Aldehyde dehydrogenase 2 (ALDH2) plays an important role in the detoxification of reactive aldehydes under oxidative stress. Because an estimated 50% of East Asians carry a common ALDH2 deficient ...variant with decreased enzyme activity and are more susceptible to toxic aldehydes, more recent findings have highlighted the therapeutic potential of ALDH2 activators in aldehyde-related diseases such as cardiovascular injury. Drug repurposing has unique advantages in providing new lead compounds with good drug-like properties. Herein, we identified Tadalafil from DrugBank as a novel ALDH2 activator using a combination strategy of docking-based and pharmacophore-based virtual screening based on exploring the activation mechanism. Then a hit-based substructure search was completed and has led to the discovery of 5 hits, among which A1 showed better ALDH2 activation activity than Tadalafil. This study provides a good basis for the further research of ALDH2 activators.
Type 2 diabetes (T2DM) is a well known risk factor for Alzheimer’s disease. Mitochondria are the center of intracellular energy metabolism and the main source of reactive oxygen species. ...Mitochondrial dysfunction has been identified as a key factor in diabetes-associated brain alterations contributing to neurodegenerative events. Defective insulin signaling may act in concert with neurodegenerative mechanisms leading to abnormalities in mitochondrial structure and function. Mitochondrial dysfunction triggers neuronal energy exhaustion and oxidative stress, leading to brain neuronal damage and cognitive impairment. The normality of mitochondrial function is basically maintained by mitochondrial quality control mechanisms. In T2DM, defects in the mitochondrial quality control pathway in the brain have been found to lead to mitochondrial dysfunction and cognitive impairment. Here, we discuss the association of mitochondrial dysfunction with T2DM and cognitive impairment. We also review the molecular mechanisms of mitochondrial quality control and impacts of mitochondrial quality control on the progression of cognitive impairment in T2DM.
Abstract Pelvic organ prolapse (POP) occurs only in women and becomes more common as women age. However, the surgical practices remain poorly evaluated. The realization of a simulator of the dynamic ...behavior of the pelvic organs is then identified as a need. It allows the surgeon to estimate the functional impact of his actions before his implementation. In this work, the simulation will be based on a patient-specific approach in which each geometrical model will be carried out starting from magnetic resonance image (MRI) acquisition of pelvic organs of one patient. To determine the strain and stress in the soft biological tissues, hyperelastic constitutive laws are used in the context of finite element analysis. The Yeoh model has been implemented into an in-house finite element code FER to model these organ tissues taking into account large deformations with multiple contacts. The 2D and 3D models are considered in this preliminary study and the results show that our method can help to improve the understanding of different forms of POP.
Hope is the emotional feeling experienced when a desired outcome happens with a positive probability. This article provides a behavioral definition of preference for hope. The definition requires the ...decision maker to have two behavioral patterns: hope preservation by delaying the resolution of uncertainty, and hope-seeking by taking risk. I show that if people have a preference for hope, then it violates simultaneously the axiom of time neutrality, dynamic consistency and expected stationarity.
•I provide a behavioral definition of preference for hope with two separate parts.•First, with a preference for hope people avoid safe but hopeless options.•Second, with a preference for hope people delay the resolution of uncertainty.•Combining the two parts implies three well-known assumptions are all violated.
Pathogen-host interactions play an important role in understanding the mechanism by which a pathogen can infect its host. Some approaches for predicting pathogen-host association have been developed, ...but prediction accuracy is still low. In this paper, we propose a bipartite network module-based approach to improve prediction accuracy. First, a bipartite network with pathogens and hosts is constructed. Next, pathogens and hosts are divided into different modules respectively. Then, modular information on the pathogens and hosts is added into a bipartite network projection model and the association scores between pathogens and hosts are calculated. Finally, leave-one-out cross-validation is used to estimate the performance of the proposed method. Experimental results show that the proposed method performs better in predicting pathogen-host association than other methods, and some potential pathogen-host associations with higher prediction scores are also confirmed by the results of biological experiments in the publically available literature.
The modification of apolar carbon materials by heteroatom doping is an effective method that can effectively improve the surface polarity of carbon materials. In the main body of the lithium–sulfur ...battery cathode, the structural properties of the carbon material itself with porous structure and large specific surface area provide sufficient space for sulfur accommodation and mitigate the bulk effect of the sulfur cathode (79%). The polarized surface of the reconstructed carbon material possesses strong adsorption effect on LiPs, which mitigates the notorious “shuttle effect.” In this paper, the surface structure of the Ketjen black cathode body was reconstructed by B and N double heteroatoms to polarize it. The modified polarized Ketjen black improves the adsorption and anchoring ability of LiPs during the reaction and accelerates their kinetic conversion, while its own uniformly distributed small mesopores and oversized BET structural properties are beneficial to mitigate the bulk effect of sulfur cathodes. Lithium–sulfur batteries using B and N modified cathodes have an initial discharge capacity of 1344.49 mAh/g at 0.1 C and excellent cycling stability at 0.5 C (381.4 mAh/g after 100 cycles).
Stimulation of CD95/Fas drives and maintains cancer stem cells (CSCs). We now report that this involves activation of signal transducer and activator of transcription 1 (STAT1) and induction of ...STAT1-regulated genes and that this process is inhibited by active caspases. STAT1 is enriched in CSCs in cancer cell lines, patient-derived human breast cancer, and CD95high-expressing glioblastoma neurospheres. CD95 stimulation of cancer cells induced secretion of type I interferons (IFNs) that bind to type I IFN receptors, resulting in activation of Janus-activated kinases, activation of STAT1, and induction of a number of STAT1-regulated genes that are part of a gene signature recently linked to therapy resistance in five primary human cancers. Consequently, we identified type I IFNs as drivers of cancer stemness. Knockdown or knockout of STAT1 resulted in a strongly reduced ability of CD95L or type I IFN to increase cancer stemness. This identifies STAT1 as a key regulator of the CSC-inducing activity of CD95.
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•Stimulation of CD95 induces cancer stemness through induction of type I IFNs•Cancer stem cells express a STAT1-regulated gene signature•Radiation-resistant SCC and CD95-stimulated breast cancer cells express an IFN gene signature•Type I IFNs stimulate cancer stemness of breast cancer cells
Chronic stimulation of the death receptor CD95/Fas by CD95 ligand induces cancer stemness. Qadir et al. report that this activity involves induction of type I interferons followed by activation of STAT1 and Janus kinases downstream of the type I interferon receptors.
Although all-trans retinoic acid (ATRA)-induced differentiation has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological disease, resistance to ATRA in ...high-risk APL patients remains a clinical challenge. In this paper, we discovered that dihydroorotate dehydrogenase (DHODH) inhibition overcame ATRA resistance. 416, a potent DHODH inhibitor previously obtained in our group, inhibited the occurrence of APL in cells and model mice. Excitingly, 416 effectively overcame ATRA resistance in vitro and in vivo by inducing apoptosis and differentiation. Further mechanistic studies showed that PML/RARα lost the regulation of Bcl-2 and c-Myc in NB4-R1 cells, which probably contributed to ATRA resistance. Notably, 416 maintained its Bcl-2 and c-Myc down-regulation effect in NB4-R1 cells and overcome ATRA resistance by inhibiting DHODH. In conclusion, our study highlights the potential of 416 for APL therapy and overcoming ATRA resistance, supporting the further development of DHODH inhibitors for clinical use in refractory and relapsed APL.
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•416 inhibited the progression of ATRA-sensitive APL in vitro and in vivo.•416 overcame ATRA resistance in vitro and in vivo.•416 induced apoptosis and differentiation of NB4 cells by targeting DHODH.•Dysregulation of Bcl-2 and c-Myc by PML/RARα in NB4-R1 cells led to ATRA resistance.•416 overcame ATRA resistance by downregulating Bcl-2 and c-Myc.
Both genetic and environmental factors are implicated in type 1 diabetes (T1D). Because environmental factors can trigger epigenetic changes, we hypothesized that variations in histone ...post-translational modifications (PTMs) at the promoter/enhancer regions of T1D susceptible genes may be associated with T1D. We therefore evaluated histone PTM variations at known T1D susceptible genes in blood cells from T1D patients versus healthy nondiabetic controls, and explored their connections to T1D. We used the chromatin immunoprecipitation-linked to microarray approach to profile key histone PTMs, including H3-lysine 4 trimethylation (H3K4me3), H3K27me3, H3K9me3, H3K9 acetylation (H3K9Ac), and H4K16Ac at genes within the T1D susceptible loci in lymphocytes, and H3K4me3, H3K9me2, H3K9Ac, and H4K16Ac at the insulin-dependent diabetes mellitus 1 region in monocytes of T1D patients and healthy controls separately. We screened for potential variations in histone PTMs using computational methods to compare datasets from T1D and controls. Interestingly, we observed marked variations in H3K9Ac levels at the upstream regions of HLA-DRB1 and HLA-DQB1 within the insulin-dependent diabetes mellitus 1 locus in T1D monocytes relative to controls. Additional experiments with THP-1 monocytes demonstrated increased expression of HLA-DRB1 and HLA-DQB1 in response to interferon-γ and TNF-α treatment that were accompanied by changes in H3K9Ac at the same promoter regions as that seen in the patient monocytes. These results suggest that the H3K9Ac status of HLA-DRB1 and HLA-DQB1, two genes highly associated with T1D, may be relevant to their regulation and transcriptional response toward external stimuli. Thus, the promoter/enhancer architecture and chromatin status of key susceptible loci could be important determinants in their functional association to T1D susceptibility.
Both genetic and epigenetic factors are implicated in Type 1 diabetes (T1D).
Variations in histone H3-lysine 9 acetylation are detected around the promoter/enhancer regions of key T1D susceptible genes in monocytes of T1D subjects versus normals.
The chromatin status of this key region is altered in T1D.
Epigenetic variations at T1D susceptible genes may be functionally important.
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