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OBJECTIVE: In this study, we developed an exercise training protocol for assessing both blood pressure dynamics and mRNA expression levels of purine receptors in various vascular tissues during physical activity. The objective is to assess the impact of exercise training on blood pressure regulation in spontaneously hypertensive rats (SHR) and purine receptors in vascular tissues. METHODS: Wistar Kyoto (WKY) and SHR rats were randomly allocated into sedentary (Sed) and exercise training (ExT) groups. Rats in the Sed groups were allowed unrestricted movement, whereas those in the ExT groups underwent a 16-week regimen of low- to moderate-intensity treadmill exercise. Throughout the intervention period, blood pressure measurements and body weight recordings were conducted. Additionally, mRNA expressions of purine receptors P2X1, P2Y1, and P2Y2 in renal artery (RA), internal carotid artery (Int), thoracic aorta (Aor), and caudal artery (Cau) tissues were assessed. RESULTS: In the Sed group, body weight of SHR rats was observed to be lower compared to the three other groups. Over the course of the exercise regimen, blood pressure in the ExT group of SHR rats reduced gradually, converging towards levels similar to those observed in WKY rats by the conclusion of the exercise period. Regarding mRNA expression patterns of P2X1 receptors across the four blood vessels, WKY and SHR rats demonstrated similar sequences, consistently displaying the highest expression levels in the Cau. Conversely, mRNA expressions of P2Y1 and P2Y2 receptors exhibited distinct sequences across the four blood vessels in both WKY and SHR rats. Notably, compared to the Sed group of WKY rats, mRNA expression of P2X1 receptor in the Int of SHR rats revealed an increase, while expressions in the Aor of WKY rats and the Cau of SHR rats decreased following exercise. Expression of P2Y1 receptor mRNA decreased across all four types of blood vessels in SHR rats. Post-exercise, P2Y1 receptor mRNA expression increased in the Aor, decreased in the Cau of WKY rats, and increased in the Int and renal artery (RA) of SHR rats. Conversely, expressions of P2Y2 receptor mRNA decreased in the Int and Aor of SHR rats. Except for the Aor of WKY rats, expressions of P2Y2 receptor mRNA increased in the other arteries of both rat types following exercise. CONCLUSION: Differences in the distribution of purine receptor subtypes among distinct arterial segments in both WKY and SHR rats were observed. Exercise training was found to enhance mRNA expression levels of P2Y receptors in these rat models. This finding implies that exercise training might reduce hypertension in SHR rats by bolstering the purinergic relaxation response.
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Biodegradable mulch residues contribute significantly to the presence of microplastics in soil ecosystems. The environmental impact of microplastics, especially biodegradable microplastics (bio-MPs), on soil and plants is of increasing concern. In this study, the responses of five crop species potted in soil treated with different mass concentrations of bio-MPs were assessed for one month. The shoot and root biomasses of cabbages and strawberries were inhibited by bio-MPs treatment. There was little variation in the growth indicators of identical plants with the addition of different mass concentrations of bio-MPs; however, a significant difference was observed among different plants with the addition of the same concentration of bio-MPs. The detrimental effects of bio-MPs were more pronounced in strawberries and cabbages than in the other plant species. Moreover, bio-MPs can affect the availability of soil nutrients and enzyme activities. Structural equation modeling showed that changes in soil properties may indirectly affect plant growth and nutrient uptake when exposed to bio-MPs. This study provides a theoretical basis for understanding the ecological effects of biodegradable mulch films.
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Biodegradación Ambiental , Microplásticos , Contaminantes del Suelo , Suelo , Suelo/química , Microplásticos/toxicidad , Desarrollo de la Planta/efectos de los fármacos , Plásticos Biodegradables , Plantas/efectos de los fármacosRESUMEN
Copper(II) chloride anionic coordination complexes with different imidazole-derived ligands due to the potential cytotoxic activity play the important role in protein. By investigating the experimental electron paramagnetic resonance (EPR) and ultraviolet-visible (UV-vis) spectra of [CuCl(C6H10N2)4]Cl, [CuCl(C6H10N2)4]Cl, [CuCl2(C4H6N2)4], and [Cu2Cl2(C5H8N2)6]Cl2·2H2O, the local structure of the corresponding Cu2+ centers and the role of different ligands are obtained. Based on the well-agreed EPR parameters and the d-d transitions (10Dq), the four Cu2+ centers show tetragonal and orthorhombic distortion, corresponding to the different anisotropies of EPR signals. In addition, the general rules of governing the impact of methanol in imidazolylalkyl derivatives are also discussed, especially the influence on the local environment (symmetry, distortion, covalency, and crystal field) of above four copper(II) chloride anionic coordination complexes. Therefore, the obtained results in this study will be beneficial to provide a theoretical basis for the experimental design of desired copper-containing imidazolyl alkyl derivatives.
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The threat of microplastic pollution in soil ecosystems has caused widespread concern. In order to clarify the effect of polyethylene microplastics on soil properties, a 4-month soil incubation experiment was conducted in this study to investigate the effect of different mass fraction (1 %, 2.5 %, and 5 %) and particle sizes (30 mesh and 100 mesh) of polyethylene microplastics on soil chemical properties, nutrient contents, and enzyme activities. The results showed that:â When the particle size was 100 mesh, microplastics at the mass concentrations of the 2.5 % and 5 % treatments significantly reduced soil pH, and the exposure of polyethylene microplastics had no significant effect on soil conductivity. â¡ Compared to that in CK, the addition of microplastics reduced soil available potassium, available phosphorus, and nitrate nitrogen to varying degrees. The addition of 100 mesh microplastics significantly increased soil organic matter and ammonium nitrogen. ⢠When the particle size was 100 mesh, compared to that in CK, treatments of all concentrations significantly increased soil catalase activity and alkaline phosphatase, showing an increasing but not significant trend, and the 5 % concentration treatment significantly decreased soil sucrase activity. ⣠Changes in soil properties were influenced by the addition of microplastics of different concentrations and sizes, with higher concentrations and smaller particle sizes having more significant effects. In conclusion, the effects of microplastics on soil properties were not as pronounced as expected, and future research should focus on the mechanisms involved in the different effects.
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Microplásticos , Fósforo , Polietileno , Contaminantes del Suelo , Suelo , Suelo/química , Contaminantes del Suelo/análisis , Fósforo/análisis , Nitrógeno , Catalasa/metabolismo , Nutrientes/análisis , Tamaño de la Partícula , Fosfatasa Alcalina/metabolismoRESUMEN
The arthropod exoskeleton provides protection and support and is vital for survival and adaption. The integrity and mechanical properties of the exoskeleton are often impaired after pathogenic infection; however, the detailed mechanism by which infection affects the exoskeleton remains largely unknown. Here, we report that the damage to the shrimp exoskeleton is caused by modulation of host lipid profiles after infection with white spot syndrome virus (WSSV). WSSV infection disrupts the mechanical performance of the exoskeleton by inducing the expression of a chitinase (Chi2) in the sub-cuticle epidermis and decreasing the cuticle chitin content. The induction of Chi2 expression is mediated by a nuclear receptor that can be activated by certain enriched long-chain saturated fatty acids after infection. The damage to the exoskeleton, an aftereffect of the induction of host lipogenesis by WSSV, significantly impairs the motor ability of shrimp. Blocking the WSSV-caused lipogenesis restored the mechanical performance of the cuticle and improved the motor ability of infected shrimp. Therefore, this study reveals a mechanism by which WSSV infection modulates shrimp internal metabolism resulting in phenotypic impairment, and provides new insights into the interactions between the arthropod host and virus.
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Exoesqueleto , Metabolismo de los Lípidos , Penaeidae , Virus del Síndrome de la Mancha Blanca 1 , Animales , Penaeidae/virología , Penaeidae/metabolismo , Exoesqueleto/metabolismo , Exoesqueleto/virología , Virus del Síndrome de la Mancha Blanca 1/fisiología , Metabolismo de los Lípidos/fisiología , Interacciones Huésped-Patógeno , Lipogénesis/fisiologíaRESUMEN
Azaphilones represent a particular group of fascinating pigments from fungal source, with easier industrialization and lower cost than the traditional plant-derived pigments, and they also display a wide range of pharmacological activities. Herein, 28 azaphilone analogs, including 12 new ones, were obtained from the fermentation culture of a marine fungus Penicillium sclerotium UJNMF 0503. Their structures were elucidated by MS, NMR and ECD analyses, together with NMR and ECD calculations and biogenetic considerations. Among them, compounds 1 and 2 feature an unusual natural benzo[d][1,3]dioxepine ring embedded with an orthoformate unit, while 3 and 4 represent the first azaphilone examples incorporating a novel rearranged 5/6 bicyclic core and a tetrahydropyran ring on the side chain, respectively. Our bioassays revealed that half of the isolates exhibited neuroprotective potential against H2O2-induced injury on RSC96 cells, while compound 13 displayed the best rescuing capacity toward the cell viability by blocking cellular apoptosis, which was likely achieved by upregulating the PI3K/Akt signaling pathway.
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Apoptosis , Benzopiranos , Relación Dosis-Respuesta a Droga , Peróxido de Hidrógeno , Fármacos Neuroprotectores , Penicillium , Fosfatidilinositol 3-Quinasas , Pigmentos Biológicos , Proteínas Proto-Oncogénicas c-akt , Apoptosis/efectos de los fármacos , Penicillium/química , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/aislamiento & purificación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasas/metabolismo , Pigmentos Biológicos/farmacología , Pigmentos Biológicos/química , Pigmentos Biológicos/aislamiento & purificación , Peróxido de Hidrógeno/farmacología , Peróxido de Hidrógeno/antagonistas & inhibidores , Estructura Molecular , Benzopiranos/farmacología , Benzopiranos/química , Benzopiranos/aislamiento & purificación , Relación Estructura-Actividad , Animales , Supervivencia Celular/efectos de los fármacos , Ratas , Transducción de Señal/efectos de los fármacosRESUMEN
Quantitative analysis of Rumex nepalensis var. remotiflorus revealed that its roots contain rich anthraquinones, which has emodin, chrysophanol, and physcion contents of up to 0.30, 0.67, and 0.98 mg/g, respectively. Further phytochemical study led to the isolation and purification of seven undescribed phenolic constituents, including one flavan derivative with a 13-membered ring, polygorumin A (1), two dianthrone glucosides, polygonumnolides F and G (2, 3), two diphenylmethanones, rumepalens A and B (4, 5), and a pair of epimeric oxanthrone C-glucosides, rumejaposides K and L (6a, 6b) from the roots of R. nepalensis var. remotiflorus. Furthermore, 1 undescribed natural product, 1-ß-D-glucoside-6'-[(2E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoate]-3-hydroxy-5-methylphenyl (19), and 21 known phenolic compounds were obtained from the aforementioned plant for the first time. Their structures were elucidated through extensive spectroscopic data analysis. Notably, compounds 1, 4-5, and 7-9 exhibited inhibitory activity on α-glucosidase with IC50 values ranging from 1.61 ± 0.17 to 32.41 ± 0.87 µM. In addition, the isolated dianthrone, chrysophanol bianthrone (14), showed obvious cytotoxicity against four human cancer cell lines (HL-60, SMMC-7721, A-549, and MDA-MB-231) with IC50 values ranging from 3.81 ± 0.17 to 35.15 ± 2.24 µM. In silico target prediction and molecular docking studies demonstrated that the mechanism of the anticancer activity of 14 may be related to the interaction with protein kinase CK2.
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Antineoplásicos Fitogénicos , Inhibidores de Glicósido Hidrolasas , Fenoles , Rumex , alfa-Glucosidasas , Humanos , Fenoles/farmacología , Fenoles/química , Fenoles/aislamiento & purificación , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/química , Inhibidores de Glicósido Hidrolasas/aislamiento & purificación , Rumex/química , alfa-Glucosidasas/metabolismo , alfa-Glucosidasas/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Estructura Molecular , Ensayos de Selección de Medicamentos Antitumorales , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Línea Celular Tumoral , Raíces de Plantas/química , Relación Dosis-Respuesta a Droga , Proliferación Celular/efectos de los fármacosRESUMEN
PURPOSE: The aim of this study is to investigate the effect of double-tract reconstruction on short-term clinical outcome, quality of life and nutritional status of patients after proximal gastrectomy by comparing with esophagogastrostomy and total gastrectomy with Roux-en-Y reconstruction. METHODS: The clinical data of patients who underwent double tract reconstruction (DTR), esophagogastrostomy (EG), total gastrectomy with Roux-en-Y reconstruction (TG-RY) were retrospectively collected from May 2020 to May 2022. The clinical characteristics, short-term surgical outcomes, postoperative quality of life and nutritional status were compared among the three groups. RESULTS: Compared with the DTR group, the operation time in the TG group was significantly shorter (200(180,240) minutes vs. 230(210,255) minutes, p < 0.01), and more lymph nodes were removed (28(22, 25) vs. 22(19.31), p < 0.01), there were no significant differences in intraoperative blood loss, first flatus time, postoperative hospital stay and postoperative complication rate among the three groups. Postoperative digestive tract angiography was completed in 36 patients in the DTR group, of which 21 (58.3%) showed double-tract type of food passing. The incidence of postoperative reflux symptoms was 9.2% in the DTR group, 43.8% in the EG group and 23.2% in the TG group, repectively (P < 0.01). EORTCQLQ-STO22 questionnaire survey showed that compared with EG group, DTR group had fewer reflux symptoms (P < 0.05), fewer anxiety symptoms (P < 0.05) and more swallowing symptoms (P < 0.05). Compared with TG group, DTR group had fewer reflux symptoms (P < 0.05). There were no other significant differences between the two groups. Compared with TG group and EG group, DTR can better maintain postoperative BMI, and there is no statistical difference between the three groups in terms of hemoglobin and albumin. CONCLUSIONS: Although partial double-tract reconstruction approach does not always ensure food to enter the distal jejunum along the two pathways as expected, it still shows satisfactory anti-reflux effect. Moreover, it might improve patients' quality of life and maintain better nutritional status comparing with gastroesophageal anastomosis and total gastrectomy with Roux-en-Y reconstruction.
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Índice de Masa Corporal , Gastrectomía , Calidad de Vida , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/cirugía , Masculino , Femenino , Gastrectomía/métodos , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Anastomosis en-Y de Roux/métodos , Estado Nutricional , Complicaciones Posoperatorias/epidemiología , Resultado del Tratamiento , Procedimientos de Cirugía Plástica/métodos , Tempo OperativoRESUMEN
Cannabidiol (CBD), a natural component extracted from Cannabis sativa L. exerts neuroprotective, antioxidant, and anti-inflammatory effects in Alzheimer's disease (AD), a disease characterized by impaired cognition and accumulation of amyloid-B peptides (Aß). Interactions between the gut and central nervous system (microbiota-gut-brain axis) play a critical role in the pathogenesis of neurodegenerative disorder AD. At present investigations into the mechanisms underlying the neuroprotective action of CBD in AD are not conclusive. The aim of this study was thus to examine the influence of CBD on cognition and involvement of the microbiota-gut-brain axis using a senescence-accelerated mouse prone 8 (SAMP8) model. Data demonstrated that administration of CBD to SAMP8 mice improved cognitive function as evidenced from the Morris water maze test and increased hippocampal activated microglia shift from M1 to M2. In addition, CBD elevated levels of Bacteriodetes associated with a fall in Firmicutes providing morphologically a protective intestinal barrier which subsequently reduced leakage of intestinal toxic metabolites. Further, CBD was found to reduce the levels of hippocampal and colon epithelial cells lipopolysaccharide (LPS), known to be increased in AD leading to impaired gastrointestinal motility, thereby promoting neuroinflammation and subsequent neuronal death. Our findings demonstrated that CBD may be considered a beneficial therapeutic drug to counteract AD-mediated cognitive impairment and restore gut microbial functions associated with the observed neuroprotective mechanisms.
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Enfermedad de Alzheimer , Cannabidiol , Disfunción Cognitiva , Ratones , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Cannabidiol/farmacología , Cannabidiol/uso terapéutico , Eje Cerebro-Intestino , Cognición , Disfunción Cognitiva/tratamiento farmacológico , Modelos Animales de EnfermedadRESUMEN
One of the main pathological features noted in Alzheimer's disease (AD) is the presence of plagues of aggregated ß-amyloid (Aß1-42)-peptides. Excess deposition of amyloid-ß oligomers (AßO) are known to promote neuroinflammation. Sequentially, following neuroinflammation astrocytes become activated with cellular characteristics to initiate activated astrocytes. The purpose of this study was to determine whether total flavonoids derived from Dracocephalum moldavica L. (TFDM) inhibited Aß1-42-induced damage attributed to activated C8-D1A astrocytes. Western blotting and ELISA were used to determine the expression of glial fibrillary acidic protein (GFAP), and complement C3 to establish the activation status of astrocytes following induction from exposure to Aß1-42. Data demonstrated that stimulation of C8-D1A astrocytes by treatment with 40 µM Aß1-42 for 24 hr produced significant elevation in protein expression and protein levels of acidic protein (GFAP) and complement C3 accompanied by increased expression and levels of inflammatory cytokines. Treatment with TFDM or the clinically employed drug donepezil in AD therapy reduced production of inflammatory cytokines, and toxicity initiated following activation of C8-D1A astrocytes following exposure to Aß1-42. Therefore, TFDM similar to donepezil inhibited inflammatory secretion in reactive astrocytes, suggesting that TFDM may be considered as a potential compound to be utilized in AD therapy.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Lamiaceae , Humanos , Péptidos beta-Amiloides/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Flavonoides/farmacología , Complemento C3/metabolismo , Complemento C3/farmacología , Complemento C3/uso terapéutico , Enfermedades Neuroinflamatorias , Astrocitos/metabolismo , Donepezilo/metabolismo , Donepezilo/farmacología , Donepezilo/uso terapéutico , Citocinas/metabolismo , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/toxicidadRESUMEN
Ferroptosis is a nonapoptotic, iron-catalyzed form of regulated cell death. It has been shown that high glucose (HG) could induce ferroptosis in vascular endothelial cells (VECs), consequently contributing to the development of various diseases. This study synthesized and evaluated a series of novel ferrostatin-1 (Fer-1) derivatives fused with a benzohydrazide moiety to prevent HG-induced VEC ferroptosis. Several promising compounds showed similar or improved inhibitory effects compared to positive control Fer-1. The most effective candidate 12 exhibited better protection against erastin-induced ferroptosis and high glucose-induced ferroptosis in VECs. Mechanistic studies revealed that compound 12 prevented mitochondrial damage, reduced intracellular ROS accumulation, upregulated the expression of GPX4, and decreased the amounts of ferrous ion, LPO and MDA in VECs. However, compound 12 still exhibited undesirable microsomal stability like Fer-1, suggesting the need for further optimization. Overall, the present findings highlight ferroptosis inhibitor 12 as a potential lead compound for treating ferroptosis-associated vascular diseases.
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Oxidized low density lipoprotein (oxLDL)-induced endothelial oxidative damage promotes the development of atherosclerosis. Caveolae play an essential role in maintaining the survival and function of vascular endothelial cell (VEC). It is reported that the long coiled-coil protein NECC2 is localized in caveolae and is associated with neural cell differentiation and adipocyte formation, but its role in VECs needs to be clarified. Our results showed NECC2 expression increased in the endothelium of plaque-loaded aortas and oxLDL-treated HUVECs. Down-regulation of NECC2 by NECC2 siRNA or compound YF-307 significantly inhibited oxLDL-induced VEC apoptosis and the adhesion factors expression. Remarkably, inhibition of NECC2 expression in the endothelium of apoE-/- mice by adeno-associated virus (AAV)-carrying NECC2 shRNA or compound YF-307 alleviated endothelium injury and restricted atherosclerosis development. The immunoprecipitation results confirmed that NECC2 interacted with Tyk2 and caveolin-1(Cav-1) in VECs, and NECC2 further promoted the phosphorylation of Cav-1 at Tyr14 b y activating Tyk2 phosphorylation. On the other hand, inhibiting NECC2 levels suppressed oxLDL-induced phosphorylation of Cav-1, uptake of oxLDL by VECs, accumulation of intracellular reactive oxygen species and activation of NF-κB. Our findings suggest that NECC2 may contribute to oxLDL-induced VEC injury and atherosclerosis via modulating Cav-1 phosphorylation through Tyk2. This work provides a new concept and drug target for treating atherosclerosis.
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Aterosclerosis , Animales , Ratones , Apolipoproteínas/efectos adversos , Apolipoproteínas/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerosis/metabolismo , Endotelio/metabolismo , Lipoproteínas LDL/metabolismo , Estrés OxidativoRESUMEN
A significant amount of residual plastic film fragments (RPFF) accumulate in soil because of the widespread use and insufficient recycling of mulch films, substantially contaminating the ecosystem with plastic waste. However, information on RPFF abundance in agricultural soils that use long-term plastic film mulch is limited. In this study, 304 soil samples from 11 cities in Hebei Province, China, were used to examine the presence of RPFF in agricultural soils. We discovered that the main recycling techniques used in Hebei Province were manual picking (48.00%) and manual-mechanical recycling (31.90%), with the majority of recovered mulch (63.15%) disposed as waste. Residual plastic film fragment concentrations ranged from 0.48 to 155.33 kg/ha, with an average of 25.23 kg/ha. The north-central portion of Hebei Province has a more severe residual film pollution problem than the other regions. Notable variations in RPFF amounts were observed among plots planted with different crops and with years of mulching, peaking at 29.50 kg/ha after 5-10 years of mulching. Consequently, to reduce the amount of plastic waste that continues to accumulate in soils owing to agricultural needs, the management of plastic mulch, including its use, recycling, and disposal must be improved.
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Disease emergence is the consequence of host-pathogen-environment interactions. Ammonia is a key stress factor in aquatic environments that usually increases the risk of pathogenic diseases in aquatic animals. However, the molecular regulatory mechanisms underlying the enhancement of viral infection following ammonia stress remain largely unknown. Here, we found that ammonia stress enhances white spot syndrome virus infection in kuruma shrimp (Marsupenaeus japonicus) by targeting the antiviral interferon-like system through heat shock factor 1 (Hsf1). Hsf1 is an ammonia-induced transcription factor. It regulates the expression of Cactus and Socs2, which encode negative regulators of NF-κB signaling and Jak/Stat signaling, respectively. By inhibiting these two pathways, ammonia-induced Hsf1 suppressed the production and function of MjVago-L, an arthropod interferon analog. Therefore, this study revealed that Hsf1 is a central regulator of suppressed antiviral immunity after ammonia stress and provides new insights into the molecular regulation of immunity in stressful environments. IMPORTANCE: Ammonia is the end product of protein catabolism and is derived from feces and unconsumed foods. It threatens the health and growth of aquatic animals. In this study, we demonstrated that ammonia stress suppresses shrimp antiviral immunity by targeting the shrimp interferon-like system and that heat shock factor 1 (Hsf1) is a central regulator of this process. When shrimp are stressed by ammonia, they activate Hsf1 for stress relief and well-being. Hsf1 upregulates the expression of negative regulators that inhibit the production and function of interferon analogs in shrimp, thereby enhancing white spot syndrome viral infection. Therefore, this study, from a molecular perspective, explains the problem in the aquaculture industry that animals living in stressed environments are more susceptible to pathogens than those living in unstressed conditions. Moreover, this study provides new insights into the side effects of heat shock responses and highlights the complexity of achieving cellular homeostasis under stressful conditions.
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Penaeidae , Virosis , Virus del Síndrome de la Mancha Blanca 1 , Animales , Interferones/metabolismo , Virus del Síndrome de la Mancha Blanca 1/fisiología , Amoníaco/metabolismo , Respuesta al Choque TérmicoRESUMEN
Steroid-based drugs are now mainly produced by the microbial transformation of phytosterol, and a two-step bioprocess is adopted to reach high space-time yields, but byproducts are frequently observed during the bioprocessing. In this study, the catabolic switch between the C19- and C22-steroidal subpathways was investigated in resting cells of Mycobacterium neoaurum NRRL B-3805, and a dose-dependent transcriptional response toward the induction of phytosterol with increased concentrations was found in the putative node enzymes including ChoM2, KstD1, OpccR, Sal, and Hsd4A. Aldolase Sal presented a dominant role in the C22 steroidal side-chain cleavage, and the byproduct was eliminated after sequential deletion of opccR and sal. Meanwhile, the molar yield of androst-1,4-diene-3,17-dione (ADD) was increased from 59.4 to 71.3%. With the regard of insufficient activity of rate-limiting enzymes may also cause byproduct accumulation, a chromosomal integration platform for target gene overexpression was established supported by a strong promoter L2 combined with site-specific recombination in the engineered cell. Rate-limiting steps of ADD bioconversion were further characterized and overcome. Overexpression of the kstD1 gene further strengthened the bioconversion from AD to ADD. After subsequential optimization of the bioconversion system, the directed biotransformation route was developed and allowed up to 82.0% molar yield with a space-time yield of 4.22 g·L-1·day-1. The catabolic diversion elements and the genetic overexpression tools as confirmed and developed in present study offer new ideas of M. neoaurum cell factory development for directed biotransformation for C19- and C22-steroidal drug intermediates from phytosterol. KEY POINTS: ⢠Resting cells exhibited a catabolic switch between the C19- and C22-steroidal subpathways. ⢠The C22-steroidal byproduct was eliminated after sequential deletion of opccR and sal. ⢠Rate-limiting steps were overcome by promoter engineering and chromosomal integration.
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Aldehído-Liasas , Fitosteroles , Androstadienos , Diferenciación Celular , PolienosRESUMEN
Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease which damages upper and lower motor neurons (UMN and LMN) innervating the muscles of the trunk, extremities, head, neck and face in cerebrum, brain stem and spinal cord, which results in the progressive weakness, atrophy and fasciculation of muscle innervated by the related UMN and LMN, accompanying with the pathological signs leaded by the cortical spinal lateral tract lesion. The pathogenesis about ALS is not fully understood, and no specific drugs are available to cure and prevent the progression of this disease at present. In this review, we reviewed the structure and associated functions of copper-zinc superoxide dismutase 1 (SOD1), discuss why SOD1 is crucial to the pathogenesis of ALS, and outline the pathogenic mechanisms of SOD1 in ALS that have been identified at recent years, including glutamate-related excitotoxicity, mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, axonal transport disruption, prion-like propagation, and the non-cytologic toxicity of glial cells. This review will help us to deeply understand the current progression in this field of SOD1 pathogenic mechanisms in ALS.
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Esclerosis Amiotrófica Lateral , Superóxido Dismutasa-1 , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Esclerosis Amiotrófica Lateral/genética , Humanos , Superóxido Dismutasa-1/metabolismo , Superóxido Dismutasa-1/genética , Animales , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Estrés Oxidativo/fisiologíaRESUMEN
Two neolignan glycosides including a new one (1), along with seven iridoid glycosides (3 - 9) and nine flavonoid glycosides (10 - 18), were isolated from the leaves of Vaccinium bracteatum. Their structures were established mainly on the basis of 1D/2D NMR and ESIMS analyses, as well as comparison to known compounds in the literature. The structure of 1 with absolute stereochemistry was also confirmed by chemical degradation and ECD calculation. Selective compounds showed antiradical activity against ABTS and/or DPPH. Moreover, several isolates also suppressed the production of ROS in RAW264.7 cells and exerted neuroprotective effect toward PC12 cells.
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Flavonoides , Glicósidos , Lignanos , Hojas de la Planta , Hojas de la Planta/química , Flavonoides/química , Flavonoides/farmacología , Flavonoides/aislamiento & purificación , Animales , Ratones , Células PC12 , Glicósidos/química , Glicósidos/farmacología , Glicósidos/aislamiento & purificación , Estructura Molecular , Lignanos/química , Lignanos/farmacología , Lignanos/aislamiento & purificación , Ratas , Células RAW 264.7 , Vaccinium/química , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/aislamiento & purificación , Iridoides/química , Iridoides/farmacología , Iridoides/aislamiento & purificación , Glicósidos Iridoides/química , Glicósidos Iridoides/farmacología , Glicósidos Iridoides/aislamiento & purificación , Especies Reactivas de Oxígeno , Picratos/farmacologíaRESUMEN
In our chemical investigation into Penicillium sp. UJNMF0740 derived from mangrove sediment, fourteen indole diterpene analogs, including four new ones, are purified by multiple chromatographic separation methods, with their structures being elucidated by the analyses of NMR, HR-ESIMS, and ECD data. The antibacterial and neuroprotective effects of these isolates were examined, and only compounds 6 and 9 exhibited weak antibacterial activity, while compounds 5, 8, and 10 showed protective effects against the injury of PC12 cells induced by 6-hydroxydopamine (6-OHDA). Additionally, compound 5 could suppress the apoptosis and production of reactive oxygen species (ROS) in 6-OHDA-stimulated PC12 cells as well as trigger the phosphorylation of PI3K and Akt. Taken together, our work enriches the structural diversity of indole diterpenes and hints that compounds of this skeleton can repress the 6-OHDA-induced apoptosis of PC12 cells via regulating the PI3K/Akt signaling pathway, which provides evidence for the future utilization of this fascinating class of molecules as potential neuroprotective agents.
Asunto(s)
Diterpenos , Fármacos Neuroprotectores , Penicillium , Ratas , Animales , Células PC12 , Proteínas Proto-Oncogénicas c-akt/metabolismo , Oxidopamina/toxicidad , Fosfatidilinositol 3-Quinasas/metabolismo , Penicillium/química , Especies Reactivas de Oxígeno/metabolismo , Apoptosis , Diterpenos/farmacología , Diterpenos/química , Indoles/farmacología , Indoles/química , Antibacterianos/farmacología , Fármacos Neuroprotectores/farmacologíaRESUMEN
Peripheral nerve injury (PNI) seriously affects people's quality of life. Stem cell therapy is considered a promising new option for the clinical treatment of PNI. Dental stem cells, particularly dental pulp stem cells (DPSCs), are adult pluripotent stem cells derived from the neuroectoderm. DPSCs have significant potential in the field of neural tissue engineering due to their numerous advantages, such as easy isolation, multidifferentiation potential, low immunogenicity, and low transplant rejection rate. DPSCs are extensively used in tissue engineering and regenerative medicine, including for the treatment of sciatic nerve injury, facial nerve injury, spinal cord injury, and other neurodegenerative diseases. This article reviews research related to DPSCs and their advantages in treating PNI, aiming to summarize the therapeutic potential of DPSCs for PNI and the underlying mechanisms and providing valuable guidance and a foundation for future research.
RESUMEN
Microplastics(MPs), as a new type of environmental pollutants, have gradually attracted widespread attention since they were introduced by British scientists in 2004. Soil is an important accumulation site for microplastics, which can expand the scope of contamination and accumulate with agricultural practices such as irrigation and tillage. Microplastics in soil cause a variety of toxicities to terrestrial plants. The small particle size, difficult degradation, and strong adsorption capacity bring a challenge to the microplastic pollution treatment of soil. In this study, the toxicity of microplastics to terrestrial plants was reviewed in terms of their direct or indirect toxicity and combined effects with other pollutants, mainly in terms of mechanical injury, induction of oxidative stress, and cytotoxicity and genotoxicity to plants, resulting in plant growth and plant tissue metabolism obstruction. In general, the toxicity of microplastics depended on the polymer type, size, and dose; plant tolerance; and exposure conditions. In addition, the production of secondary microplastics and endogenous contaminants during their degradation in soil enhanced the biotoxicity of microplastics. Further, the physical, chemical, and microbial degradation mechanisms of microplastics were introduced in this study based on the current research. At first, the physical and chemical degradation of microplastics mainly occurred by changing the particle size and surface properties of microplastics and producing intermediates. Then, smaller-sized microplastics and their intermediates could eventually be converted to water and carbon dioxide through physical, chemical, and biological functions. Finally, further prospects regarding soil microplastics were introduced, and we provided information for future improvement and pollution control of microplastics.