MicroRNA-451 Regulates Angiogenesis in Intracerebral Hemorrhage by Targeting Macrophage Migration Inhibitory Factor.

Intracerebral hemorrhage (ICH) is a subtype of stroke with the highest fatality and disability rate. Up to now, commonly used first-line therapies have limited value in improving prognosis. Angiogenesis is essential to neurological recovery after ICH. Recent studies have shown that microRNA-451(miR-451) plays an important role in angiogenesis by regulating the function of vascular endothelial cells. We found miR-451 was significantly decreased in the peripheral blood of ICH patients in the acute stage. Based on the clinical findings, we conducted this study to investigate the potential regulatory effect of miR-451 on angiogenesis after ICH. The expression of miR-451 in ICH mouse model and in a hemin toxicity model of human brain microvascular endothelial cells (hBMECs) was decreased the same as in ICH patients. MiR-451 negatively regulated the proliferation, migration, and tube formation of hBMECs in vitro. MiR-451 negatively regulated the microvessel density in the perihematoma tissue and affected neural functional recovery of ICH mouse model. Knockdown of miR-451 could recovered tight junction and protect the integrity of blood-brain barrier after ICH. Based on bioinformatic programs, macrophage migration inhibitory factor (MIF) was predicted to be the target gene and identified to be regulated by miR-451 inhibiting the protein translation. And p-AKT and p-ERK were verified to be downstream of MIF in angiogenesis. These results all suggest that miR-451 will be a potential target for regulating angiogenesis in ICH.

Evolving Therapeutic Landscape of Intracerebral Hemorrhage: Emerging Cutting-Edge Advancements in Surgical Robots, Regenerative Medicine, and Neurorehabilitation Techniques.

Intracerebral hemorrhage (ICH) is the most serious form of stroke and has limited available therapeutic options. As knowledge on ICH rapidly develops, cutting-edge techniques in the fields of surgical robots, regenerative medicine, and neurorehabilitation may revolutionize ICH treatment. However, these new advances still must be translated into clinical practice. In this review, we examined several emerging therapeutic strategies and their major challenges in managing ICH, with a particular focus on innovative therapies involving robot-assisted minimally invasive surgery, stem cell transplantation, in situ neuronal reprogramming, and brain-computer interfaces. Despite the limited expansion of the drug armamentarium for ICH over the past few decades, the judicious selection of more efficacious therapeutic modalities and the exploration of multimodal combination therapies represent opportunities to improve patient prognoses after ICH.

Reversal and resumption of anticoagulants in patients with anticoagulant-associated intracerebral hemorrhage.

The use of anticoagulants has become more frequent due to the progressive aging population and increased thromboembolic events. Consequently, the proportion of anticoagulant-associated intracerebral hemorrhage (AAICH) in stroke patients is gradually increasing. Compared with intracerebral hemorrhage (ICH) patients without coagulopathy, patients with AAICH may have larger hematomas, worse prognoses, and higher mortality. Given the need for anticoagulant reversal and resumption, the management of AAICH differs from that of conventional medical or surgical treatments for ICH, and it is more specific. Understanding the pharmacology of anticoagulants and identifying agents that can reverse their effects in the early stages are crucial for treating life-threatening AAICH. When patients transition beyond the acute phase and their vital signs stabilize, it is important to consider resuming anticoagulants at the right time to prevent the occurrence of further thromboembolism. However, the timing and strategy for reversing and resuming anticoagulants are still in a dilemma. Herein, we summarize the important clinical studies, reviews, and related guidelines published in the past few years that focus on the reversal and resumption of anticoagulants in AAICH patients to help implement decisive diagnosis and treatment strategies in the clinical setting.

Intrauterine injection of bioengineered hydrogel loaded exosomes derived from HUCM stem cells and spermidine prominently augments the pregnancy rate in thin endometrium rats.

The endometrium is essential to the development of embryos and pregnancy. Human umbilical cord mesenchymal stem cells (HUCMSCs) are promising stem cell sources. HUCMSCs self-renew quickly and are painless to collect. Spermidine is an inherent polyamine needed for cellular and molecular processes that regulate physiology and function. HUCMSCs and spermidine (SN) may heal intrauterine adhesions. HUCMSCs were investigated for endometrial repair in rats. Composite hydrogels are used for medical exosome implantation, including their materials, properties, and embedding procedures. This study examined whether bioengineered hydrogel-loaded exosomes from HUCMSCs and spermidine prenatally improved conception rates in mice with poor endometrial lining. The data show that HUCMSC and SN provide a good experimental base for HUCMSC safety and intrauterine treatment in rats. Western blots, exosome structural analysis, pregnancy outcomes, flow cytometry, H&E staining, immunohistochemistry, and immunofluorescence labelling found and recovered the aberrant area. HUCM-derived stem cells and spermidine-derived exosomes biophysically match. These traits strengthen and prolong endometrial function. Pregnant rats with HUCMSC and SN had thinner endometrium. Hydrogel-incorporated HEHUCMSC and SN exosomes may improve IUI in rats with thin endometrium.

Advanced oxidation protein products attenuate the autophagy-lysosome pathway in ovarian granulosa cells by modulating the ROS-dependent mTOR-TFEB pathway.

Oxidative stress dysfunction has recently been found to be involved in the pathogenesis of premature ovarian insufficiency (POI). Previously, we found that advanced oxidation protein products (AOPPs) in plasma were elevated in women with POI and had an adverse effect on granulosa cell proliferation. However, the mechanism underlying the effects of AOPPs on autophagy-lysosome pathway regulation in granulosa cells remains unclear. In this study, the effect of AOPPs on autophagy and lysosomal biogenesis and the underlying mechanisms were explored by a series of in vitro experiments in KGN and COV434 cell lines. AOPP-treated rat models were employed to determine the negative effect of AOPPs on the autophagy-lysosome systems in vivo. We found that increased AOPP levels activated the mammalian target of rapamycin (mTOR) pathway, and inhibited the autophagic response and lysosomal biogenesis in KGN and COV434 cells. Furthermore, scavenging of reactive oxygen species (ROS) with N-acetylcysteine and blockade of the mTOR pathway with rapamycin or via starvation alleviated the AOPP-induced inhibitory effects on autophagy and lysosomal biogenesis, suggesting that these effects of AOPPs are ROS-mTOR dependent. The protein expression and nuclear translocation of transcription factor EB (TFEB), the key regulator of lysosomal and autophagic function, were also impaired by the AOPP-activated ROS-mTOR pathway. In addition, TFEB overexpression attenuated the AOPP-induced impairment of autophagic flux and lysosomal biogenesis in KGN and COV434 cells. Chronic AOPP stimulation in vivo also impaired autophagy and lysosomal biogenesis in granulosa cells of rat ovaries. The results highlight that AOPPs lead to impairment of autophagic flux and lysosomal biogenesis via ROS-mTOR-TFEB signaling in granulosa cells and participate in the pathogenesis of POI.

Successful pregnancy and delivery in a female with pituitary stalk interruption syndrome following in vitro fertilization and embryo transfer: A case report and literature review.

Pituitary stalk interruption syndrome (PSIS) in female patients is mainly characterized by short stature, primary amenorrhea, absent or incomplete sexual maturation, and infertility. Successful pregnancies among these patients are rare. In this report, we describe a successful pregnancy and delivery in a 28-year-old Chinese woman with PSIS following in vitro fertilization and embryo transfer. The patient exhibited typical symptoms, including multiple pituitary hormone deficiency, typical triad signs in magnetic resonance imaging (MRI), undetectable serum gonadotropins and estradiol levels, and invisible antral follicles in both ovaries. During the first attempted controlled ovarian hyperstimulation cycle, 14 oocytes were retrieved and six embryos were acquired. Artificial endometrial preparation and frozen-thawed embryo transfer were performed, resulting in a clinical pregnancy after the transfer of a day 5 blastocyst. The patient was closely monitored throughout the pregnancy and multiple hormone dosages were modulated accordingly. She delivered a healthy boy by elective cesarean section, and the newborn developed normally during a 1-year follow-up period. This is the first report of a successful live birth in a woman with PSIS achieved through in vitro fertilization and frozen-thawed embryo transfer. A literature review on this topic is also presented.

Surgical Robotics for Intracerebral Hemorrhage Treatment: State of the Art and Future Directions.

Intracerebral hemorrhage (ICH) is a stroke subtype with high mortality and disability, and there are no proven medical treatments that can improve the functional outcome of ICH patients. Robot-assisted neurosurgery is a significant advancement in the development of minimally invasive surgery for ICH. This review encompasses the latest advances and future directions of surgical robots for ICH. First, three robotic systems for neurosurgery applied to ICH are illustrated. Second, the key technologies of robot-assisted surgery for ICH are introduced in aspects of stereotactic technique and navigation, the puncture instrument, and hematoma evacuation. Finally, the limitations of current surgical robots are summarized, and the possible development direction is discussed, which is named "multisensor fusion and intelligent aspiration control of minimally invasive surgical robot for ICH". It is expected that the new generation of surgical robots for ICH will facilitate quantitative, precise, individualized, standardized treatment strategies for ICH.

Directional induction of neural stem cells, a new therapy for neurodegenerative diseases and ischemic stroke.

Due to the limited capacity of the adult mammalian brain to self-repair and regenerate, neurological diseases, especially neurodegenerative disorders and stroke, characterized by irreversible cellular damage are often considered as refractory diseases. Neural stem cells (NSCs) play a unique role in the treatment of neurological diseases for their abilities to self-renew and form different neural lineage cells, such as neurons and glial cells. With the increasing understanding of neurodevelopment and advances in stem cell technology, NSCs can be obtained from different sources and directed to differentiate into a specific neural lineage cell phenotype purposefully, making it possible to replace specific cells lost in some neurological diseases, which provides new approaches to treat neurodegenerative diseases as well as stroke. In this review, we outline the advances in generating several neuronal lineage subtypes from different sources of NSCs. We further summarize the therapeutic effects and possible therapeutic mechanisms of these fated specific NSCs in neurological disease models, with special emphasis on Parkinson's disease and ischemic stroke. Finally, from the perspective of clinical translation, we compare the strengths and weaknesses of different sources of NSCs and different methods of directed differentiation, and propose future research directions for directed differentiation of NSCs in regenerative medicine.

Novel Tu translation elongation factor, mitochondrial (TUFM) homozygous variant in a consanguineous family with premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction characterized by cessation of menstruation occurring before the age of 40 years. The genetic causes of idiopathic POI remain unclear. Here we recruited a POI patient from a consanguineous family to screen for potential pathogenic variants associated with POI. Genetic variants of the pedigree were screened using whole-exome sequencing analysis and validated through direct Sanger sequencing. A homozygous variant in TUFM (c.524G>C: p.Gly175Ala) was identified in this family. TUFM (Tu translation elongation factor, mitochondrial) is a nuclear-encoded mitochondrial protein translation elongation factor that plays a critical role in maintaining normal mitochondrial function. The variant position was highly conserved among species and predicted to be disease causing. Our in vitro functional studies demonstrated that this variant causes decreased TUFM protein expression, leading to mitochondrial dysfunction and impaired autophagy activation. Moreover, we found that mice with targeted Tufm variant recapitulated the phenotypes of human POI. Thus, this is the first report of a homozygous pathogenic TUFM variant in POI. Our findings highlighted the essential role of mitochondrial genes in folliculogenesis and ovarian function maintenance.

RegEMR: a natural language processing system to automatically identify premature ovarian decline from Chinese electronic medical records.

BACKGROUND: The ovarian reserve is a reservoir for reproductive potential. In clinical practice, early detection and treatment of premature ovarian decline characterized by abnormal ovarian reserve tests is regarded as a critical measure to prevent infertility. However, the relevant data are typically stored in an unstructured format in a hospital's electronic medical record (EMR) system, and their retrieval requires tedious manual abstraction by domain experts. Computational tools are therefore needed to reduce the workload. METHODS: We presented RegEMR, an artificial intelligence tool composed of a rule-based natural language processing (NLP) extractor and a knowledge-based disease scoring model, to automatize the screening procedure of premature ovarian decline using Chinese reproductive EMRs. We used regular expressions (REs) as a text mining method and explored whether REs automatically synthesized by the genetic programming-based online platform RegexGenerator + + could be as effective as manually formulated REs. We also investigated how the representativeness of the learning corpus affected the performance of machine-generated REs. Additionally, we translated the clinical diagnostic criteria into a programmable disease diagnostic model for disease scoring and risk stratification. Four hundred outpatient medical records were collected from a Chinese fertility center. Manual review served as the gold standard, and fivefold cross-validation was used for evaluation. RESULTS: The overall F-score of manually built REs was 0.9444 (95% CI 0.9373 to 0.9515), with no significant difference (paired t test p > 0.05) compared with machine-generated REs that could be affected by training set sizes and annotation portions. The extractor performed effectively in automatically tracing the dynamic changes in hormone levels (F-score 0.9518-0.9884) and ultrasonographic measures (F-score 0.9472-0.9822). Applying the extracted information to the proposed diagnostic model, the program obtained an accuracy of 0.98 and a sensitivity of 0.93 in risk screening. For each specific disease, the automatic diagnosis in 76% of patients was consistent with that of the clinical diagnosis, and the kappa coefficient was 0.63. CONCLUSION: A Chinese NLP system named RegEMR was developed to automatically identify high risk of early ovarian aging and diagnose related diseases from Chinese reproductive EMRs. We hope that this system can aid EMR-based data collection and clinical decision support in fertility centers.

Elevated cell-free mitochondria DNA level of patients with premature ovarian insufficiency.

BACKGROUND: Premature ovarian insufficiency (POI) patients present with a chronic inflammatory state. Cell-free mitochondria DNA (cf-mtDNA) has been explored as a reliable biomarker for estimating the inflammation-related disorders, however, the cf-mtDNA levels in POI patients have never been measured. Therefore, in the presenting study, we aimed to evaluate the levels of cf-mtDNA in plasma and follicular fluid (FF) of POI patients and to determine a potential role of cf-mtDNA in predicting the disease progress and pregnancy outcomes. METHODS: We collected plasma and FF samples from POI patients, biochemical POI (bPOI) patients and control women. Quantitative real-time PCR was used to measure the ratio of mitochondrial genome to nuclear genome of cf-DNAs extracted from the plasma and FF samples. RESULTS: The plasma cf-mtDNA levels, including COX3, CYB, ND1 and mtDNA79, were significantly higher in overt POI patients than those in bPOI patients or control women. The plasma cf-mtDNA levels were weakly correlated with ovarian reserve, and could not be improved by regular hormone replacement therapy. The levels of cf-mtDNA in FF, rather than those in plasma, exhibited the potential to predict the pregnancy outcomes, although they were comparable among overt POI, bPOI and control groups. CONCLUSIONS: The increased plasma cf-mtDNA levels in overt POI patients indicated its role in the progress of POI and the FF cf-mtDNA content may hold the value in predicting pregnancy outcomes of POI patients.

Effects of Dl-3-n-butylphthalide on cognitive functions and blood-brain barrier in chronic cerebral hypoperfusion rats.

Vascular cognitive impairment (VCI) has been one of the major types of cognitive impairment. Blood-brain barrier damage plays an essential part in the pathogenesis of VCI. At present, the treatment of VCI is mainly focused on prevention, with no drug clinically approved for the treatment of VCI. This study aimed to investigate the effects of DL-3-n-butylphthalide (NBP) on VCI rats. A modified bilateral common carotid artery occlusion (mBCCAO) model was applied to mimic VCI. The feasibility of the mBCCAO model was verified by laser Doppler, 13N-Ammonia-Positron Emission Computed Tomography (PET), and Morris Water Maze. Subsequently, the Morris water maze experiment, Evans blue staining, and western blot of tight junction protein were performed to evaluate the effect of different doses of NBP (40 mg/kg, 80 mg/kg) on the improvement of cognitive impairment and BBB disruption induced by mBCCAO. Immunofluorescence was employed to examine the changes in pericyte coverage in the mBCCAO model and the effect of NBP on pericyte coverage was preliminarily explored. mBCCAO surgery led to obvious cognitive impairment and the decrease of whole cerebral blood flow, among which the blood flow in the cortex, hippocampus and thalamus brain regions decreased more significantly. High-dose NBP (80 mg/kg) improved long-term cognitive function in mBCCAO rats, alleviated Evans blue leakage and reduced the loss of tight junction proteins (ZO-1, Claudin-5) in the early course of the disease, thereby exerting a protective effect on the blood-brain barrier. No significant changes in pericyte coverage were observed after mBCCAO. High-dose NBP improved cognitive function in mBCCAO rats. High-dose NBP protected the integrity of BBB by upregulating TJ protein expression, rather than regulating pericyte coverage ratio. NBP could be a potential drug for the treatment of VCI.

Dihydromyricetin attenuates intracerebral hemorrhage by reversing the effect of LCN2 via the system Xc- pathway.

BACKGROUND: The limited understanding of the pathological mechanisms of intracerebral hemorrhage (ICH) and the absence of successful therapies lead to poor prognoses for patients with ICH. Dihydromyricetin (DMY) has many physiological functions, such as regulating lipid and glucose metabolism and modulating tumorigenesis. Moreover, DMY has been proven to be an effective treatment of neuroprotection. However, no reports to date have been made regarding the impact of DMY on ICH. PURPOSE: This investigation aimed to identify the role of DMY on ICH in mice and the underlying mechanisms. METHODS/RESULTS: This study demonstrated that DMY treatment effectively reduced hematoma size and cell apoptosis of brain tissue, and improved neurobehavioral outcomes in mice with ICH. Transcriptional and network pharmacological analyses revealed that lipocalin-2 (LCN2) was a potential target of DMY in ICH. After ICH, LCN2 mRNA and protein expression in brain tissue increased and DMY could inhibit the expression of LCN2. The rescue experiment with the implementation of LCN2 overexpression verified these observations. Furthermore, after DMY treatment, there was a significant decrease in cyclooxygenase 2 (COX2), phospho-extracellular regulated protein kinase (P-ERK), iron deposition, and the number of abnormal mitochondria, which were reversed by the overexpression of LCN2. Proteomics analysis suggests that SLC3A2 may be the downstream target of LCN2, promoting ferroptosis. Finally, LCN2 was shown to bind to SLC3A2 and regulate the downstream glutathione (GSH) synthesis and Glutathione Peroxidase 4 (GPX4) expression and glutathione (GSH) synthesis, as determined by molecular docking and co-immunoprecipitation analysis. CONCLUSION: Our study confirmed for the first time that DMY might offer a favorable treatment for ICH through its action on LCN2. The possible mechanism for this could be that DMY reverses the inhibitory effect of LCN2 on the system Xc-, lessening ferroptosis in brain tissue. The findings of this study offer a greater understanding of how DMY affects ICH at a molecular level and could be conducive to developing therapeutic targets for ICH.

Effect of antiplatelet therapy on the incidence, prognosis, and rebleeding of intracerebral hemorrhage.

OBJECTIVE: Antiplatelet medications are increasingly being used for primary and secondary prevention of ischemic attacks owing to the increasing prevalence of ischemic stroke occurrences. Currently, many patients receive antiplatelet therapy (APT) to prevent thromboembolic events. However, long-term use of APT might also lead to an increased occurrence of intracerebral hemorrhage (ICH) and affect the prognosis of patients with ICH. Furthermore, some research suggest that restarting APT for patients who have previously experienced ICH may result in rebleeding events. The precise relationship between APT and ICH remains unknown. METHODS: We searched PubMed for the most recent related literature and summarized the findings from various studies. The search terms included "antiplatelet," "intracerebral hemorrhage," "cerebral microbleeds," "hematoma expansion," "recurrent," and "reinitiate." Clinical studies involving human subjects were ultimately included and interpreted in this review, and animal studies were not discussed. RESULTS: When individuals are administered APT, the risk of thrombotic events should be weighted against the risk of bleeding. In general, for some patients' concomitant with risk factors of thrombotic events, the advantages of antiplatelet medication may outweigh the inherent risk of rebleeding. However, the use of antiplatelet medications for other patients with a higher risk of bleeding should be carefully evaluated and closely monitored. In the future, a quantifiable system for assessing thrombotic risk and bleeding risk will be necessary. After evaluation, the appropriate time to restart APT for ICH patients should be determined to prevent underlying ischemic stroke events. According to the present study results and expert experience, most patients now restart APT at around 1 week following the onset of ICH. Nevertheless, the precise time to restart APT should be chosen on a case-by-case basis as per the patient's risk of embolic events and recurrent bleeding. More compelling evidence-based medicine evidence is needed in the future. CONCLUSION: This review thoroughly discusses the relationship between APT and the development of ICH, the impact of APT on the course and prognosis of ICH patients, and the factors influencing the decision to restart APT after ICH. However, different studies' conclusions are inconsistent due to the differences in quality control. To support future clinical decisions, more large-scale randomized controlled trials are required.

Clinical Efficacy of Superficial Temporal Artery-middle Cerebral Artery Bypass Grafting Surgery Combined With Temporal Muscle Patch on Patients With Moyamoya Disease.

OBJECTIVE: To analyze the clinical efficacy of superficial temporal artery-middle cerebral artery (STA-MCA) bypass grafting surgery combined with temporal muscle patch and STA-MCA bypass grafting surgery alone on patients with moyamoya disease. METHODS: Totally 73 patients confirmed with moyamoya disease in our hospital between January 2019 and December 2021 were enrolled. Among them, 43 patients treated with STA-MCA bypass grafting surgery combined with temporal muscle patch were assigned to the experiment group, whereas 30 patients treated with STA-MCA bypass grafting surgery alone to the control group. The following items of the 2 groups were compared: clinical efficacy, total effective rate, and disease control rate 6 months after surgery, the changes of modified Rankin Scale (mRS) and Karnofsky performance scale (KPS) scores before and on the seventh day and 6 months after surgery, and changes of Glasgow coma scale scores before and 24 hours after surgery. In addition, the incidences of cerebral ischemia and cerebral hemorrhage within 1 year after surgery were counted. The cerebral perfusion-associated indexes including relative mean transit time (rMTT), relative time-to-peak, relative cerebral blood flow (rCBF), and relative cerebral blood volume (rCBV) on the seventh day and 6 months after surgery were compared between the 2 groups, and the predictive value of cerebral perfusion-associated indexes before surgery for clinical efficacy on patients was analyzed. RESULTS: The Glasgow coma scale score after surgery ( P >0.05) was similar between the 2 groups, but the clinical efficacy and total effective rate of the 2 groups were notably different (both P <0.05). Compared with those before surgery, mRS scores of both groups declined, whereas KPS scores increased (both P <0.05) on the seventh day after surgery. In addition, compared with those before surgery and on the seventh day after surgery, mRS scores of both groups decreased 6 months after surgery, whereas KPS scores increased (both P <0.05). Both the groups showed decreased rMTT and rTPP, and increased rCBF and rCBV on the seventh day after surgery than those before surgery (all P <0.05). In addition, both the groups still showed decreased rMTT and rTPP, and increased rCBF and rCBV 6 months after surgery than those before surgery and on the seventh day after surgery (all P <0.05). Most notably, the experimental group displayed improved cerebral perfusion-associated indexes than the control group 6 months after surgery (all P <0.05). The relief group showed notably higher rCBF and rCBV levels than the nonrelief group (both P <0.05). According to ROC analysis, the areas under the curves of rCBF and rCBV in forecasting the clinical efficacy on patients were 0.842 and 0.823, respectively. CONCLUSION: Superficial temporal artery-middle cerebral artery bypass grafting surgery combined with temporal muscle patch can deliver a higher total clinical curative rate for patients with moyamoya disease and can alleviate their coma.

Plasma metabolomic characterization of premature ovarian insufficiency.

BACKGROUND: Premature ovarian insufficiency (POI) patients are predisposed to metabolic disturbances, including in lipid metabolism and glucose metabolism, and metabolic disorders appear to be a prerequisite of the typical long-term complications of POI, such as cardiovascular diseases or osteoporosis. However, the metabolic changes underlying the development of POI and its subsequent complications are incompletely understood, and there are few studies characterizing the disturbed metabolome in POI patients. The aim of this study was to characterize the plasma metabolome in POI by using ultrahigh-performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) metabolomics and to evaluate whether these disturbances identified in the plasma metabolome relate to ovarian reserve and have diagnostic value in POI. METHODS: This observational study recruited 30 POI patients and 30 age- and body mass index (BMI)-matched controls in the Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, from January 2018 to October 2020. Fasting venous blood was collected at 9:00 am on days 2-4 of the menstrual cycle and centrifuged for analysis. An untargeted quantitative metabolomic analysis was performed using UHPLC-MS/MS. RESULTS: Our study identified 48 upregulated and 21 downregulated positive metabolites, and 13 upregulated and 48 downregulated negative metabolites in the plasma of POI patients. The differentially regulated metabolites were involved in pathways such as caffeine metabolism and ubiquinone and other terpenoid-quinone biosynthesis. Six metabolites with an AUC value > 0.8, including arachidonoyl amide, 3-hydroxy-3-methylbutanoic acid, dihexyl nonanedioate, 18-HETE, cystine, and PG (16:0/18:1), were correlated with ovarian reserve and thus have the potential to be diagnostic biomarkers of POI. CONCLUSION: This UHPLC-MS/MS untargeted metabolomics study revealed differentially expressed metabolites in the plasma of patients with POI. The differential metabolites may not only be involved in the aetiology of POI but also contribute to its major complications. These findings offer a panoramic view of the plasma metabolite changes caused by POI, which may provide useful diagnostic and therapeutic clues for POI disease.

Derivation of maximum permissive switching time for automatic welding filter based on retinal thermal and blue light exposure limits.

Automatic welding filters are intended to protect the eyes of the welder from optical radiation generated by the welding process. Safety standards for automatic welding filters (AWFs) have been developed worldwide. However, switching time requirements have not been studied considering the exposure limits established by the International Commission on Non-Ionizing Radiation Protection (ICNIRP) or the American Conference of Governmental Industrial Hygienists (ACGIH). The aim of this study is to derive the maximum permissive switching time based on ICNIRP guidelines for exposure to intense optical radiation. The single and cumulative exposures associated with retinal thermal and blue light hazards were assessed in the welding environment. The results show that the maximum switching time is inversely proportional to the exponential function of the shade number difference. The proposed maximum switching time, 1/2 to 1/10 smaller than the current ISO, is derived from the effective blue light radiance limits. In addition, an evaluation of the periodic short circuit welding indicates that AWFs do not transmit hazardous levels of radiation in the dark state.

Study of differential proteomics in granulosa cells of premature ovarian insufficiency (POI) and the roles and mechanism of RAC1 in granulosa cells.

In the present study, we focused on characterizing the proteome in granulosa cells in patients with biochemical premature ovarian insufficiency (bPOI) in order to identify differential proteins and investigate the fundamental mechanisms of POI. A total of 2688 proteins were identified based on the data-independent acquisition method, and 70 differentially expressed proteins were significant. Bioinformatic analyses, including gene expression pattern analysis, gene ontology enrichment analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, and Search Tool for the Retrieval of Interacting Genes/Proteins analysis, revealed discrete modules and the underlying molecular mechanisms in bPOI. Importantly, we observed that Ras-related C3 botulinum toxin substrate 1 (RAC1) was downregulated in the granulosa cells of bPOI. Low expression of RAC1 may affect the development process of POI by affecting the proliferation, apoptosis, and hormone synthesis of granulosa cells. Downregulation of RAC1 expression in the KGN and COV434 cells inhibited cell proliferation, blocked cells in the G1/G0 phase, and promoted apoptosis. Western blot results showed that ß-catenin and cyclin D1 in the KGN and COV434 cells transfected with RAC1-siRNA were downregulated, while P21 and Bax were upregulated. Knocking down RAC1 in the KGN cells or adding the RAC1 enzyme inhibitor to the human luteinized granulosa cells (hLGC) inhibited the synthesis of E2, and the expression of aromatase and follicle-stimulating hormone receptor (FSHR) was reduced.

Application of Small Molecules in the Central Nervous System Direct Neuronal Reprogramming.

The lack of regenerative capacity of neurons leads to poor prognoses for some neurological disorders. The use of small molecules to directly reprogram somatic cells into neurons provides a new therapeutic strategy for neurological diseases. In this review, the mechanisms of action of different small molecules, the approaches to screening small molecule cocktails, and the methods employed to detect their reprogramming efficiency are discussed, and the studies, focusing on neuronal reprogramming using small molecules in neurological disease models, are collected. Future research efforts are needed to investigate the in vivo mechanisms of small molecule-mediated neuronal reprogramming under pathophysiological states, optimize screening cocktails and dosing regimens, and identify safe and effective delivery routes to promote neural regeneration in different neurological diseases.