Exercise promotes osteogenic differentiation by activating the long non-coding RNA H19/microRNA-149 axis.

BACKGROUND: Regular physical activity during childhood and adolescence is beneficial to bone development, as evidenced by the ability to increase bone density and peak bone mass by promoting bone formation. AIM: To investigate the effects of exercise on bone formation in growing mice and to investigate the underlying mechanisms. METHODS: 20 growing mice were randomly divided into two groups: Con group (control group, n = 10) and Ex group (treadmill exercise group, n = 10). Hematoxylin-eosin staining, immunohistochemistry, and micro-CT scanning were used to assess the bone formation-related indexes of the mouse femur. Bioinformatics analysis was used to find potential miRNAs targets of long non-coding RNA H19 (lncRNA H19). RT-qPCR and Western Blot were used to confirm potential miRNA target genes of lncRNA H19 and the role of lncRNA H19 in promoting osteogenic differentiation. RESULTS: Compared with the Con group, the expression of bone morphogenetic protein 2 was also significantly increased. The micro-CT results showed that 8 wk moderate-intensity treadmill exercise significantly increased bone mineral density, bone volume fraction, and the number of trabeculae, and decreased trabecular segregation in the femur of mice. Inhibition of lncRNA H19 significantly upregulated the expression of miR-149 and suppressed the expression of markers of osteogenic differentiation. In addition, knockdown of lncRNA H19 significantly downregulated the expression of autophagy markers, which is consistent with the results of autophagy-related protein changes detected in mouse femurs by immunofluorescence. CONCLUSION: Appropriate treadmill exercise can effectively stimulate bone formation and promote the increase of bone density and bone volume in growing mice, thus enhancing the peak bone mass of mice. The lncRNA H19/miR-149 axis plays an important regulatory role in osteogenic differentiation.

Aflatoxin B1 inhibited the development of primary myoblasts of grass carp (Ctenopharyngodon idella) by degrading extracellular matrix.

According to the International Agency for Research on Cancer (IARC), aflatoxin B1 (AFB1) has been recognized as a major contaminant in food and animal feed and which is a common mycotoxin with high toxicity. Previous research has found that AFB1 inhibited zebrafish muscle development. However, the potential mechanism of AFB1 on fish muscle development is unknown, so it is necessary to conduct further investigation. In the present research, the primary myoblast of grass carp was used as a model, we treated myoblasts with AFB1 for 24 h. Our results found that 5 µM AFB1 significantly inhibited cell proliferation and migration (P < 0.05), and 10 µM AFB1 promoted lactate dehydrogenase (LDH) release (P < 0.05). Reactive oxygen species (ROS), protein carbonyl (PC) and malondialdehyde (MDA) levels were increased in 15, 5 and 10 µM AFB1 (P < 0.05), respectively. Catalase (CAT), glutathione peroxidase (GPx) and total superoxide dismutase (T-SOD) activities were decreased in 10, 10 and 15 µM AFB1 (P < 0.05), respectively. Furthermore, 15 µM AFB1 induced oxidative damage by Nrf2 pathway, also induced apoptosis in primary myoblast of grass carp. Meanwhile, 15 µM AFB1 decreased MyoD gene and protein expression (P < 0.05). Importantly, 15 µM AFB1 decreased the protein expression of collagen Ⅰ and fibronectin (P < 0.05), and increased the protein levels of urokinase plasminogen activator (uPA), matrix metalloproteinase 9 (MMP-9), matrix metalloproteinase 2 (MMP-2), and p38 mitogen-activated protein kinase (p38MAPK) (P < 0.05). As a result, our findings suggested that AFB1 damaged the cell morphology, induced oxidative damage and apoptosis, degraded ECM components, in turn inhibiting myoblast development by activating the p38MAPK/urokinase-type plasminogen activator (uPA)/matrix metalloproteinase (MMPs)/extracellular matrix (ECM) signaling pathway.

Phosphoglycerate Kinase 1: An Effective Therapeutic Target in Cancer.

Phosphoglycerate kinase 1 (PGK1) serves as a pivotal enzyme in the cellular glycolysis pathway, facilitating adenosine-triphosphate (ATP) production in tumor cells and driving the Warburg effect. PGK1 generates ATP through the reversible phosphorylation reaction of 1,3-bisphosphoglycerate (1,3-BPG) to Mg-adenosine-5'-diphosphate (Mg-ADP). In addition to its role in regulating cellular metabolism, PGK1 plays a pivotal role in autophagy induction, regulation of the tricarboxylic acid cycle (TCA), and various mechanisms including tumor cell drug resistance, and so on. Given its multifaceted functions within cells, the involvement of PGK1 in many types of cancer, including breast cancer, astrocytoma, metastatic colon cancer, and pancreatic ductal adenocarcinoma, is intricate. Notably, PGK1 can function as an intracellular protein kinase to coordinate tumor growth, migration, and invasion via posttranslational modifications (PTMs). Furthermore, elevated expression levels of PGK1 have been observed in cancer tissues, indicating its association with unfavorable treatment outcomes and prognosis. This review provides a comprehensive summary of PGK1's expression pattern, structural features, functional properties, involvement in PTMs, and interaction with tumors. Additionally highlighted are the prospects for developing and applying related inhibitors that confirm the indispensable value of PGK1 in tumor progression.

Analyzing shifts in age-related macular degeneration research trends since 2014: A bibliometric study with triple-map Sankey diagrams (TMSD).

BACKGROUND: Age-related macular degeneration (AMD) is the primary cause of vision impairment in older adults, especially in developed countries. While many articles on AMD exist in the literature, none specifically delve into the trends based on document categories. While bibliometric studies typically use dual-map overlays to highlight new trends, these can become congested and unclear with standard formats (e.g., in CiteSpace software). In this study, we introduce a unique triple-map Sankey diagram (TMSD) to assess the evolution of AMD research. Our objective is to understand the nuances of AMD articles and show the effectiveness of TMSD in determining whether AMD research trends have shifted over the past decade. METHODS: We collected 7465 articles and review pieces related to AMD written by ophthalmologists from the Web of Science core collection, accumulating article metadata from 2014 onward. To delve into the characteristics of these AMD articles, we employed various visualization methods, with a special focus on TMSD to track research evolution. We adopted the descriptive, diagnostic, predictive, and prescriptive analytics (DDPP) model, complemented by the follower-leading clustering algorithm (FLCA) for clustering analysis. This synergistic approach proved efficient in identifying and showcasing research focal points and budding trends using network charts within the DDPP framework. RESULTS: Our findings indicate that: in countries, institutes, years, authors, and journals, the dominant entities were the United States, the University of Bonn in Germany, the year 2021, Dr Jae Hui Kim from South Korea, and the journal "Retina"; in accordance with the TMSD, AMD research trends have not changed significantly since 2014, as the top 4 categories for 3 citing, active, and cited articles have not changed, in sequence (Ophthalmology, Science & Technology - Other Topics, General & Internal Medicine, Pharmacology & Pharmacy). CONCLUSION: The introduced TMSD, which incorporates the FLCA algorithm and features in 3 columns-cited, active, and citing research categories-offers readers clearer insights into research developments compared to the traditional dual-map overlays from CiteSpace software. Such tools are especially valuable for streamlining the visualization of the intricate data often seen in bibliometric studies.

The application of machine learning on brain imaging features of different narcolepsy subtypes.

STUDY OBJECTIVES: Narcolepsy is a central hypersomnia disorder, and differential diagnoses between its subtypes can be difficult. Hence, we applied machine learning to analyze the positron emission tomography (PET) data of patients with type 1 or type 2 narcolepsy, and patients with type 1 narcolepsy and comorbid schizophrenia, to construct predictive models to facilitate the diagnosis. METHODS: This is a retrospective and prospective case-control study of adolescent and young adult patients with type 1 or type 2 narcolepsy, and type 1 narcolepsy and comorbid schizophrenia. All participants received 18-F-fluorodeoxy glucose PET, sleep studies, neurocognitive tests, sleep questionnaires, and human leukocyte antigen typing. The collected PET data were analyzed by feature selections and classification methods in machine learning to construct predictive models. RESULTS: A total of 314 participants with narcolepsy were enrolled; 204 had type 1 narcolepsy, 90 had type 2 narcolepsy, and 20 had type 1 narcolepsy and comorbid schizophrenia. We used three filter methods for feature selection followed by a comparative analysis of classification methods. To apply a small number of regions of interest (ROI) and high classification accuracy, the Naïve Bayes classifier with the Term Variance as feature selection achieved the goal with only three ROIs (left basal ganglia, left Heschl, and left striatum) and produced an accuracy of higher than 99%. CONCLUSIONS: The accuracy of our predictive model of PET data are promising and can aid clinicians in the diagnosis of narcolepsy subtypes. Future research with a larger sample size could further refine the predictive model of narcolepsy.

Allyl isothiocyanate induces DNA damage and inhibits DNA repair-associated proteins in a human gastric cancer cells in vitro.

Allyl isothiocyanate (AITC) is abundant in cruciferous vegetables and it present pharmacological activity including anticancer activity in many types of human cancer cells in vitro and in vivo. Currently, no available information to show AITC affecting DNA damage and repair-associated protein expression in human gastric cancer cells. Therefore, in the present studies, we investigated AITC-induced cytotoxic effects on human gastric cancer in AGS and SNU-1 cells whether or not via the induction of DNA damage and affected DNA damage and repair associated poteins expressions in vitro. Cell viability and morphological changes were assayed by flow cytometer and phase contrast microscopy, respectively, the results indicated AITC induced cell morphological changes and decreased total viable cells in AGS and SNU-1 cells in a dose-dependently. AITC induced DNA condensation and damage in a dose-dependently which based on the cell nuclei was stained by 4', 6-diamidino-2-phenylindole present in AGS and SNU-1 cells. DNA damage and repair associated proteins expression in AGS and SNU-1 cells were measured by Western blotting. The results indicated AITC decreased nuclear factor erythroid 2-related factor 2 (NRF2), heme oxygenase-1 (HO-1), glutathione, and catalase, but increased superoxide dismutase (SOD (Cu/Zn)), and nitric oxide synthase (iNOS) in AGS cells, however, in SNU-1 cells are increased HO-1. AITC increased DNA-dependent protein kinase (DNA-PK), phosphorylation of gamma H2A histone family member X on Ser139 (γH2AXpSer139 ), and heat shock protein 90 (HSP90) in AGS cells. AITC increased DNA-PK, mediator of DNA damage checkpoint protein 1 (MDC1), γH2AXpSer139 , topoisomerase II alpha (TOPIIα), topoisomerase II beta (TOPIIß), HSP90, and heat shock protein 70 (HSP70) in SNU-1 cells. AITC increased p53, p53pSer15 , and p21 but decreased murine double minute 2 (MDM2)pSer166 and O6 -methylguanine-DNA methyltransferase (MGMT) in AGS cells; however, it has a similar effect of AITC except increased ataxia telangiectasia and Rad3 -related protein (ATR)pSer428 , checkpoint kinase 1 (CHK1), and checkpoint kinase 2 (CHK2) in SNU-1 cells. Apparently, both cell responses to AITC are different, nonetheless, all of these observations suggest that AITC inhibits the growth of gastric cancer cells may through induction off DNA damage in vitro.

Impact of Resistance Training on Energy Intake and Appetite Regulation for Obese or Overweight Individuals: A Systematic Literature Review / Impacto del entrenamiento de resistencia en la ingesta de energía y la regulación del apetito en personas obesas o con sobrepeso: una revisión sistemática de la literatura

Individuals experiencing obesity or overweight conditions frequently encounter difficulties in managing their appetite. The sustained practice of resistance training over an extended duration presents a potential avenue for regulating appetite among this demographic. Despite the extensive examination of long-term resistance training in existing literature, a consensus on pertinent issues remains elusive, necessitating a comprehensive review. This paper aims to evaluate empirical studies examining alterations in energy intake and appetite among obese or overweight individuals engaging in prolonged resistance training regimens. Information was gathered from databases including EBSCOhost, Science Direct, PubMed, and Web of Science. Search queries were executed on Google Scholar and other sources, utilizing key terms pertinent to energy intake (or appetite), resistance training, and overweight (or obesity) for identifying relevant studies. A comprehensive evaluation of 38 full-text articles was conducted, resulting in the inclusion of eight articles in the review. The PEDro scale was utilized to assess bias and completeness risk, with no exclusion of any articles during this process. The impact of resistance training on energy intake in overweight or obese individuals was observed through sessions lasting 35–45 minutes conducted twice a week over a nine-month period. The exercise significantly influenced parameters such as energy intake, glucose levels, leptin concentrations, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), Neuropeptide Y (NPY), and adiponectin. However, no significant effects were noted on perceived fullness and hunger, ghrelin PP, or PYY. Resistance training has the potential to impact energy intake and appetite regulation in overweight or obese individuals. Further research is warranted, particularly in exploring its effects on female and adolescent populations, implementing a sample size calculation strategy, conducting comparisons across three intensities, and undertaking a comprehensive analysis of relevant variables.(AU)

Taiwanese Dermatological Association (TDA) consensus recommendations for the definition, classification, diagnosis, and management of hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory follicular disease characterized by painful, recurrent, inflamed lesions most commonly occurring in the axillary, inguinal, and anogenital regions. HS can inflict immense physical and psychological impact on patients who suffer from this distressing disease. Management of HS generally requires combining various medical and procedural treatment modalities; however, the disease is often recalcitrant to conventional treatments. In light of recent evidence supporting the effectiveness of biologic agents in the treatment of HS, the Taiwanese Dermatological Association established an expert panel of nine dermatologists to develop consensus statements aimed to provide up-to-date evidence-based guidance in optimizing HS patient management in Taiwan. The recommendations described in the statements were summarized in a management algorithm in terms of general care, topical treatment, systemic treatment, and procedural treatment.

Identifying Lymph Nodes and Their Statuses from Pretreatment Computer Tomography Images of Patients with Head and Neck Cancer Using a Clinical-Data-Driven Deep Learning Algorithm.

BACKGROUND: Head and neck cancer is highly prevalent in Taiwan. Its treatment mainly relies on clinical staging, usually diagnosed from images. A major part of the diagnosis is whether lymph nodes are involved in the tumor. We present an algorithm for analyzing clinical images that integrates a deep learning model with image processing and attempt to analyze the features it uses to classify lymph nodes. METHODS: We retrospectively collected pretreatment computed tomography images and surgery pathological reports for 271 patients diagnosed with, and subsequently treated for, naïve oral cavity, oropharynx, hypopharynx, and larynx cancer between 2008 and 2018. We chose a 3D UNet model trained for semantic segmentation, which was evaluated for inference in a test dataset of 29 patients. RESULTS: We annotated 2527 lymph nodes. The detection rate of all lymph nodes was 80%, and Dice score was 0.71. The model has a better detection rate at larger lymph nodes. For those identified lymph nodes, we found a trend where the shorter the short axis, the more negative the lymph nodes. This is consistent with clinical observations. CONCLUSIONS: The model showed a convincible lymph node detection on clinical images. We will evaluate and further improve the model in collaboration with clinical physicians.

Machine learning-based monosaccharide profiling for tissue-specific classification of Wolfiporia extensa samples.

Machine learning (ML) has been used for many clinical decision-making processes and diagnostic procedures in bioinformatics applications. We examined eight algorithms, including linear discriminant analysis (LDA), logistic regression (LR), k-nearest neighbor (KNN), random forest (RF), gradient boosting machine (GBM), support vector machine (SVM), Naïve Bayes classifier (NB), and artificial neural network (ANN) models, to evaluate their classification and prediction capabilities for four tissue types in Wolfiporia extensa using their monosaccharide composition profiles. All 8 ML-based models were assessed as exemplary models with AUC exceeding 0.8. Five models, namely LDA, KNN, RF, GBM, and ANN, performed excellently in the four-tissue-type classification (AUC > 0.9). Additionally, all eight models were evaluated as good predictive models with AUC value > 0.8 in the three-tissue-type classification. Notably, all 8 ML-based methods outperformed the single linear discriminant analysis (LDA) plotting method. For large sample sizes, the ML-based methods perform better than traditional regression techniques and could potentially increase the accuracy in identifying tissue samples of W. extensa.

Primary Graviceptive System and Astasia: A Case Report and Literature Review.

Astasia refers to the inability to maintain upright posture during standing, despite having full motor strength. Impairment of the vestibulocerebellar pathway, graviceptive system, and cingulate motor area have been proposed to be related to astasia. However, the responsible neural pathways remain unclear. We hypothesize that there is a common neural network behind astasia. To test the hypothesis, we reviewed all reported cases with astasia, including ours, and focused on the correlation between anatomical destruction and symptom presentation. A total of 26, including ours, non-psychogenic astasia patients were identified in the English literature. Seventy-three percent of them were associated with other neurologic symptoms and sixty-two percent of reported lesions were on the right side. Contralateral lateropulsion was very common, followed by retropulsion, when describing astasia. Infarction (54%) was the most reported cause. The thalamus (65%) was the most reported location. Infarctions were the fastest to recover (mean: 10.6 days), while lesions at the brainstem needed a longer time (mean: 61.6 days). By combining the character of lateropulsion in astasia and the presentation of an interrupted graviceptive system, we concluded that the primary graviceptive system may be the common neural network behind astasia. Future studies on astasia should focus on the pathological changes in the perception of verticality in the visual world and the body.

Lipidomics Profiling Reveals Serum Phospholipids Associated with Albuminuria in Early Type 2 Diabetic Kidney Disease.

Early screening and administration of DKD are beneficial for renal outcomes of type 2 diabetic patients. However, the current early diagnosis using the albuminuria/creatine ratio (ACR) contains limitations. This study aimed to compare serum lipidome variation between type 2 diabetes and early DKD patients with increased albuminuria through an untargeted lipidomics method to explore the potential lipid biomarkers for DKD identification. 92 type 2 diabetic patients were enrolled and divided into two groups: DM group (ACR < 3 mg/mmol, n = 49) and early DKD group (3 mg/mmol ≤ ACR < 30 mg/mmol, n = 43). Fasting serum was analyzed through an ultraperformance liquid mass spectrometry tandem chromatography system (LC-MS). Orthogonal partial least-squares discriminant analysis (OPLS-DA) and univariate and multivariate analysis were performed to filter differentially depressed lipids. Receiver operating characteristic (ROC) curves were used to estimate the diagnostic capability of potential lipid biomarkers. We found that serum phospholipids including phosphatidylserine (PS), sphingomyelin (SM), and phosphatidylcholine (PC) were significantly upregulated in the DKD group and were highly correlated with the ACR. In addition, a panel of two phospholipids including PS(27:0)-H and PS(30:2e)-H showed good performance to help clinical lipids in early DKD identification, which increased the area under the curve (AUC) from 0.568 to 0.954. The study exhibited the serum lipidome variation in early DKD patients, and the increased phospholipids might participate in the development of albuminuria. The panel of PS(27:0)-H and PS(30:2e)-H could be a potential biomarker for DKD diagnosis.

C21 steroidal glycosides from the root bark of Periploca sepium and their NO production inhibitory and cytotoxic activity.

A series of C21 steroidal glycosides were isolated from the root bark of Periploca sepium, including a new compound, perisepiumoside A1 (1), and six known compounds (2-7). Their structures were elucidated by analysis of HR-ESI-MS, and 1D and 2D NMR spectroscopic data. All these compounds were tested for their NO production inhibitory activity in LPS-stimulated RAW 264.7 cells. Results showed that these C21 steroidal glycosides could remarkably inhibit NO production, particularly 1 and 2 with IC50 values of 30.81 ± 0.18 µM and 44.39 ± 0.21 µM, respectively. In addition, the cytotoxicity of these compounds was measured on A549, MCF-7, and HeLa cancer cell lines. Among them, compounds 1 and 7 displayed cytotoxicity against the A549 cell line with IC50 values of 28.41 ± 0.12 µM and 39.06 ± 0.05 µM, respectively.

Electrochemical ammonia synthesis under ambient conditions using TM-embedded porphine-fused sheets as single-atom catalysts.

In this research, we systematically investigated the reaction mechanism and electrocatalytic properties of transition metal anchored two-dimensional (2D) porphine-fused sheets (TM-Por) as novel single-atom catalysts (SACs) for the electrochemical nitrogen reduction reaction (eNRR) under ambient conditions. Using high-throughput screening and first-principles calculations based on the density functional theory (DFT) method, three eNRR catalyst candidates, i.e. Mo-Por, Tc-Por, and Nb-Por, were screened out, with the eNRR onset potentials on them being -0.36, -0.53, and -0.74 V, respectively. Furthermore, these catalyst candidates all have good stability and selectivity. Analyzing the band structures found that these catalyst candidates all are metallic, which is needed for good electrocatalysts. Ab initio molecular dynamics (AIMD) simulations show that these catalyst candidates have good stability at 500 K. It is hoped that our work will open up new possibilities for the experimental synthesis of electrochemical ammonia catalysts.

Field test of quantum key distribution with high key creation efficiency.

Quantum key distribution (QKD) promises unconditional security for communication. However, the random choices of the measurement basis in QKD usually result in low key creation efficiency. This drawback is overcome in the differential-phase-shift QKD, provided that each photon can be prepared in a large number of time slots with a proper waveform. In this work we develop a miniature room-temperature 1550-nm single-photon source to generate narrowband single photon in 50 time slots with a nearly optimal waveform for achieving unity key creation efficiency. By utilizing these single photons in the field test, we demonstrate the differential-phase-shift QKD with a key creation efficiency of 97%. Our work shows that the practical QKD can benefit from the narrowband single photons with controllable waveforms.

An IgM-like inhalable ACE2 fusion protein broadly neutralizes SARS-CoV-2 variants.

Many of the currently available COVID-19 vaccines and therapeutics are not effective against newly emerged SARS-CoV-2 variants. Here, we developed the metallo-enzyme domain of angiotensin converting enzyme 2 (ACE2)-the cellular receptor of SARS-CoV-2-into an IgM-like inhalable molecule (HH-120). HH-120 binds to the SARS-CoV-2 Spike (S) protein with high avidity and confers potent and broad-spectrum neutralization activity against all known SARS-CoV-2 variants of concern. HH-120 was developed as an inhaled formulation that achieves appropriate aerodynamic properties for rodent and monkey respiratory system delivery, and we found that early administration of HH-120 by aerosol inhalation significantly reduced viral loads and lung pathology scores in male golden Syrian hamsters infected by the SARS-CoV-2 ancestral strain (GDPCC-nCoV27) and the Delta variant. Our study presents a meaningful advancement in the inhalation delivery of large biologics like HH-120 (molecular weight (MW) ~ 1000 kDa) and demonstrates that HH-120 can serve as an efficacious, safe, and convenient agent against SARS-CoV-2 variants. Finally, given the known role of ACE2 in viral reception, it is conceivable that HH-120 has the potential to be efficacious against additional emergent coronaviruses.

The Effect of Alkali Metals (Li, Na, and K) on Ni/CaO Dual-Functional Materials for Integrated CO2 Capture and Hydrogenation.

Ni/CaO, a low-cost dual-functional material (DFM), has been widely studied for integrated CO2 capture and hydrogenation. The core of this dual-functional material should possess both good CO2 capture-conversion performance and structural stability. Here, we synthesized Ni/CaO DFMs modified with alkali metals (Na, K, and Li) through a combination of precipitation and combustion methods. It was found that Na-modified Ni/CaO (Na-Ni/CaO) DFM offered stable CO2 capture-conversion activity over 20 cycles, with a high CO2 capture capacity of 10.8 mmol/g and a high CO2 conversion rate of 60.5% at the same temperature of 650 °C. The enhanced CO2 capture capacity was attributed to the improved surface basicity of Na-Ni/CaO. In addition, the incorporation of Na into DFMs had a favorable effect on the formation of double salts, which shorten the CO2 capture and release process and promoted DFM stability by hindering their aggregation and the sintering of DFMs.

Female Pattern Hair Loss: An Overview with Focus on the Genetics.

Pattern hair loss can occur in both men and women, and the underlying molecular mechanisms have been continuously studied in recent years. Male androgenetic alopecia (M-AGA), also termed male pattern hair loss, is the most common type of hair loss in men. M-AGA is considered an androgen-dependent trait with a background of genetic predisposition. The interplay between genetic and non-genetic factors leads to the phenotype of follicular miniaturization. Although this similar pattern of phenotypic miniaturization can also be found in female pattern hair loss (FPHL), the corresponding genetic factors in M-AGA do not account for the phenotype in FPHL, indicating that there are different genes contributing to FPHL. Therefore, the role of genetic factors in FPHL is still uncertain. Understanding the genetic mechanism that causes FPHL is crucial for the future development of personalized treatment strategies. This review aims to highlight the differences in the ethnic prevalence and genetic background of FPHL, as well as the current genetic research progress in nutrition, Wnt signaling, and sex hormones related to FPHL.

Ravoxertinib Improves Long-Term Neurologic Deficits after Experimental Subarachnoid Hemorrhage through Early Inhibition of Erk1/2.

Extracellular signal-regulated kinase 1 and 2 (Erk1/2) signaling has been shown to be involved in brain injury after subarachnoid hemorrhage (SAH). A first-in-human phase I study reported that ravoxertinib hydrochloride (RAH), a novel Erk1/2 inhibitor, has an acceptable safety profile and pharmacodynamic effects. Here, we showed that the level of Erk1/2 phosphorylation (p-Erk1/2) was significantly increased in the cerebrospinal fluid (CSF) of aneurysmal subarachnoid hemorrhage (aSAH) patients who developed poor outcomes. In a rat SAH model that was produced by the intracranial endovascular perforation method, western blot observed that the level of p-Erk1/2 was also increased in the CSF and basal cortex, showing a similar trend with aSAH patients. Immunofluorescence and western blot indicated that RAH treatment (i.c.v injection, 30 min post-SAH) attenuates the SAH-induced increase of p-Erk1/2 at 24 h in rats. RAH treatment can improve experimental SAH-induced long-term sensorimotor and spatial learning deficits that are evaluated by the Morris water maze, rotarod test, foot-fault test, and forelimb placing test. Moreover, RAH treatment attenuates neurobehavioral deficits, the blood-brain barrier damage, and cerebral edema at 72 h after SAH in rats. Furthermore, RAH treatment decreases the SAH-elevated apoptosis-related factor active caspase-3 and the necroptosis-related factor RIPK1 expression at 72 h in rats. Immunofluorescence analysis showed that RAH attenuated neuronal apoptosis but not neuronal necroptosis in the basal cortex at 72 h after SAH in rats. Altogether, our results suggest that RAH improves long-term neurologic deficits through early inhibition of Erk1/2 in experimental SAH.