ABSTRACT
Mitomycin C (MMC) has an antitumor effect and is considered as a broad-spectrum antibiotic. Sijunzi Decoction (SJZD), a well-known ancient Chinese prescription, is widely used in the treatment of cancer when combined with chemotherapy drugs. Studies have shown that SJZD can be combined with other drugs to enhance the therapeutic effect against cancer and inhibit the toxicity of chemotherapy drugs, but the specific mechanism is not clear. Thus, we hope to further explore the antitumor mechanism of combined SJZD and MMC. 3-(4,5-Dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide assay, flow cytometry, western blot, 1H NMR and HPLC-MS were used to study the mechanism at the cellular level. The results show that the combined administration can have a more significant effect on inhibiting the proliferation of cancer cells, promoting their apoptosis. Based on metabolomics, 38 biomarkers were found in the MMC group and 43 biomarkers were found in the combined administration group. Among them, 18 unique biomarkers were discovered in the combined administration group. Studies have shown that the antitumor mechanism of combined administration is related to amino acid metabolism, energy metabolism, lipid metabolism and nucleotide metabolism, among which amino acid metabolism is the most important. In addition, SJZD achieves the effect of toxin reduction and efficiency enhancement by improving the body's immunity and improving the oxidative stress environment.
ABSTRACT
BACKGROUND: Extracellular adenosine triphosphate (ATP) is an important signal molecule. In previous studies, intensive research had revealed the crucial roles of family with sequence similarity 3 member A (FAM3A) in controlling hepatic glucolipid metabolism, islet ß cell function, adipocyte differentiation, blood pressure, and other biological and pathophysiological processes. Although mitochondrial protein FAM3A plays crucial roles in the regulation of glucolipid metabolism via stimulating ATP release to activate P2 receptor pathways, its mechanism in promoting ATP release in hepatocytes remains unrevealed. METHODS: db/db, high-fat diet (HFD)-fed, and global pannexin 1 (PANX1) knockout mice, as well as liver sections of individuals, were used in this study. Adenoviruses and adeno-associated viruses were utilized for in vivo gene overexpression or inhibition. To evaluate the metabolic status in mice, oral glucose tolerance test (OGTT), pyruvate tolerance test (PTT), insulin tolerance test (ITT), and magnetic resonance imaging (MRI) were conducted. Protein-protein interactions were determined by coimmunoprecipitation with mass spectrometry (MS) assays. RESULTS: In livers of individuals and mice with steatosis, the expression of ATP-permeable channel PANX1 was increased (P < 0.01). Hepatic PANX1 overexpression ameliorated the dysregulated glucolipid metabolism in obese mice. Mice with hepatic PANX1 knockdown or global PANX1 knockout exhibited disturbed glucolipid metabolism. Restoration of hepatic PANX1 rescued the metabolic disorders of PANX1-deficient mice (P < 0.05). Mechanistically, ATP release is mediated by the PANX1-activated protein kinase B-forkhead box protein O1 (Akt-FOXO1) pathway to inhibit gluconeogenesis via P2Y receptors in hepatocytes. PANX1-mediated ATP release also activated calmodulin (CaM) (P < 0.01), which interacted with c-Jun N-terminal kinase (JNK) to inhibit its activity, thereby deactivating the transcription factor activator protein-1 (AP1) and repressing fatty acid synthase (FAS) expression and lipid synthesis (P < 0.05). FAM3A stimulated the expression of PANX1 via heat shock factor 1 (HSF1) in hepatocytes (P < 0.05). Notably, FAM3A overexpression failed to promote ATP release, inhibit the expression of gluconeogenic and lipogenic genes, and suppress gluconeogenesis and lipid deposition in PANX1-deficient hepatocytes and livers. CONCLUSIONS: PANX1-mediated release of ATP plays a crucial role in maintaining hepatic glucolipid homeostasis, and it confers FAM3A's suppressive effects on hepatic gluconeogenesis and lipogenesis.
Subject(s)
Adenosine Triphosphate , Connexins , Gluconeogenesis , Lipogenesis , Liver , Nerve Tissue Proteins , Animals , Connexins/metabolism , Mice , Gluconeogenesis/physiology , Nerve Tissue Proteins/metabolism , Nerve Tissue Proteins/genetics , Adenosine Triphosphate/metabolism , Lipogenesis/physiology , Liver/metabolism , Mice, Knockout , Male , Humans , Diet, High-Fat/adverse effects , CytokinesABSTRACT
Two lanthanide complexes with formulae [DyIII(LN5)(pentafluoro-PhO)3] (1) and [DyIII(LN5)(2,6-difluoro-PhO)2](BPh4) (2) (LN5 = 2,14-dimethyl-3,6,10,13,19-pentaazabicyclo[13.3.1]nonadecal (19),2,13,15,17-pentaene) were structurally and magnetically characterized. DyIII ions lie in the cavity of a five coordinate nitrogen macrocycle, and in combination with the introduction of multi-fluorinated monodentate phenoxyl coligands a high axiality coordination symmetry is built. Using the pentafluorophenol co-ligand, complex 1 with a D2d coordination environment, is obtained and displays moderate single-molecule magnets (SMMs) behavior. When difluorophenol co-ligands were used, a higher local axisymmetric pentagonal bipyramidal coordination geometry was observed in complex 2, which displays apparent slow magnetic relaxation behavior with a hysteresis temperature of up to 5 K. Further magnetic studies of diluted samples combined with ab initio calculations indicate that the high axiality plays a crucial role in suppressing quantum tunneling of magnetization (QTM) and consequently results in good slow magnetic relaxation behavior. Different fluoro-substituted phenoxyl co-ligands have phenoloxy oxygen atoms with different electrostatic potentials as well as a different number of phenoloxy coligands along the magnetic axis, resulting in different ligand field strengths and coordination symmetries.
ABSTRACT
Cadmium (Cd) is a widely distributed typical environmental pollutant and one of the most toxic heavy metals. It is well-known that environmental Cd causes testicular damage by inducing classic types of cell death such as cell apoptosis and necrosis. However, as a new type of cell death, the role and mechanism of pyroptosis in Cd-induced testicular injury remain unclear. In the current study, we used environmental Cd to generate a murine model with testicular injury and AIM2-dependent pyroptosis. Based on the model, we found that increased cytoplasmic mitochondrial DNA (mtDNA), activated mitochondrial proteostasis stress occurred in Cd-exposed testes. We used ethidium bromide to generate mtDNA-deficient testicular germ cells and further confirmed that increased cytoplasmic mtDNA promoted AIM2-dependent pyroptosis in Cd-exposed cells. Uracil-DNA glycosylase UNG1 overexpression indicated that environmental Cd blocked UNG-dependent repairment of damaged mtDNA to drive the process in which mtDNA releases to cytoplasm in the cells. Interestingly, we found that environmental Cd activated mitochondrial proteostasis stress by up-regulating protein expression of LONP1 in testes. Testicular specific LONP1-knockdown significantly reversed Cd-induced UNG1 protein degradation and AIM2-dependent pyroptosis in mouse testes. In addition, environmental Cd significantly enhanced the m6A modification of Lonp1 mRNA and its stability in testicular germ cells. Knockdown of IGF2BP1, a reader of m6A modification, reversed Cd-induced upregulation of LONP1 protein expression and pyroptosis activation in testicular germ cells. Collectively, environmental Cd induces m6A modification of Lonp1 mRNA to activate mitochondrial proteostasis stress, increase cytoplasmic mtDNA content, and trigger AIM2-dependent pyroptosis in mouse testes. These findings suggest that mitochondrial proteostasis stress is a potential target for the prevention of testicular injury.
Subject(s)
Cadmium , Mitochondria , Pyroptosis , Testis , Animals , Cadmium/toxicity , Male , Mice , Testis/drug effects , Testis/metabolism , Pyroptosis/drug effects , Mitochondria/metabolism , Mitochondria/drug effects , Environmental Pollutants/toxicity , Proteostasis , Mitochondrial Proteins/metabolism , Environmental Exposure/adverse effects , DNA, Mitochondrial , ATP-Dependent Proteases/metabolism , Proteotoxic StressABSTRACT
Two lanthanide 3D coordination polymers [Ln2(L)4Cl2(H2O)4]n (Ln = Eu (1), Gd (2)) with quinoline-2-carboxylic acid (HL) as the ligand were successfully synthesized and characterized. Complex 1 exhibits a highly sensitive and selective luminescent response to 2,6-dipicolinic acid (DPA) in tap water and is virtually unaffected by interferences such as amino acids, aromatic carboxylic acids, and ions. With the addition of DPA, the luminescence intensity of complex 1 decreases rapidly to the naked eye. The detection limit of 1 toward DPA is 3.36 µM, which is much less than the infectious dose (60 µM) of the anthrax spores, indicating the high sensitivity of 1 to DPA. This study offers a basis for employing lanthanide complexes in real sample analysis, enabling direct and efficient detection of DPA with high sensitivity and specificity. Additionally, it is noteworthy that at a magnetic field strength of 7 T and a temperature of 3 K, the maximum entropy change for complex 2 attains a value of 23.56 J kg-1 K-1.
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Triterpenoids widely exist in nature, displaying a variety of pharmacological activities. Determining triterpenoids in different matrices, especially in biological samples holds great significance. High-performance liquid chromatography (HPLC) has become the predominant method for triterpenoids analysis due to its exceptional analytical performance. However, due to the structural similarities among botanical samples, achieving effective separation of each triterpenoid proves challenging, necessitating significant improvements in analytical methods. Additionally, triterpenoids are characterized by a lack of ultraviolet (UV) absorption groups and chromophores, along with low ionization efficiency in mass spectrometry. Consequently, routine HPLC analysis suffers from poor sensitivity. Chemical derivatization emerges as an indispensable technique in HPLC analysis to enhance its performance. Considering the structural characteristics of triterpenoids, various derivatization reagents such as acid chlorides, rhodamines, isocyanates, sulfonic esters, and amines have been employed for the derivatization analysis of triterpenoids. This review comprehensively summarized the research progress made in derivatization strategies for HPLC detection of triterpenoids. Moreover, the limitations and challenges encountered in previous studies are discussed, and future research directions are proposed to develop more effective derivatization methods.
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Prolonged screen time (ST) has adverse effects on autistic characteristics and language development. However, the mechanisms underlying the effects of prolonged ST on the neurodevelopment of children with autism spectrum disorder (ASD) remain unclear. Neuroimaging technology may help to further explain the role of prolonged ST in individuals with ASD. This study included 164 cases, all cases were divided into low-dose ST exposure (LDE group 108 cases) and high-dose ST exposure (HDE group 56 cases) based on the average ST of all subjects. Spatial independent component analysis (ICA) was used to identify resting state networks (RSNs) and investigate intra- and inter-network alterations in ASD children with prolonged ST. We found that the total Childhood Autism Rating Scale (CARS) scores in the HDE group were significantly higher than those in the LDE group (36.2 ± 3.1 vs. 34.6 ± 3.9, p = 0.008). In addition, the developmental quotient (DQ) of hearing and language in the HDE group were significantly lower than those in the LDE group (31.5 ± 13.1 vs. 42.5 ± 18.5, p < 0.001). A total of 13 independent components (ICs) were identified. Between-group comparison revealed that the HDE group exhibited decreased functional connectivity (FC) in the left precuneus (PCUN) of the default mode network (DMN), the right middle temporal gyrus (MTG) of the executive control network (ECN), and the right median cingulate and paracingulate gyri (MCG) of the attention network (ATN), compared with the LDE group. Additionally, there was an increase in FC in the right orbital part of the middle frontal gyrus (ORBmid) of the salience network (SAN), compared with the LDE group. The inter-network analysis revealed increased FC between the visual network (VN) and basal ganglia (BG) and decreased FC between the sensorimotor network (SMN) and DMN, SMN and ATN, SMN and auditory network (AUN), and DMN and SAN in the HDE group, compared with the LDE group. There was a significant negative correlation between altered FC values in MTG and total CARS scores in subjects (r = - 0.18, p = 0.018). Conclusion: ASD children with prolonged ST often exhibit lower DQ of language development and more severe autistic characteristics. The alteration of intra- and inter-network FC may be a key neuroimaging feature of the effect of prolonged ST on neurodevelopment in ASD children. Clinical trial registration: ChiCTR2100051141. What is Known: ⢠Prolonged ST has adverse effects on autistic characteristics and language development. ⢠Neuroimaging technology may help to further explain the role of prolonged ST in ASD. What is New: ⢠This is the first study to explore the impact of ST on intra- and inter-network FC in children with ASD. ⢠ASD children with prolonged ST have atypical changes in intra- and inter-brain network FC.
Subject(s)
Autism Spectrum Disorder , Magnetic Resonance Imaging , Screen Time , Child , Child, Preschool , Female , Humans , Male , Autism Spectrum Disorder/physiopathology , Autism Spectrum Disorder/diagnostic imaging , Brain/diagnostic imaging , Brain/physiopathology , Nerve Net/physiopathology , Nerve Net/diagnostic imaging , Cross-Sectional Studies , Retrospective StudiesABSTRACT
BACKGROUND: The overproliferation of fibroblast-like synoviocytes (FLS) contributes to synovial hyperplasia, a pivotal pathological feature of rheumatoid arthritis (RA). Shikonin (SKN), the active compound from Lithospermum erythrorhizon, exerts anti-RA effects by diverse means. However, further research is needed to confirm SKN's in vitro and in vivo anti-proliferative functions and reveal the underlying specific molecular mechanisms. PURPOSE: This study revealed SKN's anti-proliferative effects by inducing both apoptosis and autophagic cell death in RA FLS and adjuvant-induced arthritis (AIA) rat synovium, with involvement of regulating the AMPK/mTOR/ULK-1 pathway. METHODS: SKN's influences on RA FLS were assessed for proliferation, apoptosis, and autophagy with immunofluorescence staining (Ki67, LC3B, P62), EdU incorporation assay, staining assays of Hoechst, Annexin V-FITC/PI, and JC-1, transmission electron microscopy, mCherry-GFP-LC3B puncta assay, and western blot. In AIA rats, SKN's anti-arthritic effects were assessed, and its impacts on synovial proliferation, apoptosis, and autophagy were studied using Ki67 immunohistochemistry, TUNEL, and western blot. The involvement of AMPK/mTOR/ULK-1 pathway was examined via western blot. RESULTS: SKN suppressed RA FLS proliferation with reduced cell viability and decreased Ki67-positive and EdU-positive cells. SKN promoted RA FLS apoptosis, as evidenced by apoptotic nuclear fragmentation, increased Annexin V-FITC/PI-stained cells, reduced mitochondrial potential, elevated Bax/Bcl-2 ratio, and increased cleaved-caspase 3 and cleaved-PARP protein levels. SKN also enhanced RA FLS autophagy, featuring increased LC3B, reduced P62, autophagosome formation, and activated autophagic flux. Autophagy inhibition by 3-MA attenuated SKN's anti-proliferative roles, implying that SKN-induced autophagy contributes to cell death. In vivo, SKN mitigated the severity of rat AIA while also reducing Ki67 expression, inducing apoptosis, and enhancing autophagy within AIA rat synovium. Mechanistically, SKN modulated the AMPK/mTOR/ULK-1 pathway in RA FLS and AIA rat synovium, as shown by elevated P-AMPK and P-ULK-1 expression and decreased P-mTOR expression. This regulation was supported by the reversal of SKN's in vitro and in vivo effects upon co-administration with the AMPK inhibitor compound C. CONCLUSION: SKN exerted in vitro and in vivo anti-proliferative properties by inducing apoptosis and autophagic cell death via modulating the AMPK/mTOR/ULK-1 pathway. Our study revealed novel molecular mechanisms underlying SKN's anti-RA effects.
Subject(s)
AMP-Activated Protein Kinases , Apoptosis , Arthritis, Experimental , Arthritis, Rheumatoid , Autophagy-Related Protein-1 Homolog , Autophagy , Naphthoquinones , Signal Transduction , Synoviocytes , TOR Serine-Threonine Kinases , Animals , TOR Serine-Threonine Kinases/metabolism , Apoptosis/drug effects , Arthritis, Rheumatoid/drug therapy , Naphthoquinones/pharmacology , Signal Transduction/drug effects , Autophagy/drug effects , Autophagy-Related Protein-1 Homolog/metabolism , AMP-Activated Protein Kinases/metabolism , Rats , Arthritis, Experimental/drug therapy , Synoviocytes/drug effects , Synoviocytes/metabolism , Male , Cell Proliferation/drug effects , Humans , Rats, Sprague-DawleyABSTRACT
Low testosterone (T) levels are associated with many common diseases, such as obesity, male infertility, depression, and cardiovascular disease. It is well known that environmental cadmium (Cd) exposure can induce T decline, but the exact mechanism remains unclear. We established a murine model in which Cd exposure induced testicular T decline. Based on the model, we found Cd caused mitochondrial fusion disorder and Parkin mitochondrial translocation in mouse testes. MFN1 overexpression confirmed that MFN1-dependent mitochondrial fusion disorder mediated the Cd-induced T synthesis suppression in Leydig cells. Further data confirmed Cd induced the decrease of MFN1 protein by increasing ubiquitin degradation. Testicular specific Parkin knockdown confirmed Cd induced the ubiquitin-dependent degradation of MFN1 protein through promoting Parkin mitochondrial translocation in mouse testes. Expectedly, testicular specific Parkin knockdown also mitigated testicular T decline. Mito-TEMPO, a targeted inhibitor for mitochondrial reactive oxygen species (mtROS), alleviated Cd-caused Parkin mitochondrial translocation and mitochondrial fusion disorder. As above, Parkin mitochondrial translocation induced mitochondrial fusion disorder and the following T synthesis repression in Cd-exposed Leydig cells. Collectively, our study elucidates a novel mechanism through which Cd induces T decline and provides a new treatment strategy for patients with androgen disorders.
Subject(s)
Cadmium , Environmental Pollutants , Leydig Cells , Testis , Testosterone , Ubiquitin-Protein Ligases , Male , Animals , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/genetics , Cadmium/toxicity , Testosterone/metabolism , Testis/drug effects , Testis/metabolism , Leydig Cells/drug effects , Leydig Cells/metabolism , Environmental Pollutants/toxicity , Mice , Mitochondria/drug effects , Mitochondria/metabolism , Mice, Inbred C57BL , GTP Phosphohydrolases/metabolism , GTP Phosphohydrolases/geneticsABSTRACT
OBJECTIVES: We examined the antirheumatoid effects of piperlongumine (PLM) on rat adjuvant-induced arthritis (AIA) and explored the underlying mechanisms involved. METHODS: PLM (2.5, 5, and 10 mg/kg) was administered intraperitoneally to AIA rats to assess its effectiveness. Blood, thymus, spleen, ankle joint, and synovial tissue samples were gathered for subsequent analyses, like enzyme-linked immunosorbent assay, thymus/spleen index measurement, ankle joint pathological examination, immunohistochemistry assay, polymerase chain reaction, and western blot assay. Moreover, the involvement of osteoprotegerin (OPG)/receptor activators of nuclear factor κB ligand (RANKL)/nuclear factor-κB (NF-κB) signaling was investigated. KEY FINDINGS: PLM effectively relieved inflammation and joint destruction in AIA rats, as indicated by reductions in hind paw swelling, arthritis index, thymus/spleen index, ankle joint pathological damage, production of TNF-α, IL-1ß, and IL-6 in both serum and synovium, and osteoclast formation. Also, PLM treatment raised OPG production, reduced RANKL expression, and elevated the OPG/RANKL ratio in synovial tissues. Furthermore, PLM prevented IκBα degradation and phosphorylation, resulting in a reduced expression of the nuclear NF-κB p65 protein in AIA rat synovial tissues. CONCLUSIONS: PLM demonstrated strong antiarthritic effects in rats with AIA by influencing the OPG/RANKL/NF-κB signaling pathway, highlighting its potential clinical relevance in treating rheumatoid arthritis.
Subject(s)
Arthritis, Experimental , Dioxolanes , NF-kappa B , Osteoprotegerin , RANK Ligand , Signal Transduction , Animals , Arthritis, Experimental/drug therapy , Arthritis, Experimental/metabolism , Arthritis, Experimental/pathology , RANK Ligand/metabolism , Signal Transduction/drug effects , Osteoprotegerin/metabolism , NF-kappa B/metabolism , Rats , Male , Dioxolanes/pharmacology , Rats, Sprague-Dawley , Antirheumatic Agents/pharmacology , Osteoclasts/drug effects , Osteoclasts/metabolism , PiperidonesABSTRACT
Borneol, camphor, and bornyl acetate are highly promising monoterpenoids widely used in medicine, flavor, food, and chemical applications. Bornyl diphosphate (BPP) serves as a common precursor for the biosynthesis of these monoterpenoids. Although bornyl diphosphate synthase (BPPS) that catalyzes the cyclization of geranyl diphosphate (GPP) to BPP has been identified in multiple plants, the enzyme responsible for the hydrolysis of BPP to produce borneol has not been reported. Here, we conducted in vitro and in vivo functional characterization to identify the Nudix hydrolase WvNUDX24 from W. villosa, which specifically catalyzes the hydrolysis of BPP to generate bornyl phosphate (BP), and then BP forms borneol under the action of phosphatase. Subcellular localization experiments indicated that the hydrolysis of BPP likely occurs in the cytoplasm. Furthermore, site-directed mutagenesis experiments revealed that four critical residues (R84, S96, P98, and G99) for the hydrolysis activity of WvNUDX24. Additionally, the functional identification of phosphatidic acid phosphatase (PAP) demonstrated that WvPAP5 and WvPAP10 were able to hydrolyze geranylgeranyl diphosphate (GGPP) and farnesyl diphosphate (FPP) to generate geranylgeranyl phosphate (GGP) and farnesyl phosphate (FP), respectively, but could not hydrolyze BPP, GPP, and neryl diphosphate (NPP) to produce corresponding monophosphate products. These findings highlight the essential role of WvNUDX24 in the first step of BPP hydrolysis to produce borneol and provide genetic elements for the production of BPP-related terpenoids through plant metabolic engineering and synthetic biology.
Subject(s)
Camphanes , Nudix Hydrolases , Plant Proteins , Pyrophosphatases , Pyrophosphatases/metabolism , Pyrophosphatases/genetics , Plant Proteins/metabolism , Plant Proteins/genetics , Camphanes/metabolism , Brassicaceae/genetics , Brassicaceae/enzymology , Brassicaceae/metabolism , Polyisoprenyl Phosphates/metabolismABSTRACT
Enhancing electrochemiluminescence (ECL) properties of luminophores is a hot direction in the current ECL field. Herein, we found that covalent rigidification of the aggregation-induced emission luminogens (AIEgens) TABE (TABE = tetra-(4-aldehyde-(1,1-biphenyl))ethylene) into covalent organic framework nanosheets (TABE-PZ-CON, PZ = piperazine) could result in stronger ECL emission than those of TABE aggregates and TABE monomers. We termed the interesting phenomenon "covalent rigidification-triggered electrochemiluminescence (CRT-ECL) enhancement". The superior ECL performance of TABE-PZ-CON not only because massive TABE luminogens were covalently assembled into the rigid TABE-PZ-CON network, which limited the intramolecular motions of TABE and hampered the radiationless transition, but also because the ultrathin porous TABE-PZ-CON significantly reduced the transportation distance of ions, electrons, and coreactants, which enabled the electrochemical excitation of more TABE luminogens and thus enhanced the ECL efficiency. Bearing in mind the exceptional ECL performance of TABE-PZ-CON, it was utilized as a high-efficient ECL indicator in combination with the DNA walker and duplex-specific nuclease-assisted target recycling amplification strategies to design an "off-on" ECL biosensor for the ultrasensitive assay of microRNA-21, exhibiting a favorable response range (100 aM-1 nM) with an ultralow detection limit of 17.9 aM. Overall, this work offers a valid way to inhibit the intramolecular motions of AIEgens for ECL enhancement, which gives a new vision for building high-performance AIEgen-based ECL materials, thus offering more chances for assembling hypersensitive ECL biosensors.
Subject(s)
Biosensing Techniques , Metal-Organic Frameworks , MicroRNAs , Metal-Organic Frameworks/chemistry , Luminescent Measurements , Electrochemical Techniques , Photometry , MicroRNAs/chemistry , Limit of DetectionABSTRACT
In traditional Chinese medicine, Radix Astragali has played a vital role in treating progressive fibrotic diseases. One of its main active components, astragaloside IV, is a promising anti-fibrotic treatment despite its extremely low bioavailability. Our study aimed to optimize sodium astragalosidate (SA) by salt formation to improve solubility and oral absorption for anti-fibrotic therapy in vivo. Isoproterenol-induced myocardial fibrosis rat models and obese BKS-db mice presenting diabetic kidney fibrosis were used in this study. Daily oral administration of SA (20 mg/kg) for 14 days ameliorated cardiac fibrosis by reducing collagen accumulation and fibrosis-related inflammatory signals, including TNF-α, IL-1ß, and IL-6. In db/db mice, SA (5,10, and 20 mg/kg per day for 8 weeks) dose-dependently alleviated lipid metabolism impairment and renal dysfunction when administered orally. Furthermore, Western blot and immunohistochemistry analyses demonstrated that SA treatment inhibited renal fibrosis by suppressing TGF-ß1/Smads signaling. Taken together, our findings provide the oral-route medication availability of SA, which thus might offer a novel lead compound in preclinical trial-enabling studies for developing a long-term therapy to treat and prevent fibrosis.
ABSTRACT
Intestinal ischemia-reperfusion (IIR) injury is associated with inflammation and oxidative stress, yet its precise mechanisms remain not fully understood. IIR injury is closely linked to the gut microbiota and its metabolites. The anti-inflammatory and antioxidant effects of Lactiplantibacillus plantarum are specific to IIR. In our study, we conducted a 30-day pre-treatment of SD rats with both a standard strain of Lactiplantibacillus plantarum and Lactiplantibacillus plantarum GL001. After a 7-day cessation of treatment, we induced an IIR injury model to investigate the mechanisms by which Lactiplantibacillus plantarum alleviates IIR damage. The results demonstrate that Lactiplantibacillus plantarum effectively mitigates the inflammatory and oxidative stress damage induced by IIR. Lactiplantibacillus plantarum GL001 can improve the gut microbiota by reducing the abundance of harmful bacteria and increasing the abundance of beneficial bacteria. In IIR intestinal tissue, the levels of secondary bile acids are elevated. The content of the bacterial metabolite Calcimycin increases. Annotations of metabolic pathways suggest that Lactiplantibacillus plantarum GL001 can alleviate IIR damage by modulating calcium-phosphorus homeostasis through the regulation of parathyroid hormone synthesis, secretion, and action. Microbiota-metabolite correlation analysis reveals a significant negative correlation between calcimycin and Lactonacillus and a significant positive correlation between calcimycin and Shigella. There is also a significant positive correlation between calcimycin and secondary bile acids. Lactiplantibacillus plantarum GL001 can alleviate oxidative damage induced by IIR through improvements in gut microbiota and intestinal tissue metabolism.
Subject(s)
Oxidative Stress , Reperfusion Injury , Rats , Animals , Calcimycin/pharmacology , Rats, Sprague-Dawley , Reperfusion Injury/metabolism , Bacteria , Bile Acids and SaltsABSTRACT
BACKGROUND: Studies in adults have shown that low baseline muscle mass at intensive care unit (ICU) admission was associated with poor clinical outcomes. However, no information on the relationship between baseline muscle quality or mass and clinical outcomes in critically ill children was found. METHODS: 3775 children were admitted to the pediatric ICU (PICU), 262 were eligible for inclusion. Abdominal computed tomography was performed to assess baseline skeletal muscle mass and quality. Patients were categorized to normal or low group based on the cutoff value for predicting hospital mortality of the skeletal muscle index (SMI; 30.96 cm2 /m2 ) and skeletal muscle density (SMD; 41.21 Hounsfield units). RESULTS: Body mass index (BMI) (18.07 ± 4.44 vs 15.99 ± 4.51) and BMI-for-age z score (0.46 [-0.66 to 1.74] vs -0.87 [-1.69 to 0.05]) were greater in the normal-SMI group, the length of PICU stay was longer in the low-SMI group (16.00 days [8.50-32.50] vs 13.00 days [7.50-20.00]), and the in-PICU mortality rate in the normal-SMI group (10.00%) was lower than the low-SMI group (22.6%). Children with low SMD had a higher in-PICU mortality rate (25.6% vs 7.7%), were younger (36.00 months [12.00-120.00] vs 84.00 months [47.50-147.50]) and weighed less (16.40 kg [10.93-37.25] vs 23.00 kg [16.00-45.00]). Mortality was greater in patients with lower SMD and prolonged hospital stay (log-rank, P = 0.007). SMD was an independent predictor for length of PICU stay and in-PICU mortality. CONCLUSIONS: Low baseline skeletal muscle quality in critically ill children is closely tied with a higher in-PICU mortality and longer PICU stay and is an independent risk factor for unfavorable clinical outcomes.
ABSTRACT
Dispersity (D) as a critical parameter indicates the level of uniformity of the polymer molar mass or chain length. In the past several decades, the development of explicit equations for calculating D experiences a continual revolution. This viewpoint tracks the historical evolution of the explicit equations from living to reversible-deactivation polymerization systems. Emphasis is laid on displaying the charm of explicit D equations in batch reversible-deactivation radical polymerization (RDRP), with highlights of the relevant elegant mathematical manipulations. Some representative emerging applications enabled by the existing explicit equations are shown, involving nitroxide-mediated polymerization (NMP), atom transfer radical polymerization (ATRP), and reversible addition-fragmentation chain transfer (RAFT) polymerization systems. Stemming from the several outlined challenges and outlooks, sustained concerns about the explicit D equations are still highly deserved. It is expected that these equations will continue to play an important role not only in traditional polymerization kinetic simulation and design of experiments but also in modern intelligent manufacturing of precision polymers and classroom education.
ABSTRACT
Acute pancreatitis (AP) is an inflammatory disease of the exocrine pancreas. Disruptions in organelle homeostasis, including macroautophagy/autophagy dysfunction and endoplasmic reticulum (ER) stress, have been implicated in human and rodent pancreatitis. Syntaxin 17 (STX17) belongs to the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) subfamily. The Qa-SNARE STX17 is an autophagosomal SNARE protein that interacts with SNAP29 (Qbc-SNARE) and the lysosomal SNARE VAMP8 (R-SNARE) to drive autophagosome-lysosome fusion. In this study, we investigated the role of STX17 in the pathogenesis of AP in male mice or rats induced by repeated intraperitoneal injections of cerulein. We showed that cerulein hyperstimulation induced AP in mouse and rat models, which was characterized by increased serum amylase and lipase activities, pancreatic edema, necrotic cell death and the infiltration of inflammatory cells, as well as markedly decreased pancreatic STX17 expression. A similar reduction in STX17 levels was observed in primary and AR42J pancreatic acinar cells treated with CCK (100 nM) in vitro. By analyzing autophagic flux, we found that the decrease in STX17 blocked autophagosome-lysosome fusion and autophagic degradation, as well as the activation of ER stress. Pancreas-specific STX17 knockdown using adenovirus-shSTX17 further exacerbated pancreatic edema, inflammatory cell infiltration and necrotic cell death after cerulein injection. These data demonstrate a critical role of STX17 in maintaining pancreatic homeostasis and provide new evidence that autophagy serves as a protective mechanism against AP.
Subject(s)
Ceruletide , Pancreatitis , Male , Mice , Animals , Rats , Humans , Acute Disease , Ceruletide/toxicity , Disease Models, Animal , Pancreatitis/chemically induced , Autophagy/physiology , SNARE Proteins/metabolism , EdemaABSTRACT
Wurfbainia longiligularis and Wurfbainia villosa are both rich in volatile terpenoids and are 2 primary plant sources of Fructus Amomi used for curing gastrointestinal diseases. Metabolomic profiling has demonstrated that bornyl diphosphate (BPP)-related terpenoids are more abundant in the W. villosa seeds and have a wider tissue distribution in W. longiligularis. To explore the genetic mechanisms underlying the volatile terpenoid divergence, a high-quality chromosome-level genome of W. longiligularis (2.29 Gb, contig N50 of 80.39 Mb) was assembled. Functional characterization of 17 terpene synthases (WlTPSs) revealed that WlBPPS, along with WlTPS 24/26/28 with bornyl diphosphate synthase (BPPS) activity, contributes to the wider tissue distribution of BPP-related terpenoids in W. longiligularis compared to W. villosa. Furthermore, transgenic Nicotiana tabacum showed that the GCN4-motif element positively regulates seed expression of WvBPPS and thus promotes the enrichment of BPP-related terpenoids in W. villosa seeds. Systematic identification and analysis of candidate TPS in 29 monocot plants from 16 families indicated that substantial expansion of TPS-a and TPS-b subfamily genes in Zingiberaceae may have driven increased diversity and production of volatile terpenoids. Evolutionary analysis and functional identification of BPPS genes showed that BPP-related terpenoids may be distributed only in the Zingiberaceae of monocot plants. This research provides valuable genomic resources for breeding and improving Fructus Amomi with medicinal and edible value and sheds light on the evolution of terpenoid biosynthesis in Zingiberaceae.
Subject(s)
Alkyl and Aryl Transferases , Terpenes , Humans , Terpenes/metabolism , Diphosphates , Plant Breeding , Fruit/genetics , Fruit/metabolism , Plants/metabolism , Alkyl and Aryl Transferases/geneticsABSTRACT
The authors wish to make the following corrections to this paper [...].
ABSTRACT
BACKGROUND: Computed tomography (CT) imaging features are associated with risk stratification of gastric gastrointestinal stromal tumors (GISTs). AIM: To determine the multi-slice CT imaging features for predicting risk stratification in patients with primary gastric GISTs. METHODS: The clinicopathological and CT imaging data for 147 patients with histologically confirmed primary gastric GISTs were retrospectively analyzed. All patients had received dynamic contrast-enhanced CT (CECT) followed by surgical resection. According to the modified National Institutes of Health criteria, 147 lesions were classified into the low malignant potential group (very low and low risk; 101 lesions) and high malignant potential group (medium and high-risk; 46 lesions). The association between malignant potential and CT characteristic features (including tumor location, size, growth pattern, contour, ulceration, cystic degeneration or necrosis, calcification within the tumor, lymphadenopathy, enhancement patterns, unenhanced CT and CECT attenuation value, and enhancement degree) was analyzed using univariate analysis. Multivariate logistic regression analysis was performed to identify significant predictors of high malignant potential. The receiver operating curve (ROC) was used to evaluate the predictive value of tumor size and the multinomial logistic regression model for risk classification. RESULTS: There were 46 patients with high malignant potential and 101 with low-malignant potential gastric GISTs. Univariate analysis showed no significant differences in age, gender, tumor location, calcification, unenhanced CT and CECT attenuation values, and enhancement degree between the two groups (P > 0.05). However, a significant difference was observed in tumor size (3.14 ± 0.94 vs 6.63 ± 3.26 cm, P < 0.001) between the low-grade and high-grade groups. The univariate analysis further revealed that CT imaging features, including tumor contours, lesion growth patterns, ulceration, cystic degeneration or necrosis, lymphadenopathy, and contrast enhancement patterns, were associated with risk stratification (P < 0.05). According to binary logistic regression analysis, tumor size [P < 0.001; odds ratio (OR) = 26.448; 95% confidence interval (CI): 4.854-144.099)], contours (P = 0.028; OR = 7.750; 95%CI: 1.253-47.955), and mixed growth pattern (P = 0.046; OR = 4.740; 95%CI: 1.029-21.828) were independent predictors for risk stratification of gastric GISTs. ROC curve analysis for the multinomial logistic regression model and tumor size to differentiate high-malignant potential from low-malignant potential GISTs achieved a maximum area under the curve of 0.919 (95%CI: 0.863-0.975) and 0.940 (95%CI: 0.893-0.986), respectively. The tumor size cutoff value between the low and high malignant potential groups was 4.05 cm, and the sensitivity and specificity were 93.5% and 84.2%, respectively. CONCLUSION: CT features, including tumor size, growth patterns, and lesion contours, were predictors of malignant potential for primary gastric GISTs.