Syringin protects against colitis by ameliorating inflammation.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition with high incidence. Syringin exhibits multiple pharmacological properties, including anti-inflammatory effects. However, the effect of syringin on inflammation of IBD is still unclear. Here, the dextran sulfate sodium (DSS)-induced colitis model was established in vivo. Rat intestinal epithelium IEC6 cells were treated with lipopolysaccharide (LPS) in vitro. Syringin inhibited DSS or LPS-induced overproduction of proinflammatory cytokines (IL-1ß, IL-6, TNF-α) and proinflammatory substances (iNOS, COX-2). Moreover, syringin inactivated the proinflammatory NF-κB p65 pathway by decreasing IκBα phosphorylation at Ser 32. The activation of antioxidant Nrf2 signaling pathway was promoted by syringin. Additionally, LPS-induced inflammation in IEC6 cells was also suppressed by NF-κB inhibitor PDTC and Nrf2 activator RTA408. The anti-inflammatory effects of syringin were comparable to these two reagents. Taken together, our results suggest that syringin shows protective effects on intestinal inflammation through inhibiting NF-κB, while activating Nrf2 signaling pathway in colitis.

Performance analysis of a coherent free space optical communication system based on experiment.

Based on our previous study and designed experimental AO system with a 97-element continuous surface deformable mirror, we conduct the performance analysis of a coherent free space optical communication (FSOC) system for mixing efficiency (ME), bit error rate (BER) and outage probability under different Greenwood frequency and atmospheric coherent length. The results show that the influence of the atmospheric temporal characteristics on the performance is slightly stronger than that of the spatial characteristics when the receiving aperture and the number of sub-apertures are given. This analysis result provides a reference for the design of the coherent FSOC system.

Mink (Mustela vison) Gut Microbial Communities from Northeast China and Its Internal Relationship with Gender and Food Additives.

It is well documented that the microbial interactions and biodiversity play an important role in health and disease in mammalian species. There is a rare study about gut microbiota of Mustelidae family. In this study, 40 male and female minks from Northeast China were divided into three groups and fed until they reached maturity. The V3 region of 16S rRNA genes was amplified and sequenced using NGS. There were 526 OTUs principally concentrated among five bacterial phyla. Two points about mink's body weight gaining were observed: (1) the weight of male individuals increased more rapidly than female individuals; (2) the weight of individuals whose feed was supplemented with Chinese herb additives increased more rapidly than individuals without giving food additives. The differences of microorganism abundance were shown in two points: (1) two genera which had ≥2-fold change difference were found between male and female minks. (2) Ten genera which had a ≥2-fold change difference were found among minks with and without Chinese herb additive. Findings from this study provide new and fundamental knowledge on the gut microbiota composition of minks farmed in Northeast China, which can contribute to the general well-being of minks worldwide.

Current advances of small molecule E3 ligands for proteolysis-targeting chimeras design.

Proteolysis-targeting chimeras (PROTACs) as an emerging drug discovery modality has been extensively concerned in recent years. Over 20 years development, accumulated studies have demonstrated that PROTACs show unique advantages over traditional therapy in operable target scope, efficacy, and overcoming drug resistance. However, only limited E3 ligases, the essential elements of PROTACs, have been harnessed for PROTACs design. The optimization of novel ligands for well-established E3 ligases and the employment of additional E3 ligases remain urgent challenges for investigators. Here, we systematically summarize the current status of E3 ligases and corresponding ligands for PROTACs design with a focus on their discovery history, design principles, application benefits, and potential defects. Meanwhile, the prospects and future directions for this field are briefly discussed.

Discovery of Pyrimidinediamine Derivatives as Potent Methuosis Inducers for the Treatment of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a leading malignancy among women that currently lack effective targeted therapeutic agents, and the limitations of treatment have prompted the emergence of new strategies. Methuosis is a novel vacuole-presenting cell death modality that promotes tumor cell death. Hence, a series of pyrimidinediamine derivatives were designed and synthesized through evaluation of their abilities that inhibit proliferation as well as induce methuosis against TNBC cells. Among them, JH530 showed excellent anti-proliferative activities and vacuolization capacity in TNBC. The mechanism research indicated that JH530 caused cell death through inducing methuosis of cancer cells. Furthermore, JH530 inhibited tumor growth remarkably in the HCC1806 xenograft model without an apparent decrease in body weight. Overall, JH530 is a methuosis inducer that displayed remarkable suppression of TNBC growth in vitro and in vivo, which provides a basis for the future progress of more small molecules for TNBC treatment.

Discovery of a Highly Potent and Selective MYOF Inhibitor with Improved Water Solubility for the Treatment of Gastric Cancer.

Myoferlin (MYOF) mediates the growth and metastasis of various cancers as an emerging therapeutic target by regulating exocytosis and endocytosis. However, the previously reported MYOF inhibitor, 6y, failed to be a favorable candidate agent due to its poor physicochemical properties, such as water solubility, in preclinical studies. Naturally, a novel range of MYOF inhibitors was synthesized and optimized based on the lead compound 6y. The optimal compound HJ445A potently repressed the proliferation of gastric cancer cells with IC50 values of 0.16 and 0.14 µM in MGC803 and MKN45, respectively. Moreover, HJ445A bound to the MYOF-C2D domain with a KD of 0.17 µM, and HJ445A prevented the migration of gastric cancer cells by reversing the epithelial-mesenchymal transition (EMT) process and inhibited the colony formation of the MKN45 cells in a concentration-dependent manner. Notably, the water solubility of HJ445A was significantly improved compared to 6y, with about 170-fold enhancement. Additionally, HJ445A also demonstrated superior antitumor efficacy in vivo.

Ophiogomphus tibeticus sp. nov. from Sichuan, China (Anisoptera: Gomphidae).

A new gomphid species, Ophiogomphus tibeticus sp. nov., from Zoige alpine Wetland, Sichuan is described and illustrated. Assignment to the genus Ophiogomphus Selys, 1854 is based on both morphological and molecular analyses. This new species differs from other known Ophiogomphus mainly in the shape of the caudal appendages.

B-cell Lymphoma 6 Inhibitors: Current Advances and Prospects of Drug Development for Diffuse Large B-cell Lymphomas.

B-cell lymphoma 6 (BCL6) is a transcriptional repressor that regulates the differentiation of B lymphocytes and mediates the formation of germinal centers (GCs) by recruiting corepressors through the BTB domain of BCL6. Physiological processes regulated by BCL6 involve cell activation, differentiation, DNA damage, and apoptosis. BCL6 is highly expressed when the gene is mutated, leading to the malignant proliferation of cells and drives tumorigenesis. BCL6 overexpression is closely correlated with tumorigenesis in diffuse large B-cell lymphoma (DLBCL) and other lymphomas, and BCL6 inhibitors can effectively inhibit some lymphomas and overcome resistance. Therefore, targeting BCL6 might be a promising therapeutic strategy for treating lymphomas. Herein, we comprehensively review the latest development of BCL6 inhibitors in diffuse large B-cell lymphoma and discuss the overview of the pharmacophores of BCL6 inhibitors and their efficacies in vitro and in vivo. Additionally, the current advances in BCL6 degraders are provided.

Discovery of 1,5-diaryl-1,2,4-triazole derivatives as myoferlin inhibitors and their antitumor effects in pancreatic cancer.

Aim: The first inhibitor targeting myoferlin (MYOF), WJ460, bears poor metabolic stability and water solubility. Therefore, this study aimed to improve the drug-like properties of WJ460. Materials & methods: The authors synthesized an array of 1,5-diaryl-1,2,4-triazole analogs and appraised the binding activities with MYOF and their antiproliferative and antimigratory activities against pancreatic cancer cells. Results: Molecular docking and surface plasmon resonance results showed that E4 was directly bound to the MYOF-C2D domain. E4 effectively inhibited the proliferation and migration of pancreatic cancer cells in vitro. An in silico study suggested that the water solubility of E4 was improved by about 22-times than that of WJ460. Conclusion: The findings suggested that the druglike ability of E4 was significantly improved.

Discovery of a Novel Potent STAT3 Inhibitor HP590 with Dual p-Tyr705/Ser727 Inhibitory Activity for Gastric Cancer Treatment.

Accumulating evidence has documented that STAT3 phosphorylation at Tyr705 and Ser727 jointly promotes the initiation and progression of gastric cancer. However, most reported STAT3 inhibitors have mainly focused on suppressing STAT3 phosphorylation at Tyr705 while ignoring the tumorigenic effects of phosphorylation at Ser727. Herein, we described the design, synthesis, and structure-activity relationship studies on a series of triaromatic heterocyclic derivatives as potent dual phosphorylation STAT3 inhibitors. These efforts led to the discovery of the best compound 3h (HP590) among the investigated ones, a novel, highly potent, and orally bioavailable STAT3 inhibitor possessing lower nanomolar inhibitory activity toward p-Tyr705 and p-Ser727. Target validation revealed that HP590 selectively targets STAT3 to remarkably inhibit its canonical and noncanonical activation and corresponding biological functions, thereby resulting in the growth inhibition of gastric cancer in vitro and in vivo, highlighting the therapeutic potential of dual phosphorylation STAT3 inhibitors for gastric cancer.

A potent and selective small molecule inhibitor of myoferlin attenuates colorectal cancer progression.

As a pivotal vesicular trafficking protein, Myoferlin (MYOF) has become an attractive target for cancer therapy. However, the roles of MYOF in colorectal cancer invasion remain enigmatic, and MYOF-targeted therapy in this malignancy has not been explored. In the present study, we provided the first functional evidence that MYOF promoted the cell invasion of colorectal cancer. Furthermore, we identified a novel small molecule inhibitor of MYOF (named YQ456) that showed high binding affinity to MYOF (KD  = 37 nM) and excellent anti-invasion capability (IC50  = 110 nM). YQ456 was reported for the first time to interfere with the interactions between MYOF and Ras-associated binding (Rab) proteins at low nanomolar levels. This interference disrupted several vesicle trafficking processes, including lysosomal degradation, exosome secretion, and mitochondrial dynamics. Further, YQ456 exhibited excellent inhibitory effects on the growth and invasiveness of colorectal cancer. As the first attempt, the anticancer efficacy of YQ456 in the patient-derived xenograft (PDX) mouse model indicated that targeting MYOF may serve as a novel and practical therapeutic approach for colorectal cancer.

Rediscovery of Protohynobius puxiongensis (Caudata: Hynobiidae) and its phylogenetic position based on complete mitochondrial genomes.

The mysterious Asian hynobiid salamander, Protohynobius puxiongensis, was described based on a single specimen collected in 1965 and never found again since then. Because the specimen had an internasal bone, Pr. puxiongensis was thought to retain a primitive character lost by a common ancestor of all other hynobiid salamanders, and it was thus considered to be not only a new genus, but also a new subfamily. This conclusion bothered herpetologists for decades because it was based on only one specimen and one character without other living specimens being rediscovered. After years of field effort, we rediscovered living individuals of Pr. puxiongensis at its type locality. All characters observed in rediscovered specimens are identical to the original description of the holotype except the internasal bone, implying that the internasal bone observed in the holotype may be just an individual variation. To examine the phylogenetic position of Pr. puxiongensis, we sequenced complete mitochondrial genomes for this species, together with two Pseudohynobius species. By combining 18 published hynobiid mitochondrial genomes and our new sequences, we reconstructed a comprehensive phylogenetic relationship of Hynobiidae at the genus level. Our results indicate that Pr. puxiongensis is deeply nested within the hynobiid phylogeny. It is the sister group of the Pseudohynobius species, and the validity of subfamily Protohynobiinae is not supported.

An Emerging Therapeutic Approach by Targeting Myoferlin (MYOF) for Malignant Tumors.

Myoferlin (MYOF), as a member of the ferlin family, is a type II transmembrane protein with a single transmembrane domain at the carbon terminus. Studies have shown that MYOF is involved in pivotal physiological functions related to numerous cell membranes, such as extracellular secretion, endocytosis cycle, vesicle trafficking, membrane repair, membrane receptor recycling, and secreted protein efflux. Recently, the studies have also revealed that MYOF is overexpressed in a variety of cancers such as colorectal cancer, pancreatic cancer, breast cancer, melanoma, gastric cancer, and non-small-cell lung cancer. High expression of MYOF is associated with the high invasion of tumors and poor clinical prognosis. MYOF medicates the expression, secretion, and distribution of proteins, which were closely related to cancers, as well as the energy utilization of cancer cells, lipid metabolism and other physiological activities by regulating the physiological processes of membrane transport. In this short article, we briefly summarize the latest progress related to MYOF, indicating that small molecule inhibitors targeting the MYOF-C2D domain can selectively inhibit the proliferation and migration of cancer cells, and MYOF may be a promising target for the treatment of malignant tumors.

Synthesis and Biological Evaluation of B-Cell Lymphoma 6 Inhibitors of N-Phenyl-4-pyrimidinamine Derivatives Bearing Potent Activities against Tumor Growth.

The transcriptional repressor B-cell lymphoma 6 (BCL6) is frequently misregulated in diffuse large B-cell lymphoma (DLBCL) and has emerged as an attractive drug target for the treatments of lymphoma. In this article, a series of N-phenyl-4-pyrimidinamine derivatives were designed and synthesized as potent BCL6 inhibitors by optimizing hit compound N4-(3-chloro-4-methoxyphenyl)-N2-isobutyl-5-fluoro-2,4-pyrimidinediamine on the basis of the structure-activity relationship. Among them, compound 14j displayed the most potent activities, which significantly blocked the interaction of BCL6 with its corepressors, reactivated BCL6 target genes in a dose-dependent manner, and had better effects compared with the two positive controls. Further studies indicated that a low dose of 14j could effectively inhibit germinal center formation. More importantly, 14j not only showed potent inhibition of DLBCL cell proliferation in vitro but also strongly suppressed the growth of DLBCL in vivo.

Performance analysis of 349-element adaptive optics unit for a coherent free space optical communication system.

As a continuation of our previous work [Optics Express.25, 15229(2017)] in which we have verified the performance of a coherent free space optical communication (FSOC) system with a 97-element adaptive optics (AO) system, in this paper, we evaluated the performance improvement of the coherent FSOC system using a large-scale high-speed AO system with a 349-element continuous surface deformable mirror. The mixing efficiency (ME) and bit-error-rate (BER) under different Greenwood frequency (GF) were calculated as the performance metric of coherent FSOC system. The performance of FSOC system using such a large-scale AO system was quantitatively verified for the first time. The obtained results showed that the performance was obviously improved when a larger-scale high-speed AO system is employed in coherent FSOC system. This analysis result provides a performance verification for large-scale high-speed AO systems used in FSOC system which is beneficial for coherent FSOC system parameters design.