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AbstractIn this study, four series of piperazine derivatives were designed, synthesised and subjected to biological test, and compound 6a with potential antidepressant activity was obtained. An affinity assay of compound 6a with 5-hydroxytryptamine (serotonin, 5-HT)1A receptor (5-HT1AR) was undertaken, and the effects on the 5-HT level in the brains of mice were also tested. The results showed that compound 6a had the best affinity with 5-HT1AR (Ki = 1.28 nM) and significantly increased the 5-HT level. The expression levels of 5-HT1AR, BDNF, and PKA in the hippocampus were analysed by western blot and immunohistochemistry analyses. The results showed that the expression of 5-HT1AR, BDNF, and PKA in the model group was reduced compared to that of the control group, and compound 6a could reverse this phenomenon. Molecular docking was performed to investigate the interactions of the studied compound 6a with 5-HT1AR on the molecular level.

Infections caused by multidrug-resistant pathogens have emerged as a serious threat to public health. To develop new antibacterial agents to combat such drug-resistant bacteria, a class of novel amphiphilic xanthoangelol-derived compounds were designed and synthesized by mimicking the structure and function of antimicrobial peptides (AMPs). Among them, compound 9h displayed excellent antimicrobial activity against the Gram-positive strains tested (MICs = 0.5–2 μg/mL), comparable to vancomycin, and with low hemolytic toxicity and good membrane selectivity. Additionally, compound 9h demonstrated rapid bactericidal effects, low resistance frequency, low cytotoxicity, and good plasma stability. Mechanistic studies further revealed that compound 9h had good membrane-targeting ability and was able to destroy the integrity of bacterial cell membranes, causing an increase in intracellular ROS and the leakage of DNA and proteins, thus accelerating bacterial death. These results make 9h a promising antimicrobial candidate to combat bacterial infection.

The Chinese hamster ovarian (CHO) cells serve as a common choice in biopharmaceutical production, traditionally cultivated in stirred tank bioreactors (STRs). Nevertheless, the pursuit of improved protein quality and production output for commercial purposes demand exploration into new bioreactor types. In this context, inverted frustoconical shaking bioreactors (IFSB) present unique physical properties distinct from STRs. This study aims to compare the production processes of an antibody-based biotherapeutic in both bioreactor types, to enhance production flexibility. The findings indicate that, when compared to STRs, IFSB demonstrates the capability to produce an antibody-based biotherapeutic with either comparable or enhanced bioprocess performance and product quality. IFSB reduces shear damage to cells, enhances viable cell density (VCD), and improves cell state at a 5-L scale. Consequently, this leads to increased protein expression (3.70 g/L vs 2.56 g/L) and improved protein quality, as evidenced by a reduction in acidic variants from 27.0% to 21.5%. Scaling up the culture utilizing the Froude constant and superficial gas velocity ensures stable operation, effective mixing, and gas transfer. The IFSB maintains a high VCD and cell viability at both 50-L and 500-L scales. Product expression levels range from 3.0 to 3.6 g/L, accompanied by an improved acidic variants attribute of 20.6%–22.7%. The IFSB exhibits superior productivity and product quality, underscoring its potential for incorporation into the manufacturing process for antibody-based biotherapeutics. These results establish the foundation for IFSB to become a viable option in producing antibody-based biotherapeutics for clinical and manufacturing applications.

The aging population has become an issue that cannot be ignored, and research on aging is receiving increasing attention. PL 1-3 possesses diverse pharmacological properties including anti-oxidative stress, inhibits inflammatory responses and anti-apoptosis. This study showed that PL 1-3 could protect mice, especially the brain, against the aging caused by D-galactose (D-gal). D-gal could cause oxidative stress, inflammation, apoptosis and tissue pathological injury and so on in aging mice. The treatment of PL 1-3 could increase the anti-oxidative stress ability in the serum, liver, kidney and brain of aging mice, via increasing the total antioxidant capacity and the levels of anti-oxidative defense enzymes (superoxide dismutase, glutathione peroxidase, and catalase), and reducing the end product of lipid peroxidation (malondialdehyde). In the brain, in addition to the enhanced anti-oxidative stress via upregulating the level of the nuclear factor erythroid 2-related factor 2 and heme oxygenase 1, PL 1-3 could improve the dysfunction of the cholinergic system via reducing the active of acetylcholinesterase so as to increase the level of acetylcholine, increase the anti-inflammatory and anti-apoptosis activities via downregulating the expressions of pro-inflammatory cytokines (interleukin-6 and tumor necrosis factor-α) and pro-apoptosis proteins (Bcl-2 associated X protein and Caspase-3) in the D-gal-induced aging mice, to enhance the anti-aging ability via upregulating the expression of sirtuin 1 and downregulating the expressions of p53, p21, and p16. Besides, PL 1-3 could reverse the liver, kidney and spleen damages induced by D-gal in aging mice. These results suggested that PL 1-3 may be developed as an anti-aging drug for the prevention and intervention of age-related diseases.

3,4-disubstituted maleimides find wide applications in various pharmacologically active compounds. This study presents a highly effective approach for synthesizing derivatives of 3,4-disubstituted maleimides through the direct isomerization of α-succinimide-substituted allenoates, followed by a cascade γ′-addition and aryl imines using PR3 as a catalyst. The resulting series of 3,4-disubstituted maleimides exhibited excellent stereoselectivities, achieving yields of up to 86%. To our knowledge, the phosphine-mediated γ′-addition reaction of allenoates is seldom reported.

Abscisic acid (ABA) is a drought-stress-responsive hormone that plays an important role in the stomatal activity of plant leaves. Currently, ABA glycosides have been identified in apples, but their glycosyltransferases for glycosylation modification of ABA are still unidentified. In this study, the mRNA expression of glycosyltransferase gene MdUGT73AR4 was significantly up-regulated in mature apple leaves which were treated in drought stress by Real-Time PCR. It was hypothesised that MdUGT73AR4 might play an important role in drought stress. In order to further characterise the glycosylation modification substrate of glycosyltransferase MdUGT73AR4, we demonstrated through in vitro and in vivo functional validation that MdUGT73AR4 can glycosylate ABA. Moreover, the overexpression lines of MdUGT73AR4 significantly enhance its drought stress resistance function. We also found that the adversity stress transcription factor AREB1B might be an upstream transcription factor of MdUGT73AR4 by bioinformatics, EMSA, and ChIP experiments. In conclusion, this study found that the adversity stress transcription factor AREB1B was significantly up-regulated at the onset of drought stress, which in turn positively regulated the downstream glycosyltransferase MdUGT73AR4, causing it to modify ABA by mass glycosylation and promoting the ABA synthesis pathway, resulting in the accumulation of ABA content, and displaying a stress-resistant phenotype.

In this paper, an interesting γ′-carbon 1,6-conjugate addition for phosphine-catalyzed α-succinimide substituted allenoates has been disclosed. A wide array of substrates was found to participate in the reaction, resulting in the production of diverse 4-diarylmethylated 3,4-disubstituted maleimides with satisfactory to outstanding yields. Furthermore, a plausible mechanism for the reaction was proposed by the investigators.

Nicosulfuron, an acetolactate synthase (ALS) inhibitor herbicide, is a broad-spectrum and highly effective post-emergence herbicide. Glycosyltransferases (GTs) are widely found in organisms and transfer sugar molecules from donors to acceptors to form glycosides or sugar esters, thereby altering the physicochemical properties of the acceptor molecule, such as participating in detoxification. In this study, nine glycosyltransferases in group D of the apple glycosyltransferase family I were predicted to possibly be involved in the detoxification metabolism of ALS-inhibiting herbicides based on gene chip data published online. In order to confirm this, we analysed whether the expression of the nine glycosyltransferase genes in group D was induced by the previously reported ALS-inhibiting herbicides by real-time PCR (polymerase chain reaction). It was found that the ALS-inhibiting herbicide nicosulfuron significantly increased the expression of the MdUGT73CG22 gene in group D. Further investigation of the mechanism of action revealed that the apple glycosyltransferase MdUGT73CG22 glycosylated and modified nicosulfuron both in vivo and ex vivo to form nicosulfuron glycosides, which were involved in detoxification metabolism. In conclusion, a new glycosyltransferase, MdUGT73CG22, was identified for the first time in this study, which can glycosylate modifications of the ALS-inhibiting herbicide nicosulfuron and may be involved in the detoxification process in plants, which can help to further improve the knowledge of the non-targeted mechanism of herbicides.

With the intensification of population aging, aging-related diseases are attracting more and more attention, thus, the study of aging mechanisms and anti-aging drugs is becoming increasingly urgent. Resveratrol is a potential candidate as an anti-aging agent, but its low bioavailability limits its application in vivo. In this work, a 4-hydroxy-3′-trifluoromethoxy-substituted resveratrol derivative (4–6), owing to its superior cell accumulation, could inhibit NO production in an inflammatory cell model, inhibit oxidative cytotoxicity, and reduce ROS accumulation and the population of apoptotic cells in an oxidative stress cell model. In D-galactose (D-gal)-stimulated aging mice, 4–6 could reverse liver and kidney damage; protect the serum, brain, and liver against oxidative stress; and increase the body’s immunity in the spleen. Further D-gal-induced brain aging studies showed that 4–6 could improve the pathological changes in the hippocampus and the dysfunction of the cholinergic system. Moreover, protein expression related to aging, oxidative stress, and apoptosis in the brain tissue homogenate measured via Western blotting also showed that 4–6 could ameliorate brain aging by protecting against oxidative stress and reducing apoptosis. This work revealed that meta-trifluoromethoxy substituted 4–6 deserved to be further investigated as an effective anti-aging candidate drug.

The need for co-ordinate, high-level, and stable expression of multiple genes is essential for the engineering of biosynthetic circuits and metabolic pathways. This work outlines the functionality and design of IRES- and 2 A-peptide-based constructs by comparing different strategies for co-expression in polycistronic vectors. In particular, 2 A sequences are small peptides, mostly derived from viral polyproteins, that mediate a ribosome-skipping event such that several, different, separate proteins can be generated from a single open reading frame. When applied to metabolic engineering and synthetic gene circuits, 2 A peptides permit to achieve co-regulated and reliable expression of various genes in eukaryotic cells.

To study the seismic performance of high-strength reinforced concrete frame joints, cyclic loading tests were carried out on six concrete beam-column joints configured with the new Cold-rolled Ribbed Bar (CRB) 735 high-strength steel reinforcement and one joint with Hot-rolled Ribbed Bar (HRB) 400 ordinary steel reinforcement to obtain the effects of the axial compression ratio and the stirrup ratio in the joint core on the seismic performance of the joints. The test results show that the following: (1) Increasing the axial compression ratio can improve the energy dissipation characteristics of the joints configured with CRB735, but cannot effectively improve the ultimate shear capacity of the joints. Larger axial compression ratio will cause earlier cracks in the core area and reduce the ductility of the specimens by 6.1~27.9%. (2) Increasing the stirrup ratio in the joint core will increase the shear capacity of the joint by 5.3~8.1% while also increasing the failure displacement by 2.8~14.9%. (3) When the joints are configured with CRB735 stirrups, the rate of stiffness degradation from core cracking to the yielding stage of the specimens will be effectively delayed. (4) Compared with the joint configured with HRB400, the ultimate loading process of the joints using CRB735 is shorter, the yield load and yield displacement are higher, and the specimens are close to the ultimate state when they reach yield. Finally, the shear capacity of concrete beam-column joints configured with CRB735 can be calculated using the relevant shear capacity equation in GB50010-2010 Code for Design of Concrete Structures, and has a certain safety reserve. In the equation, the yield strength of CRB735 steel reinforcement is recommended to be 735 MPa.

In this paper, eccentric compressive tests and theoretical studies of grade 735 MPa reinforced concrete columns were conducted. The eccentric distance and strength of the longitudinal reinforcement were used as experimental parameters to investigate the bearing capacity, failure mode, and strength of eccentric compressive behavior of NPR735 high-strength steel bars. When the load eccentricity of the reinforced concrete columns was small or longitudinal, the reinforcement ratio was large, and small eccentricity failure occurred. The results were similar to the failure mode of ordinary concrete columns with traditional steel bars. When the load eccentricity decreased, the bearing capacity increased, but the deflection and ductility of the specimen decreased. When the strength of the longitudinal reinforcement increased, the bearing capacity of the specimen increased slightly. Finally, according to current design methods in the concrete structure design code, the bearing capacity of the eccentric compressive column was obtained, and the calculated results were compared with the experimental results to verify the applicability of the concrete structure design code GB50010-2010 to concrete columns with grade 735 MPa reinforcement.

Diabetes mellitus (DM), a chronic metabolic disorder characterized by high blood glucose, not only poses a serious threat to human life and health, but also places an economic burden on society. Currently available antidiabetic pharmacological agents have some adverse effects, which have stimulated researchers to explore novel antidiabetic agents with different mechanisms of action. G-protein Coupled Receptor 120 (GPR120), also known as free fatty acid receptor 4 (FFAR4), which is activated by medium-chain and long-chain fatty acids, has emerged as an interesting potential target for the treatment of metabolic disorders. Herein, we designed and synthesized a series of novel GPR120 agonists based on the structure of TUG-891, which is susceptible to β-oxidation and loses its GPR120 agonistic activity in vivo. Among the designed compounds, 14d showed excellent agonistic activity and selectivity and could improve glucose tolerance in normal mice in a dose-dependent manner. In addition, the compound 14d displayed good antidiabetic effects in diet-induced obese (DIO) mice and elevated insulin levels. Molecular simulations illustrated that compound 14d could enter the active site of GPR120 and interact with ARG99, which plays an important role in GPR120 activation. Based on these observations, compound 14d may be a promising lead compound deserving of further biological evaluation and structural modifications.

To discover new acetyl-CoA carboxylase (ACCase) inhibiting-based herbicides, twenty-nine novel quinazolin-4(3H)-one derivatives were designed and synthesized based on the aryloxyphenoxypropionate motif. The bioassay results showed that most of the target compounds showed better pre-emergent herbicidal activity against monocotyledonous weeds in a greenhouse. Especially, when applied at 375 g ha−1 under pre-emergence conditions, compound QPP-7 displayed excellent herbicidal activity against monocotyledonous weeds (i.e., E. crusgalli, D. sanguinalis, P. alopecuroides, S. viridis, E. indica, A. fatua, E. dahuricu, S. alterniflora) with inhibition rate >90%, and displayed excellent crop safety to O. sativa, T. aestivum, G. spp, and A. hypogaea. The study of structure-activity relationship (SAR) revealed that the herbicidal activity of target compounds is strongly influenced by the spatial position of R group and the bulk of R1 group on quinazolin-4(3H)-one, and the (R = 6-F, R1 = Me) pattern is confirmed as the optimal orientation. Furthermore, the molecular docking study and the good inhibitory activity of QPP-7 against E. crusgalli ACCase enzyme (IC50 = 54.65 nM) indicated that it may be a ACCase inhibitor. Taken together, the present work demonstrated that compound QPP-7 could serve as a potential lead structure for further developing novel ACCase inhibiting-based herbicide.

The maximum clique problem (MCP) is a classical NP-hard problem in combinatorial optimization, which has important applications in many fields. In this paper, a heuristic algorithm MEAMCP based on Membrane Evolutionary Algorithm (MEA) is proposed to solve MCP. First, we introduce the general structure of MEA, which includes four kinds of membrane operators: selection, division, fusion and cytolysis. MEA evolves the feasible solution population through the membrane operator. Second, MEAMCP is proposed and we discuss how to initialize the population and implement the four kinds of membrane operators. Finally, MEAMCP is tested on DIMACS benchmark datasets and compared with other MCP algorithms. The experiment results demonstrate that MEAMCP has better stability.

GPR120 is a promising target for the treatment of type 2 diabetes (T2DM), which is activated by free fatty acids (FFAs) and stimulates the release of glucagon-like peptide-1(GLP-1). GLP-1, as an incretin, can enhance glucose-dependent secretion of insulin from pancreatic beta cells and reduce blood glucose. In this study, a series of novel GPR120 agonists were designed and synthesized to improve the stability and hydrophilicity of the phenylpropanoic acid GPR120 agonist TUG-891. Compound 11b showed excellent GPR120 agonistic activity and pharmacokinetic properties, and could reduce the blood glucose of normal mice in a dose-dependent manner. In addition, no hypoglycemic side effects were observed even at a dose of 100 mg/kg. Moreover, 11b showed good anti-hyperglycemic effects in diet-induced obese (DIO) mice. Molecular simulation illustrated that compound 11b could enter the active site of GPR120 and interact with ARG99. Taken together, the results indicate that compound 11b might be a promising drug candidate for the treatment of T2DM.

In this study, a series of coumarin derivatives were designed and synthesized, their structures were characterized using nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) testing methods. In the pharmacological experiment, two behavior-monitoring methods, the forced swim test (FST) and the tail suspension test (TST), were used to determine the antidepressant activity of coumarin derivatives. Compounds that showed potential activity were analyzed for their effects on 5-hydroxytryptamine (5-HT) levels in the brains of mice. Molecular docking experiments to simulate the possible interaction of these compounds with the 5-HT1A receptor was also be predicted. The results of the pharmacological experiments showed that most coumarin derivatives exhibited significant antidepressant activity. Among these compounds, 7-(2-(4-(4-fluorobenzyl)piperazin-1-yl)-2-oxoethoxy)-2H-chromen-2-one (6i) showed the highest antidepressant activity. The results of the measurement of 5-HT levels in the brains of mice indicate that the antidepressant activity of coumarin derivatives may be mediated by elevated 5-HT levels. The results of molecular docking demonstrated that compound 6i had a significant interaction with amino acids around the active site of the 5-HT1A receptor in the homology model. The physicochemical and pharmacokinetic properties of the target compounds were also predicted using Discovery Studio (DS) 2020 and Chemdraw 14.0.

Aim : To explore the efficacy of tear trough deformity treatment with the use of hyaluronic acid gel or autologous fat for soft tissue augmentation and fat repositioning via arcus marginalis release. Material and methods : Seventy-eight patients with the tear trough were divided into three groups. Class I has tear trough without bulging orbital fat or excess of the lower eyelid skin. Class II is associated with mild to moderate orbital fat bulging, without excess of the lower eyelid skin. Class III is associated with severe orbital fat bulging and excess of the lower eyelid skin. Class I or II was treated using hyaluronic acid gel or autologous fat injections. Class III was treated with fat repositioning via arcus marginalis release. The patients with a deep nasojugal groove of class III were treated with injecting autologous fat into the tear trough during fat repositioning lower blepharoplasty as a way of supplementing the volume added by the repositioned fat. Results : Seventy-eight patients with tear trough deformity were confirmed from photographs taken before and after surgery. There were some complications, but all had complete resolution. Conclusions : Patients with mild to moderate peri-orbital volume loss without severe orbital fat bulging may be good candidates for hyaluronic acid filler or fat grafting alone. However, patients with more pronounced deformities, severe orbital fat bulging and excess of the lower eyelid skin are often better served by fat repositioning via arcus marginalis release and fat grafting.

In this study, we synthetized a series of 5-aryl-4,5-dihydrotetrazolo[1,5-a]thieno[2,3-e]pyridine derivatives containing tetrazole and other heterocycle substituents, i.e., triazole, methyltriazole, and triazolone. The forced swim test (FST) and tail suspension test (TST) were used to evaluate the antidepressant activity of the target compounds. The compound 5-[4-(trifluoromethyl)phenyl]-4,5-dihydrotetrazolo[1,5-a]thieno[2,3-e]pyridine (4i) showed the highest antidepressant activity, with a reduced immobility time of 55.33% when compared with the control group. Using an open-field test, compound 4i was shown to not affect spontaneous activity of mice. The determination of in vivo 5-hydroxytryptamine (5-HT) concentration showed that compound 4i may have an effect in the mouse brain. The biological activities of all synthetized compounds were verified by molecular docking studies. Compound 4i showed significant interactions with residues of the 5-HT1A receptor homology model.

Study Purpose: Malignant central airway obstruction (CAO) in non-small cell lung cancer (NSCLC) is associated with high morbidity and requires endobronchial palliative treatment to re-establish a free air passage. We investigate intratumoral therapy combining anti-angiogenic and cytotoxic as a feasible therapeutic modality to treat malignant CAO.Study Design: Ten NSCLC subjects with symptomatic malignant CAO underwent endobronchial intratumoral cisplatin and Endostar co-injection after tumour debulking next to systemic cisplatin-based chemotherapy. Injection was performed immediately after debulking surgery and was then carried out on day 2, day 6 and day 10 past systemic chemotherapy. Nine subjects of control group constantly received traditional cisplatin-based chemotherapy. Bronchoscopy, CT scanning, histology, FEV1/FVC ratio, Karnofsky performance (KPS) and shortness of breath scores were analysed to assess therapeutic efficacy.Results: All 10 subjects benefited from the intratumoral cisplatin and endostar co-injection and systemic chemotherapy combination therapy. Bronchoscopy and CT scanning analyses showed a massive airway widening after treatment. Increased KPS and reduced shortness of breath score were also observed. A substantial improvement of lung function was further confirmed by increased FEV1/FVC ratio. For subjects of control group, the improvement was moderate and obviously not as optimal as the 10 subjects with intratumoral injection.Conclusions: We have shown that the intratumoral injection of cytotoxic cisplatin plus anti-angiogenic Endostar is an effective and safe adjuvant therapeutic option to treat malignant CAO in clinical practice. This time-staggered local and systemic treatment combination improves quality of life and clinical parameters, thus may provide a feasible therapeutic option for symptomatic CAO. [ABSTRACT FROM AUTHOR]