DMFGAN: a multifeature data augmentation method for grape leaf disease identification.

The use of deep learning techniques to identify grape leaf diseases relies on large, high-quality datasets. However, a large number of images occupy more computing resources and are prone to pattern collapse during training. In this paper, a depth-separable multifeature generative adversarial network (DMFGAN) was proposed to enhance grape leaf disease data. First, a multifeature extraction block (MFEB) based on the four-channel feature fusion strategy is designed to improve the quality of the generated image and avoid the problem of poor feature learning ability of the adversarial generation network caused by the single-channel feature extraction method. Second, a depth-based D-discriminator is designed to improve the discriminator capability and reduce the number of model parameters. Third, SeLU activation function was substituted for DCGAN activation function to overcome the problem that DCGAN activation function was not enough to fit grape leaf disease image data. Finally, an MFLoss function with a gradient penalty term is proposed to reduce the mode collapse during the training of generative adversarial networks. By comparing the visual indicators and evaluation indicators of the images generated by different models, and using the recognition network to verify the enhanced grape disease data, the results show that the method is effective in enhancing grape leaf disease data. Under the same experimental conditions, DMFGAN generates higher quality and more diverse images with fewer parameters than other generative adversarial networks. The mode breakdown times of generative adversarial networks in training process are reduced, which is more effective in practical application.

Maternal medically diagnosed infection and antibiotic prescription during pregnancy and risk of childhood cancer: A population-based cohort study in Taiwan, 2004 to 2015.

While associations between maternal infections during pregnancy and childhood leukemia in offspring have been extensively studied, the evidence for other types of childhood cancers is limited. Additionally, antibiotic exposure during pregnancy could potentially increase the risk of childhood cancers. Our study investigates associations between maternal infections and antibiotic prescriptions during pregnancy and the risk of childhood cancer in Taiwan. We conducted a population-based cohort study using the Taiwan Maternal and Child Health Database (TMCHD), linked with national health and cancer registries. The study included 2 267 186 mother-child pairs, and the median follow-up time was 7.96 years. Cox proportional hazard models were utilized to estimate effects. Maternal infections during pregnancy were associated with a moderate increase in the risk of childhood hepatoblastoma (adjusted hazard ratio [HR] = 1.34; 95% confidence interval [CI]: 0.90-1.98) and a weaker increase in the risk of childhood acute lymphoblastic leukemia (ALL) (adjusted HR = 1.15; 95% CI: 0.99-1.35). Antibiotic prescriptions during pregnancy were also associated with an elevated risk of childhood ALL (adjusted HR = 1.30; 95% CI: 1.04-1.63), particularly with tetracyclines (adjusted HR = 2.15; 95% CI: 1.34-3.45). Several specific antibiotics were also associated with an increased risk of hepatoblastoma and medulloblastoma. Children exposed in utero to antibiotic prescription or both infections and antibiotics during pregnancy were at higher risk of developing ALL. Our findings suggest that there are associations between maternal infections, antibiotic use during pregnancy and the risk of several childhood cancers in addition to ALL and highlight the importance of further research in this area.

Involvement of CD44 and MAPK14-mediated ferroptosis in hemorrhagic shock.

To elucidate the induction of ferroptotic pathways and the transcriptional modulation of pivotal genes in the context of hemorrhagic shock. The R software was used to analyze the GSE64711 dataset, isolating genes relevant to ferroptosis. Enrichment analyses and protein interaction networks were assembled. Using WGCNA hub genes were identified and intersected with ferroptosis-related genes, highlighting hub genes CD44 and MAPK14. In a rat hemorrhagic shock model, cardiac ROS, Fe2+, MDA, and GSH levels were assessed. Key ferroptotic proteins (SLC7A11/GPX4) in myocardial tissues were examined via western blot. Hub genes, CD44 and MAPK14, expressions were confirmed through immunohistochemistry. Analyzing the GSE64711 dataset revealed 337 differentially expressed genes, including 12 linked to ferroptosis. Enrichment analysis highlighted pathways closely related to ferroptosis. Using Genemania, we found these genes mainly affect ROS metabolism and oxidative stress response. WGCNA identified CD44 and MAPK14 as hub genes. Rat myocardial tissue validation showed significant cardiac damage and elevated ROS and MDA levels, and decreased GSH levels in the hemorrhagic shock model. The ferroptotic pathway SLC7A11/GPX4 was activated, and immunohistochemistry showed a significant increase in the expression levels of CD44 and MAPK14 in the hemorrhagic shock rat model. We demonstrated the presence of tissue ferroptosis in hemorrhagic shock by combining bioinformatics analysis with in vivo experimentation. Specifically, we observed the activation of the SLC7A11/GPX4 ferroptotic pathway. Further, CD44 and MAPK14 were identified as hub genes in hemorrhagic shock.

Effects of hypertension and use of antihypertensive drugs in pregnancy on the risks of childhood cancers in Taiwan.

BACKGROUND: Childhood cancers are associated with high mortality and morbidity, and some maternal prescription drug use during pregnancy has been implicated in cancer risk. There are few studies on the effects of hypertension, preeclampsia, and the use of antihypertensives in pregnancy on children's cancer risks. OBJECTIVE: This population-based cohort study analyzed the relationship between hypertension, preeclampsia, and antihypertensives taken during pregnancy and the risks of childhood cancers in the offspring. METHODS: Data on all children born in Taiwan between 2004 and 2015 (N = 2,294,292) were obtained from the Maternal and Child Health Database. This registry was linked with the National Health Insurance Database and Cancer Registry to get the records of maternal use of diuretics or other antihypertensives in pregnancy and records of children with cancer diagnosed before 13 years. We used Cox proportional hazard modeling to estimate the influence of maternal health conditions and antihypertensive drug exposure on the risks of developing childhood cancers. RESULTS: Offspring of mothers with hypertension (chronic or gestational) had a higher risk of acute lymphocytic lymphoma [hazard ratio (HR) = 1.87, 95% Confidence Interval (CI) 1.32 - 2.65] and non-Hodgkin's lymphoma (HR = 1.96, 95% CI 1.34 - 2.86). We estimated only a weak increased cancer risk in children whose mothers used diuretics (HR = 1.16, 95% CI 0.77 - 1.74) or used antihypertensives other than diuretics (HR = 1.15, 95% CI 0.86 - 1.54) before birth. CONCLUSIONS: In this cohort study, children whose mothers had chronic and gestational hypertension had an increased risk of developing childhood cancer.

From "wet" matrices to "dry" blood spot sampling strategy: a versatile LC-MS/MS assay for simultaneous monitoring caffeine and its three primary metabolites in preterm infants.

OBJECTIVES: To update traditional "wet" matrices to dried blood spot (DBS) sampling, based on the liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) technique, and develop a method for simultaneous analyzing caffeine and its three primary metabolites (theobromine, paraxanthine, and theophylline), supporting routine therapeutic drug monitoring (TDM) for preterm infants. METHODS: DBS samples were prepared by a two-step quantitative sampling method, i.e., volumetric sampling of a quantitative 10 µL volume of peripheral blood and an 8 mm diameter whole punch extraction by a methanol/water (80/20, v/v) mixture containing 125 mM formic acid. Four paired stable isotope labeled internal standards and a collision energy defect strategy were applied for the method optimization. The method was fully validated following international guidelines and industrial recommendations on DBS analysis. Cross validation with previously developed plasma method was also proceeded. The validated method was then implemented on the TDM for preterm infants. RESULTS: The two-step quantitative sampling strategy and a high recovery extraction method were developed and optimized. The method validation results were all within the acceptable criteria. Satisfactory parallelism, concordance, and correlation were observed between DBS and plasma concentrations of the four analytes. The method was applied to provide routine TDM services to 20 preterm infants. CONCLUSIONS: A versatile LC-MS/MS platform for simultaneous monitoring caffeine and its three primary metabolites was developed, fully validated, and successfully applied into the routine clinical TDM practices. Sampling method switching from "wet" matrices to "dry" DBS will facilitate and support the precision dosing of caffeine for preterm infants.

A national-wide survey on clinical implementation of PGx testing into precision therapeutics for Chinese children: a long way before standard clinical practice.

BACKGROUND: Pharmacogenetics/pharmacogenomics (PGx) focuses on the genetic variation that causes the heterogeneity of pharmacokinetics and drug response among individuals and has the potential to predict individual efficacy and/or side effects. This study aims to investigate and understand the implementation of genetic testing for the personalized medication (GTPM) in children's hospitals in Mainland China. METHODS: A survey was conducted on 50 children's hospitals from 31 provinces, municipalities, and autonomous regions across Mainland China, and statistical analysis and recommendations were made. RESULTS: Questionnaire response was rate of 76.0% (38/50). Data from 15 hospitals conducting GTPM were included in this study, but only 6 hospitals had offered PGx tests for no less than five drug-related genes, and only 5 hospitals had covered more than ten drugs, which was a small scale overall. 20.0% of the laboratories did not conduct internal quality control, and 33.3% did not participate in inter-laboratory quality assessment. 46.7% of the practitioners did not receive external training. The primary goal for GTPM was to optimize drug dosage in the 15 hospitals, while the main challenge for GTPM was the implementation cost. CONCLUSION: Although GTPM in pediatrics has made major progress in Mainland China in recent years, there were still various problems in terms of software, hardware configuration, personnel allocation, business scale, quality control, and result interpretation. This requires joint efforts of health administration, medical insurance departments, researchers, and hospitals to promote and improve GTPM.

Strategies for subtyping primary aldosteronism.

Adrenal venous sampling (AVS) is a crucial method for the lateralization of primary aldosteronism (PA). It is advised to halt the use of the patient's antihypertensive medications and correct hypokalemia prior to undergoing AVS. Hospitals equipped to conduct AVS should establish their own diagnostic criteria based on current guidelines. If the patient's antihypertensive medications cannot be discontinued, AVS can be performed as long as the serum renin level is suppressed. The Task Force of Taiwan PA recommends using a combination of adrenocorticotropic hormone stimulation, quick cortisol assay, and C-arm cone-beam computed tomography to maximize the success of AVS and minimize errors by using the simultaneous sampling technique. If AVS is not successful, an NP-59 (131 I-6-ß-iodomethyl-19-norcholesterol) scan can be used as an alternative method to lateralize PA. We depicted the details of the lateralization procedures (mainly AVS, and alternatively NP-59) and their tips and tricks for confirmed PA patients who would consider to undergo surgical treatment (unilateral adrenalectomy) if the subtyping shows unilateral disease.

The role of confirmatory tests in the diagnosis of primary aldosteronism.

Confirmatory tests for diagnosis of primary aldosteronism (PA) play an important role in sparing patients with a false-positive aldosterone-to-renin ratio (ARR) screening test from undergoing invasive subtyping procedures. We recommend that patients with a positive ARR test should undergo at least one confirmatory test to confirm or exclude the diagnosis of PA before directly proceeding to subtype studies, except for patients with significant PA phenotypes, including spontaneous hypokalemia, plasma aldosterone concentration >20 ng/dL plus plasma renin activity below a detectable level. Although a gold standard confirmatory test has not been identified, we recommend that saline infusion test and captopril challenge test, which were widely used in Taiwan. Patients with PA have been reported to have a higher prevalence of concurrent autonomous cortisol secretion (ACS). ACS is a biochemical condition of mild cortisol overproduction from adrenal lesions, but without the typical clinical features of overt Cushing's syndrome. Concurrent ACS may result in incorrect interpretation of adrenal venous sampling (AVS) and may lead to adrenal insufficiency after adrenalectomy. We recommend screening for ACS in patients with PA scheduled for AVS examinations as well as for adrenalectomy. We recommend the 1-mg overnight dexamethasone suppression test as screening method to detect ACS.

All-Cause and Cause-Specific Mortality in Parents After the Death of a Child in Taiwan: A Population-Based Cohort Study.

OBJECTIVE: Research from Western countries suggests that there is an increase in mortality in parents bereaved by the death of a child. Few studies have investigated this issue in a non-Western context. We explored the impact of the death of a child on parental mortality in Taiwan. METHOD: By linking population-based national registers, we followed the 2004-2014 birth cohort ( N = 2,083,972) up until 2016. A total of 11,755 child deaths were identified. For each deceased child, four living children matched on age and sex were randomly selected; their parents were the comparison group. We used Cox proportional hazards regression models to compare the mortality risk of bereaved parents with the comparison group up until 2017. RESULTS: Overall mortality risk was increased in parents who experienced the death of a child; the risk was higher in bereaved mothers (adjusted hazard ratio = 4.91, 95% confidence interval = 3.96-6.09) than fathers (adjusted hazard ratio = 1.82, 95% confidence interval = 1.55-2.13). The risk did not differ according to the sex of the child, but parents whose children died of unexpected causes (i.e., suicide/accidents/violence) were at greater risk than those dying of other causes. Risk was higher when the child was older than 1 year at the time of death than for deaths before age 1 year. CONCLUSIONS: Parents who lost a child were at increased mortality risk in this East Asian population. Special attention should be paid to the health of bereaved parents and explore the pathways leading to their risk.

CaMKII and CaV3.2 T-type calcium channel mediate Connexin-43-dependent inflammation by activating astrocytes in vincristine-induced neuropathic pain.

Vincristine (VCR), an alkaloid isolated from vinca, is a commonly used chemotherapeutic drug. However, VCR therapy can lead to dose-dependent peripheral neurotoxicity, mainly manifesting as neuropathic pain, which is one of the dominant reasons for limiting its utility. Experimentally, we discovered that VCR-induced neuropathic pain (VINP) was accompanied by astrocyte activation; the upregulation of phospho-CaMKII (p-CaMKII), CaV3.2, and Connexin-43 (Cx43) expression; and the production and release of inflammatory cytokines and chemokines in the spinal cord. Similar situations were also observed in astrocyte cultures. Interestingly, these alterations were all reversed by intrathecal injection of KN-93 (a CaMKII inhibitor) or L-Ascorbic acid (a CaV3.2 inhibitor). In addition, KN-93 and L-Ascorbic acid inhibited the increase in [Ca2+]i associated with astrocyte activation. We also verified that knocking down or inhibiting Cx43 level via intrathecal injection of Cx43 siRNA or Gap27 (a Cx43 mimetic peptide) relieved pain hypersensitivity and reduced the release of inflammatory factors; however, they did not affect astrocyte activation or p-CaMKII and CaV3.2 expression. Besides, the overexpression of Cx43 through the transfection of the Cx43 plasmid did not affect p-CaMKII and CaV3.2 expressions in vitro. Therefore, CaMKII and CaV3.2 may activate astrocytes by increasing [Ca2+]i, thereby mediating Cx43-dependent inflammation in VINP. Moreover, we demonstrated that the CaMKII signalling pathway was involved in VCR-induced inflammation, apoptosis, and mitochondrial damage. Collectively, our findings show a novel mechanism by which CaMKII and CaV3.2 mediate Cx43-dependent inflammation by activating astrocytes in neuropathic pain induced by VCR.

Personalizing atomoxetine dosing in children with ADHD: what can we learn from current supporting evidence.

PURPOSE: There is marked heterogeneity in treatment response of atomoxetine in patients with attention deficit/hyperactivity disorder (ADHD), especially for the pediatric population. This review aims to evaluate current evidence to characterize the dose-exposure relationship, establish clinically relevant metrics for systemic exposure to atomoxetine, define a therapeutic exposure range, and to provide a dose-adaptation strategy before implementing personalized dosing for atomoxetine in children with ADHD. METHODS: A comprehensive search was performed across electronic databases (PubMed and Embase) covering the period of January 1, 1985 to July 10, 2022, to summarize recent advances in the pharmacokinetics, pharmacogenomics/pharmacogenetics (PGx), therapeutic drug monitoring (TDM), physiologically based pharmacokinetics (PBPK), and population pharmacokinetics (PPK) of atomoxetine in children with ADHD. RESULTS: Some factors affecting the pharmacokinetics of atomoxetine were summarized, including food, CYP2D6 and CYP2C19 phenotypes, and drug‒drug interactions (DDIs). The association between treatment response and genetic polymorphisms of genes encoding pharmacological targets, such as norepinephrine transporter (NET/SLC6A2) and dopamine ß hydroxylase (DBH), was also discussed. Based on well-developed and validated assays for monitoring plasma concentrations of atomoxetine, the therapeutic reference range in pediatric patients with ADHD proposed by several studies was summarized. However, supporting evidence on the relationship between systemic atomoxetine exposure levels and clinical response was far from sufficient. CONCLUSION: Personalizing atomoxetine dosage may be even more complex than anticipated thus far, but elucidating the best way to tailor the non-stimulant to a patient's individual need will be achieved by combining two strategies: detailed research in linking the pharmacokinetics and pharmacodynamics in pediatric patients, and better understanding in nature and causes of ADHD, as well as environmental stressors.

Proactive therapeutic drug monitoring of vincristine in pediatric and adult cancer patients: current supporting evidence and future efforts.

Vincristine (VCR), an effective antitumor drug, has been utilized in several polytherapy regimens for acute lymphoblastic leukemia, neuroblastoma and rhabdomyosarcoma. However, clinical evidence shows that the metabolism of VCR varies greatly among patients. The traditional based body surface area (BSA) administration method is prone to insufficient exposure to VCR or severe VCR-induced peripheral neurotoxicity (VIPN). Therefore, reliable strategies are urgently needed to improve efficacy and reduce VIPN. Due to the unpredictable pharmacokinetic changes of VCR, therapeutic drug monitoring (TDM) may help to ensure its efficacy and to manage VIPN. At present, there is a lot of supporting evidence for the suitability of applying TDM to VCR therapy. Based on the consensus guidelines drafted by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT), this review aimed to summarize various available data to evaluate the potential utility of VCR TDM for cancer patients. Of note, valuable evidence has accumulated on pharmacokinetics variability, pharmacodynamics, drug exposure-clinical response relationship, biomarkers for VIPN prediction, and assays for VCR monitoring. However, there are still many relevant clinical pharmacological questions that cannot yet be answered merely based on insufficient evidence. Currently, we cannot recommend a therapeutic exposure range and cannot yet provide a dose-adaptation strategy for clinicians and patients. In areas where the evidence is not yet sufficient, more research is needed in the future. The precision medicine of VCR cannot rely on TDM alone and needs to consider the clinical, environmental, genetic background and patient-specific factors as a whole.

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Atomoxetine is the first non-stimulant drug for the treatment of children and adults with attention deficit hyperactivity disorder (ADHD), and its safety and efficacy show significant differences in the pediatric population. This article reviews the genetic factors influencing the pharmacokinetic differences of atomoxetine from the aspect of the gene polymorphisms of the major metabolizing enzyme CYP2D6 of atomoxetine, and then from the perspective of therapeutic drug monitoring, this article summarizes the reference ranges of the effective concentration of atomoxetine in children with ADHD proposed by several studies. In general, there is an association between the peak plasma concentration of atomoxetine and clinical efficacy, but with a lack of data from the Chinese pediatric population. Therefore, it is necessary to establish related clinical indicators for atomoxetine exposure, define the therapeutic exposure range of children with ADHD in China, and combine CYP2D6 genotyping to provide support for the precision medication of atomoxetine.

Population pharmacokinetic modeling of caffeine in preterm infants with apnea of prematurity: New findings from concomitant erythromycin and AHR genetic polymorphisms.

Current standard-dose caffeine therapy results in significant intersubject variability. The aims of this study were to develop and evaluate population pharmacokinetic (PPK) models of caffeine in preterm infants through comprehensive screening of covariates and then to propose model-informed precision dosing of caffeine for this population. A total of 129 caffeine concentrations from 96 premature neonates were incorporated into this study. Comprehensive medical record and genotype data of these neonates were collected for analysis. PPK modeling was performed by a nonlinear mixed effects modeling program (NONMEM). Final models based on the current weight (CW) or body surface area (BSA) were evaluated via multiple graphic and statistical methods. The model-informed dosing regimen was performed through Monte Carlo simulations. In addition to CW or BSA, postnatal age, coadministration with erythromycin (ERY), and aryl hydrocarbon receptor coding gene (AHR) variant (rs2158041) were incorporated into the final PPK models. Multiple evaluation results showed satisfactory prediction performance and stability of the CW- and BSA-based models. Monte Carlo simulations demonstrated that trough concentrations of caffeine in preterm infants would be affected by concomitant ERY therapy and rs2158041 under varying dose regimens. For the first time, ERY and rs2158041 were found to be associated with the clearance of caffeine in premature infants. Similar predictive performance and stability were obtained for both CW- and BSA-based PPK models. These findings provide novel insights into caffeine precision therapy for preterm infants.

Therapeutic effects of JLX001 on neuronal necroptosis after cerebral ischemia-reperfusion in rats.

In recent years, more attention has been given to novel patterns of cell death observed during ischemia/reperfusion (I/R). Necroptosis is a regulable secondary cell death pathway; necroptosis is different from traditional forms of cell death, and it is regulated by the RIPK1-RIPK3-MLKL signaling pathway. JLX001 is the double hydrochloride of the natural compound cyclovirobuxine D (CVB-D). Previous studies have confirmed that CVB-D exerts a significant effect on cardiovascular and cerebrovascular diseases and that JLX001 can reduce ischemic brain injury by inhibiting cell apoptosis. For the first time, this project explored the in vivo and in vitro inhibitory effects of the therapeutic administration of JLX001 on the neuronal necroptosis caused by cerebral ischemia-reperfusion injury (CIRI). The middle cerebral artery occlusion reperfusion (MCAO/R) model was used to simulate I/R injury in rats in vivo, and oxygen-glucose deprivation and reperfusion (OGD/R) was used to simulate I/R injury in vitro. After the administration of JLX001, the relative expression of necroptosis-related molecules was measured by ELISA, RT-PCR, HE staining, immunofluorescence and Western blotting. The results showed that JLX001 significantly reduced pathological damage and the cerebral infarction rate in rat brain tissues, and the expression of neuronal necroptosis-related molecules was reduced, suggesting that JLX001 may regulate CIRI through the classic RIPK1-RIPK3-MLKL necroptosis pathway.

Therapeutic drug monitoring of caffeine and its primary metabolites in plasma using LC-ESI-MS/MS for apnea of prematurity treatment: Evaluation of ultrapure water as a surrogate matrix.

The growing evidence has endorsed the view that therapeutic drug monitoring of caffeine for apnea of prematurity is helpful for dose tailoring when the therapeutic response is lacking or toxicity is suspected. However, plasma without caffeine is difficult to obtain. Therefore, a method was developed and validated to measure caffeine and its three primary metabolites (paraxanthine, theobromine and theophylline) using LC-ESI-MS/MS in human plasma and several surrogate matrices. The chromatographic separation of analytes was finally achieved on a Waters Symmetry C18 (4.6 × 75 mm, 3.5 µm) column. Several strategies were successfully applied to overcome the matrix effects: (a) appropriate dilution for sample cleanup; (b) a starting lower proportion of organic phase; and (c) multiple individual stable-labeled isotopic internal standards. The parallelism between the authentic matrix and surrogate matrices was convincing. The recovery of the analytes in both human plasma and rat plasma was acceptable over the linear range (0.500-50.0 µg/ml for caffeine and 0.0100-1.00 µg/ml for three metabolites). The method was successfully applied in 118 samples from 74 preterm infants with apnea of prematurity. The rat plasma or ultrapure water as a surrogate matrix is worthy of recommendation for routine therapeutic drug monitoring of caffeine.

An LC-ESI-MS/MS assay for the therapeutic drug monitoring of 15 antiseizure medications in plasma of children with epilepsy.

Oral antiseizure medications are the preferred option for the clinical treatment of epilepsy. Therapeutic drug monitoring has become an important means of achieving individualized treatment of epilepsy. A sensitive, accurate and rapid LC-ESI-MS/MS method was developed and validated for the simultaneous determination of 15 antiseizure medications in human plasma (carbamazepine, gabapentin, pregabalin, phenytoin, zonisamide, oxcarbazepine, tiagabine, lamotrigine, topiramate, phenobarbital, lacosamide, primidone, 10,11-Dihydro-10-hydroxy carbamazepine, ethosuximide, and levetiracetam). The sample preparation procedure was an one-step protein precipitation with methanol. Mass detection was performed in ionization polarity switching mode (positive-negative-positive) using multiple reaction monitoring mode. A "boot-shaped" gradient elution program was applied to separate and concentrate those target analytes, resulting in symmetrical peak shapes within 10 min, without endogenous interference. The method showed great linearity over the concentration ranges with acceptable correlation coefficients (0.9966-0.9996). The precision and accuracy values for intra- and inter-assays were within ±15%. Consequently, the method was successfully implemented on pediatric patients undergoing mono- or polytherapy for epilepsy and provided timely concentration results to ordering clinicians.

Oxidative Stress and Antioxidative Therapy in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is clinically characterized by a progressive increase in pulmonary artery pressure, followed by right ventricular hypertrophy and subsequently right heart failure. The underlying mechanism of PAH includes endothelial dysfunction and intimal smooth muscle proliferation. Numerous studies have shown that oxidative stress is critical in the pathophysiology of PAH and involves changes in reactive oxygen species (ROS), reactive nitrogen (RNS), and nitric oxide (NO) signaling pathways. Disrupted ROS and NO signaling pathways cause the proliferation of pulmonary arterial endothelial cells (PAECs) and pulmonary vascular smooth muscle cells (PASMCs), resulting in DNA damage, metabolic abnormalities, and vascular remodeling. Antioxidant treatment has become a main area of research for the treatment of PAH. This review mainly introduces oxidative stress in the pathogenesis of PAH and antioxidative therapies and explains why targeting oxidative stress is a valid strategy for PAH treatment.

The splicing factor SRSF1 stabilizes the mRNA of TSLP to enhance acute lung injury.

Acute lung injury (ALI) is a severe disease with a high rate of morbidity and mortality, characterized by excessive and uncontrolled inflammatory response in lung. Recent studies demonstrated that serine arginine-rich splicing factor 1 (SRSF1) is involved in inflammation. However, whether SRSF1 modulates ALI remains to be determined. In this study, we established an ALI mouse model that induced by lipopolysaccharide (LPS), with or without the treatment of SRSF1 antibody. Our result showed that SRSF1 expression was elevated in LPS-induced ALI. Importantly, treatment with SRSF1 antibody notably ameliorated ALI in mice, as determined by reduction in lung W/D ratios, histopathological changes, lung inflammation and TSLP expression. Besides, exposure of human alveolar epithelial A549 cells to LPS enhanced the expression of both SRSF1 and TSLP, while knockdown or overexpression of SRSF1 significantly lowered or upregulated the expression of TSLP induced by LPS. Interestingly, the expression of SRSF1 and TSLP showed a positive correlation in normal human lung tissues. Mechanistically, we found that SRSF1 directly bound with the mRNA of TSLP and may exert its function by stabilizing the mRNA of TSLP in LPS-induced ALI. Therefore, our results indicated that SRSF1 may be an important contributor in lung inflammation of LPS-induced ALI and SRSF1 signaling blocking may serve as a potential treatment of ALI.

Corin plays a protective role via upregulating MAPK and downregulating eNOS in diabetic nephropathy endothelial dysfunction.

Diabetic nephropathy (DN) is one of the leading causes of mortality in diabetic patients, but its pathogenesis is unclear. We aimed to study the role of the pro-ANP convertase Corin in the pathogenesis of DN. Corin and ANP expression in DN rat kidneys and high-glucose-treated HK-2 cells was analyzed by real-time PCR, western blotting, and immunohistochemical staining. The effect of Corin-siRNA or ANP-siRNA HK-2 cells on EA.hy926 cell migration was determined by scratch-wound healing assay. The expression of mitogen-activated protein kinase (MAPK) and endothelial NO synthase (eNOS) in EA.hy926 cells treated with conditioned medium from Corin-siRNA- or ANP-siRNA-transfected HK-2 cells was determined by western blotting. We found a significant reduction in Corin and ANP expression in DN rat kidneys. These results were recapitulated in HK-2 cells treated with high glucose. EA.hy926 cells treated with conditioned medium from Corin-deficient HK-2 cells had inhibited migration, increased MAPK activity, and decreased eNOS activity. Similar effects were observed with ANP-siRNA transfection. Finally, adding ANP to the Corin-deficient HK-2 conditioned medium rescued the above defects, indicating that Corin mediates its effects through ANP. In conclusion, Corin plays a renoprotective role through pro-ANP processing, and defects in Corin cause endothelial dysfunction through MAPK and eNOS signaling in DN.