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Abstract Background Nonalcoholic fatty liver disease (NAFLD) is a chronic disease with an increasing incidence, which can further develop into liver fibrosis and hepatocellular carcinoma at the end stage. Alantolactone (Ala), a sesquiterpene lactone isolated from Asteraceae, has shown anti-inflammatory effects in different models. However, the therapeutic effect of Ala on NAFLD is not clear. Methods C57BL/6 mice were fed a high-fat diet (HFD) to induce NAFLD. After 16 weeks, Ala was administered by gavage to observe its effect on NAFLD. RNA sequencing of liver tissues was performed to investigate the mechanism. In vitro, mouse cell line AML-12 was pretreated with Ala to resist palmitic acid (PA)-induced inflammation, oxidative stress and fibrosis. Results Ala significantly inhibited inflammation, fibrosis and oxidative stress in HFD-induced mice, as well as PA-induced AML-12 cells. Mechanistic studies showed that the effect of Ala was related to the induction of Nrf2 and the inhibition of NF-κB. Taken together, these findings suggested that Ala exerted a liver protective effect on NAFLD by blocking inflammation and oxidative stress. Conclusions The study found that Ala exerted a liver protective effect on NAFLD by blocking inflammation and oxidative stress, suggesting that Ala is an effective therapy for NAFLD.

Abstract 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.

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.

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.

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.

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.

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.

Previous studies have shown that amnestic mild cognitive impairment (aMCI) involves in the morphological abnormalities of multiple regions, including cortical thickness, sulcus depth, surface area, gray matter volume, jacobian metric and average curvature. All the measures have unique neuropathological and genetic meanings. However, most existing methods simply average or concatenate these measures when constructing the classifiers, which may include redundant information and ignore the relationships among them. In this study, we treat each measure as a task in our multitask learning framework. Considering the actual situation that we do not know the correlation between tasks in advance, we use a robust multitask feature learning (rMTFL) method to select a group of features among correlated measures and provide additional information by identifying outlier tasks at the same time. Then, we train several SVM classifiers and for each measure, we input the selected features into the corresponding SVM classifier. Finally, we use an ensemble classification strategy to combine the results of these classifiers based on the accuracy to make the final prediction. We use the leave-one-out cross-validation to evaluate our proposed method with 46 amnestic mild cognitive impairment (aMCI) and 52 normal controls (NC). The results show that rMTFL algorithm is superior to the group lasso method and average curvature is the outlier task based on multidimensional surface measures.

ObjectiveThis study focuses on the deposition characteristics of oil mist on metal and fabric surfaces in ship cabin. MethodsOil mist is released in an experimental cabin and allowed to deposit on the target surfaces. The mass difference before and after deposition on the surfaces is weighed to determine the deposition mass, and the oil mist deposition characteristics of surfaces with different orientations and materials are compared. The deposition on the horizontal downward surface is reasonably assumed to be gas phase deposition. Its contribution is then estimated and the particle phase deposition velocity is calculated. ResultsThe deposition mass on the horizontal upward surface of the metal is 3.98 times and 4.66 times greater than that on the vertical surface and horizontal downward surface. For fabric surfaces, the deposition mass on the horizontal upward surface is 1.08 times and 1.20 times greater than that of the vertical surface and horizontal downward surface. For material comparison, the deposition mass on the horizontal upward, vertical and horizontal downward surfaces of the fabric is 49.1 times, 169.8 times and 155.5 times greater than that of the metal surface facing in the same direction respectively. Estimates show that the contribution of phase deposition to the metal horizontal and vertical surfaces are 21.5% and 79.2% respectively. The contribution of phase deposition to the fabric surfaces is about 90%. ConclusionsThe oil mist deposition on fabric surfaces is much stronger than that on metal surfaces. The deposition on the metal horizontal upward surface is much greater than that on the vertical surface and horizontal downward surface. The deposition differences between the fabric surfaces in the three orientations are not significant. Regardless of orientation or material, gas phase deposition cannot be ignored as it plays a dominant role in ship cabin environments.