LSD1 inhibitors from the roots of Pueraria lobata.

One new 6a,11a-dehydropterocarpan derivative, 6-O-methyl-anhydrotuberosin (1), one new 6a-hydroxypterocarpan, (6aR,11aR,11bR)-hydroxytuberosone (7), and seven known compounds including two 6a,11a-dehydropterocarpans (2 and 4), two coumestans (3 and 5), one isoflavonoid (6) and two other phenolic compounds (8 and 9) were isolated from the roots of Pueraria lobata. The structures of the isolated compounds were elucidated with spectroscopic and spectrometric methods (1 D and 2DNMR, HRESIMS). Compounds 1, 2, 4-5 showed potent LSD1 inhibitory activities with IC50 values ranging from 1.73 to 4.99 µM. Furthermore, compound 2 showed potent cytotoxicity against gastric cancer cell lines MGC-803 and BGC-823, and lung cancer cell lines H1299 and H460.

[Mechanism of Puerariae Lobatae Radix against lung cancer by inhibiting histone demethylase LSD1].

Histone lysine-specific demethylase 1(LSD1) has become a promising molecular target for lung cancer therapy. Upon the screening platform for LSD1 activity, some Chinese herbal extracts were screened for LSD1 activity inhibition, and the underlying mechanism was preliminarily investigated at both molecular and cellular levels. The results of LSD1 inhibition showed that Puerariae Lobatae Radix extract can effectively reduce LSD1 expression to elevate the expression of H3 K4 me2 and H3 K9 me2 substrates in H1975 and H1299 cells. Furthermore, Puerariae Lobatae Radix was evaluated for its anti-lung cancer activity. It had a potent inhibitory ability against the proliferation and colony formation of both H1975 and H1299 cells. Flow cytometry and DAPI staining assays indicated that Puerariae Lobatae Radix can induce the apoptosis of lung cancer cells. In addition, it can significantly suppress the migration and reverse the epithelial-mesenchymal transition(EMT) process of lung cancer cells by activating E-cadherin and suppressing the expression of N-cadherin, slug and vimentin. To sum up, Puerariae Lobatae Radix displayed a robust inhibitory activity against lung cancer, and the mechanism may be related to the down-regulation of LSD1 expression to induce the cell apoptosis and suppress the cell migration and EMT process. These findings will provide new insights into the action of Puerariae Lobatae Radix as an anti-lung cancer agent and offer new ideas for the study on the anti-cancer action of Chinese medicine based on the epigenetic modification.

USP28 contributes to the proliferation and metastasis of gastric cancer.

USP28, a member of the deubiquitinating enzymes family, plays a vital role in the physiological process of cell proliferation, differentiation and apoptosis, DNA repair, immune response, and stress response. USP28 has been reported to be overexpressed in bladder cancer, colon cancer, breast carcinomas, and so on. Nevertheless, the role of USP28 in gastric cancer has not yet been investigated. In our study, we examined the USP28 expression in 87 paired samples of gastric cancer and normal gastric tissues. We found that USP28 was overexpressed in gastric cancer compared with normal gastric tissues (P < 0.01), and its overexpression was related to the degree of differentiation and metastases. Inhibiting USP28 expression in vitro suppressed the proliferation and invasion of gastric cancer cells by downregulating lysine specific demethylase 1. On the basis of our data, it can be concluded that USP28 may be a novel therapeutic target for gastric cancer.

Multifractal and lacunarity analyses of microvascular morphology in eyes with diabetic retinopathy: A projection artifact resolved optical coherence tomography angiography study.

OBJECTIVE: To evaluate the degree of microvascular impairment in DR using multifractal and lacunarity analyses and to compare the diagnostic ability between traditional Euclidean measures (fovea avascular zone area and vessel density) and fractal geometric features. METHODS: This retrospective cross-sectional study included a total of 143 eyes of 94 patients with different stages of DR. The retinal microvasculature was imaged by projection removed OCTA. We examined the degree of association between fractal metrics of the retinal microvasculature and DR severity. The area under the ROC curve was used to estimate the diagnostic performance. RESULTS: With increasing DR severity, the multifractal spectrum shifted toward the left bottom and exhibited less left skewness and asymmetry. The vessel density, multifractal features, and lacunarity measured from the DCP were strongly associated with DR severity. The multifractal feature D5 showed the highest diagnostic ability. The combination of multifractal features further improved the discriminating power. CONCLUSIONS: Multifractal and lacunarity analyses can be potentially valuable tools for assessment of microvascular impairments in DR. Multifractal geometric parameters exhibit a better discriminatory performance than Euclidean measures, particularly for detection of the early stages of DR.

Lysine-specific demethylase 1 activation by vitamin B2 attenuates efficacy of apatinib for proliferation and migration of gastric cancer cell MGC-803.

B vitamins play an essential role in the biosynthesis of nucleotides, replication of DNA, supply of methyl-groups, growth and repair of cells, aberrancies of which have all been implicated in carcinogenesis. Although the potential role of vitamin B in relation to the risk of cancer, including breast, and colorectal cancer, has been investigated in several observational studies, the mechanism of action is still unclear. In this study, vitamin B2 exhibited efficient activation of LSD1 by occupying the active sites where FAD stands. Interestingly, vitamin B2 significantly downregulated expression of CD86, a sensitive surrogate biomarker of LSD1 inhibition, and showed marked activation of gastric cancer cell migration and invasion. Meanwhile, vitamin B2 induced activation of LSD1 may attenuate the proliferation inhibition, and anti-migration effects of apatinib in gastric cancer cells. These findings suggested that vitamin B supplementation may interfere with the efficacy of apatinib in patients with gastric cancer.

Cysteine-Accelerated Methanogenic Propionate Degradation in Paddy Soil Enrichment.

Propionate degradation is a critical step during the conversion of complex organic matter under methanogenic conditions, and it requires a syntrophic cooperation between propionate-oxidizing bacteria and methanogenic archaea. Increasing evidences suggest that interspecies electron transfer for syntrophic metabolism is not limited to the reducing equivalents of hydrogen and formate. This study tested the ability of an electron shuttle to mediate interspecies electron transfer in syntrophic methanogenesis. We found that cysteine supplementation (100, 400, and 800 µM) accelerated CH4 production from propionate in paddy soil enrichments. Of the concentrations tested, 100 µM cysteine was the most effective at enhancing propionate degradation to CH4, and the rates of CH4 production and propionate degradation were increased by 109 and 79%, respectively, compared with the cysteine-free control incubations. We eliminated the possibility that the stimulatory effect of cysteine on methanogenesis was attributable to the function of cysteine as a methanogenic substrate in the presence of propionate. The potential catalytic effect involved cysteine serving as an electron carrier to mediate interspecies electron transfer in syntrophic propionate oxidization. The redox potential of cystine/cysteine, which is dependent on the concentration, might be more suitable to facilitate interspecies electron transfer between syntrophic partners at a concentration of 100 µM. Pelotomaculum, obligately syntrophic, propionate-oxidizing bacteria, and hydrogenotrophic methanogens of the family Methanobacteriaceae are predominant in cysteine-mediated methanogenic propionate degradation. The stimulatory effect of cysteine on syntrophic methanogenesis offers remarkable potential for improving the performance of anaerobic digestion and conceptually broaden strategies for interspecies electron transfer in syntrophic metabolism.

1,2,3-Triazole-Dithiocarbamate Hybrids, a Group of Novel Cell Active SIRT1 Inhibitors.

BACKGROUND/AIMS: Human SIRT1 is reported to be involved in tumorgenesis, mainly due to its modulating effect on p53 by deacetylation on lysine382. A large quantity of SIRT1 inhibitors was applied in chemotherapeutic study, but few of them were applied into clinical trials. METHODS AND RESULTS: In the current study, a novel series of compounds with 1,4-bispiperazinecarbodithioic acid methyl esters scaffold were characterized to have inhibitory potency to SIRT1 by molecular docking and biochemical evaluation. Further cell level study revealed that one of the most potent SIRT1 inhibitors, compound 3a, is cell active. It can upregulate the amount of p53 by accumulating the K382 acetylation of p53, which lead to the stabilization of p53 in human gastric cancer cell line MGC-803 cells. Meanwhile, we also found compound 3a can inactivate SIRT2 in cells, which suggests the compound as a non-selective SIRT inhibitor. CONCLUSION: All these findings indicate that compound 3a is a potent, reversible and cell active SIRT1 inhibitor and deserves further investigation as an anticancer agent or a biological tool.

Secondary Mineralization of Ferrihydrite Affects Microbial Methanogenesis in Geobacter-Methanosarcina Cocultures.

UNLABELLED: The transformation of ferrihydrite to stable iron oxides over time has important consequences for biogeochemical cycling of many metals and nutrients. The response of methanogenic activity to the presence of iron oxides depends on the type of iron mineral, but the effects of changes in iron mineralogy on methanogenesis have not been characterized. To address these issues, we constructed methanogenic cocultures of Geobacter and Methanosarcina strains with different ferrihydrite mineralization pathways. In this system, secondary mineralization products from ferrihydrite are regulated by the presence or absence of phosphate. In cultures producing magnetite as the secondary mineralization product, the rates of methanogenesis from acetate and ethanol increased by 30.2% and 135.3%, respectively, compared with a control lacking ferrihydrite. Biogenic magnetite was proposed to promote direct interspecies electron transfer between Geobacter and Methanosarcina in a manner similar to that of c-type cytochrome and thus facilitate methanogenesis. Vivianite biomineralization from ferrihydrite in the presence of phosphate did not significantly influence the methanogenesis processes. The correlation between magnetite occurrence and facilitated methanogenesis was supported by increased rates of methane production from acetate and ethanol with magnetite supplementation in the defined cocultures. Our data provide a new perspective on the important role of iron biomineralization in biogeochemical cycling of carbon in diverse anaerobic environments. IMPORTANCE: It has been found that microbial methanogenesis is affected by the presence of iron minerals, and their influences on methanogenesis are associated with the mineralogical properties of the iron minerals. However, how changes in iron mineralogy affect microbial methanogenesis has not been characterized. To address this issue, we constructed methanogenic cocultures of Geobacter and Methanosarcina strains with different ferrihydrite mineralization pathways. The experimental results led to two contributions, i.e., (i) the transformation of iron minerals might exert an important influence on methanogenesis under anaerobic conditions and (ii) both biogenic and chemical magnetite can accelerate syntrophic ethanol oxidization between Geobacter metallireducens and Methanosarcina barkeri This study sheds new light on the important role of iron biomineralization in the biogeochemical cycling of carbon in diverse anaerobic environments, particularly in iron-rich natural and agricultural wetland soils.

Baicalin, a natural LSD1 inhibitor.

Baicalin is one of the active ingredients in the skullcap, with a variety of pharmacological effects, such as blood pressure reduction, sedation, liver-protection, gallbladder-protection, anti-bacteria, and anti-inflammation. In our study, baicalin was first characterized as a LSD1 inhibitor with an IC50 of 3.01µM and showed strong LSD1 inhibitory effect in cells. Baicalin may serve as a template for designing flavone-based LSD1 inhibitors.

A Systematic Review of Histone Lysine-Specific Demethylase 1 and Its Inhibitors.

Histone lysine-specific demethylase 1 (LSD1) is the first discovered and reported histone demethylase by Dr. Shi Yang's group in 2004. It is classified as a member of amine oxidase superfamily, the common feature of which is using the flavin adenine dinucleotide (FAD) as its cofactor. Since it is located in cell nucleus and acts as a histone methylation eraser, LSD1 specifically removes mono- or dimethylated histone H3 lysine 4 (H3K4) and H3 lysine 9 (H3K9) through formaldehyde-generating oxidation. It has been indicated that LSD1 and its downstream targets are involved in a wide range of biological courses, including embryonic development and tumor-cell growth and metastasis. LSD1 has been reported to be overexpressed in variety of tumors. Inactivating LSD1 or downregulating its expression inhibits cancer-cell development. LSD1 targeting inhibitors may represent a new insight in anticancer drug discovery. This review summarizes recent studies about LSD1 and mainly focuses on the basic physiological function of LSD1 and its involved mechanisms in pathophysiologic conditions, as well as the development of LSD1 inhibitors as potential anticancer therapeutic agents.

Densely connected convolutional networks for ultrasound image based lesion segmentation.

Delineating lesion boundaries play a central role in diagnosing thyroid and breast cancers, making related therapy plans and evaluating therapeutic effects. However, it is often time-consuming and error-prone with limited reproducibility to manually annotate low-quality ultrasound (US) images, given high speckle noises, heterogeneous appearances, ambiguous boundaries etc., especially for nodular lesions with huge intra-class variance. It is hence appreciative but challenging for accurate lesion segmentations from US images in clinical practices. In this study, we propose a new densely connected convolutional network (called MDenseNet) architecture to automatically segment nodular lesions from 2D US images, which is first pre-trained over ImageNet database (called PMDenseNet) and then retrained upon the given US image datasets. Moreover, we also designed a deep MDenseNet with pre-training strategy (PDMDenseNet) for segmentation of thyroid and breast nodules by adding a dense block to increase the depth of our MDenseNet. Extensive experiments demonstrate that the proposed MDenseNet-based method can accurately extract multiple nodular lesions, with even complex shapes, from input thyroid and breast US images. Moreover, additional experiments show that the introduced MDenseNet-based method also outperforms three state-of-the-art convolutional neural networks in terms of accuracy and reproducibility. Meanwhile, promising results in nodular lesion segmentation from thyroid and breast US images illustrate its great potential in many other clinical segmentation tasks.

JANet: A joint attention network for balancing accuracy and speed in left ventricular ultrasound video segmentation.

Multiple cardiac diseases are closely associated with functional parameters of the left ventricle, but functional parameter quantification still requires manual involvement, a time-consuming and less reproducible task. We develop a joint attention network (JANet) and expand it into two versions (V1 and V2) that can be used to segment the left ventricular region in echocardiograms to assist physicians in diagnosis. V1 is a smaller model with a size of 56.3 MB, and V2 has a higher accuracy. The proposed JANet V1 and V2 achieve a mean dice score (DSC) of 93.59/93.69(V1/V2), respectively, outperforming the state-of-the-art models. We grade 1264 patients with 87.24/87.50 (V1/V2) accuracy when using the 2-level classification criteria and 83.62/84.18 (V1/V2) when using the 5-level classification criteria. The results of the consistency analysis show that the proposed method is comparable to that of clinicians.

Factors influencing the distribution, risk, and transport of microplastics and heavy metals for wildlife and habitats in "island" landscapes: From source to sink.

Microplastics (MPs) and heavy metals (HMs) are important pollutants in terrestrial ecosystems. In particular, the "island" landscape's weak resistance makes it vulnerable to pollution. However, there is a lack of research on MPs and HMs in island landscapes. Therefore, we used Helan Mountain as the research area. Assess the concentrations, spatial distribution, ecological risks, sources, and transport of MPs and HMs in the soil and blue sheep (Pseudois nayaur) feces. Variations in geographical distribution showed a connection between human activity and pollutants. Risk assessment indicated soil and wildlife were influenced by long-term pollutant polarization and multi-element inclusion (Igeo, Class I; PHI, Class V; RI (MPs), 33 % Class II, and 17 % Class IV; HI = 452.08). Source apportionment showed that tourism and coal combustion were the primary sources of pollutants. Meanwhile, a new coupling model of PMF/Risk was applied to quantify the source contribution of various risk types indicated transportation roads and tourism sources were the main sources of ecological and health risks, respectively. Improve the traceability of pollution source risks. Furthermore, also developed a novel tracing model for pollutant transportation, revealing a unique "source-sink-source" cycle in pollutant transportation, which provides a new methodological framework for the division of pollution risk areas in nature reserves and the evaluation of spatial transport between sources and sinks. Overall, this study establishes a foundational framework for conducting comprehensive risk assessments and formulating strategies for pollution control and management.

High strength, controlled release of curcumin-loaded ZIF-8/chitosan/zein film with excellence gas barrier and antibacterial activity for litchi preservation.

Polysaccharide films containing protein additives have good application prospects in agriculture and food field. However, interfacial incompatibility between hydrophobic proteins and hydrophilic polymers remains a major technical challenge. In this work, the interfacial compatibility between hydrophobic zein and hydrophilic chitosan (CS) is improved by the chemical crosslinking between zinc ions of curcumin-loaded zeolitic imidazolate framework-8 (Cur-ZIF-8) with CS and zein. With the improvement of interface compatibility, the results show that the elongation at break and O2 barrier property of synthesized Cur-ZIF-8/CS/Zein are 9.2 and 1.5 times higher than CS/Zein, respectively. And the Cur-ZIF-8/CS/Zein exhibits superior antibacterial and antioxidant properties as well. Importantly, Cur-ZIF-8/CS/Zein can also be used as an intelligent-responsive release platform for curcumin. As a result, Cur-ZIF-8/CS/Zein can keep the freshness and appearance of litchi at least 8 days longer than that of CS/Zein. Therefore, this study provides a novel method to improve the interfacial compatibility between hydrophobic proteins and hydrophilic polymers, and is expected to expand the application of protein/polymer composites in agriculture and food field.

Performance of iCare quantitative computed tomography in bone mineral density assessment of the hip and vertebral bodies in European spine phantom.

BACKGROUND: Osteoporosis is a systemic bone disease which can increase the risk of osteoporotic fractures. Dual-energy X-ray absorptiometry (DXA) is considered as the clinical standard for diagnosing osteoporosis by detecting the bone mineral density (BMD) in patients, but it has flaws in distinguishing between calcification and other degenerative diseases, thus leading to inaccurate BMD levels in subjects. Mindways quantitative computed tomography (Mindways QCT) is a classical QCT system. Similar to DXA, Mindways QCT can directly present the density of trabecular bone, vascular or tissue calcification; therefore, it is more accurate and sensitive than DXA and has been widely applied in clinic to evaluate osteoporosis. iCare QCT osteodensitometry was a new phantom-based QCT system, recently developed by iCare Inc. (China). It has been gradually applied in clinic by its superiority of taking 3-dimensional BMD of bone and converting BMD values to T value automatically. This study aimed at evaluating the osteoporosis detection rate of iCare QCT, compared with synchronous Mindways QCT (USA). METHODS: In this study, 131 patients who underwent hip phantom-based CT scan were included. Bone mineral density (BMD) of the unified region of interests (ROI) defined at the European spine phantom (ESP, German QRM) including L1 (low), L2 (medium), and L3 (high) vertebral bodies was detected for QCT quality control and horizontal calibration. Every ESP scan were taken for 10 times, and the mean BMD values measured by iCare QCT and Mindways QCT were compared. Hip CT scan was conducted with ESP as calibration individually. T-scores gained from iCare QCT and Mindways QCT were analyzed with Pearson correlation test. The detection rates of osteoporosis were compared between iCare QCT and Mindways QCT. The unified region of interests (ROI) was delineated in the QCT software. RESULTS: The results showed that there was no significant difference between iCare QCT and Mindways QCT in the evaluation of L1, L2, and L3 vertebrae bodies in ESP. A strong correlation between iCare QCT and Mindways QCT in the assessment of hip T-score was found. It was illustrated that iCare QCT had a higher detection rate of osteoporosis with the assessment of hip T-score than Mindways QCT did. In patients < 50 years subgroup, the detection rate of osteoporosis with iCare QCT and Mindways QCT was equal. In patients ≥ 50 years subgroup, the detection rate of osteoporosis with iCare QCT (35/92, 38.0%) was higher than that with Mindways QCT. In female subgroup, the detection rate of osteoporosis with iCare QCT was significantly higher than Mindways QCT. In male subgroup, the detection rate of osteoporosis with iCare QCT was also markedly higher than Mindways QCT. The detection rate of osteoporosis by iCare QCT was higher than Mindways QCT with hip bone assessment. Of course, the results of the present study remain to be further verified by multicenter studies in the future.

Radix Rehmanniae Praeparata (Shu Dihuang) exerts neuroprotective effects on ICV-STZ-induced Alzheimer's disease mice through modulation of INSR/IRS-1/AKT/GSK-3ß signaling pathway and intestinal microbiota.

Radix Rehmanniae Praeparata (RRP, Shu Dihuang in Cinese) is widely used as primal medicine in Chinese herbal formula for the treatment of Alzheimer's disease (AD). However, the underlying mechanism of RRP for AD remains unclear. The aim of this study was to investigate the therapeutic effect of RRP on intracerebroventricular injection of streptozotocin (ICV-STZ)-induced AD model mice and its potential mechanism. ICV-STZ mice were continuously gavaged with RRP for 21 days. The pharmacological effects of RRP were evaluated by behavioral tests, brain tissue H&E staining and hippocampal tau protein phosphorylation levels. The expression levels of insulin receptor (INSR), IRS-1, pSer473-AKT/AKT and pSer9-GSK-3ß/GSK-3ß proteins in hippocampal and cortical tissues were detected by Western-blot method. The 16S rRNA gene sequencing was used to analyze the changes of intestinal microbiota in mice. The compounds in RRP were analyzed by mass spectrometry and their binding ability to INSR proteins was detected by molecular docking. The results showed that RRP ameliorated cognitive dysfunction and neuronal pathological changes of brain tissue in ICV-STZ mice, reduced tau protein hyperphosphorylation, INSR, IRS-1, pSer473-AKT/AKT, and pSer9-GSK-3ß/GSK-3ß levels in hippocampal and cortical tissues. Meanwhile, RRP reversed ICV-STZ-induced dysregulation of intestinal microbiota in AD mice. Mass spectrometry analysis showed that the RRP consisted mainly of seven compounds, namely Acteoside (Verbascoside), 5-Hydroxymethyl-2-furaldehyde (5-HMF), Apigenin7-O-glucuronide, Icariin, Gallic acid, Quercetin-3ß-D-glucoside, and Geniposide. Molecular docking results further indicated that the compounds in RRP have binding ability to INSR protein and potential multiple synergistic effects. RRP ameliorates cognitive dysfunction and brain histopathological changes in AD mice. The mechanism of RRP ameliorating AD may be related to the regulation of INSR/IRS-1/AKT/GSK-3ß signaling pathway and intestinal microbiota. This study supports the potential anti-AD efficacy of RRP and initially reveals the pharmacological mechanism of RRP, providing a theoretical basis for further clinical application of RRP.

Cholecystokinin Signaling can Rescue Cognition and Synaptic Plasticity in the APP/PS1 Mouse Model of Alzheimer's Disease.

Synaptic impairment and loss are an important pathological feature of Alzheimer's disease (AD). Memory is stored in neural networks through changes in synaptic activity, and synaptic dysfunction can cause cognitive dysfunction and memory loss. Cholecystokinin (CCK) is one of the major neuropeptides in the brain, and plays a role as a neurotransmitter and growth factor. The level of CCK in the cerebrospinal fluid is decreased in AD patients. In this study, a novel CCK analogue was synthesized on the basis of preserving the minimum bioactive fragment of endogenous CCK to investigate whether the novel CCK analogue could improve synaptic plasticity in the hippocampus of the APP/PS1 transgenic mouse model of AD and its possible molecular biological mechanism. Our study found that the CCK analogue could effectively improve spatial learning and memory, enhance synaptic plasticity in the hippocampus, normalize synapse numbers and morphology and the levels of key synaptic proteins, up-regulate the PI3K/Akt signaling pathway and normalize PKA, CREB, BDNF and TrkB receptor levels in APP/PS1 mice. The amyloid plaque load in the brain was reduced by CCK, too. The use of a CCKB receptor antagonist and targeted knockdown of the CCKB receptor (CCKBR) attenuated the neuroprotective effect of the CCK analogue. These results demonstrate that the neuroprotective effect of CCK analogue is achieved by activating the PI3K/Akt as well as the PKA/CREB-BDNF/TrkB signaling pathway that leads to protection of synapses and cognition.

The neuroprotective effects of Liuwei Dihuang medicine in the APP/PS1 mouse model are dependent on the PI3K/Akt signaling pathway.

Alzheimer's disease (AD) is an age-related neurodegenerative disease that progressively impairs cognitive function and memory. The occurrence and development of Alzheimer's disease involves many processes. In response to the complex pathogenesis of AD, the Traditional Chinese medicine formula Liuwei Dihuang Pill (LWD) has been shown to improve the cognitive function of AD animal models. However, the active ingredients and mechanism of action of LWD have not been fully elucidated. In this study, network pharmacological analysis predicted 40 candidate compounds in LWD, acting on 227 potential targets, of which 185 were associated with AD. Through network pharmacological analysis, the mechanism of action of LWD therapy AD is related to the inhibition of inflammatory response, regulation of neuronal state, and autophagy. In this experiment, LWD was detected in the APP/PS1 transgenic mouse model. The objective was to observe the effects of LWD on hippocampal learning and memory ability, Aß clearance, autophagy and inflammatory response in APP/PS1 mice. The results showed that LWD improved long-term memory and working memory in APP/PS1 mice compared with the WT group. At the same time, LWD can increase the expression of hippocampal autophagy biomarkers, reduce the precipitation of Aß, and the activation of microglia and astrocytes. Its mechanism may be related to the regulation of the PI3K/Akt signaling pathway. Thus, we demonstrate for the first time that LWD has a neuroprotective effect on APP/PS1 mice and provide theoretical foundation for the development of a new clinical treatment for AD.

Design, synthesis and in vitro/in vivo anticancer activity of tranylcypromine-based triazolopyrimidine analogs as novel LSD1 inhibitors.

Histone lysine specific demethylase 1 (LSD1) is responsible for the demethylation of mono-/dimethylated lysine residue on histone proteins. LSD1 plays an extensive and essential role in the pathogenesis and progression of many human diseases such as cancers, and thus is becoming an attractive therapeutic target for cancer treatment. Tranylcypromine (TCP) is an important chemical template for developing irreversible LSD1 inhibitors, representing a major chemotype of clinical candidates. Here we report a novel pool of TCP derivatives with triazolopyrimidine as a privileged heterocylic motif. Starting from ticagrelor, a clinically available antiplatelet agent, as a hit compound, our medicinal efforts have led to the identification of compound 9j with nanomolar inhibitory potency against LSD1 as well as broad-spectrum antiproliferative activities against tumor cells. Enzyme studies show that compound 9j is selective over MAO-A/B enzymes, and also cellular active to elevate the expression of H3K4me2 by inhibiting LSD1 in cells. Furthermore, in a H1650 xenograft mouse model, oral administration of compound 9j at low 10 and 20 mg/kg dosages could enable a significant reduction in tumor size and a remarkable extension of survival. The current work is expected to provide an additional strategy to achieve new TCP-based LSD1 inhibitors.

Inhibition of ferroptosis through regulating neuronal calcium homeostasis: An emerging therapeutic target for Alzheimer's disease.

Alzheimer's disease (AD), a chronic and progressive neurodegenerative disease, generates a serious threat to the health of the elderly. The AD brain is microscopically characterized by amyloid plaques and neurofibrillary tangles. There are still no effective therapeutic drugs to restrain the progression of AD though much attention has been paid to exploit AD treatments. Ferroptosis, a type of programmed cell death, has been reported to promote the pathological occurrence and development of AD, and inhibition of neuronal ferroptosis can effectively improve the cognitive impairment of AD. Studies have shown that calcium (Ca2+) dyshomeostasis is closely related to the pathology of AD, and can drive the occurrence of ferroptosis through several pathways, such as interacting with iron, and regulating the crosstalk between endoplasmic reticulum (ER) and mitochondria. This paper mainly reviews the roles of ferroptosis and Ca2+ in the pathology of AD, and highlights that restraining ferroptosis through maintaining the homeostasis of Ca2+ may be an innovative target for the treatment of AD.