ABSTRACT
The mechanisms behind the selection and initial recruitment of primordial follicles (PmFs) from the non-growing PmF pool during each estrous cycle in females remain largely unknown. This study demonstrates that PmFs closest to the ovulatory follicle are preferentially activated in mouse ovaries under physiological conditions. PmFs located within 40 µm of the ovulatory follicles were more likely to be activated compared to those situated further away during the peri-ovulation period. Repeated superovulation treatments accelerated the depletion of the PmF reserve, whereas continuous suppression of ovulation delayed PmF reserve consumption. Spatial transcriptome sequencing of peri-ovulatory follicles revealed that ovulation primarily induces the degradation and remodeling of the extracellular matrix (ECM). This ECM degradation reduces mechanical stress around PmFs, thereby triggering their activation. Specifically, Cathepsin L (CTSL), a cysteine proteinase and lysosomal enzyme involved in ECM degradation, initiates the activation of PmFs adjacent to ovulatory follicles in a distance-dependent manner. These findings highlight the link between ovulation and selective PmF activation, and underscore the role of CTSL in this process under physiological conditions.
Subject(s)
Cathepsin L , Extracellular Matrix , Ovarian Follicle , Ovulation , Animals , Female , Mice , Ovarian Follicle/metabolism , Cathepsin L/metabolism , Ovulation/physiology , Extracellular Matrix/metabolism , Ovary/metabolism , Estrous Cycle/physiologyABSTRACT
Sleep deprivation (SD) is commonplace in today's fast-paced society. SD is a severe public health problem globally since it may cause cognitive decline and even neurodegenerative disorders like Alzheimer's disease. Melatonin (MT) is a natural chemical secreted by the pineal gland with neuroprotective effects. The purpose of this study was to investigate the protective effect and mechanism of MT on chronic sleep deprivation-induced cognitive impairment. A 3-week modified multi-platform method was used to create the SD rat model. The Morris water maze test (MWM), Tissue staining (including Hematoxylin and Eosin (H & E) staining, Nissl staining, and immunofluorescence), Western blot, Enzyme-linked immunosorbent assay (ELISA), and Quantitative real-time polymerase chain reaction (qPCR) were used to investigate the protective effect and mechanism of MT in ameliorating cognitive impairment in SD rats. The results showed that MT (50 and 100 mg/kg) significantly improved cognitive function in rats, as evidenced by a shortening of escape latency and increased time of crossing the platform and time spent in the quadrant. Additionally, MT therapy alleviated hippocampus neurodegeneration and neuronal loss while lowering levels of pathogenic factors (LPS) and inflammatory indicators (IL-1ß, IL-6, TNF-α, iNOS, and COX2). Furthermore, MT treatment reversed the high expression of Aß42 and Iba1 as well as the low expression of ZO-1 and occludin, and inhibited the SD-induced TLR4/MyD88/NF-κB signaling pathway. In summary, MT ameliorated spatial recognition and learning memory dysfunction in SD rats by reducing neuroinflammation and increasing neuroprotection while inhibiting the TLR4/MyD88/NF-κB signaling pathway. Our study supports the use of MT as an alternate treatment for SD with cognitive impairment.
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Helicobacter pylori (H. pylori) infection is the primary risk factor for the progress of gastric diseases. The persistent stomach colonization of H. pylori is closely associated with the development of gastritis and malignancies. Although the involvement of progranulin (PGRN) in various cancer types has been well-documented, its functional role and underlying mechanisms in gastric cancer (GC) associated with H. pylori infection remain largely unknown. This report demonstrated that PGRN was up-regulated in GC and associated with poor prognosis, as determined through local and public database analysis. Additionally, H. pylori induced the up-regulation of PGRN in gastric epithelial cells both in vitro and in vivo. Functional studies have shown that PGRN promoted the intracellular colonization of H. pylori. Mechanistically, H. pylori infection induced autophagy, while PGRN inhibited autophagy to promote the intracellular colonization of H. pylori. Furthermore, PGRN suppressed H. pylori-induced autophagy by down-regulating decorin (DCN) through the mTOR pathway. In general, PGRN inhibited autophagy to facilitate intracellular colonization of H. pylori via the PGRN/mTOR/DCN axis. This study provides new insights into the molecular mechanisms underlying the progression of gastric diseases, suggesting PGRN as a potential therapeutic target and prognostic predictor for these disorders.
Subject(s)
Autophagy , Epithelial Cells , Gastric Mucosa , Helicobacter Infections , Helicobacter pylori , Progranulins , Stomach Neoplasms , TOR Serine-Threonine Kinases , Progranulins/metabolism , TOR Serine-Threonine Kinases/metabolism , Humans , Epithelial Cells/microbiology , Epithelial Cells/metabolism , Helicobacter Infections/microbiology , Helicobacter Infections/metabolism , Animals , Stomach Neoplasms/microbiology , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Gastric Mucosa/microbiology , Gastric Mucosa/metabolism , Mice , Signal TransductionABSTRACT
Postharvest chilling injury (PCI) is a physiological disorder that often impairs tomato fruit ripening; this reduces fruit quality and shelf-life, and even accelerates spoilage at low temperatures. The CBF gene family confers cold tolerance in Arabidopsis thaliana, and constitutive overexpression of CBF in tomato increases vegetative chilling tolerance, in part by retarding growth, but, whether CBF increases PCI tolerance in fruit is unknown. We hypothesized that CBF1 overexpression (OE) would be induced in the cold and increase resistance to PCI. We induced high levels of CBF1 in fruit undergoing postharvest chilling by cloning it from S. lycopersicum and S. habrochaites, using the stress-inducible RD29A promoter. Harvested fruit were cold-stored (2.5°C) for up to three weeks, then rewarmed at 20°C for three days. Transgene upregulation was triggered during cold storage from 8.6- to 28.6-fold in SlCBF1-OE, and between 3.1- to 8.3-fold in ShCBF1-OE fruit, but developmental abnormalities in the absence of cold induction were visible. Remarkably, transgenic fruit displayed worsening of PCI symptoms, i.e., failure to ripen after rewarming, comparatively higher susceptibility to decay relative to wild-type (WT) fruit, lower total soluble solids, and the accumulation of volatile compounds responsible for off-odors. These symptoms correlated with CBF1 overexpression levels. Transcriptomic analysis revealed that the ripening and biotic and abiotic stress responses were altered in the cold-stored transgenic fruit. Seedlings grown from 'chilled' and 'non-chilled' WT fruit, in addition to 'non-chilled' transgenic fruit were also exposed to 0°C to test their photosynthetic response to chilling injury. Chilled WT seedlings adjusted their photosynthetic rates to reduce oxidative damage; 'non-chilled' WT seedlings did not. Photosynthetic parameters between transgenic seedlings were similar at 0°C, but SlCBF1-OE showed more severe photoinhibition than ShCBF1-OE, mirroring phenotypic observations. These results suggest that 1) CBF1 overexpression accelerated fruit deterioration in response to cold storage, and 2) Chilling acclimation in fructus can increase chilling tolerance in seedling progeny of WT tomato.
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Alzheimer's disease (AD) is the most common neurodegenerative disease in the central nervous system, characterized by memory and cognitive dysfunction. Acupuncture is an effective means to alleviate the symptoms of AD. Recent studies have shown that microglia play an important role in the occurrence and development of AD. Acupuncture can regulate the activity of microglia, inhibit neuroinflammation, regulate phagocytosis, and clear Aß Pathological products such as plaque can protect nerve cells and improve cognitive function in AD patients. This article summarizes the relationship between microglia and AD, as well as the research progress in the mechanism of acupuncture regulating microglia in the treatment of AD. The mechanism of acupuncture regulating microglia in the treatment of AD is mainly reviewed from two aspects: inhibiting neuroinflammatory activity and regulating phagocytic function.
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Sequential working memory (SWM), referring to the temporary storage and manipulation of information in order, plays a fundamental role in brain cognitive functions. The serial position effect refers to the phenomena that recall accuracy of an item is associated to the order of the item being presented. The neural mechanism underpinning the serial position effect remains unclear. The synaptic mechanism of working memory proposes that information is stored as hidden states in the form of facilitated neuronal synapse connections. Here, we build a continuous attractor neural network with synaptic short-term plasticity (STP) to explore the neural mechanism of the serial position effect. Using a delay recall task, our model reproduces the the experimental finding that as the maintenance period extends, the serial position effect transitions from the primacy to the recency effect. Using both numerical simulation and theoretical analysis, we show that the transition moment is determined by the parameters of STP and the interval between presented stimulus items. Our results highlight the pivotal role of STP in processing the order information in SWM.
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Currently, carbon-based porous materials for hydrogen (H2) storage and carbon dioxide (CO2) capture are mostly applied at higher pressures (30-300 bar). However, applications for H2 storage and CO2 capture under ambient pressure conditions are significant for the development of portable, household, and miniaturized H2 energy technologies. This demands a higher standard for the interface microenvironment of adsorbents. Derived from polyurethane foams (PUFs) solid waste, the hierarchical porous foam carbon with interpenetrating-type pore structures exhibits high specific surface area (SBET = 1753 m2/g), abundant oxygen and nitrogen functional groups, and a hierarchical nanopore structure (VUltra = 0.232 cm3/g, VMicro = 0.628 cm3/g and VMeso = 0.186 cm3/g) through the mild-homogeneous sonication-assisted activation process. Under the limited adsorption of pore interface microenvironment composed by hierarchical nanopore structure and dipole-induced interaction (H(â ¡)-H(â )···N/O and O(â ¡) = C(â ) = O(â ¡)···N/O), it exhibits an excellent H2 storage density (2.92 wt% at 77 K, 1 bar) and CO2 capture capacity (5.28 mmol/g at 298 K, 1 bar). This research approach can serve as a reference for the dual-functional design of porous foam carbon, and promote the development of adsorption materials for CO2 capture and energy gas storage under ambient conditions.
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Tomato fruit ripening is triggered by the demethylation of key genes, which alters their transcriptional levels thereby initiating and propagating a cascade of physiological events. What is unknown is how these processes are altered when fruit are ripened using postharvest practices to extend shelf-life, as these practices often reduce fruit quality. To address this, postharvest handling-induced changes in the fruit DNA methylome and transcriptome, and how they correlate with ripening speed, and ripening indicators such as ethylene, abscisic acid, and carotenoids, were assessed. This study comprehensively connected changes in physiological events with dynamic molecular changes. Ripening fruit that reached 'Turning' (T) after dark storage at 20°C, 12.5°C, or 5°C chilling (followed by 20°C rewarming) were compared to fresh-harvest fruit 'FHT'. Fruit stored at 12.5°C had the biggest epigenetic marks and alterations in gene expression, exceeding changes induced by postharvest chilling. Fruit physiological and chronological age were uncoupled at 12.5°C, as the time-to-ripening was the longest. Fruit ripening to Turning at 12.5°C was not climacteric; there was no respiratory or ethylene burst, rather, fruit were high in abscisic acid. Clear differentiation between postharvest-ripened and 'FHT' was evident in the methylome and transcriptome. Higher expression of photosynthetic genes and chlorophyll levels in 'FHT' fruit pointed to light as influencing the molecular changes in fruit ripening. Finally, correlative analyses of the -omics data putatively identified genes regulated by DNA methylation. Collectively, these data improve our interpretation of how tomato fruit ripening patterns are altered by postharvest practices, and long-term are expected to help improve fruit quality.
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OBJECTIVE: This study aimed to compare the changes in corneal morphological characteristics in corneal topography assessments performed after wearing orthokeratology (OK) lenses with different back optic zone diameters (BOZDs). These changes included the change ratios of the apical corneal power (ACP), the maximum relative corneal refractive power (mRCRP), and the treatment zone diameter (TZD). METHODS: Data from 133 children with myopia (average age 9.50 ± 1.23 years) treated at Fudan University Eye and Ear, Nose, and Throat Hospital were retrospectively analyzed. All participants wore the same brand of tangent-design OK lens (corneal refractive therapy, CRT). According to the BOZD, the patients were divided into two groups, of 5.0 and 6.0 mm BOZD, respectively. Corneal topography was analyzed at baseline, as well as 1 day, 1 week, and 1 month after wearing the lenses, and the change ratios of ACP, mRCRP, and TZD were compared between the two groups. RESULTS: The change ratio of the ACP did not differ significantly between the BOZD 5.0 and 6.0 groups after 1 day or 1 week of lens wear (P = 0.170 and P = 0.113, respectively). However, after 1 month of lens wear, the change ratio of the ACP in the BOZD 5.0 group was significantly larger than that in the BOZD 6.0 group (P < 0.001). After 1 month of lens wear, the mRCRP along the horizontal and vertical meridians was higher (P < 0.05) and the TZD was significantly smaller (P < 0.001) in the BOZD 5.0 group than in the BOZD 6.0 group. CONCLUSION: In CRT OK lenses, a small BOZD lens can produce faster corneal shaping, a larger mRCRP, and a smaller TZD, which may have a better effect on slowing ocular axial length elongation. The lens parameters are also a factor affecting the TZD.
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The circadian clock coordinates the daily rhythmicity of biological processes, and its dysregulation is associated with various human diseases. Despite the direct targeting of rhythmic genes by many prevalent and World Health Organization (WHO) essential drugs, traditional approaches can't satisfy the need of explore multi-timepoint drug administration strategies across a wide range of drugs. Here, droplet-engineered primary liver organoids (DPLOs) are generated with rhythmic characteristics in 4 days, and developed Chronotoxici-plate as an in vitro high-throughput automated rhythmic tool for chronotherapy assessment within 7 days. Cryptochrome 1 (Cry1) is identified as a rhythmic marker in DPLOs, providing insights for rapid assessment of organoid rhythmicity. Using oxaliplatin as a representative drug, time-dependent variations are demonstrated in toxicity on the Chronotoxici-plate, highlighting the importance of considering time-dependent effects. Additionally, the role of chronobiology is underscored in primary organoid modeling. This study may provide tools for both precision chronotherapy and chronotoxicity in drug development by optimizing administration timing.
Subject(s)
Liver , Organoids , Organoids/drug effects , Organoids/metabolism , Liver/drug effects , Animals , Humans , Mice , Oxaliplatin , Circadian Clocks/drug effectsABSTRACT
Chromatin replication is intricately intertwined with the recycling of parental histones to the newly duplicated DNA strands for faithful genetic and epigenetic inheritance. The transfer of parental histones occurs through two distinct pathways: leading strand deposition, mediated by the DNA polymerase ε subunits Dpb3/Dpb4, and lagging strand deposition, facilitated by the MCM helicase subunit Mcm2. However, the mechanism of the facilitation of Mcm2 transferring parental histones to the lagging strand while moving along the leading strand remains unclear. Here, we show that the deletion of Pol32, a nonessential subunit of major lagging-strand DNA polymerase δ, results in a predominant transfer of parental histone H3-H4 to the leading strand during replication. Biochemical analyses further demonstrate that Pol32 can bind histone H3-H4 both in vivo and in vitro. The interaction of Pol32 with parental histone H3-H4 is disrupted through the mutation of the histone H3-H4 binding domain within Mcm2. Our findings identify the DNA polymerase δ subunit Pol32 as a critical histone chaperone downstream of Mcm2, mediating the transfer of parental histones to the lagging strand during DNA replication.
Subject(s)
DNA Replication , DNA-Directed DNA Polymerase , Saccharomyces cerevisiae Proteins , DNA Polymerase III/metabolism , DNA Polymerase III/genetics , Histones/metabolism , Minichromosome Maintenance Complex Component 2/metabolism , Minichromosome Maintenance Complex Component 2/genetics , Protein Binding , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Saccharomyces cerevisiae Proteins/genetics , DNA-Directed DNA Polymerase/metabolismABSTRACT
BACKGROUND: Bidirectional communication between the gut microbiota and the brain may play an essential role in the cognitive dysfunction associated with chronic sleep deprivation(CSD). Salvia miltiorrhiza Bunge (Danshen, DS), a famous Chinese medicine and functional tea, is extensively used to protect learning and memory capacities, although the mechanism of action remains unknown. PURPOSE: The purpose of this research was to explore the efficacy and the underlying mechanism of DS in cognitive dysfunction caused by CSD. METHODS: DS chemical composition was analyzed by UPLC-QTOF-MS/MS. Forty rats were randomly assigned to five groups (n = 8): control (CON), model (MOD), low- (1.35 g/kg, DSL), high-dose (2.70 g/kg, DSH) DS group, and Melatonin(100 mg/kg, MT) group. A CSD rat model was established over 21 days. DS's effects and the underlying mechanism were explored using the open-field test(OFT), Morris water-maze(MWM), tissue staining(Hematoxylin and Eosin Staining, Nissl staining, Alcian blue-periodic acid SCHIFF staining, and Immunofluorescence), enzyme-linked immunosorbent assay, Western blot, quantitative real-time polymerase chain reaction(qPCR), and 16S rRNA sequencing. RESULTS: We demonstrated that CSD caused gut dysbiosis and cognitive dysfunction. Furthermore, 16S rRNA sequencing demonstrated that Firmicutes and Proteobacteria were more in fecal samples from model group rats, whereas Bacteroidota and Spirochaetota were less. DS therapy, on the contrary hand, greatly restored the gut microbial community, consequently alleviating cognitive impairment in rats. Further research revealed that DS administration reduced systemic inflammation via lowering intestinal inflammation and barrier disruption. Following that, DS therapy reduced Blood Brain Barrier(BBB) and neuronal damage, further decreasing neuroinflammation in the hippocampus(HP). Mechanistic studies revealed that DS therapy lowered lipopolysaccharide (LPS) levels in the HP, serum, and colon, consequently blocking the TLR4/MyD88/NF-κB signaling pathway and its downstream pro-inflammatory products(IL-1ß, IL-6, TNF-α, iNOS, and COX2) in the HP and colon. CONCLUSION: DS treatment dramatically improved spatial learning and memory impairments in rats with CSD by regulating the composition of the intestinal flora, preserving gut and brain barrier function, and reducing inflammation mediated by the LPS-TLR4 signaling pathway. Our findings provide novel insight into the mechanisms by which DS treats cognitive dysfunction caused by CSD.
Subject(s)
Cognitive Dysfunction , Drugs, Chinese Herbal , Rats, Sprague-Dawley , Salvia miltiorrhiza , Sleep Deprivation , Animals , Salvia miltiorrhiza/chemistry , Sleep Deprivation/complications , Sleep Deprivation/drug therapy , Cognitive Dysfunction/drug therapy , Male , Drugs, Chinese Herbal/pharmacology , Rats , Gastrointestinal Microbiome/drug effects , Disease Models, Animal , Hippocampus/drug effects , Hippocampus/metabolism , NF-kappa B/metabolism , Morris Water Maze Test/drug effects , Maze Learning/drug effectsABSTRACT
Many psychiatric disorders exhibit sex differences, but the underlying mechanisms remain poorly understood. We analyzed transcriptomics data from 2160 postmortem adult prefrontal cortex brain samples from the PsychENCODE consortium in a sex-stratified study design. We compared transcriptomics data of postmortem brain samples from patients with schizophrenia (SCZ), bipolar disorder (BD), and autism spectrum disorder (ASD) with transcriptomics data of postmortem control brains from individuals without a known history of psychiatric disease. We found that brain samples from females with SCZ, BD, and ASD showed a higher burden of transcriptomic dysfunction than did brain samples from males with these disorders. This observation was supported by the larger number of differentially expressed genes (DEGs) and a greater magnitude of gene expression changes observed in female versus male brain specimens. In addition, female patient brain samples showed greater overall connectivity dysfunction, defined by a higher proportion of gene coexpression modules with connectivity changes and higher connectivity burden, indicating a greater degree of gene coexpression variability. We identified several gene coexpression modules enriched in sex-biased DEGs and identified genes from a genome-wide association study that were involved in immune and synaptic functions across different brain cell types. We found a number of genes as hubs within these modules, including those encoding SCN2A, FGF14, and C3. Our results suggest that in the context of psychiatric diseases, males and females exhibit different degrees of transcriptomic dysfunction and implicate immune and synaptic-related pathways in these sex differences.
Subject(s)
Autopsy , Brain , Mental Disorders , Sex Characteristics , Transcriptome , Humans , Female , Male , Transcriptome/genetics , Brain/metabolism , Brain/pathology , Mental Disorders/genetics , Mental Disorders/pathology , Bipolar Disorder/genetics , Bipolar Disorder/metabolism , Bipolar Disorder/pathology , Schizophrenia/genetics , Schizophrenia/metabolism , Schizophrenia/pathology , Gene Expression Profiling , Genome-Wide Association Study , Adult , Autism Spectrum Disorder/genetics , Autism Spectrum Disorder/metabolism , Autism Spectrum Disorder/pathology , Gene Regulatory Networks , Middle AgedABSTRACT
The pressing demand for propylene has spurred intensive research on the catalytic dehydrogenation of propane to produce propylene. Gallium-based catalysts are regarded as highly promising due to their exceptional dehydrogenation activity in the presence of CO2. However, the inherent coking issue associated with high temperature reactions poses a constraint on the stability development of this process. In this study, we employed the electrospinning method to prepare a range of Ga2O3-Al2O3 mixed oxide one-dimensional nanofiber catalysts with varying molar ratios for CO2 oxidative dehydrogenation of propane (CO2-OPDH). The propane conversion was up to 48.4 % and the propylene selectivity was high as 96.8 % at 500 °C, the ratio of propane to carbon dioxide is 1:2. After 100 h of reaction, the catalyst still maintains approximately 10 % conversion and exhibits a propylene selectivity of around 98 %. The electrospinning method produces one-dimensional nanostructures with a larger specific surface area, unique multi-stage pore structure and low-coordinated Ga3+, which enhances mass transfer and accelerates reaction intermediates. This results in less coking and improved catalyst stability. The high activity of the catalyst is attributed to an abundance of low-coordinated Ga3+ ions associated with weak/medium-strong Lewis acid centers. In situ infrared analysis reveals that the reaction mechanism involves a two-step dehydrogenation via propane isocleavage, with the second dehydrogenation of Ga-OR at the metal-oxygen bond being the decisive speed step.
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The advent of optical metrology applications has necessitated the development of compact, reliable, and cost-effective picosecond lasers operating around 900â nm, specifically catering to the requirements of precise ranging. In response to this demand, our work introduces an innovative solution-an all-fiber, all-polarization-maintaining (PM) figure-9 mode-locked laser operating at 915â nm. The proposed figure-9 Nd-doped fiber laser has a 69.2 m long cavity length, strategically designed and optimized to yield pulses with a combination of high pulse energy and low repetition rate. The laser can generate 915â nm laser pulses with a pulse energy of 4.65 nJ, a pulse duration of 15.2 ps under the repetition rate of 3.05â MHz. The 1064â nm amplified spontaneous emission (ASE) is deliberately filtered out, in order to prevent parasitic lasing and increase the spectral proportion of the 915â nm laser. The all-PM fiber configuration of this laser imparts exceptional mode-locking performance and environmental robustness, which is confirmed by long-term output power and spectral stability test. This compact and long-term reliable fiber laser could be a promising light source for applications like inter-satellite ranging.
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The utilization of carbon-based fibers as a fundamental constituent holds strong appeal for diverse materials and devices. However, the poor fiber graphitic structure resulting from the heat treatment of atactic polyacrylonitrile (PAN) precursors often leads to a modest performance of carbon-based fibers. This paper takes electrospun carbon nanofibers (CNFs) as the research object and provides a seed-assisted graphitization strategy to improve the fiber graphitic structures. The typical melamine/cyanuric acid self-assembly precursor of graphitic carbon nitride is applied as supramolecular seeds in CNFs and demonstrates significant promotion of fiber graphitization, while it decomposes at elevated temperatures. Further studies show that the higher carbon content contributes to the better heat resistance of seeds; thus, nanoscale 2,6-diaminopyridine/cyanuric acid and 2,4,6-triaminopyrimidine/barbituric acid supramolecular seeds are developed. Both systems can be uniformly distributed in PAN precursors through in situ self-assembly and withstand high-temperature carbonization without severe pyrolysis. The dispersed seeds contribute to the formation of fibrillar PAN crystals and promote their conversion to ordered graphitic domains through nucleation and templating roles. The obtained CNFs exhibit increased crystallinity and graphitization degree with improved orientation and refined size of fiber crystals. As a result, the strength, modulus, and elongation at break of CNFs are comprehensively enhanced.
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The hearts of subjects with diabetes are vulnerable to ischemia-reperfusion injury (IRI). In contrast, experimentally rodent hearts have been shown to be more resistant to IRI at the very early stages of diabetes induction than the heart of the non-diabetic control mice, and the mechanism is largely unclear. Ferroptosis has recently been shown to play an important role in myocardial IRI including that in diabetes, while the specific mechanisms are still unclear. Non-diabetic control (NC) and streptozotocin-induced diabetic (DM) mice were treated with the antioxidant N-acetylcysteine (NAC) in drinking water for 4 week starting at 1 week after diabetes induction. Mice were subjected to myocardial IRI induced by occluding the coronary artery for 30 min followed by 2 h of reperfusion, subsequently at 1, 2, and 5 week of diabetes induction. The post-ischemic myocardial infarct size in the DM mice was smaller than that in NC mice at 1 week of diabetes but greater than that in the NC mice at 2 and 5 week of diabetes, which were associated with a significant increase of ferroptosis at 2 and 5 week but a significant reduction of ferroptosis at 1 week of diabetes. NAC significantly attenuated post-ischemic ferroptosis as well as oxidative stress and reduced infarct size at 2 and 5 week of diabetes. Application of erastin, a ferroptosis inducer, reversed the cardioprotective effects of NAC. It is concluded that increased oxidative stress and ferroptosis are the major factors attributable to the increased vulnerability to myocardial IRI in diabetes and that attenuation of ferroptosis represents a major mechanism whereby NAC confers cardioprotection against myocardial IRI in diabetes.
Subject(s)
Acetylcysteine , Antioxidants , Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 1 , Ferroptosis , Mice, Inbred C57BL , Myocardial Reperfusion Injury , Animals , Myocardial Reperfusion Injury/prevention & control , Myocardial Reperfusion Injury/pathology , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/physiopathology , Acetylcysteine/pharmacology , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/complications , Male , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/metabolism , Antioxidants/pharmacology , Ferroptosis/drug effects , Myocardial Infarction/prevention & control , Myocardial Infarction/pathology , Myocardial Infarction/metabolism , Myocardial Infarction/physiopathology , Myocardial Infarction/drug therapy , Time Factors , Myocardium/pathology , Myocardium/metabolism , Mice , Oxidative Stress/drug effectsABSTRACT
Due to the strong selectivity and permeability of tumor tissue, anti-cancer peptide-drug conjugates (PDCs) can accumulate high concentration of toxic payloads at the target, effectively killing tumor cells. This approach holds great promise for tumor-targeted treatment. In our previous study, we identified the optimal peptide P1 (NPNWGRSWYNQRFK) targeting HER2 from pertuzumab, a monoclonal antibody that blocks the HER2 signaling pathway. Here, a series of PDCs were constructed through connecting P1 and CPT with different linkers. Among these, Z8 emerged as the optimal compound, demonstrating good antitumor activity and targeting ability in biological activity tests. Z8 exhibited IC50 values of 1.04 ± 0.24 µM and 1.91 ± 0.71 µM against HER2-positive SK-BR-3 and NCI-N87 cells, respectively. Moreover, superior antitumor activity and higher biosafety of Z8 were observed compared to the positive control CPT in vivo, suggesting a novel idea for the construction of PDCs.
Subject(s)
Antineoplastic Agents , Camptothecin , Cell Proliferation , Drug Screening Assays, Antitumor , Peptides , Receptor, ErbB-2 , Humans , Receptor, ErbB-2/metabolism , Receptor, ErbB-2/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Camptothecin/pharmacology , Camptothecin/chemistry , Structure-Activity Relationship , Animals , Cell Proliferation/drug effects , Peptides/chemistry , Peptides/pharmacology , Peptides/chemical synthesis , Molecular Structure , Dose-Response Relationship, Drug , Mice , Drug Discovery , Cell Line, Tumor , Female , Mice, Inbred BALB C , Mice, NudeABSTRACT
Background/Objective: as internet use becomes increasingly ingrained in contemporary society, internet addiction (IA) has emerged as a global public health concern. There is ongoing debate regarding whether IA represents a distinct psychological disorder or a secondary manifestation of other existing disorders. This study aimed to examine the pathological relationship between IA and emotional disorders (ED). Method: this study compared pre-treatment characteristics and treatment process of three groups of patients (N=1292) in a naturalistic treatment setting: IA only, ED only, and comorbidity of IA and ED. Results: the IA only group differed from the other groups by reporting the highest levels of life satisfaction, adaptive emotion regulation, as well as risk behavior urges at intake. In addition, the IA only group displayed the lowest level of depressive and anxiety symptoms throughout the treatment. Conclusion: our findings contribute to a better understanding of the discreteness of IA as a potential psychological disorder and inform more effective treatment strategies for IA and its comorbid conditions.
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Background: Prevention of diabetic heart myocardial ischemia-reperfusion (IR) injury (MIRI) is challenging. Propofol attenuates MIRI through its reactive oxygen species scavenging property at high doses, while its use at high doses causes hemodynamic instability. Salvianolic acid A (SAA) is a potent antioxidant that confers protection against MIRI. Both propofol and SAA affect metabolic profiles through regulating Adenosine 5'-monophosphate-activated protein kinase (AMPK). The aim of this study was to investigate the protective effects and underlying mechanisms of low doses of propofol combined with SAA against diabetic MIRI. Methods: Diabetes was induced in mice by a high-fat diet followed by streptozotocin injection, and MIRI was induced by coronary artery occlusion and reperfusion. Mice were treated with propofol at 46 mg/kg/h without or with SAA at 10 mg/kg/h during IR. Cardiac origin H9c2 cells were exposed to high glucose (HG) and palmitic acid (PAL) for 24 h in the absence or presence of cluster of differentiation 36 (CD36) overexpression or AMPK gene knockdown, followed by hypoxia/reoxygenation (HR) for 6 and 12 h. Results: Diabetes-exacerbated MIRI is evidenced as significant increases in post-ischemic infarction with reductions in phosphorylated (p)-AMPK and increases in CD36 and ferroptosis. Propofol moderately yet significantly attenuated all the abovementioned changes, while propofol plus SAA conferred superior protection against MIRI to that of propofol. In vitro, exposure of H9c2 cells under HG and PAL decreased cell viability and increased oxidative stress that was concomitant with increased levels of ferroptosis and a significant increase in CD36, while p-AMPK was significantly reduced. Co-administration of low concentrations of propofol and SAA at 12.5 µM in H9c2 cells significantly reduced oxidative stress, ferroptosis and CD36 expression, while increasing p-AMPK compared to the effects of propofol at 25 µM. Moreover, either CD36 overexpression or AMPK silence significantly exacerbated HR-induced cellular injuries and ferroptosis, and canceled propofol- and SAA-mediated protection. Notably, p-AMPK expression was downregulated after CD36 overexpression, while AMPK knockdown did not affect CD36 expression. Conclusions: Combinational usage of propofol and SAA confers superior cellular protective effects to the use of high-dose propofol alone, and it does so through inhibiting HR-induced CD36 overexpression to upregulate p-AMPK.