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A novel intercalated nanocomposite of mercapto-modified cellulose/bentonite (LCS-BE-SH) was synthesized by high-speed shearing method in one step at room temperature, and was applied to remove Cd from solution and remediate Cd-contaminated soil. Results revealed that cellulose long-chain molecules have intercalated into bentonite nanolayers and interlayer spacing was increased to 1.411 nm, and grafting –SH groups improved adsorption selectivity, which enabled LCS-BE-SH to have distinct capability of Cd adsorption (q max = 147.21 mg/g). Kinetic and thermodynamics showed that Cd adsorption onto LCS-BE-SH was well fitted by pseudo-second-order and Langmuir adsorption isotherm. Characterizations of the adsorbents revealed that synergistic effect of complexation (e.g., CdS, CdO) and precipitation (e.g., Cd(OH) 2 , CdCO 3) mechanism played a major role in Cd removal. In soil remediation, application of LCS-BE-SH was most effective (67.31 %) in Cd immobilization compared to the control (8.85 %), which reduced exchangeable Cd from 37.03 % to 11.44 %. Meanwhile, soil pH, soil organic matter, available phosphorus, and enzyme activities (catalase, urease, and dehydrogenase) were improved LCS-BE-SH treatment. The main immobilization mechanism in soil included complexation (e.g., CdS, CdO) and precipitation (e.g., Cd(OH) 2 , Cd–Fe-hydroxide). Overall, this work applied a promising approach for Cd removal in aqueous and Cd remediation in soil by using an effective eco-friendly LCS-BE-SH nanocomposites. [Display omitted] • Mercapto-modified cellulose/bentonite intercalated nanocomposite was synthesized. • Cellulose was intercalated into bentonite nanolayers by high-speed shearing methods. • Adsorption selectivity by grafting –SH improved Cd adsorption of nanocomposite. • Such remediation improved Cd immobilization, soil fertility and soil enzyme. • Mechanism of Cd removal in aqueous and remediation of Cd-contaminated soil was revealed. [ABSTRACT FROM AUTHOR]

Summary: Root lodging poses a major threat to maize production, resulting in reduced grain yield and quality, and increased harvest costs.Here, we combined expressional, genetic, and cytological studies to demonstrate a role of ZmYUC2 and ZmYUC4 in regulating gravitropic response of the brace root and lodging resistance in maize.We show that both ZmYUC2 and ZmYUC4 are preferentially expressed in root tips with partially overlapping expression patterns, and the protein products of ZmYUC2 and ZmYUC4 are localized in the cytoplasm and endoplasmic reticulum, respectively. The Zmyuc4 single mutant and Zmyuc2/4 double mutant exhibit enlarged brace root angle compared with the wild‐type plants, with larger brace root angle being observed in the Zmyuc2/4 double mutant. Consistently, the brace root tips of the Zmyuc4 single mutant and Zmyuc2/4 double mutant accumulate less auxin and are defective in proper reallocation of auxin in response to gravi‐stimuli. Furthermore, we show that the Zmyuc4 single mutant and the Zmyuc2/4 double mutant display obviously enhanced root lodging resistance.Our combined results demonstrate that ZmYUC2‐ and ZmYUC4‐mediated local auxin biosynthesis is required for normal gravity response of the brace roots and provide effective targets for breeding root lodging resistant maize cultivars. [ABSTRACT FROM AUTHOR]

Rationale: Drug combinations are commonly used in pain management, which can produce potent analgesic effects with reduced dosage and adverse effects. Objective: This study was designed to evaluate the anti-nociceptive effects and adverse effects of new combinations of flupirtine (a Kv7 potassium channel opener) and antihistamines (promethazine, fexofenadine) on acute and chronic pain in mice, and the possible mechanisms behind the synergistic analgesic effects were preliminarily investigated. Methods: In acetic acid writhing test, carrageenan-induced inflammatory pain model, and paclitaxel-induced neuropathic pain model, the interaction indexes (γ) between flupirtine and antihistamines were determined by isobolographic analysis. Furthermore, the Kv7 channel blocker XE991 was used to determine whether the effects of single agents and drug combinations on paclitaxel- and carrageenan-induced mechanical allodynia were mediated by Kv7 channels. Finally, hepatotoxicity markers, liver histopathology, and the rotarod test were used to investigate the adverse effects of drugs in combination doses. Results: The interaction indexes of flupirtine-promethazine and flupirtine-fexofenadine in all the above three pain models were lower than 1. The analgesic effects of flupirtine (13 mg/kg), promethazine (5 mg/kg), fexofenadine (20 mg/kg), and their combinations were antagonized significantly by XE991 (3 mg/kg). And the adverse effects of flupirtine and antihistamines in combination doses were not significantly different from the vehicle group. Conclusions: Flupirtine and antihistamines produced synergistic analgesic effects in all the above pain models. The analgesic effects of antihistamines were partially mediated by Kv7/M channels, and the activation of Kv7/M channels may be partly responsible for the synergistic analgesic effects between flupirtine and antihistamines. [ABSTRACT FROM AUTHOR]

Increasing planting density has been adopted as an effective means to increase maize (Zea mays) yield. Competition for light from neighbors can trigger plant shade avoidance syndrome, which includes accelerated flowering. However, the regulatory networks of maize inflorescence development in response to high-density planting remain poorly understood. In this study, we showed that shade-mimicking treatments cause precocious development of the tassels and ears. Comparative transcriptome profiling analyses revealed the enrichment of phytohormone-related genes and transcriptional regulators among the genes co-regulated by developmental progression and simulated shade. Network analysis showed that three homologous Squamosa promoter binding protein (SBP)-like (SPL) transcription factors, Unbranched2 (UB2), Unbranched3 (UB3), and Tasselsheath4 (TSH4), individually exhibited connectivity to over 2,400 genes across the V3-to-V9 stages of tassel development. In addition, we showed that the ub2 ub3 double mutant and tsh4 single mutant were almost insensitive to simulated shade treatments. Moreover, we demonstrated that UB2/UB3/TSH4 could directly regulate the expression of Barren inflorescence2 (BIF2) and Zea mays teosinte branched1/cycloidea/proliferating cell factor30 (ZmTCP30). Furthermore, we functionally verified a role of ZmTCP30 in regulating tassel branching and ear development. Our results reveal a UB2/UB3/TSH4-anchored transcriptional regulatory network of maize inflorescence development and provide valuable targets for breeding shade-tolerant maize cultivars. Three homologous SPL transcription factors, Unbranched2 (UB2), Unbranched3 (UB3), and Tasselsheath4 (TSH4), act as a central hub in regulating maize inflorescence development in response to shade. [ABSTRACT FROM AUTHOR]

Here, we explored the possible interaction between duloxetine and SEP-363856 (SEP-856) in depression-related reactions. The results showed that oral administration of duloxetine showed powerful antidepressant-like effects in both the forced swimming test (FST) and the suspension tail test (TST). SEP-856 orally administered alone also exerted an antidepressant-like effect in FST and TST, especially at doses of 0.3, 1, and 10 mg/kg. In addition, duloxetine (15 mg/kg) and SEP-856 (15 mg/kg) both showed antidepressant-like effects in the sucrose preference test (SPT). Most importantly, in the above experiments, compared with duloxetine alone, the simultaneous use of duloxetine and SEP-856 caused a more significant antidepressant-like effect. It is worth noting that doses of drug combination in FST and TST did not change the motor activities of mice in the open-field test (OFT). Thus, duloxetine and SEP-856 seem to play a synergistic role in regulating depression-related behaviors and might be beneficial for refractory depression. [ABSTRACT FROM AUTHOR]

Olanzapine is a commonly used drug in the treatment of schizophrenia, but its clinical application has been restricted by metabolic-related side effects. In order to mitigate the weight gain side effects caused by olanzapine, other drugs with different targets were selected for combined use and evaluated in animal models of schizophrenia. SEP-363856 is a novel psychotropic agent which is under phase III clinical trials for schizophrenia treatment. The aim of the research was to evaluate whether co-administration of olanzapine and SEP-363856 exerts synergistic anti-schizophrenic effects in the apomorphine (APO)-induced climbing test, the MK-801-induced hyperactivity test, and the Morris water maze test, and therefore reduces the weight gain side effects induced by olanzapine. Through isobolographic analysis, the results showed a synergistic interaction in the climbing test; the experimental ED30 (3 mg/kg) was significantly smaller (p < 0.05) than the theoretical ED30 (5 mg/kg). Additionally, such potentiating effects appeared additive in the MK-801 challenge experiment. Co-treatment with an effective dose of olanzapine and a low dose of SEP-363856 reversed MK-801-induced cognitive impairment symptoms in mice. Moreover, combination treatment with olanzapine and SEP-363856 controls sustained weight gain in mice with chronic exposure to olanzapine. These results support further clinical trials to test the effectiveness of co-treatment of olanzapine and SEP-363856 for controlling symptoms and weight gain in patients with schizophrenia during antipsychotic treatments. [ABSTRACT FROM AUTHOR]

A new series of thiophenpiperazine amide derivatives as potent dual ligands for the μ-opioid (MOR) and sigma-1 (σ 1 R) receptors are reported. Compound 23 exhibited good affinity to σ 1 R (K i = 44.7 ± 7.05 nM) and high selectivity to σ 2 R. Furthermore, Compound 23 exerted MOR agonism and σ1R antagonism and potent analgesic activity in animal moldes (the abdominal constriction test (ED 50 = 3.83 mg/kg) and carrageenan-induced inflammatory hyperalgesia model (ED 50 = 5.23 mg/kg)). We obtained new dual ligands that might serve as starting points for preparing targeted tools. Furthermore, 23 may be a useful chemical probe for understanding more fully analgesic effects associated with MOR agonism and σ 1 R antagonism. • A series of thiophenpiperazine amide derivatives were synthesised. • The structure activity relationships of the targeted compounds were summarised. • Selected compounds exhibited the desirable potent σ 1 R antagonism and MOR agonism profiles. • The most active compound exerted potent analgesic activity in in vivo animal model. [ABSTRACT FROM AUTHOR]

Oxycodone is one of the most prescribed narcotic medications for the treatment of moderate to severe pain in clinical practice. During long-term stability studies of oxycodone hydrochloride for injection performed as per ICH Q1A (R2) guidelines, an unknown degradation product, impurity-I, increased over time and reached a level of 0.21% after 24 months, based on the results of HPLC analysis. The observed impurity was preliminarily characterized as an oxycodone aldol dimer by using two-dimensional (2D) liquid chromatography (LC) coupled with quadrupole time-of-flight mass spectrometry (QTOF MS/MS) analysis. Impurity-I was synthesized and its molecular structure confirmed based on detailed analysis of 1D-NMR (1H, 13C, and DEPT) and 2D-NMR (1H–1H COSY, HSQC, and HMBC) spectroscopy data. The plausible mechanism for the formation of impurity-I was an aldol condensation reaction under weakly acidic conditions. In addition, the potential toxicity of impurity-I was assessed by in silico toxicity predictions using the TOPKAT software. [ABSTRACT FROM AUTHOR]

[Display omitted] • Twenty-three novel heterocyclic 2-phenylacetate derivatives were designed and synthesized as water-soluble and rapid recovery hypnotic agents. • Compounds 13–15 showed potent hypnotic potency and higher therapeutic indexes than propanidid or propofol in rabbits. • The recovery time of compounds 13–15 was shorter than that of propanidid or propofol in rabbits. In this work, a series of novel heterocyclic 2-phenylacetate derivatives were designed and synthesized as water-soluble and rapid recovery hypnotic agents. After introducing heterocyclic ring to the amide group of propanidid, the obtained propanidid derivatives showed greatly improved hydrophilicity and good anesthetic activity. In three animal experiments (mice, rats, and rabbits), compounds 13–15 showed potent hypnotic potency (HD 50 = 7.6, 6.5, 7.4 mg/kg in rabbits, respectively) and higher therapeutic indexes (TI = 17.3, 16.6, 15.2 in rabbits, respectively) than propanidid (TI = 14.7 in rabbits) or propofol (TI = 5.4 in rabbits). Moreover, the recovery time of compounds 13–15 (time to walk, 96.6, 79.6, 81.4 s in rabbits, respectively) were shorter than that of propanidid (124.5 s in rabbits) or propofol (425.3 s in rabbits). The experimental results suggested the potential of compounds 13–15 as water-soluble anesthetics with rapid recovery profile. [ABSTRACT FROM AUTHOR]

To develop safer and potent analgesics, we designed, synthesized, and evaluated a new series of benzylaminofentanyl derivates as bifunctional μ opioid receptor (MOR) and σ 1 receptor (σ 1 R) ligands. Compound 68 (Tao-191) showed desirable MOR agonism (K i = 6.5 nΜ; EC 50 = 48.5 nΜ, E max = 66.3%) and σ 1 R antagonism (K i = 35.7 nM) in vitro , and exerted powerful analgesic effects in the abdominal constriction test (ED 50 = 0.32 mg/kg, in mice), formalin-induced pain test (phase II, ED 50 = 2.26 mg/kg, in rats), and paclitaxel-induced neuropathic pain model (ED 50 = 0.30 mg/kg, in mice). The contributions of MOR and σ 1 R to its antinociceptive effect were verified by combined administration with the MOR antagonist naloxone and the σ 1 R agonist PRE-084, respectively. At equianalgesic doses, compound 68 induced fewer MOR-related side effects—including physical and psychological dependence, respiratory depression, constipation, and acute hyperlocomotion—than fentanyl. The results provide a rationale for further exploration of the action and safety of dual MOR/σ 1 R ligands as a promising avenue for the development of potent and safe analgesics. [Display omitted] • A series of benzylaminofentanyl derivates were synthesized as bifunctional MOR/σ 1 R ligands to develop safer analgesics. • Compound 68 showed desirable MOR agonism (EC 50 = 48.5 nΜ, E max = 66.3%) and σ 1 R antagonism (K i = 35.7 nM) in vitro. • Compound 68 exerted powerful analgesic effects in abdominal constriction test and formalin-induced pain test in rodents. • At equianalgesic doses, compound 68 induced fewer MOR-related side effects than fentanyl in mice. [ABSTRACT FROM AUTHOR]

Olanzapine (OLZ) is a second-generation atypical anti-schizophrenia drug, and it had been developed into various formulations, including immediate release and long-acting formulations. Specific solubility properties of OLZ are very important to design formulations for specific administration. In present work, two novel cocrystals of OLZ were synthesized and characterized (OLZ-KAE·0.75EA·0.25H 2 O, OLZ-ORC, KAE = kaempferol, ORC = orcinol). Single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), synchronous thermal analysis and attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) were used to characterize the structure of the cocrystals. Hirshfeld surface analysis was used to understand intermolecular interactions in cocrystals. In OLZ-KAE·0.75EA·0.25H 2 O cocrystal, the ethyl acetate (EA) and H 2 O exist as channel crystalline solvate, and they can easily escape from the lattice channel. Powder dissolution study showed that OLZ-ORC improved the dissolution rate of OLZ in PH 6.8 phosphate buffer. However, OLZ-KAE·0.75EA·0.25H 2 O and its desolvation product decreased the dissolution rate of OLZ, and the release rate kept sustained and stable, which was very suitable for sustained release and long-acting muscle injection formulations. • Two novel cocrystals of olanzapine with kaempferol or orcinol were synthesized and characterized. • The desolvation of olanzapine with kaempferol cocrystal were studied by variable-temperature X-ray powder diffraction. • Cocrystal of olanzapine with kaempferol decreased the dissolution rate of olanzapine. • Cocrystal of olanzapine with orcinol enhanced the dissolution rate of olanzapine. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Eighteen phenylpiperazine-phenylacetate derivatives with hypnotic potencies were synthesized. • Compound 10 showed apparently rapid recovery and higher safety than propanidid in animal models. • Compound 10 had a greater binding affinity for the GABA A receptor and a lower affinity for the off-target receptors. In this paper, we designed and synthesized a series of novel phenylpiperazine-phenylacetate derivatives as rapid recovery hypnotic agents. The best compound 10 had relatively high affinity for the GABA A receptor and low affinity for thirteen other off-target receptors. In three animal models (mice, rats, and rabbits), compound 10 exerted potent hypnotic effects (HD 50 = 5.2 mg/kg in rabbits), comparable duration of the loss of righting reflex (LORR), and significant shorter recovery time (time to walk) than propanidid. Furthermore, compound 10 (TI = 18.1) showed higher safety profile than propanidid (TI = 14.7) in rabbits. Above results suggested that compound 10 may have predictable and rapid recovery profile in anesthesia. [ABSTRACT FROM AUTHOR]

Palbociclib (PAL) is an effective anti-breast cancer drug, but its use has been partly restricted due to poor bioavailability (resulting from extremely low water solubility) and serious adverse reactions. In this study, two cocrystals of PAL with resorcinol (RES) or orcinol (ORC) were prepared by evaporation crystallization to enhance their solubility. The cocrystals were characterized by single crystal X-ray diffraction, Hirshfeld surface analysis, powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Fourier transform infrared and scanning electron microscopy. The intrinsic dissolution rates of the PAL cocrystals were determined in three different dissolution media (pH 1.0, pH 4.5 and pH 6.8), and both cocrystals showed improved dissolution rates at pH 1.0 and pH 6.8 in comparison to the parent drug. In addition, the cocrystals increased the solubility of PAL at pH 6.8 by 2–3 times and showed good stabilities in both the accelerated stability testing and stress testing. The PAL-RES cocrystal also exhibited an improved relative bioavailability (1.24 times) than PAL in vivo pharmacokinetics in rats. Moreover, the in vitro cytotoxicity assay of PAL-RES showed an increased IC50 value for normal cells, suggesting a better biosafety profile than PAL. Co-crystallization may represent a promising strategy for improving the physicochemical properties of PAL with better pharmacokinetics. [ABSTRACT FROM AUTHOR]

Here, we describe the optimization, synthesis, and associated pharmacological analgesic activities of a new series of bifunctional piperidinamide derivatives as sigma-1 receptor (σ 1 R) antagonists and mu opioid receptor (MOR) agonists. The new compounds were evaluated in vitro in σ 1 R and MOR binding assays. The most promising compound 114 (also called HKC-126), showed superior affinities for σ 1 R and MOR and good selectivity to additional receptors related to pain. Compound 114 showed powerful dose-dependent analgesic effects in the acetic acid writhing test, formalin test, hot plate test, and chronic constriction injury (CCI) neuropathic pain model. In contrast to an equianalgesic dose of fentanyl, compound 114 produced fewer opioid-like side effects, such as reward liability, respiratory depression, physical dependence, and sedation. Lastly, the pharmacokinetic properties of this drug were also acceptable, and these results suggest that compound 114 , as a mixed σ 1 R/MOR ligand, has potential for treating neuropathic pain. [Display omitted] 1. A new series of bifunctional piperidinamide derivatives were synthesized and evaluated biological activity. 2. Compound 114 showed superior affinities for σ 1 R and MOR and good selectivity to additional receptors related to pain. 3. Compound 114 showed powerful dose-dependent analgesic effects in different models. 4. Compound 114 produced fewer opioid-like side effects, such as reward liability, respiratory depression, physical dependence and sedation than fentanyl at an equianalgesic dose. [ABSTRACT FROM AUTHOR]

Opioid analgesics are highly effective painkillers for the treatment of moderate or severe pain, but they are associated with a number of undesirable adverse effects, including the development of tolerance, addiction, constipation and life-threatening respiratory depression. The development of new and safer analgesics with innovative mechanisms of action, which can enhance the efficacy in comparison to available treatments and reduce their side effects, is urgently needed. The sigma-1 receptor (σ 1 R), a unique Ca2+-sensing chaperone protein, is expressed throughout pain-modulating tissues and affects neurotransmission by interacting with different protein partners, including molecular targets that participate in nociceptive signalling, such as the μ-opioid receptor (MOR), N -methyl- d - aspartate receptor (NMDAR) and cannabinoid 1 receptor (CB 1 R). Overwhelming pharmacological and genetic evidence indicates that σ 1 R antagonists induce anti-hypersensitive effects in sensitising pain conditions (e.g. chemically induced, inflammatory and neuropathic pain) and enhance opioid analgesia but not opioid-mediated detrimental effects. It has been suggested that balanced modulation of MORs and σ 1 Rs may improve both the therapeutic efficacy and safety of opioids. This review summarises the functional profiles of ligands with mixed MOR agonist and σ 1 R antagonist activities and highlights their therapeutic potentials for pain management. Dual MOR agonism/σ 1 R antagonism represents a promising avenue for the development of potent and safer analgesics. [Display omitted] • σ 1 R antagonists exhibit anti-hypersensitive effects in sensitising pain conditions. • σ 1 R antagonists enhance opioid analgesia but not opioid-mediated unwanted effects. • Bifunctional MOR and σ 1 R ligands possess wider therapeutic window with fewer adverse effects. • Representative ligands with MOR agonist and σ 1 R antagonist activities were summarised. • Dual MOR-agonism/σ 1 R-antagonism represents a promising avenue for the development of potent and safer analgesics. [ABSTRACT FROM AUTHOR]