)
DNA , Fluorescent Dyes , DNA Probes/genetics , Nucleic Acid Hybridization/methodsABSTRACT
The chondrogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) has been used in the treatment and repair of cartilage defects; however, the in-depth regulatory mechanisms by which RNA modifications are involved in this process are still poorly understood. Here, we found that Sox9, a critical transcription factor that mediates chondrogenic differentiation, exhibited enhanced translation by ribosome sequencing in chondrogenic pellets, which was accompanied by increased 5-methylcytosine (m5C) and N6-methyladenosine (m6A) levels. Nsun4-mediated m5C and Mettl3-mediated m6A modifications were required for Sox9-regulated chondrogenic differentiation. Interestingly, we showed that in the 3'UTR of Sox9 mRNA, Nsun4 catalyzed the m5C modification and Mettl3 catalyzed the m6A modification. Furthermore, we found that Nsun4 and Mettl3 co-regulated the translational reprogramming of Sox9 via the formation of a complex. Surface plasmon resonance (SPR) assays showed that this complex was assembled along with the recruitment of Ythdf2 and eEF1α-1. Moreover, BMSCs overexpressing Mettl3 and Nsun4 can promote the repair of cartilage defects in vivo. Taken together, our study demonstrates that m5C and m6A co-regulate the translation of Sox9 during the chondrogenic differentiation of BMSCs, which provides a therapeutic target for clinical implications.
Subject(s)
Chondrogenesis , Mesenchymal Stem Cells , Adenosine , Cell Differentiation/genetics , Chondrogenesis/genetics , RNA, MessengerABSTRACT
Calorie restriction (CR) and fasting are common approaches to weight reduction, but the maintenance is difficult after resuming food consumption. Meanwhile, the gut microbiome associated with energy harvest alters dramatically in response to nutrient deprivation. Here, we reported that CR and high-fat diet (HFD) both remodeled the gut microbiota with similar microbial composition, Parabacteroides distasonis was most significantly decreased after CR or HFD. CR altered microbiota and reprogramed metabolism, resulting in a distinct serum bile acid profile characterized by depleting the proportion of non-12α-hydroxylated bile acids, ursodeoxycholic acid and lithocholic acid. Downregulation of UCP1 expression in brown adipose tissue and decreased serum GLP-1 were observed in the weight-rebound mice. Moreover, treatment with Parabacteroides distasonis or non-12α-hydroxylated bile acids ameliorated weight regain via increased thermogenesis. Our results highlighted the gut microbiota-bile acid crosstalk in rebound weight gain and Parabacteroides distasonis as a potential probiotic to prevent rapid post-CR weight gain.
Subject(s)
Gastrointestinal Microbiome , Animals , Bacteroidetes , Bile Acids and Salts , Caloric Restriction , Diet, High-Fat/adverse effects , Gastrointestinal Microbiome/physiology , Mice , Mice, Inbred C57BL , Weight GainABSTRACT
The extracellular substrate-binding proteins (SBPs) of ATP-binding cassette (ABC) importers tend to be expressed in excess relative to their cognate translocators, but how the stoichiometry of ABC transporters is controlled remains unclear. Here, we elucidated a mechanism contributing to differential gene expression in operons encoding ABC importers by employing cellulolytic Clostridia species, specifically Ruminiclostridium cellulolyticum. We found that there were usually stem-loop structures downstream of SBP genes, which could prematurely terminate the transcription of ABC importers and were putative internal intrinsic terminators, resulting in high transcript levels of upstream SBP genes and low transcript levels of downstream cognate translocator genes. This was determined by their termination efficiencies. Internal terminators had a lower U content in their 3' U-rich tracts and longer GC-rich stems, which distinguishes them from canonical terminators and potentially endows them with special termination efficiencies. The pairing of U-rich tracts and the formation of unpaired regions in these internal terminators contributed to their folding energies, affecting the stability of their upstream SBP transcripts. Our findings revealed a strategy of internal transcriptional terminators controlling in vivo stoichiometry of their flanking transcripts. IMPORTANCE Operons encoding protein complexes or metabolic pathways usually require fine-tuned gene expression ratios to create and maintain the appropriate stoichiometry for biological functions. In this study, a strategy for controlling differential expression of genes in an operon was proposed by utilizing ABC importers from Ruminiclostridium cellulolyticum. We found that a stem-loop structure is introduced into the intergenic regions of operons encoding ABC importers as the putative internal terminator, which results in the premature termination of transcription. Consequently, the stoichiometric ratio of genes flanking terminators is precisely determined by their termination efficiencies and folding energies at the transcriptional level. Thus, it can be utilized as a promising synthetic biology tool to control the differential expression of genes in an operon.
Subject(s)
ATP-Binding Cassette Transporters , Operon , ATP-Binding Cassette Transporters/genetics , Transcription, GeneticABSTRACT
Ferroptosis is a type of cell death induced by the iron-dependent accumulation of lipid hydroperoxides and reactive oxygen species (ROS) in cells. Inhibiting ferroptosis is important for improving the survival of transplanted bone marrow-derived mesenchymal stem cells (BMSCs). Although it is known that NOP2/Sun RNA methyltransferase 5 (NSUN5) post-transcriptionally regulates ferroptosis in BMSCs through RNA methylation, the precise mechanisms underlying these effects have not been reported. In this study, we demonstrate that NSUN5 is downregulated in erastin-induced ferroptosis in BMSCs. Ferroptosis was inhibited by the overexpression of NSUN5 or ferritin heavy chain/light-chain (FTH1/FTL) and was enhanced by NSUN5 knockdown. RNA immunoprecipitation experiments revealed that NSUN5 binds to FTH1/FTL, while NSUN5 depletion reduced the levels of 5-methylcytosine in FTH1/FTL RNA and increased intracellular iron concentrations, resulting in the downregulation of glutathione peroxidase 4 (GPX4) and the accumulation of ROS and lipid peroxidation products. Co-immunoprecipitation experiments demonstrated that the recognition of FTH1 and FTL by NSUN5 is dependent on the recruitment of tumor necrosis factor receptor-associated protein 1 (TRAP1). These results suggested that the NSUN5-FTH1/FTL pathway mediates ferroptosis in BMSCs and that the therapeutic targeting of components of this pathway may promote resistance to ferroptosis and improve the survival of transplanted BMSCs.
ABSTRACT
AIMS: Ruminiclostridium cellulolyticum, an anaerobic cellulolytic bacterium producing an efficient cellulolytic extracellular complex named cellulosome, is a promising host for biofuel production from lignocellulose. This study aims to develop a rapid transformation method for R. cellulolyticum avoiding its restriction system. METHODS AND RESULTS: The CceI restriction system is a major barrier to introduction of foreign DNA into R. cellulolyticum cells. To improve the transformation efficiency of R. cellulolyticum, the gene encoding CceI methyltransferase (M.CceI) of R. cellulolyticum H10 was functionally expressed in Escherichia coli, resulting in an in vivo methylation system for transformation of R. cellulolyticum. The electrotransformation experiments of R. cellulolyticum H10 with the E. coli-Clostridium shuttle plasmid pMTC6 showed that the transformation efficiency reached up to 2.6 × 103 ±0.23 × 103 CFU per µg plasmid DNA. The results demonstrated that the system is able to confer the M.CceI-specific DNA methylation pattern to its resident plasmid, which makes the plasmid resistant to the CceI restriction and efficiently transferred into R. cellulolyticum. CONCLUSIONS: In this study, we generated an in vivo methylation system of R. cellulolyticum, allowing interspecies DNA transfer and improving transformation efficiency. SIGNIFICANCE AND IMPACT OF THE STUDY: This research result will greatly facilitate the metabolic engineering of R. cellulolyticum for biofuel production directly from cellulose.
Subject(s)
Clostridium cellulolyticum , Escherichia coli , Clostridium cellulolyticum/genetics , Clostridium cellulolyticum/metabolism , DNA Methylation , Escherichia coli/genetics , Escherichia coli/metabolism , Metabolic Engineering , Plasmids/geneticsABSTRACT
Cinnamon protects against irritable bowel syndrome with diarrhea (IBS-D) in humans, but its efficacy and underlying mechanism of action remain poorly understood. Maternally separated (MS) IBS-D rat model and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced post-inflammatory IBS-D rat model are characterized by visceral hyperalgesia and diarrhea. This study used the two models to evaluate the effect of cinnamon extract (CE) on bowel symptoms. The MS rat model was also used to explore its underlying anti-IBS mechanism. cinnamon extract reduced defecation frequency and visceral hyperalgesia in MS rats in a dose-dependent manner and effectively improved visceral hyperalgesia in TNBS rats. The efficacy of cinnamon extract was comparable to the positive drug serotonin receptor 3 (5-HT3) selective antagonist, Ramosetron. Excessive 5-HT, a well-known pathogenic factor for IBS, in the colon and circulation of IBS rats was reduced after cinnamon extract intervention. Both, gene and protein levels of the colonic 5-HT synthetase, Tryptophan Hydroxylase 1 (Tph1), were also decreased in CE-treated IBS rats. In addition, a luciferase assay revealed that cinnamon extract and its major components, catechin, procyanidin B1/2, cinnamic acid, and cinnamyl alcohol, significantly inhibited Tph1 transcription activity in vitro. These findings illustrated that aqueous cinnamon extract partially attenuated bowel symptoms in IBS models by directly inhibiting Tph1 expression and controlling 5-HT synthesis. This provides a scientific viewpoint for the use of cinnamon as a folk medication to treat IBS.
ABSTRACT
The N6-methyladenosine (m6A) RNA modification regulates the expression of genes associated with various biological and pathological processes, including spontaneous abortion (SA). The aim of this study was to determine the role of the m6A demethylase fat mass and obesity (FTO)- associated protein in SA. The FTO,IGF2BP1 and IGF2BP2 mRNA levels were significantly lower in the chorionic villi obtained from spontaneously aborted pregnancies compared to that of normal pregnancies, while the expression levels of METTL3 and WTAP were significantly elevated. However, ALKBH5, YTHDF2, and IGF2BP3 were elevated with no statistical significance between groups. In addition, MDA was elevated and SOD levels were decreased in the villi tissues of the SA group compared to the normal group, which was indicative of placental oxidative stress in the former. Furthermore, the expression of FTO and HLA-G were significantly decreased in the trophoblasts of the SA patients compared to that of normal pregnant women, while that of m6A was markedly higher in the former. In addition, the HLA-G and VEGFR mRNA levels were downregulated in the SA versus the control group, and that of MMP2, MMP7, MMP9 and VEGFA were upregulated. Finally, The RIP assay showed significantly decreased levels of FTO-bound HLA-G, VEGFR and MMP9 RNA in SA patients (P < 0.05), which corresponded to an increase in transcripts enriched with the m6A antibody (P < 0.05). However, compared with normal pregnant women, the levels of HLA-G, VEGFA, VEGFR, and MMP2 mRNA bound by YTHDF2 were significantly decreased in SA patients. Compared to the normal pregnant women, both FTO- and m6A-bound MMP7 were significantly increased in SA patients (P < 0.05), but YTHDF2 almost unbound to MMP7 mRNA. In summary, the downregulation of FTO in the chorionic villi disrupts immune tolerance and angiogenesis at the maternal-fetal interface, resulting in aberrant methylation and oxidative stress that eventually leads to SA.