Enlightening epigenetics: optochemical tools illuminate the path.

Optochemical tools have become potent instruments for understanding biological processes at the molecular level, and the past decade has witnessed their use in epigenetics and epitranscriptomics (also known as RNA epigenetics) for deciphering gene expression regulation. By using photoresponsive molecules such as photoswitches and photocages, researchers can achieve precise control over when and where specific events occur. Therefore, these are invaluable for studying both histone and nucleotide modifications and exploring disease-related mechanisms. We systematically report and assess current examples in the field, and identify open challenges and future directions. These outstanding proof-of-concept investigations will inspire other chemical biologists to participate in these emerging fields given the potential of photochromic molecules in research and biomedicine.

In Situ Inhibitor Synthesis and Screening by Fluorescence Polarization: An Efficient Approach for Accelerating Drug Discovery.

Target-directed dynamic combinatorial chemistry has emerged as a useful tool for hit identification, but has not been widely used, in part due to challenges associated with analyses involving complex mixtures. We describe an operationally simple alternative: in situ inhibitor synthesis and screening (ISISS), which links high-throughput bioorthogonal synthesis with screening for target binding by fluorescence. We exemplify the ISISS method by showing how coupling screening for target binding by fluorescence polarization with the reaction of acyl-hydrazides and aldehydes led to the efficient discovery of a potent and novel acylhydrazone-based inhibitor of human prolyl hydroxylase 2 (PHD2), a target for anemia treatment, with equivalent in vivo potency to an approved medicine.

Preferred Conformation-Guided Discovery of Potent and Orally Active HIF Prolyl Hydroxylase 2 Inhibitors for the Treatment of Anemia.

In this work, we discovered a novel series of prolyl hydroxylase 2 (PHD2) inhibitors with improved metabolic properties based on a preferred conformation-guided drug design strategy. Piperidinyl-containing linkers with preferred metabolic stability were designed to match the dihedral angle of the desired docking conformation in the PHD2 binding site with the lowest energy conformation. Based on the piperidinyl-containing linkers, a series of PHD2 inhibitors with high PHD2 affinity and favorable druggability were obtained. Remarkably, compound 22, with an IC50 of 22.53 nM toward PHD2, significantly stabilized hypoxia-inducible factor α (HIF-α) and upregulated the expression of erythropoietin (EPO). Furthermore, oral administration of 22 dose-dependently stimulated erythropoiesis in vivo. Preliminary preclinical studies showed that 22 has good pharmacokinetic properties and an excellent safety profile, even at 10 times the efficacious dose (200 mg/kg). Taken together, these results indicate that 22 is a promising candidate for anemia treatment.

Tetrahydropyridin-4-ylpicolinoylglycines as novel and orally active prolyl hydroxylase 2 (PHD2) inhibitors for the treatment of renal anemia.

Prolyl hydroxylase 2 (PHD2) is a key regulatory enzyme responsible for the degradation of hypoxia-inducible factor-α (HIF-α). Pharmacological inhibition of PHD2 stabilizes HIF-α and induces the production of endogenous erythropoietin (EPO), which is regarded as a promising strategy for the treatment of renal anemia. To date, a series of PHD2 inhibitors have been approved or advanced into clinical studies. In this study, we developed a new type of PHD2 inhibitors with the tetrahydropyridin-4-ylpicolinoylglycine scaffold by using a scaffold hopping strategy. Among them, compound 25 showed potent inhibition toward PHD2 with an IC50 of 6.55 ± 0.41 nM. Furthermore, compound 25 upregulated reticulocytes in C57BL/6 mice. The subacute toxicological assay demonstrated 25 has no obvious toxicity in vivo. Overall, compound 25 is a promising candidate for the treatment of renal anemia.

In Situ Inhibitor Synthesis and Screening by Fluorescence Polarization: An Efficient Approach for Accelerating Drug Discovery.

Target-directed dynamic combinatorial chemistry has emerged as a useful tool for hit identification, but has not been widely used, in part due to challenges associated with analyses involving complex mixtures. We describe an operationally simple alternative: in situ inhibitor synthesis and screening (ISISS), which links high-throughput bioorthogonal synthesis with screening for target binding by fluorescence. We exemplify the ISISS method by showing how coupling screening for target binding by fluorescence polarization with the reaction of acyl-hydrazides and aldehydes led to the efficient discovery of a potent and novel acylhydrazone-based inhibitor of human prolyl hydroxylase 2 (PHD2), a target for anemia treatment, with equivalent in vivo potency to an approved medicine.

Discovery of a Potent and Orally Bioavailable Hypoxia-Inducible Factor 2α (HIF-2α) Agonist and Its Synergistic Therapy with Prolyl Hydroxylase Inhibitors for the Treatment of Renal Anemia.

Activation of hypoxia-inducible factor 2 (HIF-2) has emerged as a potent renal anemia treatment strategy. Here, the benzisothiazole derivative 26 was discovered as a novel HIF-2α agonist, which first demonstrated nanomolar activity (EC50 = 490 nM, Emax = 349.2%) in the luciferase reporter gene assay. Molecular dynamics simulations indicated that 26 could allosterically enhance HIF-2 dimerization. Furthermore, compound 26 had a good pharmacokinetic profile (the oral bioavailability in rats was 41.38%) and an in vivo safety profile (the LD50 in mice was greater than 708 mg·kg-1). In the in vivo efficacy assays, the combination of 26 and the prolyl hydroxylase inhibitor, AKB-6548, was confirmed for the first time to synergistically increase the plasma erythropoietin level in mice (from 260 to 2296 pg·mL-1) and alleviate zebrafish anemia induced by doxorubicin. These results provide new insights for HIF-2α agonists and the treatment of renal anemia.

Submarine groundwater discharge-driven nutrient fluxes in a typical mangrove and aquaculture bay of the Beibu Gulf, China.

To understand the role of submarine groundwater discharge (SGD) in a mangrove combined aquaculture ecosystem, groundwater samples and timeseries observations (27 h) of 224Ra, 223Ra, and nutrients were obtained during wet and dry seasons in Zhenzhu Bay, a typical mangrove and aquaculture ecosystem along the Beibu Gulf in China. The SGD rates in Zhenzhu Bay were estimated to be 22.3-44.5 cm/d in the wet season and 41.1-58.1 cm/d in the dry season, which were 0.8-1.6 and 9.8-14.1 times higher than the corresponding river water discharge values, respectively. Furthermore, SGD-driven dissolved inorganic nitrogen, dissolved inorganic orthophosphate, and dissolved inorganic silicate accounted for 72%, 56%, and 60% of the total nutrient input, respectively, during wet season, which increased to 93%, 98%, and 89% during dry season. The findings highlight that SGD plays an important role in the dissolved inorganic nutrient sources of Zhenzhu Bay, and that the effective utilization and management of the bay should consider SGD.

The prolyl hydroxylase inhibitor roxadustat: Paradigm in drug discovery and prospects for clinical application beyond anemia.

Prolyl hydroxylase (PHD) inhibitors, such as roxadustat, can stabilize hypoxia-inducible factor (HIF)-2α and induce erythropoietin (EPO) production under normal conditions. Roxadustat was recently approved as a first-in-class orally active drug for the treatment of renal anemia. In addition, it has garnered growing therapeutic interest for use against various diseases, such as carcinoma, neurological diseases, ocular diseases, and tissue and organ injuries. In this review, we systemically review target validation, hit identification, and further key clinical trials of roxadustat. The prospective clinical applications of PHD inhibitors are then discussed based on this marketed drug.

Physical dosimetry reconstructions of significant radiation exposure at an industrial accelerator facility in Tianjin (China).

The goal of this thesis is to estimate the physical radiation doses for two victims who were accidently exposed to an industrial electron beam at an industrial accelerator facility on 7 July 7 2016 in Tianjin, China. On the basis of the radiation source parameters, irradiation situation and irradiation time, physical dose reconstruction was carried out at the accident site by using a Bottle-Manikin-Absorption (BOMAB) phantom and an Alderson Radiation Therapy (ART) phantom. With thermoluminscent dosimeters (TLDs), skin estimation was conducted for the feet, calves, upper arms, left side of the body and neck, and the mean dose was estimated to be 14.1 ± 5.6 Gy. The foot and leg skin received the highest dose, which was >16.3 Gy. In addition, the mean dose estimated for the eye lens was 0.18 ± 0.07 Gy. The organ effective dose estimated and the total organs effective dose estimated were 0.46-4.94 mSv and 0.21 Sv, respectively. In the course of the accident, the damage caused by the electron radiation field to the exposed person was mainly to the skin, and the contributions to other radiation-sensitive organs were small. The damage to the organs other than the skin was mainly caused by the X-rays generated by the bremsstrahlung of the electron beam from the environment or the human body.

A small-molecule probe for monitoring binding to prolyl hydroxylase domain 2 by fluorescence polarisation.

Inhibition of the dioxygen sensing hypoxia-inducible factor prolyl hydroxylases has potential therapeutic benefit for treatment of diseases, including anaemia. We describe the discovery of a small-molecule probe useful for monitoring binding to human prolyl hydroxylase domain 2 (PHD2) via fluorescence polarisation. The assay is suitable for high-throughput screening of PHD inhibitors with both weak and strong affinities, as shown by work with clinically used inhibitors and naturally occurring PHD inhibitors.

Photoactivatable Prolyl Hydroxylase 2 Inhibitors for Stabilizing the Hypoxia-Inducible Factor with Light.

HIF prolyl hydroxylase 2 (PHD2) inhibitors represent a novel approach for treating HIF-related diseases. This study reports the first application of photoremovable protecting group to the photoactivatable inhibitor (7) of PHD2. It allows the inhibitory activity for PHD2 to be controlled by light irradiation, subsequently stabilizing HIF and promoting expression of the target gene. Light activation to stabilize HIF offers promising potentials for the tissue-specific therapies for HIF-related disease by light irradiation onto target tissues.

210Po and 210Pb disequilibrium at the PN section in the East China Sea.

Lead-210 and 210Po have been widely used as tracers for quantifying particulate scavenging in the upper layer of the oceanic water column. In this study, we investigated the 210Po/210Pb disequilibrium in the water column of the PN section in the East China Sea (ECS) during autumn 2013. In most of the water column, a deficiency of 210Po was observed with respect to its parent nuclide 210Pb (i.e., a 210Po/210Pb activity ratio < 1.0). The (210Po/210Pb)dissolved, (210Po/210Pb)particulate and (210Po/210Pb)total activity ratios ranged from 0.29 to 0.71 (average: 0.53 ± 0.13, n = 27), 0.31 to 1.42 (average: 0.70 ± 0.27, n = 27) and 0.22 to 0.62 (average: 0.50 ± 0.12, n = 27), respectively. The distribution coefficients (Kd) of 210Po and 210Pb were 12.1× 104 ml g-1 and 8.8× 104 ml g-1, with an average (210Po/210Pb) total activity ratio of (0.50 ± 0.12, n = 27). However, over the continental shelf, planktonic detritus and fecal pellets appear to be the main carriers for 210Po, which preferentially scavenges 210Po and produces a lower (210Po/210Pb) total activity ratio (0.49 ± 0.12, n = 22) with a Kd for 210Po of 13.8× 104 ml g-1 in the water column. The variations in the fractionation factor (1.48 ± 0.66) of 210Po/210Pb reveal distinct differences between the distribution and scavenging of 210Po and 210Pb by particulate matter in different marine environments: in the estuarine zone (a high turbidity area), terrigenous suspended particulate matter scavenges 210Pb from the water column, while in areas dominated by biogenic particular matter, 210Po is preferentially scavenged from the water column. Using the 210Po/210Pb disequilibrium in the water column, we estimated the removal fluxes of POC from the upper waters downward to be 25.0 mg C m-2 d-1, comparable to those in other marginal seas. Moreover, a decreasing trend of POC removal fluxes was observed with increasing distance offshore.