Pramipexole attenuates 6-OHDA-induced Parkinson's disease by mediating the Nurr1/NF-κB pathway.

Neuroinflammation is the key factor associated with the progression of Parkinson's disease (PD). Pramipexole (PPX) has anti-inflammatory and antioxidant properties. This study explored the effects of PPX on PD and its related mechanisms. A PD rat model was established using 6-hydroxydopamine (6-OHDA). Thirty rats were divided into the following three groups: control, PD, and PD + PPX. The rats in the PD and PD + PPX groups were first administered 6-OHDA and then respectively treated with saline and PPX. Afterward, rotational behavior tests were performed to evaluate the efficiency of PPX. The level of tyrosine hydroxylase (TH) was measured using immunohistochemical staining. Subsequently, real-time quantitative PCR (RT-qPCR) and western blot were used to determine the expression of α-synuclein (α-syn), nuclear receptor subfamily 4 group A member 2 (Nurr1), and nuclear factor kappa B (NF-κB). PPX improved the motor behavior of PD rats caused by 6-OHDA. The number of TH-positive neurons in the PD group was significantly lower than that in the control group (P < 0.05), while PPX could rescue 6-OHDA-induced TH loss. RT-qPCR and western blot showed that Nurr1 expression was significantly downregulated in the PD group compared to that of the control group (P < 0.05), while after PPX treatment, its expression was significantly upregulated (P < 0.05). For α-syn and NF-κB, 6-OHDA significantly upregulated their expressions (P < 0.05), whereas PPX reversed them. PPX improved the motor behavior of PD through mediating the inflammatory response and regulating the Nurr1/NF-κB signaling pathway.

The outcome and burden of Chinese patients with neurodegenerative diseases: A 10-year clinical feature study.

BACKGROUND: As the Chinese population continues to age, the incidence of neurodegenerative diseases (NDDs) has increased dramatically, which results in heavy medical and economic burden for families and society. OBJECTIVE: The objective of this study was to evaluate NDDs in a southern Chinese hospital over a 10-year period and examine trends in demographics, outcome, length of stay (LOS) and cost. METHODS: Retrospective medical records of patients from January 2010 to December 2019 were collected, including 7231 patients with NDDs (as case group) and 9663 patients without any NDDs (as control group). The information of social demographic data, admission source, reasons for admission, outcomes, LOS, and cost were extracted and analysed. RESULT: The average hospitalisation age of the patients with NDDs is over 65 years (peak age 70-89 years). Compared with the control group, the case group had a longer LOS and a higher cost and the numbers of patients with NDDs increased yearly from 2010 to 2019. The LOS shortened while the cost increased. Clinical features affected LOS and cost. Patients suffering from infection, abnormal blood pressure and the imbalance of water-electrolyte homoeostasis as main reasons for admission were decreased; however, heart disease, cerebrovascular accident and mental diseases were significantly increased, the overall change trend of fracture/trauma remained stable. The rate of discharge to home care and mortality declined; discharge to other medical or community facilities increased over 10 years. CONCLUSION: The majority of NDDs patients tended to be older. During the last 10 years from 2010 to 2019, the numbers of NDDs patients increased yearly, the trend of LOS became shortening and the cost gradually increasing. The main reasons of admission and outcomes of hospital showed different trends.

Discovery of a Manduca sexta Allatotropin Antagonist from a Manduca sexta Allatotropin Receptor Homology Model.

Insect G protein coupled receptors (GPCRs) have important roles in modulating biology, physiology and behavior. They have been identified as candidate targets for next-generation insecticides, yet these targets have been relatively poorly exploited for insect control. In this study, we present a pipeline of novel Manduca sexta allatotropin (Manse-AT) antagonist discovery with homology modeling, docking, molecular dynamics simulation and structure-activity relationship. A series of truncated and alanine-replacement analogs of Manse-AT were assayed for the stimulation of juvenile hormone biosynthesis. The minimum sequence required to retain potent biological activity is the C-terminal amidated octapeptide Manse-AT (6-13). We identified three residues essential for bioactivity (Thr4, Arg6 and Phe8) by assaying alanine-replacement analogs of Manse-AT (6-13). Alanine replacement of other residues resulted in reduced potency but bioactivity was retained. The 3D structure of the receptor (Manse-ATR) was built and the binding pocket was identified. The binding affinities of all the analogs were estimated by calculating the free energy of binding. The calculated binding affinities corresponded to the biological activities of the analogs, which supporting our localization of the binding pocket. Then, based on the docking and molecular dynamics studies of Manse-AT (10-13), we described it can act as a potent Manse-AT antagonist. The antagonistic effect on JH biosynthesis of Manse-AT (10-13) validated our hypothesis. The IC50 value of antagonist Manse-AT (10-13) is 0.9 nM. The structure-activity relationship of antagonist Manse-AT (10-13) was also studied for the further purpose of investigating theoretically the structure factors influencing activity. These data will be useful for the design of new Manse-AT agonist and antagonist as potential pest control agents.

Design, synthesis and fungicidal activity of N-substituted benzoyl-1,2,3,4-tetrahydroquinolyl-1-carboxamide.

To find a new lead compound with high biological activity, a series of N-substituted benzoyl-1,2,3,4-tetrahydroquinolyl-1-carboxamide were designed using linking active substructures method. The target compounds were synthesized from substituted benzoic acid by four steps and their structures were confirmed by (1)H NMR, IR spectrum and elemental analysis. The in vitro bioassay results indicated that some target compounds exhibited excellent fungicidal activities, and the position of the substituents played an important role in fungicidal activities. Especially, compound 5n, exhibited better fungicidal activities than the commercial fungicide flutolanil against two tested fungi Valsa mali and Sclerotinia sclerotiorum, with EC50 values of 3.44 and 2.63mg/L, respectively. And it also displayed good in vivo fungicidal activity against S. sclerotiorum with the EC50 value of 29.52mg/L.

A Mechanism Study on the Antioxidant Pathway of Keap1-Nrf2-ARE Inhibiting Ferroptosis in Dopaminergic Neurons.

BACKGROUND: The pathology of Parkinson's disease (PD) indicates that iron deposition exists in dopaminergic neurons, which may be related to the death of cellular lipid iron peroxide. The extracellular autophagy adaptor SQSTM1(p62) of dopamine (DA) neurons can activate the intracellular Keap1-Nrf2-ARE signaling pathway to inhibit ferroptosis, which has a protective effect on DA neurons. OBJECTIVE: The objective of this study was to investigate the protective mechanism of the Keap1-Nrf2-ARE antioxidant pathway against iron death in dopaminergic neurons. METHODS: The experiment was divided into a control group (Control group), 1-methyl-4-phenylpyridiniumion control group (MPP+ Control group), p62 overexpression group (MPP+OV-p62), and p62 overexpression no-load group (MPP+ OV-P62-NC). The inhibitors brusatol and ZnPP inhibited the activation of NF-E2-related factor 2(Nrf2) and Heme oxygenase-1(HO-1), respectively, and were divided into brusatol group (MPP+OV-p62+brusatol) and ZnPP group (MPP+OV-p62+ZnPP). RT-qPCR was used to detect transfection efficiency, and Cell Counting Kit-8 (CCK8) was used to detect cell activity. FerroOrange, 2,7-Dichlorodihydrofluorescein diacetate (DCFH-DA), and Liperfluo probes were used to detect intracellular iron, reactive oxygen species (ROS), and lipid peroxidation (LPO) levels. Western Blotting detected the levels of Nrf2, HO-1, Kelch-like ECH-associated protein1 (Keap1), and their downstream Glutathione peroxidase 4(GPX4) and Acyl-CoA synthetase long-chain family member 4(ACSL4). The levels of L-Glutathione (GSH) and Malondialdehyde (MDA) were detected by GSH and MDA kits, and the activation of Keap1-Nrf2-ARE pathway was verified at the cellular level to have an antioxidant protective effect on iron death in dopaminergic neurons. RESULTS: (1) The results of RT-qPCR showed that compared with the control group, the expression of the p62 gene was significantly increased in the MPP+OV-p62 groups (p = 0.039), and the p62 gene was significantly increased in the brusatol and ZnPP groups, indicating successful transfection (p =0.002; p=0.008). (2) The immunofluorescence probe flow results showed that compared to the normal control group, the contents of three kinds of probes in MPP+ model group were significantly increased (p =0.001; p <0.001; p<0.001), and the contents of three kinds of probes in MPP+OV-p62 group were decreased compared to the MPP+ model group (p =0.004). The results indicated that the levels of iron, ROS, and LPO were increased in the MPP+ group and decreased in the MPP+OV-p62 group. (3) Compared with the control group, the expressions of Nrf2, HO-1, and GPX4 in the MPP+OV-p62 group were increased (p =0.007; p =0.004; p=0.010), and the expressions of Keap1 and ACSL4 in MPP+p62 overexpression group were decreased (p =0.017; p =0.005). Compared with the MPP+ control group, Nrf2 and GPX4 were increased in the MPP+OV-p62 group, and ACSL4 was decreased in the MPP+OV-p62 group (p =0.041; p <0.001; p <0.001). The results of the GSH and MDA kit showed that compared with the normal control group, the content of GSH in the MPP+ control group was decreased (p < 0.01), and the content of MDA was increased (p < 0.01). Compared with the MPP+ model group, GSH content was increased (P = 0.003), and MDA content was decreased in the MPP+OV-p62 group (p < 0.001). Nrf2, HO-1, and GPX4 increased in the MPP+p62 overexpression group but decreased in the brusatol group and ZnPP group (p < 0.001). CONCLUSION: Based on the transfection of P62 plasmid, it was found that P62 plasmid can inhibit the lipid peroxidation of iron death in dopaminergic nerve cells by activating the Nrf2 signaling pathway, thus playing a protective role in dopaminergic nerve cells.

Rational design, synthesis and binding mechanisms of novel benzyl geranate derivatives as potential eco-friendly aphid repellents.

BACKGROUND: The push-pull strategy is considered as a promising eco-friendly method for pest management. Plant volatile organic compounds (PVOCs) act as semiochemicals constitute the key factor in implementing this strategy. Benzyl alcohol and geraniol, as functional PVOCs, were reported to regulate insect behavior, showing the potential application in pest control. Using geraniol as lead, a geraniol derivative 5i with fine repellent activity was discovered in our previous work. In order to explore novel, eco-friendly aphid control agents, a series of benzyl geranate derivatives was designed and synthesized using 5i as the lead and benzyl alcohol as the active fragment. RESULTS: Benzyl alcohol was firstly evaluated to have repellent activity to Acyrthosiphon pisum. Based on this repellent fragment, a series of novel benzyl geranate derivatives was rationally designed and synthesized using a scaffold-hopping strategy. Among them, compound T9, with a binding affinity (Kd = 0.43 µm) and a substantial repellency of 64.7% against A. pisum, is the most promising compound. Molecule docking showed that hydrophobic and hydrogen-bonding interactions substantially influenced the binding affinity of compounds with ApisOBP9. Additionally, T9 exhibited low-toxicity to honeybees and ladybugs. CONCLUSION: Using a simple scaffold-hopping strategy combined with active fragment benzyl alcohol, a new derivative T9, with high aphid-repellency and low-toxicity to nontarget organisms, can be considered as a novel potential eco-friendly aphid control agent for sustainable agriculture. © 2023 Society of Chemical Industry.

Sustainable Natural Resources for Aphid Management: ß-Ionone and Its Derivatives as Promising Ecofriendly Botanical-Based Products.

ß-Ionone, sustainably derived from Petunia hybrida as a natural bioresource, was identified as a lead compound for integrated aphid management. A series of ß-ionone derivatives containing ester groups were designed and synthesized for the purpose of discovering renewable botanical-based products. The odorant-binding protein (OBP) binding test indicated that ß-ionone and its derivatives displayed binding affinities with Acyrthosiphon pisum OBP9 (ApisOBP9) and Harmonia axyridis OBP15 (HaxyOBP15). Bioactivity assays revealed that most ß-ionone derivatives exhibited a higher repellent activity than that of ß-ionone. ß-Ionone and derivatives 4g and 4l displayed attractiveness to H. axyridis. Specifically, 4g was a highly promising derivative, possessing good repellent activity against A. pisum and attractiveness to H. axyridis. Molecular dynamics simulations revealed that integrating the hydrophobic ester group into the ß-ionone framework strengthened the van der Waals interactions of 4g with ApisOBP9/HaxyOBP15, improving the binding affinity with OBPs and producing higher push-pull activity than ß-ionone; 4g also had low toxicity toward nontarget organisms. Thus, 4g is a potential ecofriendly, botanical-based option for aphid management.

Progesterone and DNA damage encourage uterine cell proliferation and decidualization through up-regulating ribonucleotide reductase 2 expression during early pregnancy in mice.

Embryo implantation into the maternal uterus is a crucial step for the successful establishment of mammalian pregnancy. Following the attachment of embryo to the uterine luminal epithelium, uterine stromal cells undergo steroid hormone-dependent decidualization, which is characterized by stromal cell proliferation and differentiation. The mechanisms underlying steroid hormone-induced stromal cell proliferation and differentiation during decidualization are still poorly understood. Ribonucleotide reductase, consisting of two subunits (RRM1 and RRM2), is a rate-limiting enzyme in deoxynucleotide production for DNA synthesis and plays an important role in cell proliferation and tumorgenicity. Based on our microarray analysis, Rrm2 expression was significantly higher at implantation sites compared with interimplantation sites in mouse uterus. However, the expression, regulation, and function of RRM2 in mouse uterus during embryo implantation and decidualization are still unknown. Here we show that although both RRM1 and RRM2 expression are markedly induced in mouse uterine stromal cells undergoing decidualization, only RRM2 is regulated by progesterone, a key regulator of decidualization. Further studies showed that the induction of progesterone on RRM2 expression in stromal cells is mediated by the AKT/c-MYC pathway. RRM2 can also be induced by replication stress and DNA damage during decidualization through the ATR/ATM-CHK1-E2F1 pathway. The weight of implantation sites and deciduoma was effectively reduced by specific inhibitors for RRM2. The expression of decidual/trophoblast prolactin-related protein (Dtprp), a reliable marker for decidualization in mice, was significantly reduced in deciduoma and steroid-induced decidual cells after HU treatment. Therefore, RRM2 may be an important effector of progesterone signaling to induce cell proliferation and decidualization in mouse uterus.

Aphid-repellent, ladybug-attraction activities, and binding mechanism of methyl salicylate derivatives containing geraniol moiety.

BACKGROUND: Aphids have been mainly controlled by traditional chemical insecticides, resulting in unamiable risk to the environment over the last decades. Push-pull strategy is regarded as a promising eco-friendly approach for aphid management through repelling aphid away and attracting their natural enemy. Methyl salicylate (MeSA), one of typical HIPVs (herbivore-induced plant volatiles), can repel aphids and attract ladybugs. Our previous studies discovered a new lead compound 3e, a salicylate-substituted carboxyl (E)-ß-farnesene derivative that had effective aphid-repellent activity. However, whether 3e has attractive activity to ladybug like MeSA is unknown. Meanwhile, to discover a new derivative for both deterring aphid and recruiting ladybug is meaningful for green control of aphids. RESULTS: Through the structural optimization of 3e, 14 new derivatives were designed and synthesized. Among them, compounds 4e and 4i had good aphid (Acyrthosiphon pisum) repellent activity, and compounds 3e, 4e and 4i had significant ladybug (Harmonia axyridis) attractive activity to males. Particularly, 4i exhibited manifest attractive effect on the females as well. Binding mechanism showed that 4i not only bound effectively with the aphid (Acyrthosiphon pisum) target ApisOBP9 thanks to its multiple hydrophobic interactions and hydrogen-bond, but also had strong binding affinity with ladybug target HaxyOBP15 due to the suitable steric space. Additionally, 4i displayed low toxicity to bee Apis mellifera. CONCLUSION: Compound 3e does exhibit attractive activity to male ladybug as MeSA. However, the new derivative 4i, with both pleasant aphid-repellent and ladybug-attraction activities, can be considered as a novel potential push-pull candidate for aphid control in sustainable agriculture. © 2022 Society of Chemical Industry.

Low HDL Cholesterol Is Associated with Reduced Bleeding Risk in Patients Who Underwent PCI: Findings from the PRACTICE Study.

BACKGROUND: We sought to examine the dose-response relationship between high-density lipoprotein cholesterol (HDL-C) and bleeds in coronary artery disease (CAD) patients who underwent percutaneous coronary intervention (PCI). METHODS: All the 15,250 participants were from the Personalized Antiplatelet Therapy According to CYP2C19 Genotype in Coronary Artery Disease (PRACTICE) study, which is a large, single-center, prospective cohort study based on case records and a follow-up registry performed in the First Affiliated Hospital of Xinjiang Medical University from December 2016 to October 2021. We divided all the patients into five groups according to their HDL-C levels: the ≤35 mg/dL group (n = 4,732), 35 to 45 mg/dL group (n = 6,049), 45 to 55 mg/dL group (n = 2,826), 55 and 65 mg/dL group (n = 1,117), and >65 mg/dL group (n = 526). The incidence of bleeds, mortality, ischemic events, and net adverse clinical events (NACEs) among the five groups was compared. RESULTS: A total of 713 bleeds, 1,180 ischemic events, 456 deaths, and 1,893 NACEs were recorded during the up to 60-month follow-up period. After adjusting for confounders, we observed a nonlinear relation for bleeds, with the highest risk at intermediate HDL-C levels (45-55 mg/dL). We also identified a dose-response relationship for ischemic events. A threshold value of HDL-C ≤35 mg/dL (adjusted hazard ratio = 0.560, 95% confidence interval: 0.360-0.872, p = 0.010) was associated with a decreased risk for bleeds in the multivariable Cox regression model. The results were consistent in multiple sensitivity analyses and propensity score-matching analysis. CONCLUSION: In the present study, a nonlinear association was identified between HDL-C levels and bleeds in CAD patients who underwent PCI, with a higher risk at intermediate levels. However, further multicenter studies are warranted.

Potential toxicity and affinity of triphenylmethane dye malachite green to lysozyme.

Malachite green is a triphenylmethane dye that is used extensively in many industrial and aquacultural processes, generating environmental concerns and health problems to human being. In this contribution, the complexation between lysozyme and malachite green was verified by means of computer-aided molecular modeling, steady state and time-resolved fluorescence, and circular dichroism (CD) approaches. The precise binding patch of malachite green in lysozyme has been identified from molecular modeling and ANS displacement, Trp-62, Trp-63, and Trp-108 residues of lysozyme were earmarked to possess high-affinity for this dye, the principal forces in the lysozyme-malachite green adduct are hydrophobic and π-π interactions. Steady state fluorescence proclaimed the complex of malachite green with lysozyme yields quenching through static type, which substantiates time-resolved fluorescence measurements that lysozyme-malachite green conjugation formation has an affinity of 10(3)M(-1). Moreover, via molecular modeling and also CD data, we can safely arrive at a conclusion that the polypeptide chain of lysozyme partially destabilized upon complexation with malachite green. The data emerged here will help to further understand the toxicological action of malachite green in human body.

Binding Affinity Characterization of Four Antennae-Enriched Odorant-Binding Proteins From Harmonia axyridis (Coleoptera: Coccinellidae).

Harmonia axyridis is an important natural enemy that consumes many agricultural and forestry pests. It relies on a sensitive olfactory system to find prey and mates. Odorant-binding proteins (OBPs) as the first-step of recognizing volatiles, transport odors through sensillum lymph to odorant receptors (ORs). However, little is known about the molecular mechanisms of H. axyridis olfaction. In this study, four H. axyridis antenna specific OBP genes, HaxyOBP3, 5, 12, and 15, were bacterially expressed and the binding features of the four recombinant proteins to 40 substances were investigated using fluorescence competitive binding assays. Three-dimensional structure modeling and molecular docking analysis predicted the binding sites between HaxyOBPs and candidate volatiles. Developmental expression analyses showed that the four HaxyOBP genes displayed a variety of expression patterns at different development stages. The expression levels of HaxyOBP3 and HaxyOBP15 were higher in the adult stage than in the other developmental stages, and HaxyOBP15 was significantly transcriptionally enriched in adult stage. Ligand-binding analysis demonstrated that HaxyOBP3 and HaxyOBP12 only combined with two compounds, ß-ionone and p-anisaldehyde. HaxyOBP5 protein displayed binding affinities with methyl salicylate, ß-ionone, and p-anisaldehyde (Ki = 18.15, 11.71, and 13.45 µM). HaxyOBP15 protein had a broad binding profile with (E)-ß-farnesene, ß-ionone, α-ionone, geranyl acetate, nonyl aldehyde, dihydro-ß-ionone, and linalyl acetate (Ki = 4.33-31.01 µM), and hydrophobic interactions played a key role in the binding of HaxyOBP15 to these substances according to molecular docking. Taken together, HaxyOBP15 exhibited a broader ligand-binding spectrum and a higher expression in adult stage than HaxyOBP3, 5, and 12, indicating HaxyOBP15 may play a greater role in binding volatiles than other three HaxyOBPs. The results will increase our understanding of the molecular mechanism of H. axyridis olfaction and may also result in new management strategies (attractants/repellents) that increase the biological control efficacy of H. axyridis.

A novel bee-friendly peptidomimetic insecticide: Synthesis, aphicidal activity and 3D-QSAR study of insect kinin analogs at Phe2 modification.

BACKGROUND: As one of the most abundant and destructive pests in agriculture, aphids cause significant damage to crops due to their sap-taking and as virus vectors. Chemical insecticides are the most effective method to control aphids, but they bring insecticide resistance problems and harm nontarget organisms, especially bees, therefore the search for novel eco-friendly aphid control agents with low bee toxicity is urgent. Insect kinins are a class of small neuropeptides that control important functions in insects. In our previous study, we found insect kinin analog IV-3 has good aphicidal activity and the location of the aromatic ring on the side chain of Phe2 is the key to the formation of the ß-turn resulting in the biological activity of insect kinin analogs. However, there are few studies on insect kinin Phe2 substitution and modification, and its structure-activity relationship is still unclear. RESULTS: In this project, 44 insect kinin analogs with the Phe2 modification, replacing it with different natural or unnatural amino acids, were designed and synthesized based on the lead IV-3 to explore the role of the Phe2 residues. Bioassays with soybean aphids of Aphis glycines indicated that nine analogs have better aphicidal activity than the lead IV-3. In particular, compound L25 exhibits excellent aphicidal activity (LC50  = 0.0047 mmol L-1 ) and has low toxicity to bees. Furthermore, a reliable three-dimensional quantitative structure-activity relationship (3D-QSAR) was established to produce a helpful clue that introducing hydrophobic groups away from the backbone chain is beneficial to improve aphicidal activity. CONCLUSION: The residue Phe2 of insect kinin analogs is the key position and has a significant impact on the activity. L25 has a high toxicity for aphids, while a low toxicity to bees, and therefore can be considered as a lead compound to develop new biosafe aphid control agents. Finally, we provide a useful 3D-QSAR model as theoretical guidance for further structural optimization. © 2022 Society of Chemical Industry.

[Clinic diagnosis and treatment of patients with Cantrell syndrome].

OBJECTIVE: To analyze the diagnostic feature, treatment and prognosis of patients with Cantrell syndrome. METHODS: Clinical manifestation, diagnosis, operation and follow-up data of 5 patients with Cantrell syndrome were summarized in this retrospective analysis. RESULTS: The age of the 5 patients was 7 days-76 years, definite diagnosis was made in 3 cases and 2 cases presented feature of incomplete Cantrell syndrome. Three patients with full Cantrell syndrome were correctly diagnosed before operation and confirmed by operation. One patient with incomplete Cantrell syndrome (two-vessel stenosis) received bypass surgery. Another asymptomatic patient with incomplete Cantrell syndrome (apical diverticulum of the left ventricle) does not need operation and is under observation. During follow-up, 1 patient died at 60 months after operation and the remaining 4 patients are alive and well. CONCLUSIONS: With the development of modern imaging technology, it becomes easy to make correct diagnose Cantrell syndrome before operation. Prognosis is fine post timely operation and related intervention.

Bioactivities of synthetic salicylate-substituted carboxyl (E)-ß-Farnesene derivatives as ecofriendly agrochemicals and their binding mechanism with potential targets in aphid olfactory system.

BACKGROUND: The aphid alarm pheromone, (E)-ß-farnesene (EßF), is a natural product secreted from the aphid cornicle as a signal to warn companions of danger. Odorant binding proteins (OBPs) are the vital targets in insect signal transduction pathways. To improve bioactivity of EßF as more economic and stable aphid control agents, EßF derivatives containing an active substructure, salicylic acid moiety, were designed, synthesized, and evaluated for their bioactivities in a structure-function study under laboratory conditions. RESULTS: EßF derivatives, (E)-3,7-dimethylocta-2,6-dien-1-yl-2-hydroxy-3-methylbenzoate and (E)-3,7-dimethylocta-2,6-dien-1-yl-2-hydroxy-3-methoxybenzoate showed outstanding aphid-repellent activity at a dose of 5 µg against Acyrthosiphon pisum (repellency proportions of 67.3% and 71.2%, respectively) and Myzus persicae (repellency proportions of 80.0% and 74.4%, respectively) in laboratory. EßF and most of its derivatives bound strongly to ApisOBP9 with a higher affinity than those of the reported potential targets AphisOBP3 and ApisOBP7. The binding affinities to these three ApisOBPs were generally consistent with the in vivo aphid-repellent activity. A molecular docking study suggested that the hydrophobic effect was crucial for the interactions between the derivatives and the OBPs. CONCLUSION: New EßF derivatives containing salicylic acid moiety and their repellent activity, binding mechanism with three potential OBPs are presented. A new OBP, ApisOBP9, was characterized as a potential EßF and EßF derivatives binding protein for the first time. The hydrophobic nature of these analogues is responsible for their activity. Two analogues 3b and 3e with outstanding aphid-repellent activity could be new leads for aphid control agents.

FGF-21 ameliorates essential hypertension of SHR via baroreflex afferent function.

Hypertension is a common complication of metabolic abnormalities associated with cardiovascular system and characterized by sexual dimorphism in mammals. Fibroblast growth factor-21 (FGF-21) plays a critical role in metabolic-disorder related hypertension through the afferent loop of baroreflex. However, the gender difference in FGF-21-mediated blood pressure (BP) regulation via sexual dimorphic expression of FGFRs in the nodose (NG) and nucleus tractus solitarius (NTS) were not elucidated in physiological and genomic form of hypertension. The gene and protein expression of FGFRs were tested by qRT-PCR, immunoblotting and immunostaining; the serum level of FGF21 was tested using ELISA; The BP was monitored while FGF21 was nodose microinjected. The results showed that more potent BP reduction was confirmed in female vs. male rats by nodose microinjection of rhFGF-21 along with higher expression of FGFR2 and FGFR4 in the nodose compared with age-match male and ovariectomized (OVX) rats, rather than other receptor subtypes, which is consistent well with immunohistochemical analysis. Additionally, serum FGF-21 was significantly higher in female-WKY, and this level of FGF-21 was dramatically declined in spontaneous hypertensive rats (SHR) with significant down-regulation of FGFR1/R4 for male-SHR and FGFR2/FGFR4 for female-SHR, respectively. Apparently, high BP of SHR of either sex could be reduced by rhFGF-21 nodose microinjection. These data extends our current understanding that sexual-specific distribution/expression of FGF-21/FGFRs is likely to contribute at least partially to sexual dimorphism of baroreflex afferent function on BP regulation in rats. FGF-21-mdiated BP reduction sheds new light on clinical management of primary/genomic form of hypertension.

5-(4-Fluoro-phen-yl)-2-furylmethyl N-(2,6-difluoro-benzo-yl)carbamate.

The title compound, C(19)H(12)F(3)NO(4), was synthesized by the reaction of 5-(4-fluoro-phen-yl)-2-furan-methanol and 2,6-difluoro-benzoyl-isocyanate. The seven atoms of the fluorophenyl group are disordered over two positions with site occupancy factors ca 0.6 and 0.4. The dihedral angle between the furan and fluorophenyl rings is 1.58°. In the crystal structure, the mol-ecules are linked via inter-molecular N-H⋯O hydrogen bonds to form chains.

N'-tert-Butyl-5-(4-chloro-phen-yl)furan-2-carbohydrazide.

In the title mol-ecule, C(15)H(17)ClN(2)O(2), the furan and benzene rings form a dihedral angle of 15.35 (8)°. In the crystal structure, inter-molecular N-H⋯O hydrogen bonds link the mol-ecules into chains extended in the [010] direction.

3-[(E)-3,7-Dimethyl-octa-2,6-dien-yl]-5-methyl-N-nitro-1,3,5-oxadiazinan-4-imine.

The title compound, C(14)H(24)N(4)O(3), was synthesized by the reaction of geranyl and 3-methyl-4-nitro-imino-1,3,5-oxadiazinane. In the crystal structure, mol-ecules are assembled by weak inter-molecular C-H⋯O hydrogen bonds. The nitryl and the long carbon chain are located on the same side of the C=N bond due to the two weak intra-molecular C-H⋯N hydrogen bonds; the configuration of the oxadiazinane is Z.

Dopaminergic neurons show increased low-molecular-mass protein 7 activity induced by 6-hydroxydopamine in vitro and in vivo.

BACKGROUND: Abnormal expression of major histocompatibility complex class I (MHC-I) is increased in dopaminergic (DA) neurons in the substantia nigra (SN) in Parkinson's disease (PD). Low-molecular-mass protein 7 (ß5i) is a proteolytic subunit of the immunoproteasome that regulates protein degradation and the MHC pathway in immune cells. METHODS: In this study, we investigated the role of ß5i in DA neurons using a 6-hydroxydopamine (6-OHDA) model in vitro and vivo. RESULTS: We showed that 6-OHDA upregulated ß5i expression in DA neurons in a concentration- and time-dependent manner. Inhibition and downregulation of ß5i induced the expression of glucose-regulated protein (Bip) and exacerbated 6-OHDA neurotoxicity in DA neurons. The inhibition of ß5i further promoted the activation of Caspase 3-related pathways induced by 6-OHDA. ß5i also activated transporter associated with antigen processing 1 (TAP1) and promoted MHC-I expression on DA neurons. CONCLUSION: Taken together, our data suggest that ß5i is activated in DA neurons under 6-OHDA treatment and may play a neuroprotective role in PD.