UB2/UB3/TSH4-anchored transcriptional networks regulate early maize inflorescence development in response to simulated shade.

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.

Thiophenpiperazine amide derivatives as new dual MOR and σ1R ligands for the treatment of pain.

A new series of thiophenpiperazine amide derivatives as potent dual ligands for the µ-opioid (MOR) and sigma-1 (σ1R) receptors are reported. Compound 23 exhibited good affinity to σ1R (Ki = 44.7 ± 7.05 nM) and high selectivity to σ2R. Furthermore, Compound 23 exerted MOR agonism and σ1R antagonism and potent analgesic activity in animal moldes (the abdominal constriction test (ED50 = 3.83 mg/kg) and carrageenan-induced inflammatory hyperalgesia model (ED50 = 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 σ1R antagonism.

Removal of Cd from solution and in-situ remediation of Cd-contaminated soil by a mercapto-modified cellulose/bentonite intercalated nanocomposite.

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 (qmax = 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, CdCO3) 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.

Local auxin biosynthesis regulates brace root angle and lodging resistance in maize.

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.

Design, synthesis and evaluation of heterocyclic 2-phenylacetate derivatives as water-soluble rapid recovery hypnotics.

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 (HD50 = 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.

Evaluating the One-Year Efficacy of Combined Anti-VEGF and Dexamethasone Implant Treatment for Macular Edema in Retinal Vein Occlusions.

BACKGROUND Retinal vein occlusion-induced macular edema (RVO-ME) is a significant global cause of vision loss, with the effectiveness of combined anti-vascular endothelial growth factor (anti-VEGF) drugs and dexamethasone implantation (DEX I) being a relevant, yet not thoroughly explored, area of interest.The aim of this study was to evaluate the 1-year clinical efficacy of combination therapy using anti-vascular endothelial growth factor (VEGF) drugs and dexamethasone implantation (DEX I) in the treatment of macular edema secondary to retinal vein occlusion (RVO-ME). MATERIAL AND METHODS This retrospective study analyzed data from 34 RVO-ME patients treated at the Inner Mongolia Chaoju Eye Hospital between January 2020 and December 2021. All patients underwent initial DEX I treatment, followed by the introduction of anti-VEGF drugs, and were observed for one year. Retinal structural and vascular changes were measured using spectral domain optical coherence tomography (SD-OCT) and OCT angiography (OCTA). The study also evaluated shifts in best corrected visual acuity (BCVA) throughout the observation period. RESULTS Following the combined therapy, patients showed significant improvements in BCVA, intraocular pressure (IOP), central retinal thickness (CRT), and retinal vessel density (VD) (all P<0.05). Upon stratifying the results by RVO type, patients with branch retinal vein occlusion (BRVO)-ME displayed more significant BCVA improvement and CRT reduction at various post-treatment intervals compared to those with central retinal vein occlusion (CRVO)-ME (all P<0.05). CONCLUSIONS The combined use of anti-VEGF drugs and DEX I showed promising one-year efficacy in treating RVO-ME, with greater improvements noted in patients with BRVO-ME compared to those with CRVO-ME. Despite the positive results, close monitoring of IOP elevation, a notable side effect, remains crucial.

Design, synthesis, and evaluation of phenylpiperazine-phenylacetate derivatives as rapid recovery hypnotic agents.

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 GABAA receptor and low affinity for thirteen other off-target receptors. In three animal models (mice, rats, and rabbits), compound 10 exerted potent hypnotic effects (HD50 = 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.

The Potential Antidepressant Action of Duloxetine Co-Administered with the TAAR1 Receptor Agonist SEP-363856 in Mice.

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.

Effect of Co-Treatment of Olanzapine with SEP-363856 in Mice Models of Schizophrenia.

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.

Discovery of a new class of multi-target heterocycle piperidine derivatives as potential antipsychotics with pro-cognitive effect.

A series of benzoisoxazoleylpiperidine derivatives were synthesized by using the multi-target strategies and their potent affinities for dopamine (DA), serotonin (5-HT) and human histamine H3 receptors have been evaluated. Of these compounds, the promising candidate 4w displayed high affinities for D2, D3, 5-HT1A, 5-HT2A and H3, a moderate affinity for 5-HT6, negligible effects on the human ether-a-go-go-related gene (hERG) channel, low affinities for off-target receptors (5-HT2C, adrenergic α1 and H1). In addition, the animal behavioral study revealed that, compared to risperidone, compound 4w significantly inhibited apomorphine-induced climbing and MK-801-induced movement behaviors with a high threshold for catalepsy and low liabilities for weight gain and hyperprolactinemia. Results from the conditioned avoidance response test and novel object recognition task demonstrated that 4w had pro-cognitive effects. Thus, the antipsychotic drug-like activities of 4w indicate that it may be a potential polypharmacological antipsychotic candidate drug.

New Cocrystals of Antipsychotic Drug Aripiprazole: Decreasing the Dissolution through Cocrystallization.

Cocrystallization is an important route to tuning the solubility in drugs development, including improving and reducing. Five cocrystals of aripiprazole (ARI) with resveratrol (RSV) and kaempferol (KAE), ARI-RSV, ARI2-RSV1·MeOH, ARI-KAE, ARI-KAE·EtOH, ARI-KAE·IPA, were synthesized and characterized. The single crystal of ARI2-RSV1·MeOH, ARI-KAE·EtOH, and ARI-KAE·IPA were analyzed by single crystal X-ray diffraction (SCXRD). The SCXRD showed multiple intermolecular interactions between API and the coformers, including hydrogen bond, halogen bond, and π-π interactions. Dissolution rate of the two nonsolvate ARI-RSV and ARI-KAE cocrystals were investigated through powder dissolution experiment in pH = 4.0 acetate buffer and pH = 6.8 phosphate buffer. The result showed that RSV could reduce the dissolution rate and solubility of ARI in both medium through cocrystallization. However, KAE improved the dissolution rate and solubility of ARI in pH = 4.0 medium, on the contrary, the two solubility indicators of ARI were both reduced for ARI-KAE cocrystal.

The deletion of mutant SOD1 via CRISPR/Cas9/sgRNA prolongs survival in an amyotrophic lateral sclerosis mouse model.

The superoxide dismutase 1 (SOD1) mutation is one of the most notable causes of amyotrophic lateral sclerosis (ALS), and modifying the mutant SOD1 gene is the best approach for the treatment of patients with ALS linked to the mutations in this gene. Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas9)/sgRNA delivered by the adeno-associated virus (AAV) system is a powerful tool for genome editing in the central nervous system (CNS). Here, we tested the capacity of the AAV-SaCas9-sgRNA system to modify mutant SOD1 in SOD1G93A transgenic mice and found that AAV9-SaCas9-sgRNA5 deleted the SOD1 gene, improved the lifespan of SOD1G93A mice by 54.6%, and notably ameliorated the performance of ALS transgenic mice. An immunochemical analysis showed that the expression of mutant SOD1 was very weak in motor neurons expressing SaCas9-sgRNA5. Consequently, the area showing muscle atrophy was more notably restored in the group treated with SaCas9-sgRNA5 compared with the group treated with SaCas9-sgLacZ. In addition, deep sequencing did not show the indel mutation in the gene highly matched to sgRNA5. Hence, AAV9-SaCas9-sgRNA-based gene editing is a feasible potential treatment for patients with ALS linked to SOD1 mutations.

Design, Synthesis and Biological Investigation of Flavone Derivatives as Potential Multi-Receptor Atypical Antipsychotics.

The design of a series of novel flavone derivatives was synthesized as potential broad-spectrum antipsychotics by using multi-receptor affinity strategy between dopamine receptors and serotonin receptors. Among them, 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl) piperidin- 1-yl) butoxy)-2,2-dimethylchroman-4-one (6j) exhibited a promising preclinical profile. Compound 6j not only showed high affinity for dopamine D2, D3, and serotonin 5-HT1A, 5-HT2A receptors, but was also endowed with low to moderate activities on 5-HT2C, α1, and H1 receptors, indicating a low liability to induce side effects such as weight gain, orthostatic hypotension and QT prolongation. In vivo behavioral studies suggested that 6j has favorable effects in alleviating the schizophrenia-like symptoms without causing catalepsy. Taken together, compound 6j has the potential to be further developed as a novel atypical antipsychotic.

Synthesis and evaluation of histamine H3 receptor ligand based on lactam scaffold as agents for treating neuropathic pain.

The synthesis and H3 receptor ligand of a new series of lactam derivatives are reported. The new compounds were evaluated in vitro in H3 and H1 receptor-binding assays. The structure-activity relationship led us to the promising derivative 2-methyl-7-(3-morpholinopropoxy)-3,4-dihydroisoquinolin-1(2H)-one (11). The compound with highest affinity and greatest selectivity were further profiled, In addition, compound 11 exerted dose-dependent anti-nociceptive effects in the formalin test. These characteristics suggested that the potent and selective compound 11 could be a potent candidate for pain treatment.

Synthesis and Biological Evaluation of Sigma-1 (σ1 ) Receptor Ligands Based on Phenyl-1,2,4-oxadiazole Derivatives.

In this study, a series of phenyl-1,2,4-oxadiazole derivatives were synthesized and evaluated for anti-allodynic activity. Structure-activity relationship studies identified 1-{4-[3-(2,4-dichlorophenyl)-1,2,4-oxadiazol-5-yl]butyl}piperidine (39) with excellent affinity for the σ1 receptor and selectivity for the σ2 receptor, with poor activity to other central nervous system neurotransmitter receptors and transporters associated with pain. Compound 39 exhibited dose-dependent efficacy in suppressing the formalin-induced flinching and attenuating mechanical allodynia in chronic constriction injury-induced neuropathic rats. These results suggest that compound 39 exerts potent antihyperalgesic activity and could be considered as a promising candidate for treating neuropathic pain.

Progressive Degeneration and Inhibition of Peripheral Nerve Regeneration in the SOD1-G93A Mouse Model of Amyotrophic Lateral Sclerosis.

BACKGROUND: Myelination, degeneration and regeneration are implicated in crucial responses to injury in the peripheral nervous system. Considering the progression of amyotrophic lateral sclerosis (ALS), we used the superoxide dismutase 1 (SOD1)-G93A transgenic mouse model of ALS to investigate the effects of mutant SOD1 on the peripheral nerves. METHODS: Changes in peripheral nerve morphology were analyzed in SOD1 mutant mice at various stages of the disease by toluidine blue staining and electron microscopy (EM). Schwann cell proliferation and recruitment of inflammatory factors were detected by immunofluorescence staining and quantitative reverse transcription PCR and were compared between SOD1 mutant mice and control mice. Furthermore, western blotting (WB) and TUNEL staining were used to investigate axonal damage and Schwann cell survival in the sciatic nerves of mice in both groups. RESULTS: An analysis of the peripheral nervous system in SOD1-G93A mice revealed the following novel features: (i) Schwann cells and axons in mutant mice underwent changes that were similar to those seen in the control mice during the early development of peripheral nerves. (ii) The peripheral nerves of SOD1-G93A mice developed progressive neuropathy, which presented as defects in axons and myelin, leading to difficulty in walking and reduced locomotor capacity at a late stage of the disease. (iii) Macrophages were recruited and accumulated, and nerve injury and a deficit in the blood-nerve barrier were observed. (iv) Proliferation and the inflammatory micro-environment were inhibited, which impaired the regeneration and remyelination of axons after crush injury in the SOD1-G93A mice. CONCLUSIONS: The mutant human SOD1 protein induced axonal and myelin degeneration during the progression of ALS and participated in axon remyelination and regeneration in response to injury.

Pharmacological Characterization of H05, a Novel Serotonin and Noradrenaline Reuptake Inhibitor with Moderate 5-HT2A Antagonist Activity for the Treatment of Depression.

Multitarget antidepressants selectively inhibiting monoaminergic transporters and 5-hydroxytryptamine (5-HT) 2A receptor have demonstrated higher efficacy and fewer side effects than selective serotonin reuptake inhibitors. In the present study, we synthesized a series of novel 3-(benzo[d][1,3]dioxol-4-yloxy)-3-arylpropyl amine derivatives, among which compound H05 was identified as a lead, exhibiting potent inhibitory effects on both serotonin (Ki = 4.81 nM) and norepinephrine (NE) (Ki = 6.72 nM) transporters and moderate 5-HT2A antagonist activity (IC50 = 60.37 nM). H05 was able to dose-dependently reduce the immobility duration in mouse forced swimming test and tail suspension test, with the minimal effective doses lower than those of duloxetine, and showed no stimulatory effect on locomotor activity. The administration of H05 (5, 10, and 20 mg/kg, by mouth) significantly shortened the immobility time of adrenocorticotropin-treated rats that serve as a model of treatment-resistant depression, whereas imipramine (30 mg/kg, by mouth) and duloxetine (30 mg/kg, by mouth) showed no obvious effects. Chronic treatment with H05 reversed the depressive-like behaviors in a rat model of chronic unpredictable mild stress and a mouse model of corticosterone-induced depression. Microdialysis analysis revealed that the administration of H05 at either 10 or 20 mg/kg increased the release of 5-HT and NE from the frontal cortex. The pharmacokinetic (PK) and brain penetration analyses suggest that H05 has favorable PK properties with good blood-brain penetration ability. Therefore, it can be concluded that H05, a novel serotonin and NE reuptake inhibitor with 5-HT2A antagonist activity, possesses efficacious activity in the preclinical models of depression and treatment-resistant depression, and it may warrant further evaluation for clinical development.

Scale-Up Synthesis and Identification of GLYX-13, a NMDAR Glycine-Site Partial Agonist for the Treatment of Major Depressive Disorder.

GLYX-13, a NMDAR glycine-site partial agonist, was discovered as a promising antidepressant with rapidly acting effects but no ketamine-like side effects. However, the reported synthetic process route had deficiencies of low yield and the use of unfriendly reagents. Here, we report a scaled-up synthesis of GLYX-13 with an overall yield of 30% on the hectogram scale with a column chromatography-free strategy, where the coupling and deprotection reaction conditions were systematically optimized. Meanwhile, the absolute configuration of precursor compound of GLYX-13 was identified by X-ray single crystal diffraction. Finally, the activity of GLYX-13 was verified in the cortical neurons of mice through whole-cell voltage-clamp technique.

[The structure-activity relationships of novel α7 nicotinic acetylcholine receptor agonists based on indolizine scaffold].

Alpha7 nicotinic acetylcholine receptor（α7 nAChR） is a ligand-gated ion channel critical for cognition, learning and memory. Deficiency of neuronal α7 nAChR has been implicated in the cognitive deficits and neuropsychiatric disorders. Chemical activation of α7 nAChR improves neurological functions in animal models. In this study, we designed and synthesized a series of indolizine derivatives with various substitutions at different positions on the scaffold, and investigated their structure-activity relationships（SAR）. All compounds were screened and evaluated for their agonist activity using the two-electrode voltage clamp recording system in Xenopus oocytes expressing human α7 nAChR. Compound 16 c carrying 6-methylindolizine moiety activates α7 nAChR with EC50 at 1.60 ± 0.19 µmol·L-1 and maximum effect (Emax) of 69.0% ± 2.8% compared with 3 mmol·L-1 ACh. Compound 17 b with 8-cyclopropyl substitution shows an increased Emax of 81.1% ± 9.3% with EC50 at 2.74 ± 0.74 µmol·L-1. The SAR of the series shows that introducing the small hydrophobic groups at 6- or 8- position can improve both potency and maximum effect.