Cadmium-induced global DNA hypermethylation promoting mitochondrial dynamics dysregulation in hippocampal neurons.

Environmental cadmium exposure during pregnancy or adolescence can cause neurodevelopmental toxicity, lead to neurological impairment, and reduce cognitive abilities, such as learning and memory. However, the mechanisms by which cadmium causes neurodevelopmental toxicity and cognitive impairment are still not fully elucidated. This study used hippocampal neurons cultured in vitro to observe the impact of cadmium exposure on mitochondrial dynamics and apoptosis. Exposure to 5 µM cadmium causes degradation of hippocampal neuron cell bodies and axons, morphological destruction, low cell viability, and apoptosis increase. Cadmium exposure upregulates the expression of mitochondrial fission proteins Drp1 and Fis1, reduces the expression of mitochondrial fusion-related proteins MFN1, MFN2, and OPA1, as well as reduces the expression of PGC-1a. Mitochondrial morphology detection demonstrated that cadmium exposure changes the morphological structure of mitochondria in hippocampal neurons, increasing the number of punctate and granular mitochondria, reducing the number of tubular and reticular mitochondria, decreasing mitochondrial mass, dissipating mitochondrial membrane potential (ΔΨm), and reducing adenosine triphosphate (ATP) production. Cadmium exposure increases the global methylation level of the genome and upregulates the expression of DNMT1 and DNMT3α in hippocampal neurons. 5-Aza-CdR reduces cadmium-induced genome methylation levels in hippocampal neurons, increases the number of tubular and reticular mitochondria, and promotes cell viability. In conclusion, cadmium regulates the expression of mitochondrial dynamics-related proteins by increasing hippocampal neuron genome methylation, changing mitochondrial morphology and function, and exerting neurotoxic effects.

Pigment Characterization of the Giant-Colony-Forming Haptophyte Phaeocystis globosa in the Beibu Gulf Reveals Blooms of Different Origins.

The giant-colony-forming haptophyte Phaeocystis globosa has caused several large-scale blooms in the Beibu Gulf since 2011, but the distribution and dynamics of the blooms remained largely unknown. In this study, colonies of P. globosa, as well as membrane-concentrated phytoplankton samples, were collected during eight cruises in the Beibu Gulf from September 2016 to August 2017. Pigments were analyzed by high-performance liquid chromatography coupled with a diode array detector (HPLC-DAD). The pigment 19'-hexanoyloxyfucoxanthin (hex-fuco), generally considered a diagnostic pigment for Phaeocystis, was not detected in P. globosa colonies in the Beibu Gulf, whereas 19'-butanoyloxyfucoxanthin (but-fuco) was found in all colony samples. Moreover, but-fuco in membrane-concentrated phytoplankton samples exhibited a similar distribution pattern to that of P. globosa colonies, suggesting that but-fuco provided the diagnostic pigment for bloom-forming P. globosa in the Beibu Gulf. Based on the distribution of but-fuco in different water masses in the region prior to the formation of intensive blooms, it is suggested that P. globosa blooms in the Beibu Gulf could originate from two different sources. IMPORTANCE Phaeocystis globosa has formed intensive blooms in the South China Sea and even around the world, causing huge social economic losses and environmental damage. However, little is known about the formation mechanism and dynamics of P. globosa blooms. 19'-Hexanoyloxyfucoxanthin (hex-fuco) is often used as the pigment proxy to estimate Phaeocystis biomass, while this is challenged by the giant-colony-forming P. globosa in the Beibu Gulf, which contains only 19'-butanoyloxyfucoxanthin (but-fuco) but not hex-fuco. Using but-fuco as a diagnostic pigment, we traced two different origins of P. globosa blooms in the Beibu Gulf. This study clarifies the development process of P. globosa blooms in the Beibu Gulf, which provides a basis for the early monitoring and prevention of the blooms.

Green Tides in the Yellow Sea Promoted the Proliferation of Pelagophyte Aureococcus anophagefferens.

Harmful algal blooms formed by fast-growing, ephemeral macroalgae have expanded worldwide, yet there is limited knowledge of their potential ecological consequences. Here, we select intense green tides formed by Ulva prolifera in the Yellow Sea, China, to examine the ecological consequences of these blooms. Using 28-isofucosterol in the surface sediment as a biomarker of green algae, we identified the settlement region of massive floating green algae in the area southeast of the Shandong Peninsula in the southern Yellow Sea. The responses of the phytoplankton assemblage from the deep chlorophyll-a maximum layer were then resolved using high-throughput sequencing. We found striking changes in the phytoplankton community in the settlement region after an intensive green tide in 2016, characterized by a remarkable increase in the abundance of the pelagophyte Aureococcus anophagefferens, the causative species of ecosystem disruptive brown tides. Our study strongly suggests that the occurrence of massive macroalgal blooms may promote blooms of specific groups of microalgae through alteration of the marine environment.

The Role of CCL2/CCR2 Axis in Cerebral Ischemia-Reperfusion Injury and Treatment: From Animal Experiments to Clinical Trials.

C-C motif chemokine ligand 2 (CCL2) is a member of the monocyte chemokine protein family, which binds to its receptor CCR2 to induce monocyte infiltration and mediate inflammation. The CCL2/CCR2 signaling pathway participates in the transduction of neuroinflammatory information between all types of cells in the central nervous system. Animal studies and clinical trials have shown that CCL2/CCR2 mediate the pathological process of ischemic stroke, and a higher CCL2 level in serum is associated with a higher risk of any form of stroke. In the acute phase of cerebral ischemia-reperfusion, the expression of CCL2/CCR2 is increased in the ischemic penumbra, which promotes neuroinflammation and enhances brain injury. In the later phase, it participates in the migration of neuroblasts to the ischemic area and promotes the recovery of neurological function. CCL2/CCR2 gene knockout or activity inhibition can reduce the nerve inflammation and brain injury induced by cerebral ischemia-reperfusion, suggesting that the development of drugs regulating the activity of the CCL2/CCR2 signaling pathway could be used to prevent and treat the cell injury in the acute phase and promote the recovery of neurological function in the chronic phase in ischemic stroke patients.

Early Rehabilitation Exercise after Stroke Improves Neurological Recovery through Enhancing Angiogenesis in Patients and Cerebral Ischemia Rat Model.

Among cerebrovascular diseases, ischemic stroke is a leading cause of mortality and disability. Thrombolytic therapy with tissue plasminogen activator is the first choice for clinical treatment, but its use is limited due to the high requirements of patient characteristics. Therefore, the choice of neurological rehabilitation strategies after stroke is an important prevention and treatment strategy to promote the recovery of neurological function in patients. This study shows that rehabilitation exercise 24 h after stroke can significantly improve the neurological function (6.47 ± 1.589 vs. 3.21 ± 1.069 and 0.76 ± 0.852), exercise ability (15.68 ± 5.95 vs. 162.32 ± 9.286 and 91.18 ± 7.377), daily living ability (23.37 ± 5.196 vs. 66.95 ± 4.707 and 6.55 ± 2.873), and quality of life (114.39 ± 7.772 vs. 168.61 ± 6.323 and 215.95 ± 10.977) of patients after 1 month and 3 months, and its ability to promote rehabilitation is better than that of rehabilitation exercise administered to patients 72 h after stroke (p < 0.001). Animal experiments show that treadmill exercise 24 h after middle cerebral artery occlusion and reperfusion can inhibit neuronal apoptosis, reduce the volume of cerebral infarction on the third (15.04 ± 1.07% vs. 30.67 ± 3.06%) and fifth (8.33 ± 1.53% vs. 30.67 ± 3.06%) days, and promote the recovery of neurological function on the third (7.22 ± 1.478 vs. 8.28 ± 1.018) and fifth (4.44 ± 0.784 vs. 6.00 ± 0.767) days. Mechanistic studies have shown that treadmill exercise increases the density of microvessels, regulates angiogenesis, and promotes the recovery of nerve function by upregulating the expression of vascular endothelial growth factor and laminin. This study shows that rehabilitation exercise 24 h after stroke is conducive to promoting the recovery of patients' neurological function, and provides a scientific reference for the clinical rehabilitation of stroke patients.

The Histone Modifications of Neuronal Plasticity.

Nucleosomes composed of histone octamer and DNA are the basic structural unit in the eukaryote chromosome. Under the stimulation of various factors, histones will undergo posttranslational modifications such as methylation, phosphorylation, acetylation, and ubiquitination, which change the three-dimensional structure of chromosomes and affect gene expression. Therefore, the combination of different states of histone modifications modulates gene expression is called histone code. The formation of learning and memory is one of the most important mechanisms for animals to adapt to environmental changes. A large number of studies have shown that histone codes are involved in the formation and consolidation of learning and memory. Here, we review the most recent literature of histone modification in regulating neurogenesis, dendritic spine dynamic, synapse formation, and synaptic plasticity.

14,15-EET Reduced Brain Injury from Cerebral Ischemia and Reperfusion via Suppressing Neuronal Parthanatos.

To investigate the effect of 14,15-EET on the parthanatos in neurons induced by cerebral ischemia and reperfusion, middle cerebral artery occlusion and reperfusion (MCAO/R) and oxygen glucose deprivation/reoxygenation (OGD/R) were used to simulate cerebral ischemia reperfusion in vivo and in vitro, respectively. TTC staining and the Tunel method were used to detect cerebral infarct volume and neuronal apoptosis. Western blot and immunofluorescence were used to detect poly (ADP-ribose) polymerase-1 (PARP-1) activation and AIF nuclear translocation. The production of reactive oxygen species (ROS) and the expression of antioxidant genes were detected by Mito SOX, DCFH-DA and qPCR methods. MCAO/R increased cerebral infarct volume and neuronal apoptosis in mice, while 14,15-EET pretreatment increased cerebral infarct volume and neuronal apoptosis. OGD/R induced reactive oxygen species generation, PARP-1 cleavage, and AIF nuclear translocation in cortical neurons. 14,15-EET pretreatment could enhance the antioxidant gene expression of glutathione peroxidase (GSH-Px), heme oxygenase-1 (HO-1) and superoxide dismutase (SOD) in cortical neurons after ischemia and reperfusion. 14,15-EET inhibits the neuronal parthanatos induced by MCAO/R through upregulation of the expression of antioxidant genes and by reducing the generation of reactive oxygen species. This study advances the EET neuroprotection theory and provides a scientific basis for targeted clinical drugs that reduce neuronal parthanatos following cerebral ischemia and reperfusion.

Neuroprotective effects of epoxyeicosatrienoic acids.

Eicosatrienoic acids (EETs) are a class of intermediates produced during arachidonic acid metabolism mediated by cytochrome P450 epoxygenases that exert multiple physiological effects on the nervous system. EETs promote three metabolic processes, including esterification, hydrolysis and degradation or extension. EETs are hydrolyzed by soluble epoxide hydrolase (sEH) to form corresponding diols, thereby reducing their biological activity. Strategies regulating sEH expression or activity affect EET hydrolysis and alter relative cell concentrations, thus influencing EET function. This article summarizes the metabolic pathway of eicosatrienoic acid in organisms and highlights its neuroprotective effects on the central nervous system, which include regulating neuronal excitability, increasing cerebral blood flow, inhibiting neuronal apoptosis, reducing neuroinflammation, mitigating brain injury and promoting recovery of neurological function in subjects with nervous system diseases.

14,15-EET Suppresses Neuronal Apoptosis in Ischemia-Reperfusion Through the Mitochondrial Pathway.

Neuronal apoptosis mediated by the mitochondrial apoptosis pathway is an important pathological process in cerebral ischemia-reperfusion injury. 14,15-EET, an intermediate metabolite of arachidonic acid, can promote cell survival during ischemia/reperfusion. However, whether the mitochondrial apoptotic pathway is involved this survival mechanism is not fully understood. In this study, we observed that infarct size in ischemia-reperfusion injury was reduced in sEH gene knockout mice. In addition, Caspase 3 activation, cytochrome C release and AIF nuclear translocation were also inhibited. In this study, 14,15-EET pretreatment reduced neuronal apoptosis in the oxygen-glucose deprivation and re-oxygenation group in vitro. The mitochondrial apoptosis pathway was also inhibited, as evidenced by AIF translocation from the mitochondria to nucleus and the reduction in the expressions of cleaved-caspase 3 and cytochrome C in the cytoplasm. 14,15-EET could reduce neuronal apoptosis through upregulation of the ratio of Bcl-2 (anti-apoptotic protein) to Bax (apoptosis protein) and inhibition of Bax aggregation onto mitochondria. PI3K/AKT pathway is also probably involved in the reduction of neuronal apoptosis by EET. Our study suggests that 14,15-EET could suppress neuronal apoptosis and reduce infarct volume through the mitochondrial apoptotic pathway. Furthermore, the PI3K/AKT pathway also appears to be involved in the neuroprotection against ischemia-reperfusion by 14,15-EET.

Comparative Analysis of the Proteins with Tandem Repeats from 8 Microsporidia and Characterization of a Novel Endospore Wall Protein Colocalizing with Polar Tube from Nosema bombycis.

As a common feature of eukaryotic proteins, tandem amino acid repeat has been studied extensively in both animal and plant proteins. Here, a comparative analysis focusing on the proteins having tandem repeats was conducted in eight microsporidia, including four mammal-infecting microsporidia (Encephalitozoon cuniculi, Encephalitozoon intestinalis, Encephalitozoon hellem and Encephalitozoon bieneusi) and four insect-infecting microsporidia (Nosema apis, Nosema ceranae, Vavraia culicis and Nosema bombycis). We found that the proteins with tandem repeats were abundant in these species. The quantity of these proteins in insect-infecting microsporidia was larger than that of mammal-infecting microsporidia. Additionally, the hydrophilic residues were overrepresented in the tandem repeats of these eight microsporidian proteins and the amino acids residues in these tandem repeat sequences tend to be encoded by GC-rich codons. The tandem repeat position within proteins of insect-infecting microsporidia was randomly distributed, whereas the tandem repeats within proteins of mammal-infecting microsporidia rarely tend to be present in the N terminal regions, when compared with those present in the C terminal and middle regions. Finally, a hypothetical protein EOB14572 possessing four tandem repeats was successfully characterized as a novel endospore wall protein, which colocalized with polar tube of N. bombycis. Our study provided useful insight for the study of the proteins with tandem repeats in N. bombycis, but also further enriched the spore wall components of this obligate unicellular eukaryotic parasite.

Follistatin-like 1 (Fstl1) is a bone morphogenetic protein (BMP) 4 signaling antagonist in controlling mouse lung development.

Lung morphogenesis is a well orchestrated, tightly regulated process through several molecular pathways, including TGF-ß/bone morphogenetic protein (BMP) signaling. Alteration of these signaling pathways leads to lung malformation. We investigated the role of Follistatin-like 1 (Fstl1), a secreted follistatin-module-containing glycoprotein, in lung development. Deletion of Fstl1 in mice led to postnatal lethality as a result of respiratory failure. Analysis of the mutant phenotype showed that Fstl1 is essential for tracheal cartilage formation and alveolar maturation. Deletion of the Fstl1 gene resulted in malformed tracheal rings manifested as discontinued rings and reduced ring number. Fstl1-deficient mice displayed septal hypercellularity and end-expiratory atelectasis, which were associated with impaired differentiation of distal alveolar epithelial cells and insufficient production of mature surfactant proteins. Mechanistically, Fstl1 interacted directly with BMP4, negatively regulated BMP4/Smad1/5/8 signaling, and inhibited BMP4-induced surfactant gene expression. Reducing BMP signaling activity by Noggin rescued pulmonary atelectasis of Fstl1-deficient mice. Therefore, we provide in vivo and in vitro evidence to demonstrate that Fstl1 modulates lung development and alveolar maturation, in part, through BMP4 signaling.

Comparison of 18F-FDG PET/CT and conventional methods in diagnosing extranodal natural killer/T-cell lymphoma.

Background: The utility of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in natural killer (NK)/T-cell lymphoma patients is yet to be established. The aim of this study was to investigate the role of PET/CT scanning in detecting NK/T-cell lymphoma. Methods: We analyzed the PET/CT imaging characteristics of 38 patients with a primary diagnosis of NK/T-cell lymphoma and also compared the ability of PET/CT to detect tumor lesions with conventional methods (CMs) (physical examination, computed tomography (CT) with intravenous contrast, magnetic resonance imaging (MRI), biopsies from primary sites, and bone marrow examinations)and their impact on staging and treatment options. Biopsy and clinical follow-up (including imaging) are the gold standard for diagnosis. Results: We analyzed PET/CT images of NK/T-cell lymphomas. We found that most of the primary lesions were located in the nasal cavity, with the sinuses and the posterior pharyngeal wall being the most common sites of adjacent invasion. The majority of cases involved cervical lymph nodes, and the distribution of affected lymph nodes between the cervical and extra-cervical regions was random. There was no discernible pattern to the locations of affected tissues and organs across the body. In total, 219 lesions (including 81 nodal lesions and 138 extranodal lesions) tested positive for malignancy. The number of positive lymph node lesions detected by PET/CT and CMs was 79 (97.5 %) and 62 (76.5 %), respectively (P = 0.004). There were 53 (96.4 %) and 46 (83.6 %) cervical lymph nodes detected (P = 0.008), 26 (100 %) and 16 (61.5 %) other lymph nodes detected (P = 0.041)), respectively. The number of positive extranodal lesions detected by PET/CT and CMs was 137 (99.3 %) and 98 (71.0 %), respectively (P = 0.01), and there were no discernible differences in the upper respiratory tract. PET/CT outperformed CMs in the detection of malignant lesions by a significant margin, detecting 79 (98.8 %) extranodal lesions compared to 45 (56.3 %) by CMs (P = 0.034). PET/CT results changed the initial staging in 15.8 % of cases and the treatment plan in 10.5 % of patients. Conclusion: Our findings indicate that 18F-FDG PET/CT scanning is crucial in identifying tumor lesions, determining staging, and devising treatment strategies for individuals diagnosed with NK/T-cell lymphoma.

Prognostic value of 18F-FDG PET/CT tumor metabolic parameters and Ki-67 in pre-treatment diffuse large B-cell lymphoma.

Background: Diffuse large B-cell lymphoma (DLBCL) is a highly aggressive lymphoma. Rituximab-based conventional chemotherapy still leads to drug resistance or relapse in 30-40% of patients. Therefore, early identification of high-risk patients and accurate assessment of prognosis are very important for clinical decision-making. The aim of this study is to investigate the value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) of tumor metabolic, clinical and biological parameters in the prognostic risk stratification of DLBCL before treatment. Methods: We retrospectively collected clinical data on 63 patients with newly diagnosed DLBCL admitted to Shanxi Bethune Hospital during the period from November 2016 to April 2020 who underwent 18F-FDG PET/CT prior to treatment in a cohort study. Metabolic, clinical, and biological parameters were analyzed by Cox regression. Kaplan-Meier curves of patient survival were compared by the log-rank test. Results: The median follow-up was 21 months. The 2-year progression-free survival (PFS) was 47.62%, and the overall survival (OS) was 53.97%. The subtype, double expression, Ann Abor stage, NCCN-IPI score, Ki-67, maximum standardized uptake value (SUVmax), bulk volume glycolysis (BVG), total lesion glycolysis (TLG), total metabolic tumor volume (TMTV) were the influencing factors for PFS and OS (P<0.050) in univariate analysis. BVG (PFS: HR =6.62, P<0.001; OS: HR =3.53, P=0.029), TLG (PFS: HR =8.56, P<0.001; OS: HR =5.20, P=0.004), TMTV (PFS: HR =12.02, P=0.001; OS: HR =5.05, P=0.033) and Ki-67 were found to be independent prognostic risk stratification parameters affecting PFS and OS by multivariate regression analysis. The 2-year PFS and OS rates for patients with high BVG (≥288.00 cm3), TLG (≥1,854.00 cm3), TMTV (≥103.00 cm3), and Ki-67 (≥85%) were 20% and 28.57%, 9.68% and 22.58%, 20.51%, and 30.77%, and 25% and 33.33%, respectively; and the 2-year PFS and OS rates for patients with low BVG (<288.00 cm3), TLG (<1,854.00 cm3), TMTV (<103.00 cm3), and Ki-67 (<85%) patients were 82.14% and 85.71%, 84.37% and 84.37%, 91.67% and 91.67%, and 61.54% and 66.67%, respectively. Patients with high BVG, TLG, TMTV, and Ki-67 had a worse 2-year PFS as well as OS rate (Ki-67: P=0.0018/P=0.0025; P<0.0001 for the rest of the groups). Conclusions: Our findings suggest that BVG, TLG, TMTV, and Ki-67 are independent prognostic indicators for survival in patients with pre-treatment DLBCL, especially BVG, which is a novel prognostic indicator that has to be validated in future research.

Potential roles of hydroxybenzoate paralytic shellfish toxins in modulating toxin biokinetics in scallops.

Paralytic shellfish toxins (PSTs) produced by some marine dinoflagellates can cause severe human intoxication via vectors like bivalves. Toxic dinoflagellate Gymnodinium catenatum produce a novel group of hydroxybenzoate PSTs named GC toxins, but their biokinetics in bivalves haven't been well examined. In this experiment, we analyzed PSTs in bay scallops Argopecten irradians exposed to G. catenatum (strain MEL11) to determine their accumulation, elimination, anatomical distribution, and biotransformation. To our surprise, up to 30% of the PSTs were accumulated in the adductor muscle of scallops at the end of the experiment, and the toxicity of adductor muscle exceeded the regulatory limit of 800 µg STXeq/kg in only 6 days. High concentration of toxins in the adductor muscle are likely linked to the rapid transfer of GC toxins from viscera to other tissues. Moreover, most GC toxins in scallops were found rapidly transformed to decarbamoyl toxins through enzyme-mediated hydrolysis, which was further supported by the in vitro incubation experiments. Our study demonstrates that GC toxins actively participate in toxin distribution and transformation in scallops, which may increase the risks of food poisoning associated with the consumption of scallop adductor muscle. ENVIRONMENTAL IMPLICATION: The negative impacts of harmful algal blooms (HABs) have become a global environmental concern under the joint effects of cultural eutrophication and climate change. Our study, targeted on the biokinetics of paralytic shellfish toxins in scallops exposed to Gymnodinium catenatum producing unique GC toxins, aims to elucidate potential risks of seafood poisoning associated with GC toxins. The findings of this study will help us to understand the roles of GC toxins in seafood poisoning, and to develop effective management strategies against toxic algal blooms and phycotoxins.

Advancements in theranostic applications: exploring the role of fibroblast activation protein inhibition tracers in enhancing thyroid health assessment.

BACKGROUND: The diagnostic accuracy of [18F]-fluorodeoxyglucose ([18F]-FDG) positron emission tomography imaging in accurately identifying thyroid lesions is limited, primarily due to the physiological uptake of normal head and neck tissues and inflammatory uptake in lymph nodes. Since fibroblast activating protein is highly expressed in tumors and largely unexpressed in normal tissues, quinoline-based fibroblast activating protein inhibitors (FAPI) have emerged as promising tools in the diagnosis of cancer and other medical conditions. Several studies have reported on the feasibility and value of FAPI in thyroid cancer. MAIN BODY: In this narrative review, we summarize the current literature on state-of-the-art FAPI positron emission tomography imaging for thyroid cancer and fibroblast activating protein-targeted radionuclide therapy. We provide an overview of FAPI uptake in normal thyroid tissue, thyroid cancer and its metastases. Additionally, we highlight the difference between FAPI uptake and [18F]-FDG uptake in thyroid lesions. Furthermore, we discuss the therapeutic value of FAPI in iodine-refractory thyroid cancer. CONCLUSION: The utilization of fibroblast activating protein inhibitors in thyroid cancer holds significant promise, offering clinicians valuable insights for more precise diagnose choices and treatments strategies in the future.

Role of Peptidylarginine Deiminase 4 in Central Nervous System Diseases.

The deimination or citrullination of arginine residues in the polypeptide chain by peptidylarginine deiminase 4 alters the charge state of the polypeptide chain and affects the function of proteins. It is one of the main ways of protein post-translational modifications to regulate its function. Peptidylarginine deiminase 4 is widely expressed in multiple tissues and organs of the body, especially the central nervous system, and regulates the normal development of organisms. The abnormal expression and activation of peptidylarginine deiminase 4 is an important pathological mechanism for the occurrence and development of central nervous system diseases such as multiple sclerosis, Alzheimer's disease, cerebral ischemia reperfusion injury, and glioblastoma.

14, 15-EET alleviates neurological impairment through maintaining mitochondrial dynamics equilibrium via AMPK/SIRT1/FoxO1 signal pathways in mice with cerebral ischemia reperfusion.

AIM: To explore whether 14, 15-EET regulates mitochondrial dynamics to exert neuroprotective effects after cerebral ischemia-reperfusion and its underlying mechanisms. METHODS: The mouse middle cerebral artery occlusion reperfusion model was used to observe brain infarct volume and neuronal apoptosis by TTC staining and Tunel assay, modified neurological severity score to detect neurological impairment, HE staining and Nissl staining to observe neuron damage, western blot and immunofluorescence methods to detect the expression of mitochondrial dynamics-related proteins, transmission electron microscopy, and Golgi-Cox staining to detect mitochondrial morphology and neuronal dendritic spines. RESULTS: 14, 15-EET reduced the neuronal apoptosis and cerebral infarction volume induced by middle cerebral artery occlusion reperfusion (MCAO/R), inhibited the degradation of dendritic spines, maintained the structural integrity of neurons, and alleviated neurological impairment. Cerebral ischemia-reperfusion induces mitochondrial dynamics disorders, upregulates the expression of the mitochondrial division protein Fis 1, and inhibits the expression of mitochondrial fusion proteins MFN1, MFN2, and OPA1, while 14, 15-EET treatment reverses this process. Mechanistic studies have shown that 14, 15-EET promotes the phosphorylation of AMPK, upregulates the expression of SIRT1 and phosphorylation of FoxO1, thereby inhibiting mitochondrial division and promoting mitochondrial fusion, preserving mitochondrial dynamics, maintaining neuronal morphological and structural integrity, and alleviating neurological impairment induced by middle cerebral artery occlusion reperfusion. Compound C treatment diminishes the neuroprotective effect of 14, 15-EET following MCAO/R in mice. CONCLUSION: This study elucidates the novel neuroprotective mechanism of 14, 15-EET, providing a novel approach for the development of drugs based on mitochondrial dynamics.

Marked shifts of harmful algal blooms in the Bohai Sea linked with combined impacts of environmental changes.

The Bohai Sea, a semi-enclosed inland sea in China and an important mariculture region, has experienced extensive harmful algal blooms (HABs) and their negative impacts for several decades. To investigate the changes of HABs and their potential drivers over time and space, a dataset of 230 HAB events (1952-2017), along with corresponding environmental data (1990-2017) was compiled. The frequency of HAB events in the Bohai Sea has increased over time but plateaued in the last decade, and our analysis showed that history of HABs in the Bohai Sea could be categorized into three periods based on their frequency, scale, and HAB-forming species. The seasonal window of HAB events has started earlier and lasted longer, and the main hotspot has moved from Bohai Bay to coastal waters of Qinhuangdao over time. There were marked shifts in the representative HAB-forming microalgae, from dinoflagellates in the first period (before 2000) to haptophytes in the second period (2000-2009), and pelagophytes in the third period (2009 onwards). These community changes are accompanied by a trend toward diversification of HAB-forming microalgae, decrease in cell-size, and increase in negative impacts. Statistical analyses indicate that long-term changes in HABs in the Bohai Sea are linked with the combined effects of climate change, eutrophication and mariculture development. The results of the present study require to refine future monitoring programs, develop adaptive management strategies and predictive models for HABs in the Bohai Sea.

An investigation on bloom dynamics of Alexandrium catenella and A. pacificum and toxin accumulation in shellfish along the coast of Qinhuangdao, China.

The dinoflagellate genus Alexandrium comprises most of the toxic bloom-forming species producing paralytic shellfish toxins (PSTs) in the sea. Recently, repeated paralytic shellfish poisoning episodes have been recorded in Qinhuangdao located at the west coast of the Bohai Sea. To elucidate the relationship between toxic Alexandrium blooms and the poisoning episodes, a year-round investigation was carried out in this region from July 2020 to July 2021. Two qPCR assays were used to detect A. catenella and A. pacificum, and LC-MS/MS was applied to analyze PSTs in phytoplankton and shellfish samples. The blooms of A. catenella and A. pacificum were found in April and July, respectively, and PST content in three bivalves exhibited notable increase following the bloom of A. catenella. The results revealed bloom dynamics of the two toxic Alexandrium species in the Bohai Sea for the first time, and further confirmed A. catenella as the causative agent of poisoning episodes.

Toxin production of dinoflagellate Gymnodinium catenatum isolated from the East China Sea.

Dinoflagellate Gymnodinium catenatum is an important producer of paralytic shellfish toxins (PSTs), including a novel group of hydroxybenzoate derivatives named GC toxins. In the East China Sea, G. catenatum has been considered as the causative agent for several paralytic shellfish poisoning (PSP) episodes, yet the knowledge on their toxin production was still quite limited. In this study, toxins produced by a strain of G. catenatum (MEL11) isolated from the East China Sea were determined, using high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). Changes of toxin profile in the stain MEL11 in response to nutrient and temperature variations were also examined. A total of 11 PST components dominated by hydroxybenzoate analogs and N-sulfocarbamoyl toxins were detected, which was different from other G. catenatum strains previously established in the East China Sea in the presence of GC5 and the lack of dcGTX2&3. Cellular toxin composition and content of the strain had no apparent change within a range of temperature from 20°C to 26°C. In contrast, nutrient limitation and nitrogen source had notable impacts on toxin production. The molar percentage of GC toxins decreased remarkably at the stationary growth phase under nutrient-deprived conditions of both nitrogen (N) and phosphorus (P). The replacement of nitrate with ammonium as the source of N significantly promoted PST production by G. catenatum. The study revealed the potential diversity of toxin profiles of G. catenatum in the East China Sea, and highlighted the effects of nutrients on production of GC toxins by G. catenatum.