ABSTRACT
Diabetic vascular disease is a major complication of diabetes mellitus (DM). Chemokine C-C motif ligand 7 (CCL7) attracts macrophages and monocytes, amplifying inflammatory processes in the vasculature. We hypothesized a causal role for CCL7 in diabetic vasculopathy. CCL7 concentrations were higher in the plasma of patients with type 2 DM, as well as in supernatants from their endothelial progenitor cells (EPCs). High-glucose stimulation increased the secretion of CCL7 from human dermal microvascular endothelial cells (HDMECs) through the c-Fos and c-Jun signaling pathways. CCL7 inhibition using knockdown or neutralization antibody treatment reversed the high glucose-induced impaired tube formation and migration abilities of EPCs, human aortic endothelial cells, human coronary artery endothelial cells, and HDMECs. Administration of recombinant human CCL7 protein impaired tube formation and migration abilities by down-regulating the AKT-endothelial nitric oxide synthase and AKT/nuclear factor erythroid 2-related factor 2/heme oxygenase-1/vascular endothelial growth factor/stromal cell-derived factor-1 pathways and by up-regulating ERK/phosphorylated p65/interleukin-1ß/interleukin-6/tumor necrosis factor-α pathways through CC chemokine receptor 3 in endothelial cells. Ccl7 knockout in streptozotocin-treated mice showed improved neovasculogenesis in ischemic limbs and accelerated wound repair, with increased circulating EPCs and capillary density. CCL7 antibody treatment in db/db mice and high-fat diet-induced hyperglycemia mice showed improved neovasculogenesis in ischemic limbs and wound areas, accompanied by up-regulation of angiogenic proteins and down-regulation of inflammatory proteins. Endothelial cell-specific Ccl7-knockout mice showed ameliorated diabetic vasculopathy in streptozotocin-induced DM. This study highlights the potential of CCL7 as a therapeutic target for diabetic vasculopathy.
Subject(s)
Cell Movement , Chemokine CCL7 , Diabetes Mellitus, Experimental , Mice, Knockout , Animals , Humans , Chemokine CCL7/metabolism , Diabetes Mellitus, Experimental/complications , Cell Movement/drug effects , Mice , Diabetic Angiopathies/metabolism , Diabetic Angiopathies/pathology , Diabetic Angiopathies/drug therapy , Signal Transduction/drug effects , Male , Disease Models, Animal , Endothelial Cells/metabolism , Endothelium, Vascular/metabolism , Endothelium, Vascular/pathology , Endothelium, Vascular/drug effects , Mice, Inbred C57BL , Glucose/metabolism , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/complicationsABSTRACT
The development and refinement of functional brain circuits crucial to human cognition is a continuous process that spans from childhood to adulthood. Research increasingly focuses on mapping these evolving configurations, with the aim to identify markers for functional impairments and atypical development. Among human cognitive systems, nonsymbolic magnitude representations serve as a foundational building block for future success in mathematical learning and achievement for individuals. Using task-based frontoparietal (FPN) and salience network (SN) features during nonsymbolic magnitude processing alongside machine learning algorithms, we developed a framework to construct brain age prediction models for participants aged 7-30. Our study revealed differential developmental profiles in the synchronization within and between FPN and SN networks. Specifically, we observed a linear increase in FPN connectivity, concomitant with a decline in SN connectivity across the age span. A nonlinear U-shaped trajectory in the connectivity between the FPN and SN was discerned, revealing reduced FPN-SN synchronization among adolescents compared to both pediatric and adult cohorts. Leveraging the Gradient Boosting machine learning algorithm and nested fivefold stratified cross-validation with independent training datasets, we demonstrated that functional connectivity measures of the FPN and SN nodes predict chronological age, with a correlation coefficient of .727 and a mean absolute error of 2.944 between actual and predicted ages. Notably, connectivity within the FPN emerged as the most contributing feature for age prediction. Critically, a more matured brain age estimate is associated with better arithmetic performance. Our findings shed light on the intricate developmental changes occurring in the neural networks supporting magnitude representations. We emphasize brain age estimation as a potent tool for understanding cognitive development and its relationship to mathematical abilities across the critical developmental period of youth. PRACTITIONER POINTS: This study investigated the prolonged changes in the brain's architecture across childhood, adolescence, and adulthood, with a focus on task-state frontoparietal and salience networks. Distinct developmental pathways were identified: frontoparietal synchronization strengthens consistently throughout development, while salience network connectivity diminishes with age. Furthermore, adolescents show a unique dip in connectivity between these networks. Leveraging advanced machine learning methods, we accurately predicted individuals' ages based on these brain circuits, with a more mature estimated brain age correlating with better math skills.
Subject(s)
Frontal Lobe , Machine Learning , Magnetic Resonance Imaging , Nerve Net , Parietal Lobe , Humans , Adolescent , Child , Young Adult , Male , Female , Adult , Parietal Lobe/physiology , Parietal Lobe/diagnostic imaging , Parietal Lobe/growth & development , Frontal Lobe/physiology , Frontal Lobe/growth & development , Frontal Lobe/diagnostic imaging , Nerve Net/diagnostic imaging , Nerve Net/physiology , Nerve Net/growth & development , Mathematical Concepts , ConnectomeABSTRACT
Acute kidney injury (AKI), if not well controlled, may progress to chronic kidney disease (CKD). Diosgenin is a natural phytosteroid sapogenin from plants. This study aimed to investigate the mechanistic effects of diosgenin on AKI and AKI related development of CKD. The mouse model of ischemia/reperfusion (I/R)-induced AKI was used, and its progressive changes were followed. Human renal proximal tubular epithelial cells were used, and hypoxia stimulation was applied to mimic the in vivo I/R. Diosgenin, given after renal injury, preserved kidney function, as evidenced by a reduction in serum levels of BUN, creatinine, and UACR in both acute and chronic phases of AKI. Diosgenin alleviated I/R-induced tubular injury and prevented macrophage infiltration and renal fibrosis in AKI mice. Furthermore, diosgenin also mitigated the development of CKD from AKI with reduced renal expression of inflammatory, fibrotic, and epithelial-mesenchymal transition markers. In human renal tubular epithelial cells, diosgenin downregulated the hypoxia-induced oxidative stress and cellular damages that were dependent on the NOX4/p65 signaling pathways. Taken together, diosgenin treatment reduced I/R-induced AKI and ameliorated the progression to CKD from AKI probably by modifying the NOX4/p65 signaling pathways.
Subject(s)
Acute Kidney Injury , Diosgenin , Mice, Inbred C57BL , NADPH Oxidase 4 , Renal Insufficiency, Chronic , Signal Transduction , Diosgenin/pharmacology , Acute Kidney Injury/drug therapy , Acute Kidney Injury/metabolism , Renal Insufficiency, Chronic/drug therapy , Renal Insufficiency, Chronic/metabolism , Renal Insufficiency, Chronic/physiopathology , Animals , Humans , Mice , Signal Transduction/drug effects , NADPH Oxidase 4/metabolism , NADPH Oxidase 4/genetics , Male , Oxidative Stress/drug effects , Transcription Factor RelA/metabolism , Transcription Factor RelA/genetics , Disease Progression , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Reperfusion Injury/metabolism , Reperfusion Injury/drug therapy , Cell LineABSTRACT
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.
Subject(s)
Aging , Chemokine CCL4 , Inflammation , Mice, Knockout , Oxidative Stress , Reactive Oxygen Species , Humans , Animals , Aging/metabolism , Aging/pathology , Inflammation/pathology , Inflammation/metabolism , Chemokine CCL4/metabolism , Mice , Reactive Oxygen Species/metabolism , Male , Aged , Mice, Inbred C57BL , Endothelial Cells/metabolism , Endothelial Cells/pathology , Female , Neovascularization, Physiologic , Middle AgedABSTRACT
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.
ABSTRACT
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.
Subject(s)
Albuminuria , Biomarkers , Creatinine , Diabetes Mellitus, Type 2 , Diabetic Nephropathies , Glomerular Filtration Rate , Receptors, Tumor Necrosis Factor, Type I , Aged , Female , Humans , Male , Middle Aged , Albuminuria/urine , Albuminuria/diagnosis , Biomarkers/urine , Creatinine/urine , Diabetes Mellitus, Type 2/urine , Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/urine , Diabetic Nephropathies/diagnosis , Prospective Studies , Receptors, Tumor Necrosis Factor, Type I/urine , SolubilityABSTRACT
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.
Subject(s)
Antioxidants , Renal Insufficiency, Chronic , Humans , Antioxidants/pharmacology , Antioxidants/metabolism , Lipoproteins, HDL/pharmacology , Lipoproteins, HDL/metabolism , Indican/pharmacology , Endothelial Cells/metabolism , Renal Insufficiency, Chronic/metabolismABSTRACT
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.
Subject(s)
Gestures , Speech , Humans , Speech/physiology , Semantics , Temporal Lobe/diagnostic imaging , Temporal Lobe/physiology , Frontal Lobe/physiology , Magnetic Resonance Imaging/methodsABSTRACT
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.
Subject(s)
Cardiovascular Diseases , Diabetes Mellitus , Kidney Diseases , Humans , Chemokines , Chemokine CXCL5ABSTRACT
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.
Subject(s)
Brain Mapping , Problem Solving , Male , Young Adult , Humans , Female , Problem Solving/physiology , Brain/diagnostic imaging , Brain/physiology , Parietal Lobe/physiology , Magnetic Resonance Imaging/methodsABSTRACT
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.
Subject(s)
Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 2 , Endothelial Progenitor Cells , Humans , Mice , Animals , Diabetes Mellitus, Type 2/metabolism , Vascular Endothelial Growth Factor A , Diabetes Mellitus, Experimental/metabolism , Streptozocin/metabolism , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Endothelial Progenitor Cells/metabolism , Chemokine CXCL12/metabolism , Mice, Knockout , Wound Healing , Ischemia , Neovascularization, Physiologic/physiology , Chemokine CXCL5/genetics , Chemokine CXCL5/metabolismABSTRACT
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.
Subject(s)
Acute Kidney Injury , Renal Insufficiency, Chronic , Reperfusion Injury , Mice , Humans , Animals , Xanthine Oxidase , NADPH Oxidases , Renal Insufficiency, Chronic/pathology , Acute Kidney Injury/drug therapy , Acute Kidney Injury/prevention & control , Acute Kidney Injury/pathology , Kidney/pathology , Hydralazine/pharmacology , Enzyme Inhibitors/pharmacology , Inflammation/pathology , Reperfusion Injury/pathology , FibrosisABSTRACT
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.
Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Animals , Mice , SARS-CoV-2/metabolism , Interleukin-6 , Tumor Necrosis Factor-alpha , Inflammation , Cytokines/metabolism , Macrophages/metabolism , Immunity , Interleukin-12ABSTRACT
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.
Subject(s)
Diabetes Mellitus , Diabetic Nephropathies , Podocytes , Animals , Mice , Diabetes Mellitus/pathology , Diabetic Nephropathies/pathology , Fibrosis , Inflammation/pathology , Kidney/physiology , Kidney/pathology , Mice, KnockoutABSTRACT
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.
ABSTRACT
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.
Subject(s)
Cardiovascular Diseases , Diabetes Mellitus , Kidney Diseases , Chemokine CCL7/metabolism , Chemokines/metabolism , Humans , LigandsABSTRACT
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.
Subject(s)
Magnetic Resonance Imaging , Problem Solving , Brain/diagnostic imaging , Brain Mapping/methods , Female , Humans , Magnetic Resonance Imaging/methods , Male , Mathematics , Sex FactorsABSTRACT
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.
ABSTRACT
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.