Maintaining moderate levels of hypochlorous acid promotes neural stem cell proliferation and differentiation in the recovery phase of stroke.

JOURNAL/nrgr/04.03/01300535-202503000-00029/figure1/v/2024-06-17T092413Z/r/image-tiff It has been shown clinically that continuous removal of ischemia/reperfusion-induced reactive oxygen species is not conducive to the recovery of late stroke. Indeed, previous studies have shown that excessive increases in hypochlorous acid after stroke can cause severe damage to brain tissue. Our previous studies have found that a small amount of hypochlorous acid still exists in the later stage of stroke, but its specific role and mechanism are currently unclear. To simulate stroke in vivo, a middle cerebral artery occlusion rat model was established, with an oxygen-glucose deprivation/reoxygenation model established in vitro to mimic stroke. We found that in the early stage (within 24 hours) of ischemic stroke, neutrophils produced a large amount of hypochlorous acid, while in the recovery phase (10 days after stroke), microglia were activated and produced a small amount of hypochlorous acid. Further, in acute stroke in rats, hypochlorous acid production was prevented using a hypochlorous acid scavenger, taurine, or myeloperoxidase inhibitor, 4-aminobenzoic acid hydrazide. Our results showed that high levels of hypochlorous acid (200 µM) induced neuronal apoptosis after oxygen/glucose deprivation/reoxygenation. However, in the recovery phase of the middle cerebral artery occlusion model, a moderate level of hypochlorous acid promoted the proliferation and differentiation of neural stem cells into neurons and astrocytes. This suggests that hypochlorous acid plays different roles at different phases of cerebral ischemia/reperfusion injury. Lower levels of hypochlorous acid (5 and 100 µM) promoted nuclear translocation of ß-catenin. By transfection of single-site mutation plasmids, we found that hypochlorous acid induced chlorination of the ß-catenin tyrosine 30 residue, which promoted nuclear translocation. Altogether, our study indicates that maintaining low levels of hypochlorous acid plays a key role in the recovery of neurological function.

Structural and spectroscopic insights into fucoxanthin chlorophyll a/c-binding proteins of diatoms in diverse oligomeric states.

Diatoms, a group of prevalent marine algae, significantly contribute to global primary productivity. Their substantial biomass is linked to enhanced absorption of blue-green light underwater, facilitated by fucoxanthin chlorophyll a/c-binding proteins (FCPs), exhibiting oligomeric diversity across diatom species. Utilizing mild CN-PAGE analysis on solubilized thylakoid membranes, we displayed monomeric, dimeric, trimeric, tetrameric and pentameric FCPs in diatoms. Mass spectrometry analysis revealed each oligomeric FCP has specific protein compositions, constituting a large Lhcf family of FCP antennas. In addition, we resolved the structures of Thalassiosira pseudonana FCP (Tp-FCP) homotrimer and Chaetoceros gracilis FCP (Cg-FCP) pentamer by cryo-electron microscopy at 2.73 Å and 2.65 Å resolutions, respectively. The distinct pigment composition and organization in various oligomeric FCPs change their blue-green light-harvesting, excitation energy transfer pathways. In comparison to dimeric and trimeric FCPs, Cg-FCP tetramer and Cg-FCP pentamer exhibit stronger absorption by Chls c, red-shifted and broader Chl a fluorescence emission, as well as more robust circular dichroism signals originating from Chl a-carotenoid dimers. These spectroscopic characteristics indicate that Chl a molecules in Cg-FCP tetramer and Cg-FCP pentamer are more heterogeneous than in both dimers and Tp-FCP trimer. The structural and spectroscopic insights provided by this study contribute to a better understanding of the mechanisms that empower diatoms to adapt to fluctuating light environments.

Association of vitamin D intake during pregnancy with small vulnerable newborns: a population-based cohort study.

Maternal vitamin D deficiency is common worldwide and has a significant impact on newborns. However, whether vitamin D intake during pregnancy is related to small vulnerable newborns (SVN) has not been confirmed. Thus, we sought to examine the relationship between maternal vitamin D intake, including vitamin D supplementation and dietary intake, and the risk of SVN. A total of 2980 Chinese mother-infant pairs were included in this study. Information on vitamin D supplementation and dietary intake was prospectively collected through face-to-face interviews. The outcomes assessed included low birth weight (LBW), preterm birth (PTB), small for gestational age (SGA), and SVN (having LBW, PTB, or SGA). Logistic regression models were used to evaluate the association of vitamin D intake with different types of SVN, and a restricted cubic spline function was modeled to explore their dose-response associations. Compared to the lowest total vitamin D intake in the first trimester, the highest total vitamin D intake was associated with a 50.0% decrease in the SGA risk (OR: 0.50, 95% CI: 0.26, 0.96) and a 41.0% decrease in the SVN risk (OR: 0.59, 95% CI: 0.36, 0.95). Similar protective results were observed between vitamin D supplementation in the first trimester and SGA and SVN risks. Moreover, a significant L-shaped relationship was identified for total vitamin D intake, vitamin D supplementation, and dietary intake with the risk of different types of SVN. In conclusion, higher total vitamin D intake and supplementation in the first trimester were associated with a reduced risk of SGA and SVN.

Development and evaluation of a candidate reference measurement procedure for detecting 17α-hydroxyprogesterone in dried blood spots using isotope dilution liquid chromatography tandem mass spectrometry.

17α-Hydroxyprogesterone (17α-OHP) quantification in dried blood spots (DBS) is essential for newborn screening for congenital adrenal hyperplasia (CAH), which is challenging due to its low physiological concentration. The high false-positive rates of immunoassays necessitate the development of more accurate methods. Liquid chromatography tandem mass spectrometry (LC-MS/MS) offers increased specificity and sensitivity, yet standardized procedures for 17α-OHP measurement are required for clinical application. A candidate reference measurement procedure (cRMP) using isotope dilution LC-MS/MS was developed for 17α-OHP quantification in DBS. By utilizing stable isotope-labeled D8-17α-OHP as an internal standard, the cRMP was optimized, covering sample preparation, calibration, and LC-MS/MS analysis. The method performance was validated across several parameters, including precision, accuracy, specificity, detection limits, and matrix effects. Clinical applicability was further assessed through the establishment of reference intervals for healthy newborns. The developed cRMP exhibited a linear range of 1.00 to 80.00 ng/mL for 17α-OHP, with detection and quantification limits of 0.14 ng/mL and 0.52 ng/mL, respectively. Inter- and intraday precision demonstrated coefficients of variation within 1.27 to 5.69%. The recovery rates and matrix effects were well within acceptable limits, ensuring method reliability. Clinical application showed distinct reference intervals for healthy newborns that were unaffected by sex but influenced by weight and gestational age. This method significantly enhances CAH diagnostic accuracy in newborns, providing a valuable tool for clinical laboratories and improving newborn screening program standardization and traceability.

Mechanism of ferroptosis regulating ischemic stroke and pharmacologically inhibiting ferroptosis in treatment of ischemic stroke.

Ferroptosis is a newly discovered form of programmed cell death that is non-caspase-dependent and is characterized by the production of lethal levels of iron-dependent lipid reactive oxygen species (ROS). In recent years, ferroptosis has attracted great interest in the field of cerebral infarction because it differs morphologically, physiologically, and genetically from other forms of cell death such as necrosis, apoptosis, autophagy, and pyroptosis. In addition, ROS is considered to be an important prognostic factor for ischemic stroke, making it a promising target for stroke treatment. This paper summarizes the induction and defense mechanisms associated with ferroptosis, and explores potential treatment strategies for ischemic stroke in order to lay the groundwork for the development of new neuroprotective drugs.

Construction and synergistic anti-tumor study of a tumor microenvironment-based multifunctional nano-drug delivery system.

To solve the problems existing in the clinical application of hypericin (Hyp) and tirapazamine (TPZ), a nano-drug delivery system with synergistic anti-tumor functions was constructed using mesoporous silica nanoparticles (MSN) and sodium alginate (SA). The system exhibited excellent stability, physiological compatibility and targeted drug release performance in tumor tissues. In the in vitro and in vivo experiments, Hyp released from MSN killed tumor cells through photodynamic therapy (PDT). The degree of hypoxia in the tumor tissue site was exacerbated, enabling TPZ to fully exert its anti-tumor activity. Our studies suggested that the synergistic effects between the components of the nano-drug delivery system significantly improve the anti-tumor properties of Hyp and TPZ.

Heteroatom-doped cobalt single-atomic nanozymes with differential enzyme-like activity for bacteria-infected wound therapy.

Single-atom nanozymes (SANZs) have emerged as new media for enhancing chemodynamic therapy (CDT) to achieve desirable enzyme-like effects and excellent nanoscale specificity. However, non-optimal adsorption of Fenton-like reaction intermediates prevents SANZs from exerting kinetic activity and hinders the CDT effect. Herein, we demonstrate that heteroatom-doped Co single-atom nanozymes (SACNZs) with intrinsic charge transfer exhibit peroxidase-like properties and significantly improve the ability of CDT to treat Staphylococcus aureus-infected wounds. Density functional theory calculations showed that the S-induced charge transfer effect regulated the electronic distribution of the central metal more efficiently than P, thereby lowering the energy levels for the generation of OH and increasing the catalytic effect. Polyvinylpyrrolidone-modified SACNZs showed effects consistent with this theory in both in vitro antibacterial and in vivo ward management assays. This study systematically investigated the relationship between heteroatom-doping and the catalytic activity of metal centres, opening a new perspective for the application of CDT.

SDS3 regulates microglial inflammation by modulating the expression of the upstream kinase ASK1 in the p38 MAPK signaling pathway.

BACKGROUND: Microglia, the main innate immune cells in the central nervous system, are key drivers of neuroinflammation, which plays a crucial role in the pathogenesis of neurodegenerative diseases. The Sin3/histone deacetylase (HDAC) complex, a highly conserved multiprotein co-repressor complex, primarily performs transcriptional repression via deacetylase activity; however, the function of SDS3, which maintains the integrity of the complex, in microglia remains unclear. METHODS: To uncover the regulatory role of the transcriptional co-repressor SDS3 in microglial inflammation, we used chromatin immunoprecipitation to identify SDS3 target genes and combined with transcriptomics and proteomics analysis to explore expression changes in cells following SDS3 knocking down. Subsequently, we validated our findings through experimental assays. RESULTS: Our analysis revealed that SDS3 modulates the expression of the upstream kinase ASK1 of the p38 MAPK pathway, thus regulating the activation of signaling pathways and ultimately influencing inflammation. CONCLUSIONS: Our findings provide important evidence of the contributions of SDS3 toward microglial inflammation and offer new insights into the regulatory mechanisms of microglial inflammatory responses.

Predicting postacute phase anaemia after aneurysmal subarachnoid haemorrhage: nomogram development and validation.

BACKGROUND: Anaemia is a severe and common complication in patients with aneurysmal subarachnoid haemorrhage (aSAH). Early intervention for at-risk patients before anaemia occurs is indicated as potentially beneficial, but no validated method synthesises patients' complicated clinical features into an instrument. The purpose of the current study was to develop and externally validate a nomogram that predicted postacute phase anaemia after aSAH. METHODS: We developed a novel nomogram for aSAH patients to predict postacute phase anaemia (3 days after occurrence of aSAH, prior to discharge) on the basis of demographic information, imaging, type of treatment, aneurysm features, blood tests and clinical characteristics. We designed the model from a development cohort and tested the nomogram in external and prospective validation cohorts. We included 456 aSAH patients from The First Affiliated Hospital for the development, 220 from Sanmen People's Hospital for external validation and a prospective validation cohort that included 13 patients from Hangzhou Red Cross Hospital. We assessed the performance of the nomogram via concordance statistics and evaluated the calibration of predicted anaemia outcome with observed anaemia occurrence. RESULTS: Variables included in the nomogram were age, treatment method (open surgery or endovascular therapy), baseline haemoglobin level, fasting blood glucose level, systemic inflammatory response syndrome score on admission, Glasgow Coma Scale score, aneurysm size, prothrombin time and heart rate. In the validation cohort, the model for prediction of postacute phase anaemia had a c-statistic of 0.910, with satisfactory calibration (judged by eye) for the predicted and reported anaemia outcome. Among forward-looking forecasts, our predictive model achieved an 84% success rate, which showed that it has some clinical practicability. CONCLUSIONS: The developed and validated nomogram can be used to calculate individualised anaemia risk and has the potential to serve as a practical tool for clinicians in devising improved treatment strategies for aSAH.

CaCO3-Encapsulated polydopamine with an adsorbed TLR7 agonist for improved tumor photothermal immunotherapy.

Because of the tumor's recurrence and significant metastasis, the standard single-therapy paradigm has failed to meet clinical requirements. Recently, researchers have focused their emphasis on phototherapy and immunogenic cell death (ICD) techniques. In response to the current problems of immunotherapy, a multifunctional drug delivery nanosystem (PDA-IMQ@CaCO3-blinatumomab, PICB) was constructed by using high physiological compatibility of polydopamine (PDA) and calcium carbonate (CaCO3). Toll-like receptor 7 (TLR7) agonist imiquimod (IMQ) and bispecific antibody (BsAb) blinatumomab were loaded onto PDA-CaCO3 nanoparticles (NPs). The findings revealed that the system exhibited the advantages of good dispersion, high stability, excellent physiological compatibility, low toxicity, and high drug loading rate. Compared to the control group, it resulted in a 2.4-fold decrease in FOXP3+ regulatory T-cells within the tumor and a 5.0-fold increase in CD4+ effector T-cells, and promoted the production of damage-related molecular patterns to reinvigorate the ICD effect. PICB had a strong inhibitory effect on tumor growth in 4T1 tumor-bearing mice, and has no toxicity to other organs. Therefore, the multifunctional drug delivery nanosystem constructed in this study could effectively exert the properties of various components in vivo, fully demonstrate the synergistic effect between immunotherapy and photothermal therapy, thus significantly improving the tumor therapeutic efficacy, and has a promising clinical application.

Third-order nonlinear Hall effect in a quantum Hall system.

In two-dimensional systems, perpendicular magnetic fields can induce a bulk band gap and chiral edge states, which gives rise to the quantum Hall effect. The quantum Hall effect is characterized by zero longitudinal resistance (Rxx) and Hall resistance (Rxy) plateaus quantized to h/(υe2) in the linear response regime, where υ is the Landau level filling factor, e is the elementary charge and h is Planck's constant. Here we explore the nonlinear response of monolayer graphene when tuned to a quantum Hall state. We observe a third-order Hall effect that exhibits a nonzero voltage plateau scaling cubically with the probe current. By contrast, the third-order longitudinal voltage remains zero. The magnitude of the third-order response is insensitive to variations in magnetic field (down to ~5 T) and in temperature (up to ~60 K). Moreover, the third-order response emerges in graphene devices with a variety of geometries, different substrates and stacking configurations. We term the effect third-order nonlinear response of the quantum Hall state and propose that electron-electron interaction between the quantum Hall edge states is the origin of the nonlinear response of the quantum Hall state.

Distribution of COVID-19 Home Testing Through Community Health Centers: Results of the COVID CoNOce MÁS Study.

OBJECTIVE: To assess acceptability and feasibility of rapid at-home COVID-19 testing and reporting of test results among individuals seeking care at community health centers (CHCs) and their household members. METHODS: Participants were recruited from 2 Community Health Centers during a clinic visit or a community event. Over-the-counter COVID-19 tests were distributed to participants for self-testing and to offer testing to household members. Separate surveys were administered to collect baseline information on the study participant and to collect test results on the study participant and household members. We calculated the proportion of individuals who agreed to complete COVID home testing, those who reported test results, and the test positivity. For household members, we calculated the proportion who completed and reported results and the positivity rate. We assessed reasons for undergoing COVID-19 testing and the action taken by participants who reported positive tests. RESULTS: A total of 2189 individuals were approached by CHC staff for participation and 1013 (46.3%) agreed to participate. Among the 959 participants with complete sociodemographic data, 88% were Hispanic and 82.6% were female. The proportion providing test results was 36.2% and the test positivity was 4.2%. Among the 1927 test reports, 35.3% for the index participant and 64.4% were for household members. The largest proportion of test results were for index participants (35.3%) and the second largest was for the participant's children (32.1%), followed by parents (16.9%), and spouse/partner (13.2%). The 2 most common reasons for testing were symptoms (29%) and attending family gatherings (26%). Among test-positive individuals (n = 80), most (83.3%) noted that they isolated but only 16.3% called their provider and 1.3% visited a clinic. CONCLUSION: Our results show interest in at-home COVID-19 testing of multiple household members, as we headed into the endemic phase of the pandemic. However, reporting of test results was modest and among test-positive individuals, reporting results to a provider was very low. These results underscore the challenges with reporting and following guidelines among people undergoing home testing for COVID-19, which may have implications for future pandemics.

Transcriptomics and metabolomics reveal hypothalamic metabolic characteristics and key genes after subarachnoid hemorrhage in rats.

Subarachnoid hemorrhage (SAH) is a serious hemorrhagic event with high mortality and morbidity. Multiple injurious events produced by SAH can lead to a series of pathophysiologic processes in the hypothalamus that can severely impact patients' life. These pathophysiologic processes usually result in physiologic derangements and dysfunction of the brain and multiple organs. This dysfunction involved multiple dimensions of the genome and metabolome. In our study, we induced the SAH model in rats to obtain hypothalamic tissue and serum. The samples were subsequently analyzed by transcriptomics and metabolomics. Next, the functional enrichment analysis of the differentially expressed genes and metabolites were performed by GO and KEGG pathway analysis. Through transcriptomic analysis of hypothalamus samples, 263 up-regulated differential genes, and 207 down-regulated differential genes were identified in SAH groups compared to Sham groups. In the KEGG pathway analysis, a large number of differential genes were found to be enriched in IL-17 signaling pathway, PI3K-Akt signaling pathway, and bile secretion. Liquid chromatography-mass spectrometry metabolomics technology was conducted on the serum of SAH rats and identified 11 up-regulated and 26 down-regulated metabolites in positive ion model, and 1 up-regulated and 10 down-regulated metabolites in negative ion model. KEGG pathways analysis showed that differentially expressed metabolites were mainly enriched in pathways of bile secretion and primary bile acid biosynthesis. We systematically depicted the neuro- and metabolism-related biomolecular changes occurring in the hypothalamus after SAH by performing transcriptomics and metabolomics studies. These biomolecular changes may provide new insights into hypothalamus-induced metabolic changes and gene expression after SAH.

Abscisic acid for acute respiratory distress syndrome therapy by suppressing alveolar macrophage pyroptosis via upregulating acyloxyacyl hydrolase expression.

OBJECTIVE: Abscisic acid (ABA) is a phytohormone that inhibits airway inflammation in acute respiratory distress syndrome (ARDS) mouse models. However, the molecular mechanism underlying this phenomenon remains unclear. METHODS: Serum ABA level in patients and mice was measured via liquid chromatography-tandem mass spectrometry (LC-MS/MS). In-depth molecular mechanism was investigated through transmission electron microscopy, RNA-sequencing, and molecular docking in ARDS mice and cultured primary alveolar macrophages (AMs). RESULTS: We found that the serum ABA level was remarkably decreased in ARDS mice and patients. ABA inhibited lipopolysaccharide (LPS)-induced airway inflammation in mice; moreover, it downregulated genes associated with pyroptosis, as shown by RNA-sequencing and lung protein immunoblots. ABA inhibited the formation of membrane pores in AMs and suppressed the cleavage of gasdermin D (GSDMD) and the activation of caspase-11 and caspase-1 in vivo and in vitro; however, the overexpression of caspase-11 reversed the protective effect of ABA on LPS-induced pyroptosis of primary AMs. ABA inhibited intra-AM LPS accumulation while increasing the level of acyloxyacyl hydrolase (AOAH) in AMs, whereas AOAH deficiency abrogated the suppressive action of ABA on inflammation, pyroptosis, and intra-AM LPS accumulation in vivo and in vitro. Importantly, ABA promoted its intracellular receptor lanthionine C-like receptor 2 interacting with transcription factor peroxisome proliferator-activated receptor γ, which ultimately leading to increase AOAH expression to inactivate LPS and inhibit pyroptosis in AMs. CONCLUSIONS: ABA protected against LPS-induced lung injury by inhibiting pyroptosis in AMs via proliferator-activated receptor γ-mediated AOAH expression.

Presence of low-energy chlorophylls d in photosystem I trimer and monomer cores isolated from Acaryochloris sp. NBRC 102871.

Acaryochloris species belong to a special category of cyanobacteria possessing chlorophyll (Chl) d. One of the photosynthetic characteristics of Acaryochloris marina MBIC11017 is that the absorption spectra of photosystem I (PSI) showed almost no bands and shoulders of low-energy Chls d over 740 nm. In contrast, the absorption spectra of other Acaryochloris species showed a shoulder around 740 nm, suggesting that low-energy Chls d within PSI are diversified among Acaryochloris species. In this study, we purified PSI trimer and monomer cores from Acaryochloris sp. NBRC 102871 and examined their protein and pigment compositions and spectral properties. The protein bands and pigment compositions of the PSI trimer and monomer of NBRC102871 were virtually identical to those of MBIC11017. The absorption spectra of the NBRC102871 PSIs exhibited a shoulder around 740 nm, whereas the fluorescence spectra of PSI trimer and monomer displayed maximum peaks at 754 and 767 nm, respectively. These spectral properties were different from those of MBIC11017, indicating the presence of low-energy Chls d within the NBRC102871 PSIs. Moreover, we analyzed the NBRC102871 genome to identify amino acid sequences of PSI proteins and compared them with those of the A. marina MBIC11017 and MBIC10699 strains whose genomes are available. The results showed that some of the sequences in NBRC102871 were distinct from those in MBIC11017 and MBIC10699. These findings provide insights into the variety of low-energy Chls d with respect to the protein environments of PSI cores among the three Acaryochloris strains.

Mechanism of Reactive Oxygen/Nitrogen Species in Liver Ischemia-Reperfusion Injury and Preventive Effect of Chinese Medicine.

Liver ischemia-reperfusion injury (LIRI) is a pathological process involving multiple injury factors and cell types, with different stages. Currently, protective drugs targeting a single condition are limited in efficacy, and interventions on immune cells will also be accompanied by a series of side effects. In the current bottleneck research stage, the multi-target and obvious clinical efficacy of Chinese medicine (CM) is expected to become a breakthrough point in the research and development of new drugs. In this review, we summarize the roles of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in various stages of hepatic ischemia-reperfusion and on various types of cells. Combined with the current research progress in reducing ROS/RNS with CM, new therapies and mechanisms for the treatment of hepatic ischemia-reperfusion are discussed.

Strong evidence supports the use of estradiol therapy for the treatment of vaginal inflammation: a two-way Mendelian randomization study.

OBJECTIVE: Nowadays, there has been limited Mendelian randomization (MR) research focusing on the causal relationship between estradiol and vaginitis. Therefore, this study conducted a two-way MR study to clarify the causal effect and related influencing factors between them. METHODS: All genetic datasets were obtained using publicly available summary statistics based on individuals of European ancestry from the IEU GWAS database. MR analysis was performed using MR-Egger, weighted median (WM) and inverse variance weighted (IVW) methods to assess the causal relationship between exposure and outcome and to validate the findings by comprehensively evaluating the effects of pleiotropic effects and outliers. RESULTS: MR analysis revealed no significant causal relationship between estradiol and vaginitis risk. There was a negative correlation between estradiol and age at menarche (IVW, OR: 0.9996, 95% CI: 0.9992-1.0000, P = 0.0295; WM, OR: 0.9995, 95% CI: 0.9993-0.9998, P = 0.0003), and there was a positive correlation between age at menarche and vaginitis (IVW, OR: 1.5108, 95% CI: 1.1474-2.0930, P = 0.0043; MR-Egger, OR: 2.5575, 95% CI: 1.7664-9.6580, P = 0.0013). Estradiol was negatively correlated with age at menopause (IVW, OR: 0.9872, 95% CI: 0.9786-0.9959, P = 0.0041). However, there was no causal relationship between age at menopause and vaginitis (P > 0.05). In addition, HPV E7 Type 16, HPV E7 Type 18, and Lactobacillus had no direct causal effects on estradiol and vaginitis (P > 0.05). Sensitivity analyses revealed no heterogeneity and horizontal pleiotropy. CONCLUSION: When estrogen levels drop, it will lead to a later age of menarche, and a later age of menarche may increase the risk of vaginitis, highlighting that the longer the female reproductive tract receives estrogen stimulation, the stronger the defense ability is formed, and the prevalence of vaginitis is reduced. In conclusion, this study indirectly supports an association between reduced level of estrogen or short time of estrogen stimulation and increased risk of vaginitis.