Novel prognostic impact and cell specific role of endocan in patients with coronary artery disease.

BACKGROUND: Both the clinical and mechanistic impacts of endocan were not well elucidated especially in coronary artery disease (CAD). OBJECTIVE: This study aimed to investigate the prognostic and potential pathological role of endocan for cardiovascular (CV) events in stable CAD patients. METHODS: A total of 1,071 stable CAD patients with previous percutaneous coronary intervention (PCI) were enrolled prospectively in a nationwide Biosignature study. Another cohort of 76 CAD patients with or without PCI were enrolled for validation. Baseline biomarkers including endocan level was measured and total CV events especially hard CV events (including CV mortality, non-fatal myocardial infection and stroke) during follow-up were identified. Circulating endothelial progenitor cells (EPCs) as an in vivo biological contributor to vascular repairment from CAD patients were used for the in vitro functional study. RESULTS: After 24 months, there were 42 patients (3.92%) with hard CV events and 207 (19.3%) with total CV events in the study group. The incidence of both events was increased with the tertiles of baseline endocan level (hard events: 1.7%,3.4%, and 6.7% in 1st,2nd, and 3rd tertile respectively, p = 0.002; total events: 13.8%vs.16.2%vs.28.0%, p < 0.0001). Multivariate regression analysis revealed the independent association of endocan level with total and hard CV events. These findings were validated in another cohort with a 5-year follow-up. Furthermore, in vitro inhibition of endocan improved cell migration and tube formation capacities, and reduced cell adhesiveness of EPCs from CAD patients. CONCLUSIONS: Endocan might be a novel prognostic indicator, mechanistic mediator, and potential therapeutic target for clinical CAD.

CCL4 contributes to aging related angiogenic insufficiency through activating oxidative stress and endothelial inflammation.

Aging is a natural process associated with chronic inflammation in the development of vascular dysfunction. We hypothesized that chemokine C-C motif ligands 4 (CCL4) might play a vital role in aging-related vascular dysfunction. Circulating CCL4 was up-regulated in elderly subjects and in aged animals. CCL4 inhibition reduced generation of reactive oxygen species (ROS), attenuated inflammation, and restored cell functions in endothelial progenitor cells from elderly subjects and in aged human aortic endothelial cells. CCL4 promoted cell aging, with impaired cell functioning, by activating ROS production and inflammation. CCL4 knockout mice and therapeutic administration of anti-CCL4 neutralizing antibodies exhibited vascular and dermal anti-aging effects, with improved wound healing, via the down-regulation of inflammatory proteins and the activation of angiogenic proteins. Altogether, our findings suggested that CCL4 may contribute to aging-related vascular dysfunction via activating oxidative stress and endothelial inflammation. CCL4 may be a potential therapeutic target for vascular protections during aging.

Soluble tumor necrosis factor receptor type 1 is an alternative marker of urinary albumin-creatinine ratio and estimated glomerular filtration rate for predicting the decline of renal function in subjects with type 2 diabetes mellitus.

BACKGROUND: Urinary albumin-creatinine ratio (UACR) and estimated glomerular filtration rates (eGFR) help predict worsening diabetic kidney disease (DKD) but have their limitations. Soluble tumor necrosis factor receptor type 1 (sTNFR1) is a biomarker of DKD. The predictive abilities of sTNFR1 and UACR plus eGFR have not been compared. METHODS: This prospective cohort study included patients with type 2 diabetes (T2D) to identify the risk factors of worsening DKD. Renal events were defined as > 30 % loss in eGFR based on consecutive tests after 6 months. The associations of sTNFR1, UACR, and eGFR levels and the risks of renal events were tested using a Cox regression model and the area under the curve (AUC) was compared between sTNFR1 levels and UACR plus eGFR using receiver-operating characteristic (ROC) analysis. The accuracy of stratification was evaluated using Kaplan-Meier analysis. RESULTS: Levels of sTNFR1 and UACR were associated with risks of > 30 % decline in eGFR after adjusting for relevant factors. The association between sTNFR1 levels and renal outcomes was independent of UACR and eGFR at baseline. The AUC of sTNFR1 level was comparable with that of combined UACR and eGFR (0.73 vs. 0.71, respectively, p = 0.72) and the results persisted for quartile groups of sTNFR1 and risk categories of Kidney Disease: Improving Global Outcomes (KDIGO) (0.70 vs. 0.71, respectively, p = 0.84). Both stratifications by sTNFR1 levels and KDIGO were accurate. CONCLUSION: sTNFR1 could be an alternative marker for identifying patients with diabetes at risk of declining renal function.

High-density lipoprotein protects vascular endothelial cells from indoxyl sulfate insults through its antioxidant ability.

Chronic kidney disease (CKD) patients have a high risk of cardiovascular disease. Indoxyl sulfate (IS) is a uremic toxin that has been shown to inhibit nitric oxide production and cause cell senescence by inducing oxidative stress. High-density lipoprotein (HDL) has a protective effect on the cardiovascular system; however, its impacts on IS-damaged endothelial cells are still unknown. This study aimed to explore the effects of exogenous supplement of HDL on vascular endothelial cells in a uremia-mimic environment. Tube formation, migration, adhesion, and senescence assays were used to evaluate the cell function of human aortic endothelial cells (HAECs). Reactive oxygen species generation was measured by using Amplex red assay. L-NAME and MCI186 were used as a nitric oxide synthase inhibitor and a free radical scavenger, respectively. HDL exerted anti-inflammatory and antioxidant effects via HIF-1α/HO-1 activation and IL-1ß/TNF-α/IL-6 inhibition in IS-stimulated HAECs. HDL improved angiogenesis ability through upregulating Akt/eNOS/VEGF/SDF-1 in IS-stimulated HAECs. HDL decreased endothelial adhesiveness via downregulating VCAM-1 and ICAM-1 in IS-stimulated HAECs. Furthermore, HDL reduced cellular senescence via upregulating SIRT1 and downregulating p53 in IS-stimulated HAECs. Importantly, the above beneficial effects of HDL were mainly due to its antioxidant ability. In conclusion, HDL exerted a comprehensive protective effect on vascular endothelial cells against damage from IS through its antioxidant ability. The results of this study might provide a theoretical basis for potential HDL supplementation in CKD patients with endothelial damage.

The visuo-sensorimotor substrate of co-speech gesture processing.

Co-speech gestures are integral to human communication and exhibit diverse forms, each serving a distinct communication function. However, existing literature has focused on individual gesture types, leaving a gap in understanding the comparative neural processing of these diverse forms. To address this, our study investigated the neural processing of two types of iconic gestures: those representing attributes or event knowledge of entity concepts, beat gestures enacting rhythmic manual movements without semantic information, and self-adaptors. During functional magnetic resonance imaging, systematic randomization and attentive observation of video stimuli revealed a general neural substrate for co-speech gesture processing primarily in the bilateral middle temporal and inferior parietal cortices, characterizing visuospatial attention, semantic integration of cross-modal information, and multisensory processing of manual and audiovisual inputs. Specific types of gestures and grooming movements elicited distinct neural responses. Greater activity in the right supramarginal and inferior frontal regions was specific to self-adaptors, and is relevant to the spatiomotor and integrative processing of speech and gestures. The semantic and sensorimotor regions were least active for beat gestures. The processing of attribute gestures was most pronounced in the left posterior middle temporal gyrus upon access to knowledge of entity concepts. This fMRI study illuminated the neural underpinnings of gesture-speech integration and highlighted the differential processing pathways for various co-speech gestures.

Mechanistic role of CXCL5 in cardiovascular disease, diabetes mellitus, and kidney disease.

Chemokines, by modulating inflammation process, could contribute to the development of cardiovascular disease, diabetes mellitus (DM), and kidney disease. Chemokine CXC motif ligand 5 (CXCL5) is one of the inducible chemokines that may be involved in various inflammatory diseases. Given the bidirectional promiscuity characteristics of the chemokine system, the mechanistic roles of CXCL5 should be further explored in each specific disease. In this article, we sought to review the recent evidence on the differential effects of CXCL5 and their potential mechanisms in cardiovascular disease, DM, and renal disease individually. Future study is still required to verify if CXCL5 could be a novel therapeutic target in these diseases.

Arithmetic problem size modulates brain activations in females but not in males.

Numerous empirical studies have reported that males and females perform equally well in mathematical achievement. However, still to date, very limited is understood about the brain response profiles that are particularly characteristic of males and females when solving mathematical problems. The present study aimed to tackle this issue by manipulating arithmetic problem size to investigate functional significance using functional magnetic resonance imaging (fMRI) in young adults. Participants were instructed to complete two runs of simple calculation tasks with either large or small problem sizes. Behavioural results suggested that the performance did not differ between females and males. Neuroimaging data revealed that sex/gender-related patterns of problem size effect were found in the brain regions that are conventionally associated with arithmetic, including the left middle frontal gyrus (MFG), left intraparietal sulcus (IPS) and insula. Specifically, females demonstrated substantial brain responses of problem size effect in these regions, whereas males showed marginal effects. Moreover, the machine learning method implemented over the brain signal levels within these regions demonstrated that sex/gender is discriminable. These results showed sex/gender effects in the activating patterns varying as a function of the distinct math problem size, even in a simple calculation task. Accordingly, our findings suggested that females and males use two complementary brain resources to achieve equally successful performance levels and highlight the pivotal role of neuroimaging facilities in uncovering neural mechanisms that may not be behaviourally salient.

CXCL5 suppression recovers neovascularization and accelerates wound healing in diabetes mellitus.

BACKGROUND: Higher chemokine C-X-C motif ligand 5 (CXCL5) level was observed in type 2 diabetes mellitus (DM) patients; however, its role in diabetic vasculopathy was not clarified. This study aimed to explore the impacts and mechanistic insights of CXCL5 in neovasculogenesis and wound healing in DM. METHODS: Endothelial progenitor cells (EPCs) and human aortic endothelial cells (HAECs) were used in vitro. Streptozotocin-induced diabetic mice and Leprdb/JNarl mice were used as type 1 and type 2 DM models. Moreover, CXCL5 knockout mice were used to generate diabetic mice. Hindlimb ischemia surgery, aortic ring assays, matrigel plug assay, and wound healing assay were conducted. RESULTS: CXCL5 concentrations were increased in plasma and EPCs culture medium from type 2 DM patients. CXCL5 neutralizing antibody upregulated vascular endothelial growth factor (VEGF)/stromal cell-derived factor-1 (SDF-1) and promoted cell function in EPCs from type 2 DM patients and high glucose-treated EPCs from non-DM subjects as well as HAECs. CXCL5 directly up-regulated interleukin (IL)-1ß/IL-6/tumor necrosis factor-α and down-regulated VEGF/SDF-1 via ERK/p65 activation through chemokine C-X-C motif receptor 2 (CXCR2). CXCL5 neutralizing antibody recovered the blood flow after hindlimb ischemia, increased circulating EPC number, and enhanced VEGF and SDF-1 expression in ischemic muscle. CXCL5 suppression promoted neovascularization and wound healing in different diabetic animal models. The above observation could also be seen in streptozotocin-induced CXCL5 knockout diabetic mice. CONCLUSIONS: CXCL5 suppression could improve neovascularization and wound healing through CXCR2 in DM. CXCL5 may be regarded as a potential therapeutic target for vascular complications of DM.

Xanthine oxidase/NADPH oxidase inhibition by hydralazine attenuates acute kidney injury and prevents the transition of acute kidney injury to chronic kidney disease.

AIMS: The enhancement of inflammation and reactive oxygen species leads to the damage of renal tubular cells in acute kidney injury (AKI), and the upregulation of inflammation increases the risk of AKI being converted into chronic kidney disease (CKD). Hydralazine has shown renoprotective effects in multiple kidney diseases and was shown to be a potent xanthine oxidase (XO) inhibitor. This study aimed to investigate the mechanisms of hydralazine in ischemia-reperfusion (I/R)-stimulated renal proximal tubular epithelial cells in vitro and in AKI animals in vivo. MAIN METHODS: The effects of hydralazine in AKI-to-CKD transition were also evaluated. Human renal proximal tubular epithelial cells were stimulated by I/R conditions in vitro. To generate a mouse model of AKI, a right nephrectomy was performed, followed by left renal pedicle I/R using a small atraumatic clamp. KEY FINDINGS: In the in vitro part, hydralazine could protect renal proximal tubular epithelial cells against insults from the I/R injury through XO/NADPH oxidase inhibition. In the in vivo part, hydralazine preserved renal function in AKI mice and improved the AKI-to-CKD transition by decreasing renal glomerulosclerosis and fibrosis independently of blood pressure lowering. Furthermore, hydralazine exerted antioxidant, anti-inflammatory, and anti-fibrotic effects both in vitro and in vivo. SIGNIFICANCE: Hydralazine, as a XO/NADPH oxidase inhibitor, could protect renal proximal tubular epithelial cells from the insults of I/R and prevent kidney damage in AKI and AKI-to-CKD. The above experimental studies strengthen the possibility of repurposing hydralazine as a potential renoprotective agent through its antioxidative mechanisms.

GMI, a fungal immunomodulatory protein, ameliorates SARS-CoV-2 envelope protein-induced inflammation in macrophages via inhibition of MAPK pathway.

Clinically, COVID-19 is often accompanied by a severe immune response (cytokine storm) which produces a large number of cytokines, such as TNF-α, IL-6 and IL-12, and consequently causes acute respiratory distress syndrome (ARDS). GMI is a type of fungal immunomodulatory protein that is cloned from Ganoderma microsporum and acts as modulating immunocyte for various inflammatory diseases. This study identifies GMI as a potential anti-inflammatory agent and determines the effects of GMI on the inhibition of SARS-CoV-2-induced cytokine secretion. Functional studies showed that SARS-CoV-2 envelope (E) protein induces inflammatory process in murine macrophages RAW264.7 and MH-S cells and in phorbol 12-myristate 13-acetate (PMA)-stimulated human THP-1 cells. GMI exhibits a strong inhibitory effect for SARS-CoV-2-E-induced pro-inflammatory mediators, including NO, TNF-α, IL-6, and IL-12 in macrophages. GMI reduces SARS-CoV-2-E-induced intracellular inflammatory molecules, such as iNOS and COX-2, and inhibits SARS-CoV-2-E-stimulated phosphorylation of ERK1/2 and P38. GMI also downregulates pro-inflammatory cytokine levels in lung tissue and serum after the mice inhale SARS-CoV-2-E protein. In conclusion, this study shows that GMI acts as an agent to alleviate SARS-CoV-2-E-induced inflammation.

Macrophage inflammatory protein-1ß as a novel therapeutic target for renal protection in diabetic kidney disease.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide and the prevalence of DKD has increased over recent decades. Inflammation is involved in the development and progression of DKD. In this study, we explored the potential role of macrophage inflammatory protein-1ß (MIP-1ß) in DKD. Clinical non-diabetic subjects and DKD patients with different levels of urine albumin-to-creatinine ratio (ACR) were enrolled in the study. Leprdb/db mice and MIP-1ß knockout mice were also used as mouse models for DKD. We found that serum MIP-1ß levels were elevated in the DKD patients, especially those with ACRs that were less than or equal to 300, suggesting that MIP-1ß is activated in clinical DKD. The administration of anti-MIP-1ß antibodies attenuated DKD severity in the Leprdb/db mice, which also showed reduced glomerular hypertrophy and podocyte injury, as well as decreased inflammation and fibrosis, suggesting that MIP-1ß plays a role in the development of DKD. The MIP-1ß knockout mice showed improved renal function and decreased renal glomerulosclerosis and fibrosis in DKD. Furthermore, podocytes from the MIP-1ß knockout mice showed less high glucose-induced inflammation and fibrosis compared to those from wild-type mice. In conclusion, the inhibition or deletion of MIP-1ß protected podocytes, modulated renal inflammation, and ameliorated experimental DKD, suggesting that novel anti-MIP-1ß strategies could potentially be used to treat DKD.

Potential Impacts of Hydralazine as a Novel Antioxidant on Cardiovascular and Renal Disease-Beyond Vasodilation and Blood Pressure Lowering.

Hydralazine is a traditional antihypertensive drug that was developed several decades ago. Its most well-known effect is blood pressure lowering by arterial vasodilation. While mainly used an adjunct treatment for clinical hypertension or chronic heart failure, this old drug has also shown potential as a repurposing drug for the atherosclerosis vascular disease and various kidney diseases. Recent experimental studies suggest that hydralazine exerts antioxidative, anti-apoptotic, and HIF-1α stabilization effects for angiogenesis and vascular protection. Hydralazine also exerts reno-protective effects via its antioxidation, DNA demethylation, and anti-inflammation abilities. The above evidence provides advanced rationales for new applications of this drug beyond blood pressure lowering and arterial vasodilation. Here, we summarized the recent experimental advances in the use of hydralazine for either a vascular disease or kidney diseases, or both. Given the wide populations of people with cardiovascular and/or kidney diseases, future studies are worth validating the potential impacts of hydralazine on the clinical outcomes in selected patients.

CCL7 as a novel inflammatory mediator in cardiovascular disease, diabetes mellitus, and kidney disease.

Chemokines are key components in the pathology of chronic diseases. Chemokine CC motif ligand 7 (CCL7) is believed to be associated with cardiovascular disease, diabetes mellitus, and kidney disease. CCL7 may play a role in inflammatory events by attracting macrophages and monocytes to further amplify inflammatory processes and contribute to disease progression. However, CCL7-specific pathological signaling pathways need to be further confirmed in these chronic diseases. Given the multiple redundancy system among chemokines and their receptors, further experimental and clinical studies are needed to clarify whether direct CCL7 inhibition mechanisms could be a promising therapeutic approach to attenuating the development of cardiovascular disease, diabetes mellitus, and kidney disease.

Uncovering sex/gender differences of arithmetic in the human brain: Insights from fMRI studies.

Over the long run, STEM fields had been perceived as dominant by males, despite that numerous studies have shown that female students do not underperform their male classmates in mathematics and science. In this review, we discuss whether and how sex/gender shows specificity in arithmetic processing using a cognitive neuroscience approach not only to capture contemporary differences in brain and behavior but also to provide exclusive brain bases knowledge that is unseen in behavioral outcomes alone. We begin by summarizing studies that had examined sex differences/similarities in behavioral performance of mathematical learning, with a specific focus on large-scale meta-analytical data. We then discuss how the magnetic resonance imaging (MRI) approach can contribute to understanding neural mechanisms underlying sex-specific effects of mathematical learning by reviewing structural and functional data. Finally, we close this review by proposing potential research issues for further exploration of the sex effect using neuroimaging technology. Through the lens of advancement in the neuroimaging technique, we seek to provide insights into uncovering sex-specific neural mechanisms of learning to inform and achieve genuine gender equality in education.

CCL4 Deletion Accelerates Wound Healing by Improving Endothelial Cell Functions in Diabetes Mellitus.

Chronic inflammation in diabetes mellitus (DM) is the leading cause of non-healing wounds. Chemokine CC motif ligand 4 (CCL4) is enhanced in the circulation and in the wounds of DM patients. This study aimed to investigate the effect of endogenous CCL4 inhibition on diabetic wound healing. Endothelial progenitor cells (EPCs) and human dermal microvascular endothelial cells (HDMECs) were used. Mice were injected with streptozotocin to generate hyperglycemia. An enhanced CCL4 level as well as decreased tube formation and migration abilities were observed in high-glucose-treated HDMECs and in EPCs from type 2 DM patients. CCL4 inhibition by siRNA restored the damaged cell function by upregulating the Akt/endothelial nitric oxide synthase/vascular endothelial growth factor/stromal cell-derived factor-1α pathways. Wild-type diabetic mice had delayed wound repair, whereas the CCL4-knockout diabetic mice showed an accelerated rate of wound closure. In a Matrigel plug assay, CCL4-knockout diabetic mice showed higher blood vessel and hemoglobin levels. Higher CD31 and Ki67 expression in the wound area and Matrigel plugs was detected in the CCL4-knockout diabetic mice. CCL4-knockout mice had upregulated angiogenic factors and downregulated inflammatory factors. This study might provide the theoretical basis for CCL4 inhibition as a therapeutic option for clinical diabetic wound treatment.

Longitudinal Association of Universal Screening and Treatment for Major Depressive Disorder with Survival in Cancer Patients.

Evidence for clinical screening and intervention for depression in cancer and the effect of this intervention on cancer prognosis is suboptimal. This study substantialized a complete model with universal screening and intervention for major depressive disorder (MDD) and explored its effect on survival in patients. This longitudinal study recruited cancer patients routinely screened for MDD with a two-stage model. Data including sex, age, cancer diagnosis, first diagnosis date, date of death, cancer stage, and MDD diagnosis and treatment were collected from medical records and the national registration system for cancer. Kaplan−Meier's survival analysis and the Cox proportional hazards regression model were applied to analyze the effects of associated factors on survival. Further subgroup analysis for 14 types of cancer primary site was also performed. Overall, the hazard for patients adhering to psychiatric treatment for MDD before cancer diagnosis was not statistically different from that for patients without MDD (hazard ratio (HR) = 1.061, 95% CI: 0.889−1.267, p = 0.512). The hazard for patients adhering to psychiatric treatment after cancer diagnosis was significantly lower than that for patients without MDD (HR = 0.702, 95% CI: 0.607−0.812, p < 0.001). Those who were diagnosed with MDD after cancer diagnosis and adhered poorly to psychiatric treatment had the greatest hazard (HR = 1.829, 95% CI: 1.687−1.984, p < 0.001). The effect of intervention for MDD varied across different primary cancer types.

Collaborative Referral Model to Achieve Hepatitis C Micro-Elimination in Methadone Maintenance Treatment Patients during the COVID-19 Pandemic.

Although hepatitis C virus (HCV) prevails in patients receiving methadone maintenance treatment (MMT), most do not receive anti-HCV therapy. This single-center observational study aimed to achieve HCV micro-elimination at an MMT center during the COVID-19 pandemic using a collaborative referral model, which comprised a referral-for-diagnosis stage (January 2020 to August 2020) and an on-site-diagnosis stage (September 2020 to January 2021). A multidisciplinary team was established and all MMT center patients were enrolled. HCV micro-elimination was defined as >90% of HCV-infected patients diagnosed and >80% of HCV-viremic patients treated. A total of 305 MMT patients, including 275 (90.2%) anti-HCV seropositive patients, were enrolled. Among 189 HCV-infected patients needing referral, the accumulative percentage receiving HCV RNA testing increased from 93 (49.2%) at referral-for-diagnosis stage to 168 (88.9%) at on-site-diagnosis stage. Among 138 HCV-viremic patients, the accumulative percentage receiving direct-acting antiviral (DAA) therapy increased from 77 (55.8%) at referral-for-diagnosis stage to 129 (93.5%) at on-site-diagnosis stage. We achieved an HCV RNA testing rate of 92.4% (254/275), an HCV treatment rate of 95.8% (203/212) and a sustained virological response rate of 94.1% (191/203). The collaborative referral model is highly effective in HCV RNA testing and HCV treatment uptake among MMT patients, achieving HCV micro-elimination.

Antioxidation and Nrf2-mediated heme oxygenase-1 activation contribute to renal protective effects of hydralazine in diabetic nephropathy.

Reactive oxygen species (ROS) and oxidative stress are associated with the progression of diabetic nephropathy (DN). Hydralazine is an antihypertensive agent and may act as a xanthine oxidase (XO) inhibitor to reduce uric acid levels in a mouse renal injury model. This study aimed to investigate the potential mechanisms of hydralazine in experimental DN. Streptozotocin-induced diabetic mice were fed a high-fat diet to generate DN. Human renal proximal tubular epithelial cells were used in vitro. Nitrendipine and allopurinol which can reduce blood pressure or XO activity levels, were used as two positive controls. Hydralazine downregulated NF-κB/p38 signaling pathways and reduced TNF-α/IL-6 expressions in high glucose-stimulated renal proximal tubular epithelial cells. Hydralazine reduced in vitro ROS production via XO inhibition and nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated heme oxygenase (HO)-1 activation. Furthermore, hydralazine reduced high glucose-induced apoptosis by downregulating PARP/caspase-3 signaling. Hydralazine and allopurinol but not nitrendipine reduced serum uric acid levels and systemic inflammation. Hydralazine and allopurinol treatment improved renal function with decreased urinary albumin-to-creatinine ratios, glomerular hypertrophy, glomerulosclerosis, and fibrosis in the kidney of DN mice. While both hydralazine and allopurinol downregulated XO and NADPH oxidase expression, only hydralazine upregulated Nrf2/HO-1 renal expression, suggesting the additional effects of hydralazine independent of XO/ NADPH oxidase inhibition. In conclusion, hydralazine protected renal proximal tubular epithelial cells against the insults of high glucose and prevented renal damage via XO/NADPH oxidase inhibition and Nrf-2/HO-1 activation, suggesting the comprehensive antioxidation and anti-inflammation mechanisms for the management of DN.

Evaluation of math anxiety and its remediation through a digital training program in mathematics for first and second graders.

INTRODUCTION: Math anxiety severely impacts individuals' learning and future success. However, limited is understood about the profile in East Asian cultures where students genuinely show high-level math anxiety, despite that they outperform their Western counterparts. Here, we investigate the relation between math anxiety and math achievement in children as young as first and second graders in Taiwan. Further, we evaluate whether intensive exposure to digital game-based learning in mathematics could ameliorate math anxiety. METHODS: The study first evaluated a group of 159 first and second graders' math anxiety and its correlation with math performance. Subsequently, a quasi-experimental design was adopted: 77 of the children continued and participated in multi-component digital game training targeting enumeration, speeded calculation, and working memory. Post-assessment was administered afterward for further evaluation of training-associated effects. RESULTS: Results confirmed that math anxiety was negatively associated with school math achievement, which assessed numerical knowledge and arithmetic calculation. Furthermore, children's math anxiety was remarkably reduced via digital training in mathematics after 6-week intensive remediation. Crucially, this math anxiety relief was more prominent in those with high-level math anxiety. Although the children who underwent the training showed training-induced math achievement and working memory enhancement, this cognitive improvement appeared to be independent of the math anxiety relief. CONCLUSION: Our findings demonstrate that students can show highly negative emotions and perceptions toward learning even in high-achieving countries. Auspiciously, the feeling of distress toward learning has the feasibility to be relieved from short-term intensive training. Our study suggests a new approach of early treatments to emotional disturbance that can lead to permanent consequences in individuals.