PM2.5-induced iron homeostasis imbalance triggers cardiac hypertrophy through ferroptosis in a selective autophagy crosstalk manner.

Exposure to PM2.5 is correlated with cardiac remodeling, of which cardiac hypertrophy is one of the main clinical manifestations. Ferroptosis plays an important role in cardiac hypertrophy. However, the potential mechanism of PM2.5-induced cardiac hypertrophy through ferroptosis remains unclear. This study aimed to explore the molecular mechanism of cardiac hypertrophy caused by PM2.5 and the intervention role of MitoQ involved in this process. The results showed that PM2.5 could induce cardiac hypertrophy and dysfunction in mice. Meanwhile, the characteristics of ferroptosis were observed, such as iron homeostasis imbalance, lipid peroxidation, mitochondrial damage and abnormal expression of key molecules. MitoQ treatment could effectively mitigate these alternations. After treating human cardiomyocyte AC16 with PM2.5, ferroptosis activator (Erastin) and inhibitor (Fer-1), it was found that PM2.5 could promote ferritinophagy and lead to lipid peroxidation, mitochondrial dysfunction as well as the accumulation of intracellular and mitochondrial labile iron. Subsequently, mitophagy was activated and provided an additional source of labile iron, enhancing the sensitivity of AC16 cells to ferroptosis. Furthermore, Fer-1 alleviated PM2.5-induced cytotoxicity and iron overload in the cytoplasm and mitochondria of AC16 cells. It was worth noting that during the process of PM2.5 caused ferroptosis, abnormal iron metabolism mediated the activation of ferritinophagy and mitophagy in a temporal order. In addition, NCOA4 knockdown reversed the iron homeostasis imbalance and lipid peroxidation caused by PM2.5, thereby alleviating ferroptosis. In summary, our study found that iron homeostasis imbalance-mediated the crosstalk of ferritinophagy and mitophagy played an important role in PM2.5-induced ferroptosis and cardiac hypertrophy.

Understanding erosion resistance mechanisms of sodium aluminate silicate hydrate in erosion environments: a molecular dynamics study.

Sodium-aluminate-silicate-hydrate (NASH) gel, as the primary reaction product stimulated by alkali in silica-aluminum-rich minerals, influences the mechanical and durability properties of geopolymers. In erosion environments, NASH demonstrates superior compressive strength and erosion resistance compared to hydration products of ordinary Portland cement. However, the underlying erosion resistance mechanism of NASH under such conditions remains unclear. Therefore, this study employs molecular dynamics research methodology to investigate the alteration in performance and deterioration mechanism of NASH in erosive environments. The findings reveal that in Na2SO4 solution, the infiltration of H2O molecules and Na+ ions into the three-dimensional mesh structure of NASH results in slight expansion and reduced tensile strength. Although H2O intrusion induces hydrolysis of the three-dimensional skeleton, the adsorption sites within NASH possess the capability to capture externally introduced Na+ ions. During tensile loading, Na+ ions can interact with reactive oxygen species produced through stretching or H2O molecule-induced decomposition of the internal framework, facilitating the repair of fractured structures. Consequently, this process partially alleviates tensile rupture, modifies the fracture damage mode, enhances overall toughness, and improves resistance against sulfate attack.

Next-generation sequencing-based analysis of homologous recombination repair gene variant in ovarian cancer.

Background: Ovarian cancer is the leading cause of death from gynecological malignancies. Investigating the HRR-related gene status, notably BRCA1/2 in different regions and populations is of great significance for formulating accurate target therapy. Methods: We collected 124 ovarian cancer cases from the Affiliated Hospital of.Qingdao University, detected the genomic alteration of 32 genes by NGS, including.19 HRR-related genes, 9 proto-oncogenes and 4 tumor suppressor genes. Clinicopathological characteristics, variants, clinical significance, and correlation with prognosis were analyzed. Results: The incidence of HRR-related gene mutation was 59.68 % and no statistical significance was found with multiple clinicopathological characteristics. BRCA1/2 (27.42 %) were the most frequent mutated HRR genes. 23 (18.55 %) cases harbored gBRCA1/2 mutation, with all BRCA1 mutations were pathogenic/likely pathogenic and 2 cases of BRCA2 mutation was variant of uncertain significance. Somatic BRCA1/2 mutations were found in 12 (9.68 %) cases, and sBRCA1/2 had a higher frequency in less common ovarian cancer than high-grade serous carcinoma. HRR-related gene mutation status was associated with better prognosis than HRR wild-type. Conclusions: Somatic BRCA1/2 mutation has higher incidence in less common ovarian cancer. HRR gene mutation status is an independent prognosis factor in ovarian cancer. Clarifying the HRR gene status is important for the selection of target therapy as well as the evaluation of prognosis.

Characterization of Volatile Compounds in Donkey Meat by Gas Chromatography-Ion Mobility Spectrometry (GC-IMS) Combined with Chemometrics.

Volatile compounds (VOCs) are an important factor affecting meat quality. However, the characteristic VOCs in different parts of donkey meat remain unknown. Accordingly, this study represents a preliminary investigation of VOCs to differentiate between different cuts of donkey meat by using headspace-gas chromatography-ion mobility spectrometry (HS-GC-IMS) combined with chemometrics analysis. The results showed that the 31 VOCs identified in donkey meat, ketones, alcohols, aldehydes, and esters were the predominant categories. A total of 10 VOCs with relative odor activity values ≥1 were found to be characteristic of donkey meat, including pentanone, hexanal, nonanal, octanal, and 3-methylbutanal. The VOC profiles in different parts of donkey meat were well differentiated using three- and two-dimensional fingerprint maps. Nine differential VOCs that represent potential markers to discriminate different parts of donkey meat were identified by chemometrics analysis. These include 2-butanone, 2-pentanone, and 2-heptanone. Thus, the VOC profiles in donkey meat and specific VOCs in different parts of donkey meat were revealed by HS-GC-IMS combined with chemometrics, whcih provided a basis and method of investigating the characteristic VOCs and quality control of donkey meat.

AMPAkines have site-specific analgesic effects in the cortex.

Different brain areas have distinct roles in the processing and regulation of pain and thus may form specific pharmacological targets. Prior research has shown that AMPAkines, a class of drugs that increase glutamate signaling, can enhance descending inhibition from the prefrontal cortex (PFC) and nucleus accumbens. On the other hand, activation of neurons in the anterior cingulate cortex (ACC) is known to produce the aversive component of pain. The impact of AMPAkines on ACC, however, is not known. We found that direct delivery of CX516, a well-known AMPAkine, into the ACC had no effect on the aversive response to pain in rats. Furthermore, AMPAkines did not modulate the nociceptive response of ACC neurons. In contrast, AMPAkine delivery into the prelimbic region of the prefrontal cortex (PL) reduced pain aversion. These results indicate that the analgesic effects of AMPAkines in the cortex are likely mediated by the PFC but not the ACC.

Time-dependent regulation of respiration is widespread across plant evolution.

Establishing the temperature dependence of respiration is critical for accurate predictions of the global carbon cycle under climate change. Diurnal temperature fluctuations, or changes in substrate availability, lead to variations in leaf respiration. Additionally, recent studies hint that the thermal sensitivity of respiration could be time-dependent. However, the role for endogenous processes, independent from substrate availability, as drivers of temporal changes in the sensitivity of respiration to temperature across phylogenies has not yet been addressed. Here, we examined the diurnal variation in the response of respiration to temperatures (R-T relationship) for different lycophyte, fern, gymnosperm and angiosperm species. We tested whether time-dependent changes in the R-T relationship would impact leaf level respiration modelling. We hypothesized that interactions between endogenous processes, like the circadian clock, and leaf respiration would be independent from changes in substrate availability. Overall, we observed a time-dependent sensitivity in the R-T relationship across phylogenies, independent of temperature, that affected modelling parameters. These results are compatible with circadian gating of respiration, but further studies should analyse the possible involvement of the clock. Our results indicate time-dependent regulation of respiration might be widespread across phylogenies, and that endogenous regulation of respiration is likely affecting leaf-level respiration fluxes.

The inhibitory effect of excess calcium ions on the polymerization process of calcium aluminate silicate hydrate (CASH) gel.

Calcium ion, as an essential component in CASH, affects the aggregation and formation process of CASH, thereby influencing its microstructure and mechanical properties. However, the mechanism by which calcium ions affect the polymerization process of CASH is not yet fully understood. In this study, the effects of calcium ions on the polymerization process, coagulation state, and microstructure of CASH are investigated via molecular dynamics simulation. The results indicate that the presence of a trace amount of Ca2+ attracts oligomers towards the calcium-rich region, thus speeding up the polymerization to some extent, but as the Ca2+ content increases, more Ca2+ binds to the oxygen atoms in silica-oxygen tetrahedra and aluminum-oxygen tetrahedra, forming tight ion pairs and occupying the hydroxyl binding sites required for the polycondensation reaction. This inhibits the continuous aggregation of CASH gel and slows down the rate of polymerization. Additionally, Ca2+ attracts oxygen atoms from free water molecules and free OH-, forming Ca(OH)2 dispersed in the spatial structure, which hinders the formation of larger clusters. As a result, the higher the Ca ion content in the system, the lower the overall polymerization degree of the CASH gel, resulting in a decrease in the conversion of the Q1 dimer to Q2 and Q3 chain structures, a shorter average chain length, poorer overall connectivity, and a transition from large clusters in a better-aggregated state to dispersed small clusters. This study sheds light on the polymerization reaction mechanism of CASH gels.

Anterior cingulate cortex regulates pain catastrophizing-like behaviors in rats.

Negative pain expectation including pain catastrophizing is a well-known clinical phenomenon whereby patients amplify the aversive value of a painful or oftentimes even a similar, non-painful stimulus. Mechanisms of pain catastrophizing, however, remain elusive. Here, we modeled pain catastrophizing behavior in rats, and found that rats subjected to repeated noxious pin pricks on one paw demonstrated an aversive response to similar but non-noxious mechanical stimuli delivered to the contralateral paw. Optogenetic inhibition of pyramidal neuron activity in the anterior cingulate cortex (ACC) during the application of repetitive noxious pin pricks eliminated this catastrophizing behavior. Time-lapse calcium (Ca2+) imaging in the ACC further revealed an increase in spontaneous neural activity after the delivery of noxious stimuli. Together these results suggest that the experience of repeated noxious stimuli may drive hyperactivity in the ACC, causing increased avoidance of subthreshold stimuli, and that reducing this hyperactivity may play a role in treating pain catastrophizing.

m6A-mediated lncRNA NEAT1 plays an oncogenic role in non-small cell lung cancer by upregulating the HMGA1 expression through binding miR-361-3p.

BACKGROUND: Lung cancer is the most common primary malignant tumor of the lung, and 85% of lung cancer is non-small cell lung cancer (NSCLC). The N6-methyladenosine (m6A) and long noncoding RNAs (lncRNAs) have been widely reported to participate in the development of non-small cell lung cancer. OBJECTIVE: However, the potential molecular mechanisms of m6A-regulated lncRNAs in NSCLC still need further investigation. METHODS: The expression levels and the role of lncRNA NEAT1 in NSCLC tissues or cells were measured by RT-qPCR, Western blot, cell counting kit 8 (CCK-8), flow cytometry assay. RNA immunoprecipitation (RIP) was used to measure the levels of m6A modification of NEAT1. Bioinformatics analysis and dual-luciferase reporter gene assay were detected the relationship between miR-361-3p and NEAT1/HMGA1. Mouse xenograft tumor models were established to confirm the effects of lncRNA NEAT1 in vivo. RESULTS: In this study, we verified whether m6A-modified lncRNA nuclear enriched abundant transcript 1 (NEAT1) is involved in NSCLC progression via miR-361-3p/HMGA1 axis. Firstly, we found that lncRNA NEAT1 was upregulated in NSCLC, and was associated with a poor survival in NSCLC patients. Methyltransferase like 3 (METTL3)-mediated m6A modification stabilized and upregulated NEAT1 expression. Next, function experiment indicated that depletion of METTL3 and NEAT1 induced cell apoptosis and inhibited cell proliferation, epithelial-mesenchymal transition (EMT). Likewise, in vivo experiments further supported the oncogenic role of NEAT1 in NSCLC. In addition, the molecular mechanism was uncovered in our study, and we found that lncRNA NEAT1 promoted the expression of high-mobility group AT-hook 1 (HMGA1) by sponging miR-361-3p and then promoted tumorigenesis of NSCLC. CONCLUSION: In conclusion, our findings demonstrated that METTL3-mediated m6A modification accelerated NSCLC progression by regulating the NEAT1/miR-361-3p/HMGA1 axis, which provides important targets for the treatment of NSCLC.

Chemical upcycling of polyethylene, polypropylene, and mixtures to high-value surfactants.

Conversion of plastic wastes to fatty acids is an attractive means to supplement the sourcing of these high-value, high-volume chemicals. We report a method for transforming polyethylene (PE) and polypropylene (PP) at ~80% conversion to fatty acids with number-average molar masses of up to ~700 and 670 daltons, respectively. The process is applicable to municipal PE and PP wastes and their mixtures. Temperature-gradient thermolysis is the key to controllably degrading PE and PP into waxes and inhibiting the production of small molecules. The waxes are upcycled to fatty acids by oxidation over manganese stearate and subsequent processing. PP ꞵ-scission produces more olefin wax and yields higher acid-number fatty acids than does PE ꞵ-scission. We further convert the fatty acids to high-value, large-market-volume surfactants. Industrial-scale technoeconomic analysis suggests economic viability without the need for subsidies.

Associations of long-term particulate matter exposure with cardiometabolic diseases: A systematic review and meta-analysis.

BACKGROUND: This review aimed to establish a holistic perspective of long-term PM exposure and cardiometabolic diseases, identify long-term PM-related cardiovascular and metabolic risk factors, and provide practical significance to preventative measures. METHOD: A combination of computer and manual retrieval was used to search for keywords in PubMed (2903 records), Embase (2791 records), Web of Science (5488 records) and Cochrane Library (163 records). Finally, a total of 82 articles were considered in this meta-analysis. Stata 13.0 was accustomed to inspecting the studies' heterogeneity and calculating the combined effect value (RR) by selecting the matching models. The subgroup analysis, sensitivity analysis and publication bias tests were also performed. RESULTS: Meta-analysis figured an association between PM and cardiometabolic diseases. PM2.5 (per 10 µg/m3 increase) boosted the risk of hypertension (RR = 1.14, 95 % CI: 1.09-1.19), coronary heart disease (CHD) (RR = 1.21, 95 % CI: 1.08-1.35), diabetes (RR = 1.16, 95 % CI: 1.11-1.21) and stroke (including ischemic stroke and hemorrhagic stroke). PM10 (per 10 µg/m3 increase) elevated the incidence of hypertension (RR = 1.11, 95 % CI: 1.07-1.16) and diabetes (RR = 1.26, 95 % CI: 1.08-1.47). PM1 (per 10 µg/m3 increase) exposure increased the risk of total dyslipidemia, yielding the RR of 1.10 (95 % CI: 1.01-1.18). Furthermore, the elderly, overweight and higher background pollutant level were potentially susceptible to related diseases. CONCLUSION: There was a virtual connection between long-term exposure to PM and cardiometabolic diseases. PM2.5 or PM10 (per 10 µg/m3) increased the risk of hypertension, CHD, diabetes, stroke and dyslipidemia, causing cardiovascular "multimorbidity" in high-risk populations.

Progress of Mass Spectrometry-Based Lipidomics in the Dairy Field.

Lipids play important biological roles, such as providing essential fatty acids and signaling. The wide variety and structural diversity of lipids, and the limited technical means to study them, have seriously hampered the resolution of the mechanisms of action of lipids. With advances in mass spectrometry (MS) and bioinformatic technologies, large amounts of lipids have been detected and analyzed quickly using MS-based lipidomic techniques. Milk lipids, as complex structural metabolites, play a crucial role in human health. In this review, the lipidomic techniques and their applications to dairy products, including compositional analysis, quality identification, authenticity identification, and origin identification, are discussed, with the aim of providing technical support for the development of dairy products.

Effects of Roughage on the Lipid and Volatile-Organic-Compound Profiles of Donkey Milk.

The lipid molecules and volatile organic compounds (VOCs) in milk are heavily influenced by diet. However, little is known about how roughage affects the lipid and VOC contents of donkey milk. Accordingly, in the present study, donkeys were fed corn straw (G1 group), wheat hulls (G2 group), or wheat straw (G3 group), and the lipid and VOC profiles of their milk were determined using LC-MS and GC-MS. Of the 1842 lipids identified in donkey milk, 153 were found to be differential, including glycerolipids, glycerophospholipids, and sphingolipids. The G1 group showed a greater variety and content of triacyclglycerol species than the G2 and G3 groups. Of 45 VOCs, 31 were identified as differential, including nitrogen compounds, esters, and alcohols. These VOCs were significantly increased in the G2 and G3 groups, with the greatest difference being between the G1 and G2 groups. Thus, our study demonstrates that dietary roughage changes the lipid and VOC profiles of donkey milk.

SEL1L-HRD1 endoplasmic reticulum-associated degradation controls STING-mediated innate immunity by limiting the size of the activable STING pool.

Stimulator of interferon genes (STING) orchestrates the production of proinflammatory cytokines in response to cytosolic double-stranded DNA; however, the pathophysiological significance and molecular mechanism underlying the folding and maturation of nascent STING protein at the endoplasmic reticulum (ER) remain unknown. Here we report that the SEL1L-HRD1 protein complex-the most conserved branch of ER-associated degradation (ERAD)-is a negative regulator of the STING innate immunity by ubiquitinating and targeting nascent STING protein for proteasomal degradation in the basal state. SEL1L or HRD1 deficiency in macrophages specifically amplifies STING signalling and immunity against viral infection and tumour growth. Mechanistically, nascent STING protein is a bona fide substrate of SEL1L-HRD1 in the basal state, uncoupled from ER stress or its sensor inositol-requiring enzyme 1α. Hence, our study not only establishes a key role of SEL1L-HRD1 ERAD in innate immunity by limiting the size of the activable STING pool, but identifies a regulatory mechanism and therapeutic approach to targeting STING.

Evaluation potential effects of Picroside II on cytochrome P450 enzymes in vitro and in vivo.

ETHNOPHARMACOLOGY RELEVANCE: Picrorhiza scrophulariiflora Pennell, a well-known Chinese herb, has been traditionally utilized as an antioxidant and anti-inflammatory agent. One of its main bioactive components is Picroside II, a glycoside derivative. However, there is limited information on the effects of Picroside II on the activity of cytochrome P450 (CYP) enzymes nor on potential herb-drug interactions are rarely studied. AIM OF THE STUDY: The purpose of the study was to investigate the effects of Picroside II on the activity of cytochrome P450 enzymes in vitro and in vivo and its potential herb-drug interactions. MATERIALS AND METHODS: Specific probe substrates were employed to assess the effect of Picroside II on the activity of P450 enzymes. The inhibitory effects of Picroside II on CYP enzymes were assayed both in human (i.e., 1A, 2C9, 2C19, 2D6, 2E1, and 3A) and rat (i.e., 1A, 2C6/11, 2D1, 2E1, and 3A) liver microsomes in vitro. The inductive effects were investigated in rats following oral gavage of 2.5 mg/kg and 10 mg/kg Picroside II. A specific Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS) method was developed to determine the formation of specific metabolites. RESULTS: Enzyme inhibition results showed that Picroside II (0.5-200 µM) had no evident inhibitory effects on rat and human liver microsomes in vitro. Interestingly, the administration of multiple doses of 10 mg/kg Picroside II inhibited the activity of CYP2C6/11 by reducing the rate of formation of 4-hydroxydiclofenac and 4-hydroxymephenytoin, while Picroside II at 2.5 mg/kg increased the activity of CYP3A by promoting the formation of 1-hydroxymidazolam and 6-hydroxychlorzoxazone in rats. In addition, there were negligible effects on CYP1A, CYP2D1, and CYP2E1 in rats. CONCLUSIONS: The results indicated that Picroside II modulated the activities of CYP enzymes and was involved in CYP2C and CYP3A medicated herb-drug interactions. Therefore, careful monitoring is necessary when Picroside II is used in combination with related conventional drugs.

Oxytocin promotes prefrontal population activity via the PVN-PFC pathway to regulate pain.

Neurons in the prefrontal cortex (PFC) can provide top-down regulation of sensory-affective experiences such as pain. Bottom-up modulation of sensory coding in the PFC, however, remains poorly understood. Here, we examined how oxytocin (OT) signaling from the hypothalamus regulates nociceptive coding in the PFC. In vivo time-lapse endoscopic calcium imaging in freely behaving rats showed that OT selectively enhanced population activity in the prelimbic PFC in response to nociceptive inputs. This population response resulted from the reduction of evoked GABAergic inhibition and manifested as elevated functional connectivity involving pain-responsive neurons. Direct inputs from OT-releasing neurons in the paraventricular nucleus (PVN) of the hypothalamus are crucial to maintaining this prefrontal nociceptive response. Activation of the prelimbic PFC by OT or direct optogenetic stimulation of oxytocinergic PVN projections reduced acute and chronic pain. These results suggest that oxytocinergic signaling in the PVN-PFC circuit constitutes a key mechanism to regulate cortical sensory processing.

Ferritinophagy was involved in long-term SiNPs exposure induced ferroptosis and liver fibrosis.

SiNPs could induce liver fibrosisinvivo, but the mechanism was not completely clear. This study focused on exploring whether long-term SiNPs exposure at human-related exposure dosage could lead to ferritinophagy-mediated ferroptosis and liver fibrosis. In vivo, long-term SiNPs exposure induced liver fibrosis inrats accompanied by ferritinophagy and ferroptosis in hepatocytes. Interestingly, the progression of liver fibrosis was alleviated after exposure cessation and recovery, meanwhile ferritinophagy and ferroptosis were not further activated. In vitro, after long-term SiNPs exposure, the mitochondrial membrane ruptured, lipid peroxidation intensified, the level of redox active iron increased and the repair protein of lipid peroxidation were consumed in L-02 cells, demonstrating ferroptosis occurrence. Notably, NCOA4 knockdown inhibited ferritin degradation, alleviated the increase of intracellular ferrous iron level, reduced lipid peroxidation and the depletion of glutathione peroxidase 4 (GPX4). In conclusion, ferritinophagy mediated by NCOA4 was responsible for long-term SiNPs exposure induced hepatocytes ferroptosis and liver fibrosis, which provided a scientific basis for toxicological assessment of SiNPs and would be benefited for the safety design of SiNPs-based products.

The detrimental effects of micro-and nano-plastics on digestive system: An overview of oxidative stress-related adverse outcome pathway.

With the massive manufacture and use of plastics, plastic pollution-related environmental impacts have raised great concern in recent years. As byproducts of plastic fragmentation and degradation, microplastics (MPs) and nanoplastics (NPs) have been identified as novel pollutants that posed a threat to the ecosystem and humans. Since MPs/NPs could be transported via the food chain and retained in the water, the digestive system should be one of the major targets of MPs/NPs-related toxicity. Although considerable evidence has supported the digestive toxicity of MPs/NPs, the proposed mechanisms remained ambiguous due to the variety of study types, models, and endpoints. This review provided a mechanism-based perspective on MPs/NPs-induced digestive effects by adopting the adverse outcome pathway framework as a promising tool. The overproduction of reactive oxygen species was identified as the molecular initiating event in MPs/NPs-mediated injury to the digestive system. A series of detrimental effects including oxidative stress, apoptosis, inflammation, dysbiosis, and metabolic disorders were summarized as key events. Finally, the occurrence of these effects eventually led to an adverse outcome, suggesting a possible increase in the incidence of digestive morbidity and mortality.

Characterization of donkey-meat flavor profiles by GC-IMS and multivariate analysis.

The distinctive flavor compounds of donkey meat are unknown. Accordingly, in the present study, the volatile compounds (VOCs) in the meat from SanFen (SF) and WuTou (WT) donkeys were comprehensively analyzed by gas chromatography-ion mobility spectrometry (GC-IMS) combined with multivariate analysis. A total of 38 VOCs, of which 33.33% were ketones, 28.89% were alcohols, 20.00% were aldehydes, and 2.22% were heterocycles, were identified. Ketones and alcohols were significantly more abundant for SF than for WT, whereas aldehydes showed the opposite trend. The donkey meats from the two strains were well differentiated using topographic plots, VOC fingerprinting, and multivariate analysis. A total of 17 different VOCs were identified as potential markers for distinguishing the different strains, including hexanal-m, 3-octenal, oct-1-en-3-ol, and pentanal-d. These results indicate that GC-IMS combined with multivariate analysis is a convenient and powerful method for characterizing and discriminating donkey meat.