Compound SJ-12 attenuates streptozocin-induced diabetic cardiomyopathy by stabilizing SERCA2a.

Heart failure (HF) is one of the major causes of death among diabetic patients. Although studies have shown that curcumin analog C66 can remarkably relieve diabetes-associated cardiovascular and kidney complications, the role of SJ-12, SJ-12, a novel curcumin analog, in diabetic cardiomyopathy and its molecular targets are unknown. 7-week-old male C57BL/6 mice were intraperitoneally injected with single streptozotocin (STZ) (160 mg/kg) to develop diabetic cardiomyopathy (DCM). The diabetic mice were then treated with SJ-12 via gavage for two months. Body weight, fast blood glucose, cardiac utrasonography, myocardial injury markers, pathological morphology of the heart, hypertrophic and fibrotic markers were assessed. The potential target of SJ-12 was evaluated via RNA-sequencing analysis. The O-GlcNAcylation levels of SP1 were detected via immunoprecipitation. SJ-12 effectively suppressed myocardial hypertrophy and fibrosis, thereby preventing heart dysfunction in mice with STZ-induced heart failure. RNA-sequencing analysis revealed that SJ-12 exerted its therapeutic effects through the modulation of the calcium signaling pathway. Furthermore, SJ-12 reduced the O-GlcNAcylation levels of SP1 by inhibiting O-linked N-acetylglucosamine transferase (OGT). Also, SJ-12 stabilized Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase 2a (SERCA2a), a crucial regulator of calcium homeostasis, thus reducing hypertrophy and fibrosis in mouse hearts and cultured cardiomyocytes. However, the anti-fibrotic effects of SJ-12 were not detected in SERCA2a or OGT-silenced cardiomyocytes, indicating that SJ-12 can prevent DCM by targeting OGT-dependent O-GlcNAcylation of SP1.These findings indicate that SJ-12 can exert cardioprotective effects in STZ-induced mice by reducing the O-GlcNAcylation levels of SP1, thus stabilizing SERCA2a and reducing myocardial fibrosis and hypertrophy. Therefore, SJ-12 can be used for the treatment of diabetic cardiomyopathy.

Inhibition of MD2 by natural product-drived JM-9 attenuates renal inflammation and diabetic nephropathy in mice.

Diabetic kidney disease (DKD) is one of the severe complications of diabetes mellitus-related microvascular lesions, which remains the leading cause of end-stage kidney disease. The genesis and development of DKD is closely related to inflammation. Myeloid differentiation 2 (MD2) mediates hyperlyciemia-induced renal inflammation and DKD development and is considered as a potential therapeutic target of DKD. Here, we identified a new small-molecule MD2 inhibitor, JM-9. In vitro, JM-9 suppressed high glucose (HG) and palmitic acid (PA)-induced inflammation in MPMs, accompanied by inhibition of MD2 activation and the downstream TLR4/MyD88-MAPKs/NFκB pro-inflammatory signaling pathway. Macrophage-derived factors increased the fibrotic and inflammatory responses in renal tubular epithelial cells, which were inhibited by treating macrophages with JM-9. Then, we investigated the therapeutic effects against DKD in streptozotocin-induced type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) mouse models. Treatment with JM-9 prevented renal inflammation, fibrosis, and dysfunction by targeting MD2 in both T1DM and T2DM models. Our results show that JM-9, a new small-molecule MD2 inhibitor, protects against DKD by targeting MD2 and inhibiting MD2-mediated inflammation. In summary, JM-9 is a potential therapeutic agent for DKD.

Compound c17 alleviates inflammatory cardiomyopathy in streptozotocin-induced diabetic mice by targeting MyD88.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a common complication of diabetes mellitus and is associated with increased morbidity and mortality due to cardiac dysfunction. Chronic inflammation plays a significant role in the development of DCM, making it a promising target for novel pharmacological strategies. Our previous study has synthesized a novel compound, c17, which exhibited strong anti-inflammatory activity by specifically targeting to myeloid differentiation primary response 88 (MyD88). In this study, we evaluated the therapeutic effect of c17 in DCM. METHODS: The small molecular selective MyD88 inhibitor, c17, was used to evaluate the effect of MyD88 on DCM in both high concentration of glucose- and palmitic acid-stimulated macrophages and streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) mice. RESULTS: The treatment of c17 in T1DM mice resulted in improved heart function and reduced cardiac hypertrophy, inflammation and fibrogenesis. RNA sequencing analysis of the heart tissues revealed that c17 effectively suppressed the inflammatory response by regulating the MyD88-dependent pathway. Co-immunoprecipitation experiments further confirmed that c17 disrupted the interaction between MyD88 and Toll-like receptor 4 (TLR4), consequently inhibiting downstream NF-κB activation. In vitro studies demonstrated that c17 exhibited similar anti-inflammatory activity by targeting MyD88 in macrophages, which are the primary regulators of cardiac inflammation. Furthermore, conditioned medium derived from c17-treated macrophages showed reduced capacity to induce hypertrophy, pro-fibrotic reactions, and secondary inflammation in cardiomyocytes. CONCLUSIONS: In conclusion, the small-molecule MyD88 inhibitor, c17, effectively combated the inflammatory DCM, therefore could be a potential candidate for the treatment of this disease.

ß-elemene alleviates hyperglycemia-induced cardiac inflammation and remodeling by inhibiting the JAK/STAT3-NF-κB pathway.

BACKGROUND: Hyperglycemic induced cardiac hypertrophy and cardiac inflammation are important pathological processes in diabetic cardiomyopathy. ß-elemene (Ele) is a natural compound extracted from Curcuma Rhizoma and has anti-tumor effects. It also has therapeutic effects in some inflammatory diseases. However, the therapeutic effect of Ele on diabetic cardiomyopathy is not clear. The purpose of this study was to evaluate the effect of Ele on hyperglycemia-caused cardiac remodeling and heart failure. METHODS: C57BL/6 mice were intraperitoneally injected with streptozotocin to induce DCM, and Ele was administered intragastric after 8 weeks to investigate the effect of Ele. RNA sequencing of cardiac tissue was performed to investigate the mechanism. RESULTS: Ele markedly inhibited cardiac inflammation, fibrosis and hypertrophy in diabetic mice, as well as in high glucose-induced cardiomyocytes. RNA sequencing showed that cardioprotective effect of Ele involved the JAK/STAT3-NF-κB signaling pathway. Ele alleviated heart and cardiomyocyte inflammation in mice by blocking diabetes-induced JAK2 and STAT3 phosphorylation and NF-κB activation. CONCLUSIONS: The study found that Ele preserved the hearts of diabetic mice by inhibiting JAK/STAT3 and NF-κB mediated inflammatory responses, suggesting that Ele is an effective therapy for DCM.

Macrophage DCLK1 promotes obesity-induced cardiomyopathy via activating RIP2/TAK1 signaling pathway.

Obesity increases the risk for cardiovascular diseases and induces cardiomyopathy. Chronic inflammation plays a significant role in obesity-induced cardiomyopathy and may provide new therapeutic targets for this disease. Doublecortin-like kinase 1 (DCLK1) is an important target for cancer therapy and the role of DCLK1 in obesity and cardiovascular diseases is unclear. Herein, we showed that DCLK1 was overexpressed in the cardiac tissue of obese mice and investigated the role of DCLK1 in obesity-induced cardiomyopathy. We generated DCLK1-deleted mice and showed that macrophage-specific DCLK1 knockout, rather than cardiomyocyte-specific DCLK1 knockout, prevented high-fat diet (HFD)-induced heart dysfunction, cardiac hypertrophy, and fibrosis. RNA sequencing analysis showed that DCLK1 deficiency exerted cardioprotective effects by suppressing RIP2/TAK1 activation and inflammatory responses in macrophages. Upon HFD/palmitate (PA) challenge, macrophage DCLK1 mediates RIP2/TAK1 phosphorylation and subsequent inflammatory cytokine release, which further promotes hypertrophy in cardiomyocytes and fibrogenesis in fibroblasts. Finally, a pharmacological inhibitor of DCLK1 significantly protects hearts in HFD-fed mice. Our study demonstrates a novel role and a pro-inflammatory mechanism of macrophage DCLK1 in obesity-induced cardiomyopathy and identifies DCLK1 as a new therapeutic target for the treatment of this disease. Upon HFD/PA challenge, DCLK1 induces RIP2/TAK1-mediated inflammatory response in macrophages, which subsequently promotes cardiac hypertrophy and fibrosis. Macrophage-specific DCLK1 deletion or pharmacological inhibition of DCLK1 protects hearts in HFD-fed mice.

Bicyclol Alleviates Streptozotocin-induced Diabetic Cardiomyopathy By Inhibiting Chronic Inflammation And Oxidative Stress.

PURPOSE: Diabetic cardiomyopathy (DCM) is a common and severe complication of diabetes. Inflammation and oxidative stress play important roles in DCM development. Bicyclol is a hepatoprotective drug in China that exerts anti-inflammatory effects by inhibiting the MAPK and NF-κB pathways to prevent obesity-induced cardiomyopathy. Our purpose was to explore the effect and mechanism of bicyclol on DCM. METHODS: A type 1 diabetes mouse model was established using C57BL/6 mice by intraperitoneal injection of STZ. The therapeutic effect of bicyclol was evaluated in both heart tissues of diabetic mice and high concentration of glucose (HG)-stimulated H9c2 cells. RESULTS: We showed that bicyclol significantly attenuated diabetes-induced cardiac hypertrophy and fibrosis, which is accompanied by the preservation of cardiac function in mice. In addition, bicyclol exhibited anti-inflammatory and anti-oxidative effects both in vitro and in vivo. Furthermore, bicyclol inhibited the hyperglycemia-induced activation of MAPKs and NF-κB pathways, while upregulating the Nrf-2/HO-1 pathway to exhibit protective effects. CONCLUSION: Our data indicate that bicyclol could be a promising cardioprotective agent in the treatment of DCM.

A small-molecule JNK inhibitor JM-2 attenuates high-fat diet-induced non-alcoholic fatty liver disease in mice.

BACKGROUND: The prevalence of non-alcoholic fatty liver disease (NAFLD) has been deemed a leading cause of end-stage liver disease. As a member of the mitogen-activated protein kinase family, c-Jun N-terminal kinase (JNK) has been shown to play an important role in the pathogenesis of NAFLD. Here, we identified a novel JNK inhibitor, JM-2, and evaluated its therapeutic effects against NAFLD both in vitro and in vivo. METHODS: In vitro, JNK was blocked by JM-2 in PA-challenged hepatocytes. C57BL/6 mice were fed a high-fat diet for 6 months to develop NAFLD. Mice were treated with JM-2 by intragastric administration. RESULTS: In primary hepatocytes and AML-12 cells, JM-2 treatment significantly suppressed palmitic acid (PA)-induced JNK activation and PA-induced inflammation and cell apoptosis. In addition, JM-2 restricted the production of fibrosis- and lipid metabolism-related genes in PA-challenged hepatocytes. We evaluated the curative effect of JM-2 against NAFLD using a high-fat diet (HFD)-fed mouse model. Based on our findings, JM-2 administration significantly protected the mouse liver from HFD-induced inflammation, lipid accumulation, fibrosis, and apoptosis, accompanied with reduced JNK phosphorylation in the liver tissue. CONCLUSION: JM-2 affords a significant protective effect against HFD-induced NAFLD by inhibiting JNK activation and is potential to be developed as a candidate drug for NAFLD treatment.

Licochalcone A protects against LPS-induced inflammation and acute lung injury by directly binding with myeloid differentiation factor 2 (MD2).

BACKGROUND AND PURPOSE: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a challenging clinical syndrome that leads to various respiratory sequelae and even high mortality in patients with severe disease. The novel pharmacological strategies and therapeutic drugs are urgently needed. Natural products have played a fundamental role and provided an abundant pool in drug discovery. EXPERIMENTAL APPROACH: A compound library containing 160 natural products was used to screen potential anti-inflammatory compounds. Mice with LPS-induced ALI was then used to verify the preventive and therapeutic effects of the selected compounds. KEY RESULTS: Licochalcone A was discovered from the anti-inflammatory screening of natural products in macrophages. A qPCR array validated the inflammation-regulatory effects of licochalcone A and indicated that the potential targets of licochalcone A may be the upstream proteins in LPS pro-inflammatory signalling. Further studies showed that licochalcone A directly binds to myeloid differentiation factor 2 (MD2), an assistant protein of toll-like receptor 4 (TLR4), to block both LPS-induced TRIF- and MYD88-dependent pathways. LEU61 and PHE151 in MD2 protein are the two key residues that contribute to the binding of MD2 to licochalcone A. In vivo, licochalcone A treatment alleviated ALI in LPS-challenged mice through significantly reducing immunocyte infiltration, suppressing activation of TLR4 pathway and inflammatory cytokine induction. CONCLUSION AND IMPLICATIONS: In summary, our study identified MD2 as a direct target of licochalcone A for its anti-inflammatory activity and suggested that licochalcone A might serve as a novel MD2 inhibitor and a potential drug for developing ALI/ARDS therapy.

Dectin-1 plays a deleterious role in high fat diet-induced NAFLD of mice through enhancing macrophage activation.

The innate immune response and inflammation contribute to hepatic steatosis and non-alcoholic fatty liver disease (NAFLD). Dectin-1 is a pathogen recognition receptor in innate immunity. In this study, we investigated the role of Dectin-1 in the pathogenesis of NAFLD. We first showed that Dectin-1 expression was significantly elevated in liver tissues of patients with NASH. NAFLD was induced in mice by feeding high fat diet (HFD) for 24 weeks. At the end of treatment, mice were sacrificed, and their blood and liver tissues were collected for analyses. We showed HFD feeding also increased liver Dectin-1 levels in mice, associated with macrophage infiltration. Either gene knockout or co-administration of a Dectin-1 antagonist laminarin (150 mg/kg twice a day, ip, from 16th week to 24th week) largely protected the livers from HFD-induced lipid accumulation, fibrosis, and elaboration of inflammatory responses. In primary mouse peritoneal macrophages (MPMs), challenge with palmitate (PA, 200 µM), an abundant saturated fatty acid found in NAFLD, significantly activated Dectin-1 signaling pathway, followed by transcriptionally regulated production of pro-inflammatory cytokines. Dectin-1 was required for hepatic macrophage activation and inflammatory factor induction. Condition media generated from Dectin-1 deficient macrophages failed to cause hepatocyte lipid accumulation and hepatic stellate activation. In conclusion, this study provides the primary evidence supporting a deleterious role for Dectin-1 in NAFLD through enhancing macrophage pro-inflammatory responses and suggests that it can be targeted to prevent inflammatory NAFLD.

Curcumin analog JM-2 alleviates diabetic cardiomyopathy inflammation and remodeling by inhibiting the NF-κB pathway.

Cardiac inflammation is an important pathological process in diabetic cardiomyopathy (DCM). Curcumin is a natural compound found in the rhizome of Curcuma longa and has been shown to possess multifunctional bioactivities. In the present study, we identified a new curcumin-derived compound, JM-2, and investigated its therapeutic effects against DCM in mouse models of streptozotocin-induced type 1 diabetes mellitus (T1DM) and HFD-induced type 2 diabetes (T2DM). Treatment with JM-2 (10 mg/kg) prevented cardiac functional and structural deficits effectively and reduced cardiac inflammation and fibrosis. JM-2 administration attenuated DCM by inhibiting nuclear factor kappa-B (NF-κB) activation in the heart of both models. In addition, treatment with JM-2 completely prevented the increase in proinflammatory factors and macrophage infiltration in T1DM and T2DM mice. RNA-seq analysis showed that the anti-inflammatory activity of JM-2 was associated with the inhibition of NF-κB activation. In vitro, JM-2 suppressed high glucose (HG)-induced myocardial hypertrophy and fibrosis in H9c2 cells, accompanied by inhibition of HG-induced NF-κB activation. Collectively, our results showed that JM-2, a new curcumin analog, provides strong protection against DCM via inhibition of the NF-κB-mediated inflammation. In summary, our data suggest that the curcumin analog JM-2 may be a potential therapeutic agent for DCM.

Diacerein protects liver against APAP-induced injury via targeting JNK and inhibiting JNK-mediated oxidative stress and apoptosis.

BACKGROUND AND PURPOSE: An overdose of acetaminophen (APAP) causes acute liver damage and lead to liver failure. Therefore, it is of great clinical significance to find drugs for the treatment of APAP-induced liver injury. Diacerein is clinically used drug for the treatment of osteoarthritis. Here, we evaluate the pharmacological effects and potential mechanisms of diacerein in APAP-induced liver injury. METHODS AND RESULTS: C57BL/6 mice were treated with diacerein by gavage, followed by intraperitoneal injection of APAP (400 mg/kg) to induce acute liver injury in mice. RNA-sequencing analysis and in vitro kinase assay were performed to explore the underlying mechanisms of diacerein. The experimental results showed that pretreatment with diacerein could inhibit APAP-induced elevation of serum AST and ALT levels, hepatic histopathological damage, oxidative stress, hepatocyte death, and mitochondrial damage in mice. The RNA-sequencing analysis and in vitro kinase assay indicated that indicating that JNK (c-Jun N-terminal kinase) is involved in that liver-protective effects of Diacerein. Diacerein could directly and selectively inhibit JNK kinase phosphorylation in cell-free system. We further confirmed that diacerein inhibits APAP-activated JNK pathway to reduce injury response in mouse livers and cultured AML12 cells. Deficiency of JNK in AML12 cells abolished the anti-injury effects of diacerein. CONCLUSION: Our experimental results suggest that diacerein protects APAP-induced liver injury by the inhibition of JNK kinase phosphorylation, rendering diacerein may serve as a potential therapeutic drug for the prevention of acute liver injury.

Macrophage-specific MyD88 deletion and pharmacological inhibition prevents liver damage in non-alcoholic fatty liver disease via reducing inflammatory response.

Activation of the innate immune system through toll-like receptors (TLRs) has been repeatedly demonstrated in non-alcoholic fatty liver disease (NAFLD) and several TLRs have been shown to contribute. Myeloid differentiation primary response 88 (MyD88) is as an adapter protein for the activation of TLRs and bridges TLRs to NF-κB-mediated inflammation in macrophages. However, whether myeloid cell MyD88 contributes to NAFLD are largely unknown. To test this approach, we generated macrophage-specific MyD88 knockout mice and show that these mice are protected against high-fat diet (HFD)-induced hepatic injury, lipid accumulation, and fibrosis. These protective effects were associated with reduced macrophage numbers in liver tissues and surpassed inflammatory responses. In cultured macrophages, saturated fatty acid palmitate utilizes MyD88 to activate NF-κB and induce inflammatory and fibrogenic factors. In hepatocytes, these factors may cause lipid accumulation and a further elaboration of inflammatory cytokines. In hepatic stellate cells, macrophage-derived factors, especially TGF-ß, cause activation and hepatic fibrosis. We further show that pharmacological inhibition of MyD88 is also able to reduce NAFLD injury in HFD-fed mice. Therefore, our study has provided empirical evidence that macrophage MyD88 participates in HFD-induced NAFLD and could be targeted to prevent the development and progression of NAFLD/NASH.

A Hybrid Deep Learning Method for Early and Late Mild Cognitive Impairment Diagnosis With Incomplete Multimodal Data.

Multimodality neuroimages have been widely applied to diagnose mild cognitive impairment (MCI). However, the missing data problem is unavoidable. Most previously developed methods first train a generative adversarial network (GAN) to synthesize missing data and then train a classification network with the completed data. These methods independently train two networks with no information communication. Thus, the resulting GAN cannot focus on the crucial regions that are helpful for classification. To overcome this issue, we propose a hybrid deep learning method. First, a classification network is pretrained with paired MRI and PET images. Afterward, we use the pretrained classification network to guide a GAN by focusing on the features that are helpful for classification. Finally, we synthesize the missing PET images and use them with real MR images to fine-tune the classification model to make it better adapt to the synthesized images. We evaluate our proposed method on the ADNI dataset, and the results show that our method improves the accuracies obtained on the validation and testing sets by 3.84 and 5.82%, respectively. Moreover, our method increases the accuracies for the validation and testing sets by 7.7 and 9.09%, respectively, when we synthesize the missing PET images via our method. An ablation experiment shows that the last two stages are essential for our method. We also compare our method with other state-of-the-art methods, and our method achieves better classification performance.

MD2 deficiency prevents high-fat diet-induced AMPK suppression and lipid accumulation through regulating TBK1 in non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most predominant form of liver diseases worldwide. Recent evidence shows that myeloid differentiation factor 2 (MD2), a protein in innate immunity and inflammation, regulates liver injury in models of NAFLD. Here, we investigated a new mechanism by which MD2 participates in the pathogenesis of experimental NAFLD. METHODS: Wild-type, Md2-/- and bone marrow reconstitution mice fed with high-fat diet (HFD) were used to identify the role of hepatocyte MD2 in NAFLD. Transcriptomic RNA-seq and pathway enrich analysis were performed to explore the potential mechanisms of MD2. In vitro, primary hepatocytes and macrophages were cultured for mechanistic studies. RESULTS: Transcriptome analysis and bone marrow reconstitution studies showed that hepatocyte MD2 may participate in regulating lipid metabolism in models with NAFLD. We then discovered that Md2 deficiency in mice prevents HFD-mediated suppression of AMP-activated protein kinase (AMPK). This preservation of AMPK in Md2-deficient mice was associated with normalized sterol regulatory element binding protein 1 (SREBP1) transcriptional program and a lack of lipid accumulation in both hepatocytes and liver. We then showed that hepatocyte MD2 links HFD to AMPK/SREBP1 through TANK binding kinase 1 (TBK1). In addition, MD2-increased inflammatory factor from macrophages induces hepatic TBK1 activation and AMPK suppression. CONCLUSION: Hepatocyte MD2 plays a pathogenic role in NAFLD through TBK1-AMPK/SREBP1 and lipid metabolism pathway. These studies provide new insight into a non-inflammatory function of MD2 and evidence for the important role of MD2 in NALFD.

Effect of bisphosphonate on hip fracture in patients with osteoporosis or osteopenia according to age: a meta-analysis and systematic review.

This meta-analysis and systematic review investigated the efficacy of bisphosphonates on the incidence of hip fracture (IHF) in patients of different ages with osteoporosis or osteopenia. We searched Web of Science, Embase, the Cochrane Database, and PubMed from inception to January 10, 2021, for trials reporting the effects of bisphosphonates on the IHF. We included only randomized, double-blind, placebo-controlled clinical trials. We pooled data using a random-effects meta-analysis with risk ratios (RRs) and reported 95% CIs. We also used the Cochran Q and I² statistics to assess the heterogeneity in the results of individual studies. The primary endpoints were the total numbers of people in the bisphosphonates and placebo groups and the numbers of IHFs during the follow-up periods. Bisphosphonates reduced the IHF with an overall effect (RR: 0.66; 95% CI: 0.56 to 0.77; zoledronic acid: RR: 0.60; 95% CI: 0.46 to 0.78; risedronate: RR: 0.74; 95% CI: 0.59 to 0.94, and alendronate: RR: 0.61; 95% CI: 0.40 to 0.95). The result of the heterogeneity assessment was I²=0, p=0.97. In all age groups (all ages, ≥55 years old, ≥65 years old), bisphosphonates reduced the IHF. In the ≥55 years old and ≥65 years old age groups, the RR and 95% CI were 0.63 and 0.43 to 0.93, and 0.60 and 0.44 to 0.81, respectively. Bisphosphonate reduced the IHF in the general population and all age groups (≥55 years old and ≥65 years old). Zoledronic acid, risedronate and alendronate reduced the IHF in osteoporosis or osteopenia populations. The association between bisphosphonate and the IHF does not appear to be influenced by age.

Curcumin analogue C66 attenuates obesity-induced myocardial injury by inhibiting JNK-mediated inflammation.

Obesity has been recognized as a major risk factor for the development of chronic cardiomyopathy, which is associated with increased cardiac inflammation, fibrosis, and apoptosis. We previously developed an anti-inflammatory compound C66, which prevented inflammatory diabetic complications via targeting JNK. In the present study, we have tested the hypothesis that C66 could prevent obesity-induced cardiomyopathy by suppressing JNK-mediated inflammation. High-fat diet (HFD)-induced obesity mouse model and palmitic acid (PA)-challenged H9c2 cells were used to develop inflammatory cardiomyopathy and evaluate the protective effects of C66. Our data demonstrate a protective effect of C66 against obesity-induced cardiac inflammation, cardiac hypertrophy, fibrosis, and dysfunction, overall providing cardio-protection. C66 administration attenuates HFD-induced myocardial inflammation by inhibiting NF-κB and JNK activation in mouse hearts. In vitro, C66 prevents PA-induced myocardial injury and apoptosis in H9c2 cells, accompanied with inhibition against PA-induced JNK/NF-κB activation and inflammation. The protective effect of C66 is attributed to its potential to inhibit JNK activation, which led to reduced pro-inflammatory cytokine production and reduced apoptosis in cardiomyocytes both in vitro and in vivo. In summary, C66 provides significant protection against obesity-induced cardiac dysfunction, mainly by inhibiting JNK activation and JNK-mediated inflammation. Our data indicate that inhibition of JNK is able to provide significant protection against obesity-induced cardiac dysfunction.

Feature level-based group lasso method for amnestic mild cognitive impairment diagnosis.

BACKGROUND AND OBJECTIVE: Previous studies have indicated that brain morphological measures change in patients with amnestic mild cognitive impairment (aMCI). However, most existing classification methods cannot take full advantage of these measures. In this study, we improve traditional multitask learning framework by fully considering the relevance among related tasks and supplementary information from other unrelated tasks at the same time. METHODS: We propose a feature level-based group lasso (FL-GL) method in which a feature represents the average value of each ROI for each measure. First, we design a correlation matrix in which each row represents the relationship among different measures for each ROI. And this matrix is used to guide the feature selection based on a group lasso framework. Then, we train specific support vector machine (SVM) classifiers with the selected features for each measure. Finally, a weighted voting strategy is applied to combine these classifiers for a final prediction of aMCI from normal control (NC). RESULTS: We use the leave-one-out cross-validation strategy to verify our method on two datasets, the Xuan Wu Hospital dataset and the ADNI dataset. Compared with the traditional method, the results show that the classification accuracies can be improved by 6.12 and 4.92% with the FL-GL method on the two datasets. CONCLUSIONS: The results of an ablation study indicated that feature level-based group sparsity term was the core of our method. So, considering correlation at the feature level could improve the traditional multitask learning framework and our FL-GL method obtained better classification performance of patients with MCI and NCs.

Correlation-Aware Sparse and Low-Rank Constrained Multi-Task Learning for Longitudinal Analysis of Alzheimer's Disease.

Alzheimer's disease (AD), as a severe neurodegenerative disease, is now attracting more and more researchers' attention in the healthcare. With the development of magnetic resonance imaging (MRI), the neuroimaging-based longitudinal analysis is gradually becoming an important research direction to understand and trace the process of the AD. In addition, regression analysis has been commonly adopted in the AD pattern analysis and progression prediction. However, most existing methods assume that all input features are equally related to the output variables, which ignore the difference in terms of the correlation. In this paper, we proposed a novel multi-task learning formulation, which considers a correlation-aware sparse and low-rank constrained regularization, for accurately predicting the cognitive scores of the patients at different time points and identifying the most predictive biomarkers. In addition, an efficient iterative algorithm is developed to optimize the proposed non-smooth convex objective formulation. We also have performed experiments using data from the AD neuroimaging initiative dataset to evaluate the proposed optimization formulation. Especially, we will predict cognitive scores of multiple time points through the baseline MRI features. The results not only indicate the rationality and correctness of the proposed method for predicting disease progression but also identify some stable and important MRI features that are consistent with the previous research.