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adversely associated with serum lipid levels, and that such associations are also observed in legacy PFASs. Increased investigation into the effects of Cl-PFESAs exposure on human health is warranted.Sweetpotato (Ipomoea batatas [L.] Lam.) stem tips, which contain high concentrations of chlorogenic acid (CGA), are useful as a physiologically functional food to protect against some serious diseases. According to previous studies, exogenous application of phytohormones may be an effective agrotechnical measure to control CGA biosynthesis through the transcriptional regulation of pathway gene expressions. To understand the mechanism of CGA biosynthesis in sweetpotato, we investigated the effects of exogenous phytohormones on CGA metabolism in stem tips of sweetpotato. A significantly elevated CGA content was observed in salicylic acid (SA)-treated sweetpotato stem tips at 72 h, as well as in those subjected to abscisic acid (ABA) or gibberellic acid (GA) treatments. Dynamic expression change of seven enzyme genes involved in sweetpotato CGA biosynthesis were analyzed to determine correlations between transcript levels and CGA accumulation. As revealed by the differential expression of these genes under distinct phytohormone treatments, the regulation of specific pathway genes is a critical determinant of the accumulation of CGA in sweetpotato stem tips. selleckchem We also found that several hormone-responsive sites, such as those for ABA, GA, SA, and jasmonic acid (JA), were present in the promoter regions of sweetpotato CGA biosynthestic pathway genes. Collectively, phytohormones can regulate the transcription of CGA synthesis-related genes and ultimately affect CGA accumulation in sweetpotato stem tips, whereas the regulatory differences are mirrored by cis-acting elements in the corresponding pathway gene promoters.

To evaluate the safety, tolerability, and pharmacokinetics of soticlestat, a first-in-class cholesterol 24-hydroxylase inhibitor, in adults with developmental and/or epileptic encephalopathies (DEE).

The study comprised a 30-day, randomized, double-blind, placebo-controlled phase (Part A), followed by a 55-day open-label phase (Part B) (ClinicalTrials.gov ID NCT03166215) . In Part A, patients with DEE and at least one bilateral motor seizure during the 4-week prospective baseline period were randomized 41 to receive soticlestat or placebo, in addition to their usual antiseizure medication. In Part B, all patients received open-label soticlestat. Soticlestat doses were titrated according to tolerability to a maximum of 300 mg twice daily (BID). Safety evaluations included the incidence of treatment-emergent adverse events (TEAEs). Plasma soticlestat concentrations were measured at various times for determination of multiple-dose pharmacokinetics and 24S-hydroxycholesterol (24HC). Efficacy was assessed by eoticlestat and placebo groups, respectively, in Part A, and -36.38 % in all participants in Part B.

Soticlestat was well tolerated at doses of up to 300 mg BID and was associated with a reduction in median seizure frequency over the study duration. Further studies are warranted to assess the possible efficacy of soticlestat as adjunctive therapy in patients with DEEs such as Dravet syndrome and Lennox-Gastaut syndrome.

Soticlestat was well tolerated at doses of up to 300 mg BID and was associated with a reduction in median seizure frequency over the study duration. Further studies are warranted to assess the possible efficacy of soticlestat as adjunctive therapy in patients with DEEs such as Dravet syndrome and Lennox-Gastaut syndrome.VLPs are virus-like particles that comprise viral capsid proteins that can self-assemble and mimic the shape and size of real viral particles; however, because they do not contain genetic material they cannot infect host cells. VLPs have great potential as safe drug/vehicle candidates; therefore, they are gaining popularity in the field of preventive medicine and therapeutics. Indeed, extensive studies are underway to examine their role as carriers for immunization and as vehicles for delivery of therapeutic agents. Here, we examined the possibility of developing VLP-utilizing technology based on an efficient VLP production process and high-resolution structural analysis. Nicotiana benthamiana was used as an expression platform to produce the coat protein of the alfalfa mosaic virus (AMV-CP). About 250 mg/kg of rAMV-CP was produced from Nicotiana benthamiana leaves. Structural analysis revealed that the oligomeric status of rAMV-CP changed according to the composition and pH of the buffer. Size exclusion chromatography and electron microscopy analysis confirmed the optimal conditions for rAMV-CP VLP formation, and a 2.4 Å resolution structure was confirmed by cryo-EM analysis. Based on the efficient protein production, VLP manufacturing technology, and high-resolution structure presented herein, we suggest that rAMV-CP VLP is a useful platform for development of various new drugs.

To investigate the efficacy of a novel experimental model for exploring visual function using a contrast-optomotor response (C-OMR) assay made by applying the contrast sensitivity test to the OMR assay in zebrafish.

Zebrafish larvae were treated with 0 (control), 5, 10, or 15μM gentamicin and digoxin for 24h at four days post-fertilization (dpf). Zebrafish larvae were assessed using the C-OMR assay with graded contrast gray-white stripes at 5 dpf, and the results were expressed as the percentage of larvae that finished swimming for 30s (n=20 per each group). The same C-OMR assay was repeated four times using different larvae.

The percentage of larvae that finished swimming within 30s was significantly reduced in larvae treated with 5, 10, and 15μM gentamicin and 10 and 15μM digoxin as compared to the Control groups. The C-OMR assay could distinguish that the decrease in visual function was different depending on the concentration of gentamicin and digoxin (5, 10, and 15μM), whereas the OMR test with one contrast gray-white stripe could not.

The method of analyzing zebrafish OMR using graded contrast gray-white stripes is more sensitive than the OMR assay alone and may be more useful for assessing the drug toxicity and eye-related diseases to improve the understanding of drug-induced ocular side effects in the clinic.

The method of analyzing zebrafish OMR using graded contrast gray-white stripes is more sensitive than the OMR assay alone and may be more useful for assessing the drug toxicity and eye-related diseases to improve the understanding of drug-induced ocular side effects in the clinic.Type 2 diabetes mellitus (T2DM), characterized by hyperglycemia and insulin resistance, has been recognized as a risk factor for cognitive impairment and dementia, including Alzheimer’s disease (AD). Insulin receptor substrate2 (IRS2) is a major component of the insulin/insulin-like growth factor-1 signaling pathway. Irs2 deletion leads to life-threatening T2DM, promoting premature death in male mice regardless of their genetic background. Here, we showed for the first time that young adult male mice lacking Irs2 on a C57BL/6J genetic background (Irs2-/-/6J) survived in different experimental environments and displayed hippocampus-associated behavioral alterations. Young adult male Irs2-/-/6J mice also exhibit aberrant alterations in energy and nutrient sensors, such as AMP-activated protein kinase (AMPK) and glucose transporter3 (GLUT3), and reduced core body temperature accompanied by abnormal change in the temperature sensor in the brain. These results suggest that Irs2 deficiency-induced impairments of brain energy metabolism and thermoregulation contribute to hippocampus-associated behavioral changes in young adult male mice.Diabetic nephropathy (DN) is the primary cause of end-stage renal disease, and renal tubular cell dysfunction contributes to the pathogenesis of many kidney diseases. Our previous study demonstrated that dual-specificity protein phosphatase 1 (DUSP1) reduced hyperglycemia-mediated mitochondrial damage; however, its role in hyperglycemia-driven dysfunction of tubular cells is still not fully understood. In this study, we found that DUSP1 is reduced in human proximal tubular epithelial (HK-2) cells under high-glucose conditions. DUSP1 overexpression in HK-2 cells partially restored autophagic flux, improved mitochondrial function, and reduced reactive oxygen species generation and cell apoptosis under high-glucose conditions. Surprisingly, overexpressing DUSP1 abolished the decrease in mitochondrial parkin expression caused by high-glucose stimulation. In addition, knockdown of parkin in HK-2 cells reversed the effects of DUSP1 overexpression on mitophagy and apoptosis under high-glucose conditions. Overall, these data indicate that DUSP1 plays a defensive role in the pathogenesis of DN by restoring parkin-mediated mitophagy, suggesting that it may be considered a prospective therapeutic strategy for the amelioration of DN.Dedicator of cytokinesis 8 (DOCK8) is a guanine nucleotide exchange factor (GEF) for Cdc42. In humans, homozygous or compound heterozygous deletions in DOCK8 cause a combined immunodeficiency characterized by various allergic diseases including food allergies. Although group 2 innate lymphoid cells (ILC2s) contribute to the development of allergic inflammation by producing interleukin (IL)-5 and IL-13, the role of ILC2s in DOCK8 deficiency has not been fully explored. With the use of cytometry by time-of-flight (CyTOF), we performed high-dimensional phenotyping of intestinal immune cells and found that DOCK8-deficient (Dock8-/-) mice exhibited expansion of ILC2s and other leukocytes associated with type 2 immunity in the small intestine. Moreover, IL-5- and IL-13-producing cells markedly increased in Dock8-/- mice, and the majority of them were lineage-negative cells, most likely ILC2s. Intestinal ILC2s expanded when DOCK8 expression was selectively deleted in hematopoietic cells. Importantly, intestinal ILC2 expansion was also observed in Dock8VAGR mice having mutations in the catalytic center of DOCK8, thereby failing to activate Cdc42. Our findings indicate that DOCK8 is a negative regulator of intestinal ILC2s to inhibit their expansion via Cdc42 activation, and that deletion of DOCK8 causes a skewing to type 2 immunity in the gut.Tumor brain metastasis is a severe threat to patients’ neurological function, in which microglia may be involved in the process of tumor cell metastasis among nerve cells. Our study focused on the interaction between microglia and breast and lung cancer cells. Changes in the proliferation and migration ability of cocultured tumor cells were examined; synchrotron radiation-based fourier transform infrared microspectroscopy (SR-FTIR) was used to detect changes in the structures and contents of biomolecules within the tumor cells. The experimental results showed that the proliferation and migration ability of tumor cells increased after coculture, and the structures and contents of biological macromolecules in tumor cells changed. The absorption peak positions of the amide Ⅱ and amide Ⅰ bands observed for the four kinds of tumor cells changed, and the absorption intensities were significantly enhanced, indicating changes in the secondary structures and contents of proteins in tumor cells, which may be the root cause of the change in tumor cell characteristics.