Degraders in epigenetic therapy: PROTACs and beyond.

Epigenetics refers to the reversible process through which changes in gene expression occur without changing the nucleotide sequence of DNA. The process is currently gaining prominence as a pivotal objective in the treatment of cancers and other ailments. Numerous drugs that target epigenetic mechanisms have obtained approval from the Food and Drug Administration (FDA) for the therapeutic intervention of diverse diseases; many have drawbacks, such as limited applicability, toxicity, and resistance. Since the discovery of the first proteolysis-targeting chimeras (PROTACs) in 2001, studies on targeted protein degradation (TPD)-encompassing PROTACs, molecular glue (MG), hydrophobic tagging (HyT), degradation TAG (dTAG), Trim-Away, a specific and non-genetic inhibitor of apoptosis protein (IAP)-dependent protein eraser (SNIPER), antibody-PROTACs (Ab-PROTACs), and other lysosome-based strategies-have achieved remarkable progress. In this review, we comprehensively highlight the small-molecule degraders beyond PROTACs that could achieve the degradation of epigenetic proteins (including bromodomain-containing protein-related targets, histone acetylation/deacetylation-related targets, histone methylation/demethylation related targets, and other epigenetic targets) via proteasomal or lysosomal pathways. The present difficulties and forthcoming prospects in this domain are also deliberated upon, which may be valuable for medicinal chemists when developing more potent, selective, and drug-like epigenetic drugs for clinical applications.

Combination Therapy and Dual-Target Inhibitors Based on LSD1: New Emerging Tools in Cancer Therapy.

Lysine specific demethylase 1 (LSD1), a transcriptional modulator that represses or activates target gene expression, is overexpressed in many cancer and causes imbalance in the expression of normal gene networks. Over two decades, numerous LSD1 inhibitors have been reported, especially some of which have entered clinical trials, including eight irreversible inhibitors (TCP, ORY-1001, GSK-2879552, INCB059872, IMG-7289, ORY-2001, TAK-418, and LH-1802) and two reversible inhibitors (CC-90011 and SP-2577). Most clinical LSD1 inhibitors demonstrated enhanced efficacy in combination with other agents. LSD1 multitarget inhibitors have also been reported, exampled by clinical dual LSD1/histone deacetylases (HDACs) inhibitors 4SC-202 and JBI-802. Herein, we present a comprehensive overview of the combination of LSD1 inhibitors with various antitumor agents, as well as LSD1 multitarget inhibitors. Additionally, the challenges and future research directionsare also discussed, and we hope this review will provide new insight into the development of LSD1-targeted anticancer agents.

Recent advances in selective mono-/dichalcogenation and exclusive dichalcogenation of C(sp2)-H and C(sp3)-H bonds.

Organochalcogen compounds are prevalent in numerous natural products, pharmaceuticals, agrochemicals, polymers, biological molecules and synthetic intermediates. Direct chalcogenation of C-H bonds has evolved as a step- and atom-economical method for the synthesis of chalcogen-bearing compounds. Nevertheless, direct C-H chalcogenation severely lags behind C-C, C-N and C-O bond formations. Moreover, compared with the C-H monochalcogenation, reports of selective mono-/dichalcogenation and exclusive dichalcogenation of C-H bonds are relatively scarce. The past decade has witnessed significant advancements in selective mono-/dichalcogenation and exclusive dichalcogenation of various C(sp2)-H and C(sp3)-H bonds via transition-metal-catalyzed/mediated, photocatalytic, electrochemical or metal-free approaches. In light of the significance of both mono- and dichalcogen-containing compounds in various fields of chemical science and the critical issue of chemoselectivity in organic synthesis, the present review systematically summarizes the advances in these research fields, with a special focus on elucidating scopes and mechanistic aspects. Moreover, the synthetic limitations, applications of some of these processes, the current challenges and our own perspectives on these highly active research fields are also discussed. Based on the substrate types and C-H bonds being chalcogenated, the present review is organized into four sections: (1) transition-metal-catalyzed/mediated chelation-assisted selective C-H mono-/dichalcogenation or exclusive dichalcogenation of (hetero)arenes; (2) directing group-free selective C-H mono-/dichalcogenation or exclusive dichalcogenation of electron-rich (hetero)arenes; (3) C(sp3)-H dichalcogenation; (4) dichalcogenation of both C(sp2)-H and C(sp3)-H bonds. We believe the present review will serve as an invaluable resource for future innovations and drug discovery.

LSD1 in drug discovery: From biological function to clinical application.

Lysine-specific demethylase 1 (LSD1) is a flavin adenine dinucleotide (FAD) dependent monoamine oxidase (MAO) that erases the mono-, and dimethylation of histone 3 lysine 4 (H3K4), resulting in the suppression of target gene transcriptions. Besides, it can also demethylate some nonhistone substrates to regulate their biological functions. As reported, LSD1 is widely upregulated and plays a key role in several kinds of cancers, pharmacological or genetic ablation of LSD1 in cancer cells suppresses cell aggressiveness by several distinct mechanisms. Therefore, numerous LSD1 inhibitors, including covalent and noncovalent, have been developed and several of them have entered clinical trials. Herein, we systemically reviewed and discussed the biological function of LSD1 in tumors, lymphocytes as well as LSD1-targeting inhibitors in clinical trials, hoping to benefit the field of LSD1 and its inhibitors.

Multi-omics reveals aging-related pathway in natural aging mouse liver.

Aging is associated with gradual changes in liver structure, altered metabolites and other physiological/pathological functions in hepatic cells. However, its characterized phenotypes based on altered metabolites and the underlying biological mechanism are unclear. Advancements in high-throughput omics technology provide new opportunities to understand the pathological process of aging. Here, in our present study, both metabolomics and phosphoproteomics were applied to identify the altered metabolites and phosphorylated proteins in liver of young (the WTY group) and naturally aged (the WTA group) mice, to find novel biomarkers and pathways, and uncover the biological mechanism. Analysis showed that the body weights, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increased in the WTA group. The grips decreased with age, while the triglyceride (TG) and cholesterol (TC) did not change significantly. The increase of fibrosis, accumulation of inflammatory cells, hepatocytes degeneration, the deposition of lipid droplets and glycogen, the damaged mitochondria, and deduction of endoplasmic reticulum were observed in the aging liver under optical and electron microscopes. In addition, a network of metabolites and phosphorylated proteomes of the aging liver was established. Metabolomics detected 970 metabolites in the positive ion mode and 778 metabolites in the negative ion mode. A total of 150 pathways were pooled. Phosphoproteomics identified 2618 proteins which contained 16621 phosphosites. A total of 164 pathways were detected. 65 common pathways were detected in two omics. Phosphorylated protein heat shock protein HSP 90-alpha (HSP90A) and v-raf murine viral oncogene homolog B1(BRAF), related to cancer pathway, were significantly upregulated in aged mice liver. Western blot verified that protein expression of MEK and ERK, downstream of BRAF pathway were elevated in the liver of aging mice. However, the protein expression of BRAF was not a significant difference. Overall, these findings revealed a close link between aging and cancer and contributed to our understanding of the multi-omics changes in natural aging.

Novel acridine-based LSD1 inhibitors enhance immune response in gastric cancer.

Recently, histone lysine specific demethylase 1 (LSD1) has become an emerging and promising target for cancer immunotherapy. Herein, based on our previously reported LSD1 inhibitor DXJ-1 (also called 6x), a series of novel acridine-based LSD1 inhibitors were identified via structure optimizations. Among them, compound 5ac demonstrated significantly enhanced inhibitory activity against LSD1 with an IC50 value of 13 nM, about 4.6-fold more potent than DXJ-1 (IC50 = 73 nM). Molecular docking studies revealed that compound 5ac could dock well into the active site of LSD1. Further mechanism studies showed that compound 5ac inhibited the stemness and migration of gastric cancer cells, and reduced the expression of PD-L1 in BGC-823 and MFC cells. More importantly, BGC-823 cells were more sensitive to T cell killing when treated with compound 5ac. Besides, the tumor growth was also suppressed by compound 5ac in mice. Together, 5ac could serve as a promising candidate to enhance immune response in gastric cancer.

Exosomes from human umbilical cord mesenchymal stem cells protect aortas in Db/db mice characterized by combination of metabolomics and proteomics.

Diabetic cardiovascular complication is a common systemic disease with high morbidity and mortality worldwide. We hypothesise that exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSCs-exos) can rescue these disorders and alleviate vascular remodeling in diabetes. Morphological, non-targeted metabolomics and 4D label-free proteomics techniques were used to analyze the aortas of db/m mice as normal control group (NCA), saline treated db/db mice (DMA), and hUCMSCs-exos treated db/db mice (DMTA), and to clarify the molecular mechanism of the protection of hUCMSCs-exos in vascular remodeling from a new point of view. The results showed that 74 metabolites were changed significantly in diabetic aortas, of which 15 were almost restored by hUCMSCs-exos. In proteomics, 30 potential targets such as Stromal cell-derived factor 2-like protein 1, Leukemia inhibitory factor receptor, Peroxisomal membrane protein and E3 ubiquitin-protein ligase MYCBP2 were detected. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway-based analysis showed that Central carbon metabolism in cancer and Galactose metabolism pathway were up-regulated to near normal by hUCMSCs-exos in metabolomics, with janus associated kinase-signal transducer and activator of transcription (JAK-STAT) pathway displayed in proteomics. According to bioinformatics and integrated analysis, these targeted molecules of hUCMSCs-exos to attenuate the vascular remodeling were mainly associated with regulation of energy metabolism, oxidative stress, inflammation, and cellular communications. This study provided a reference for the therapy of diabetes-induced cardiovascular complications.

Ultra-bright and narrow-band emission from Ag atomic sized nanoclusters in a self-assembled plasmonic resonator.

We have proposed, implemented and investigated a novel, efficient quantum emitter based on an atomic-sized Ag nanocluster in a plasmonic resonator. The quantum emitter enables the realization of: (1) ultra-bright fluorescence, (2) narrow-band emission down to 4 nm, (3) ultra-short fluorescence lifetime. The fluorescence cross-section of a quantum emitter is on the order of σ ∼ 10-14 cm2, which is comparable to the largest fluorescence cross-sections of dye molecules and quantum dots, and enables a light source with a record high intensity known only for plasmon nanolasers. The results presented suggest a unique method for fabricating nanoprobes with high brightness and wavelength-tunable spectrally narrow fluorescence, which is needed for multiplex diagnostics and detection of substances at extremely low concentrations.

Efficacy of Conbercept in the Treatment of Choroidal Neovascularization Secondary to Pathologic Myopia.

Purpose: To observe the clinical efficacy of conbercept in the treatment of choroidal neovascularization (CNV) secondary to pathologic myopia. Methods: We used retrospective analysis of the clinical data of 20 patients (24 eyes) with pathologic myopia choroidal neovascularization (PM-CNV). All patients were treated with intravitreal injection of conbercept 0.5 mg (0.05 ml), a vascular endothelial growth factor (VEGF) receptor fusion protein, and all patients completed at least 6 months of follow-up. Fundus, best corrected visual acuity (BCVA), fundus fluorescein angiography (FFA), optical coherence tomography (OCT), multifocal electroretinogram (mfERG) were assessed before and after treatment. Primary outcome was the functional change in amplitude by mfERG and secondary outcome was the structural change in central macular thickness (CRT) by OCT. The CNV area, leakage of CNV lesions, ocular and systemic adverse events were observed before and after treatment. Results: The BCVA were 64.33 ± 10.83 letters, 65.42 ± 11.24 letters, 67.67 ± 7.07 letters after treatment 1, 3, 6 month, respectively, which showed improvement compared with the baseline (P < 0.05). The CRT decreased significantly from 308.50 ± 45.48 µm to 219.63 ± 30.27 µm, 221.33 ± 40.65 µm, 220.96 ± 33.09 µm after treatment 1, 3, 6 month, respectively (P < 0.05). The P1 response of mfERG amplitude improved from 40.71 ± 9.69 nv/deg2 to 50.67 ± 9.48 nv/deg2, 54.92 ± 8.45 nv/deg2, 55.67 ± 6.74 nv/deg2 after treatment 1, 3, 6 month, respectively (P < 0.05). After 6 months of treatment, the leakage of CNV lesions disappeared in 20 (83.3%) eyes, and the leakage area of CNV lesions was significantly reduced in 4 (16.7%) eyes. Conclusion: The intravitreal injection of conbercept significantly reduced CRT and the CNV area, inhibited the leakage of CNV, improved the BCVA, increased the response of mfERG amplitude, and restored the retinal function. The intravitreal injection of conbercept can change the morphology and function of the macular in PM-CNV, which is safe and effective for the treatment of PM-CNV.

Diagnostic value of orbicularis oculi muscle electromyography in functional epiphora.

BACKGROUND: Functional epiphora is a clinical condition which is not due to an anatomic defect. Most studies agree that it involves the action of the orbicularis oculi muscle, particularly its deeper segment (Horner's muscle), but the exact mechanism is not clear. AIM: To evaluate the orbicularis oculi muscle in functional epiphora patients using electromyography (EMG). METHODS: A total of 8 Chinese patients (16 eyes) with functional epiphora were enrolled in this study, and ten volunteers (10 eyes) were included as normal controls. Five epiphora patients (five eyes) with facial palsy served as positive controls. Quantitative EMG was performed in the deeper segment of orbicularis oculi muscle. The average duration of each EMG waveform was measured. RESULTS: The average duration of EMG waveforms in the normal control group, the functional epiphora group, and the facial palsy group were 6.39 ± 0.73 ms, 9.39 ± 1.32 ms and 11.2 ± 1.42 ms, respectively. The duration of EMG waveforms was significantly longer in the functional epiphora group than in the normal control group (P < 0.05), and shorter than that in the facial palsy group (P < 0.05). CONCLUSION: These data indicate the presence of neurogenic orbicularis oculi muscle damage in epiphora patients, which may be the cause of functional epiphora. The etiology of neurogenic damage in the orbicularis oculi muscle requires further investigation.

Occurrence and distribution of clinical and veterinary antibiotics in the faeces of a Chinese population.

Antibiotics ingested in the human gut may create selective pressure to change the composition of the gut microbiota, which could adversely effect the immune system of the host. However, the occurrence and distribution of antibiotics in the human gut remains unclear. A total population of 180 individuals, across three Chinses regions with different economic development levels, including children, adults, and elders, were sampled in 2017. A total of 19 representative antibiotics, including both clinical and veterinary antibiotics, were investigated in human faeces. While clinical use and prescriptions were the main exposure pathways for children, environmental media were the exposure pathway to adults. In addition, significant differences (P < 0.05) in antibiotic residues in human faeces were observed amongst various economic development levels, where human faeces from underdeveloped areas were mostly associated with higher levels of antibiotics. This study first to investigate the occurrence and distribution of typical antibiotics in the faeces of a Chinese population and thereby provide a reference for the intensive study of the effects and mechanisms of antibiotics on human gut microbiota.

Direct Amidation of Carboxylic Acids with Nitroarenes.

N-Aryl amides are an important class of compounds in pharmaceutical and agrochemical chemistry. Rapid and low-cost synthesis of N-aryl amides remains in high demand. Herein, we disclose an operationally simple process to access N-aryl amides directly from readily available nitroarenes and carboxylic acids as coupling substrates. This method involves the in situ activation of carboxylic acids to acyloxyphosphonium salt for one-pot amidation, without the need for isolation of the corresponding synthetic intermediates. Furthermore, the ease of preparation and workup allow the quick and efficient synthesis of a wide range of N-aryl amides, including several amide-based druglike and agrochemical molecules.

Identifying Patients with Atrioventricular Septal Defect in Down Syndrome Populations by Using Self-Normalizing Neural Networks and Feature Selection.

Atrioventricular septal defect (AVSD) is a clinically significant subtype of congenital heart disease (CHD) that severely influences the health of babies during birth and is associated with Down syndrome (DS). Thus, exploring the differences in functional genes in DS samples with and without AVSD is a critical way to investigate the complex association between AVSD and DS. In this study, we present a computational method to distinguish DS patients with AVSD from those without AVSD using the newly proposed self-normalizing neural network (SNN). First, each patient was encoded by using the copy number of probes on chromosome 21. The encoded features were ranked by the reliable Monte Carlo feature selection (MCFS) method to obtain a ranked feature list. Based on this feature list, we used a two-stage incremental feature selection to construct two series of feature subsets and applied SNNs to build classifiers to identify optimal features. Results show that 2737 optimal features were obtained, and the corresponding optimal SNN classifier constructed on optimal features yielded a Matthew's correlation coefficient (MCC) value of 0.748. For comparison, random forest was also used to build classifiers and uncover optimal features. This method received an optimal MCC value of 0.582 when top 132 features were utilized. Finally, we analyzed some key features derived from the optimal features in SNNs found in literature support to further reveal their essential roles.

Replication of a pathogenic non-coding RNA increases DNA methylation in plants associated with a bromodomain-containing viroid-binding protein.

Viroids are plant-pathogenic molecules made up of single-stranded circular non-coding RNAs. How replicating viroids interfere with host silencing remains largely unknown. In this study, we investigated the effects of a nuclear-replicating Potato spindle tuber viroid (PSTVd) on interference with plant RNA silencing. Using transient induction of silencing in GFP transgenic Nicotiana benthamiana plants (line 16c), we found that PSTVd replication accelerated GFP silencing and increased Virp1 mRNA, which encodes bromodomain-containing viroid-binding protein 1 and is required for PSTVd replication. DNA methylation was increased in the GFP transgene promoter of PSTVd-replicating plants, indicating involvement of transcriptional gene silencing. Consistently, accelerated GFP silencing and increased DNA methylation in the of GFP transgene promoter were detected in plants transiently expressing Virp1. Virp1 mRNA was also increased upon PSTVd infection in natural host potato plants. Reduced transcript levels of certain endogenous genes were also consistent with increases in DNA methylation in related gene promoters in PSTVd-infected potato plants. Together, our data demonstrate that PSTVd replication interferes with the nuclear silencing pathway in that host plant, and this is at least partially attributable to Virp1. This study provides new insights into the plant-viroid interaction on viroid pathogenicity by subverting the plant cell silencing machinery.

Safety and efficacy of a non-polymeric paclitaxel-eluting microporous stent in real-world percutaneous coronary intervention.

At present, there is an increasing focus on stents that have a biodegradable polymer coating, rather than a permanent polymer coating. This is due to the fact that following the implantation of a drug-eluting stent (DES) with a permanent polymer coating, the continued existence of the coating may result in a foreign body reaction and delayed re-endothelialization. The aim of the present study was to evaluate the safety and efficacy of a non-polymeric paclitaxel-eluting microporous (YINYI™) stent in real-life percutaneous coronary intervention (PCI) for patients with coronary artery disease (CAD). A total of 686 YINYI™ stents were implanted in 404 patients with CAD in a PCI procedure and outpatient follow-ups were performed 1, 6, 12 and 15 months subsequent to the PCI, respectively. The observation endpoints were major adverse cardiac events (MACEs), including cardiac death, non-fatal myocardial infarction (MI), restenosis, target lesion revascularization, stent thrombosis and recurrence of angina pectoris. The average follow-up time was 15 months. The results revealed that the cumulative incidences of MACEs were as follows: mortality, 0.99%; non-fatal MI, 0.74%; restenosis, 4.0%; and target lesion revascularization, 2.7%. The results at the short- and long-term clinical follow-ups indicated that YINYI™ stents are effective and safe for use in PCI for patients with CAD.

[The deposition of elements in the process of laser ablation of silicon].

Laser processing in the semiconductor industry (especially silicon material) has broad application prospects. The interaction between the laser and silicon is complex, and the present paper mainly studied the silicon morphology in UV laser ablation and the influence law of ambient gas. Studies have shown that the laser plasma ionization effect of silicon in the UV laser ablation has a decisive impact: the removal of the material becomes possible because of generating gasification and ionization, laser plasma shock wave can make phase transition material discharge effectively, and laser plasma spectroscopy ionization effect can make the oxygen elements in the air ionize and deposit effectively.

[Research on cells ablation characters by laser plasma].

The study on the mechanism of laser ablated cells is of importance to laser surgery and killing harmful cells. Three radiation modes were researched on the ablation characteristics of onion epidermal cells under: laser direct irradiation, focused irradiation and the laser plasma radiation. Based on the thermodynamic properties of the laser irradiation, the cell temperature rise and phase change have been analyzed. The experiments show that the cells damage under direct irradiation is not obvious at all, but the focused irradiation can cause cells to split and moisture removal. The removal shape is circular with larger area and rough fracture edges. The theoretical analysis found out that the laser plasma effects play a key role in the laser ablation. The thermal effects, radiation ionization and shock waves can increase the deposition of laser pulses energy and impact peeling of the cells, which will greatly increase the scope and efficiency of cell killing and is suitable for the cell destruction.

Inflammation inhibitory effects of sirolimus and paclitaxel-eluting stents on interleukin-1ß-induced coronary artery in-stent restenosis in pigs.

BACKGROUND: Coronary artery in-stent restenosis (ISR) and late stent thrombosis remain as important complications of stenting. The inflammation reactions to sirolimus and paclitaxel-eluting stents were investigated in a swine stenosis model induced by interleukin (IL)-1ß. METHODS: Mini pigs (n = 12; 2-3 months old and weighing 25-30 kg) were subjected to thoracotomy. Segments (10 mm) of the mid left anterior descending coronary artery and left circumflex coronary artery were exposed and aseptically wrapped with a cotton mesh soaked with IL-1ß (5 µg). After 2 weeks, the animals were anesthetized and quantitative coronary arteriography (QCA) was performed. The stenosis sites were randomized into three groups for stent insertion: a sirolimus-eluting stent (SES) group (Firebird(TM), n = 7), a paclitaxel-eluting stent (PES) group (TAXUS(TM), n = 9), and a bare-metal stent (BMS) group (YINYITM, Dalian Yinyi Biomaterials Development Co., Ltd, China, n = 8). The three different stents were randomly implanted into stenosis segments. Expression of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), P-selectin and vascular cell adhesion molecule-1 (VCAM-1) was determined by reverse transcription-coupled polymerase chain reaction (RT-PCR). RESULTS: QCA showed severe stenosis in IL-1ß treated segments. The SES and PES groups showed lower 1-month angiographic late lumen loss (LLL) within the stent and the lesion compared with BMS (P < 0.05) by follow-up QCA. The SES showed lower LLL than that of PES in reducing 1-month inflammation lesions in pigs by follow-up QCA ((0.15 ± 0.06) mm vs. (0.33 ± 0.01) mm, P < 0.0001). The neointimal hyperplasia areas in SES and PES showed lower than those of BMS (SES (11.6 ± 1.7) mm(2), PES (27.2 ± 1.6) mm(2) vs. BMS (76.2 ± 1.3) mm(2), P < 0.0001). The mRNA expression of MCP-1 by RT-PCR in SES and PES showed lower than that of BMS at 30 days after stenting (SES 0.20 ± 0.03, PES 0.48 ± 0.49 vs. BMS 0.58 ± 0.07, P < 0.05). Levels of VCAM-1 in SES were significantly lower than those of PES and BMS (SES 0.35 ± 0.08 vs. PES 0.65 ± 0.13, BMS 0.70 ± 0.06, P < 0.05). Histochemical immunostaining of vessel walls showed lower inflammatory chemokine MCP-1 expression in the SES and PES groups compared with BMS. CONCLUSION: SESs were superior in reducing 1-month angiographic LLL in inflammation lesions in pigs, strongly suggesting that SESs can suppress inflammatory reactions in ISR at multiple points.