Puerarin attenuates remifentanil­induced postoperative hyperalgesia via targeting PAX6 to regulate the transcription of TRPV1.

Remifentanil­induced hyperalgesia (RIH) is characterized by the emergence of stimulation­induced pain, including phenomena such as allodynia and thermal hyperalgesia following remifentanil infusion. As a sequence­specific DNA binding transcription factor, PAX6 positively and negatively regulates transcription and is expressed in multiple cell types in the developing and adult central nervous system. It was hypothesized that puerarin could relieve RIH via targeting PAX6 to regulate transcription of transient receptor potential cation channel subfamily V Member 1 (TRPV1). A total of 32 rats were randomly divided into five groups, namely control group, RI group, RI + 10 mg/kg puerarin group (RI + puerarin10), RI + 20 mg/kg puerarin group (RI + puerarin20), and RI + 40 mg/kg puerarin group (RI + puerarin40). Mechanical and thermal hyperalgesia were tested at ­24, 2, 6, 24 and 48 h after remifentanil infusion. Following the sacrifice of rats after the last behavioral test, western blot was used to detect the expression levels of TRPV1 in the tissues; Immunofluorescence staining and western blotting were used to detect the expression of PAX6 in the spinal cord. PharmMapper and JASPAR were used to predict the binding sites of puerarin/PAX6/TRPV1. Chromatin immunoprecipitation­PCR and dual luciferase reporter assay were used to verify the targeting relationship between PAX6 and TRPV1. Immunofluorescence was used to detect the expression levels of TRPV1 and p­NR2B. The results revealed that puerarin (10, 20, 40 mg/kg) dose­dependently reduced thermal and mechanical hyperalgesia from 2 to 48 h after remifentanil infusion. Remifentanil infusion remarkably stimulated the expression of phosphorylated (p­)NR2B. Nevertheless, the increased amount of p­NR2B by RIH was dose­dependently suppressed by puerarin in rats. In conclusion, puerarin was revealed to attenuate postoperative RIH via targeting PAX6 to regulate the transcription of TRPV1.

Extraction, purification, structural characteristics and biological properties of the polysaccharides from Armillaria mellea (Vahl) P. Kumm.: A review.

Armillaria mellea (Vahl) P. Kumm. is a well-known homoeopathic plant with medicinal and culinary uses. Modern phytochemical researchers have successfully extracted and purified over 40 types of A. mellea polysaccharides (AMPs) from the fruiting bodies, hyphae and fermentation broth of A. mellea, and some of them have been analyzed and identified by their chemical structures. The impressive biological activity of these polysaccharides has been recognized by scientists worldwide. Many studies show that AMPs have remarkable antioxidant, anti-diabetic, anti-tumor, anti-inflammatory, immunoregulatory, hypolipidemic, thrombectomy, anti-aging, pulmonary protective, hepatic protective, anti-Alzheimer's properties, etc. However, the current understanding of the relationships between their chemical structure and biological activity, toxicological effects and pharmacokinetics remains limited. This article provides a systematic review of the research conducted over the past decades on the extraction and purification methods, structural characteristics, biological activity and mechanism of action of AMPs. The aim is to provide a research base that will benefit the future application of AMPs as therapeutic drugs and functional foods, and also provide insights for the further development of AMPs.

Naked cuticle homolog 1 prevents mouse pulmonary arterial hypertension via inhibition of Wnt/ß-catenin and oxidative stress.

Pulmonary arterial hypertension (PAH) is a poorly prognostic cardiopulmonary disease characterized by abnormal contraction and remodeling of pulmonary artery (PA). Excessive proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) are considered as the major etiology of PA remodeling. As a negative regulator of Wnt/ß-catenin pathway, naked cuticle homolog 1 (NKD1) is originally involved in the tumor growth and metastasis via affecting the proliferation and migration of different types of cancer cells. However, the effect of NKD1 on PAH development has not been investigated. In the current study, downregulated NKD1 was identified in hypoxia-challenged PASMCs. NKD1 overexpression by adenovirus carrying vector encoding Nkd1 (Ad-Nkd1) repressed hypoxia-induced proliferation and migration of PASMCs. Mechanistically, upregulating NKD1 inhibited excessive reactive oxygen species (ROS) generation and ß-catenin expression in PASMCs after hypoxia stimulus. Both inducing ROS and recovering ß-catenin expression abolished NKD1-mediated suppression of proliferation and migration in PASMCs. In vivo, we also observed decreased expression of NKD1 in dissected PAs of monocrotaline (MCT)-induced PAH model. Upregulating NKD1 by Ad-Nkd1 transfection attenuated the increase in right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), pulmonary vascular wall thickening, and vascular ß-catenin expression after MCT treatment. After recovering ß-catenin expression by SKL2001, the vascular protection of external expression of NKD1 was also abolished. Taken together, our data suggest that NKD1 inhibits the proliferation, migration of PASMC, and PAH via inhibition of ß-catenin and oxidative stress. Thus, targeting NKD1 may provide novel insights into the prevention and treatment of PAH.

Nicotine perturbs the microbiota of brown planthopper (Nilaparvata lugens stål Hemiptera: Delphinidae).

Bacterial symbionts exhibiting co-evolutionary patterns with insect hosts play a vital role in the nutrient synthesis, metabolism, development, reproduction, and immunity of insects. The brown planthopper (BPH) has a strong ability to adapt to various environmental stresses and can develop resistance to broad-spectrum insecticides. We aimed to investigate whether gut symbionts of BPH play a major role in the detoxification of insecticides and host fitness in unfavorable environments. Nicotine-treated rice plants were exposed to BPH (early stage) and the gut microbiome of the emerging female adults were analyzed using high throughput sequencing (HTS). Nicotine administration altered the diversity and community structure of BPH symbionts with significant increases in bacterial members such as Microbacteriaceae, Comamondaceae, Enterobacteriaceae, and these changes may be associated with host survival strategies in adverse environments. Furthermore, the in-vitro study showed that four intestinal bacterial strains of BPH (Enterobacter NLB1, Bacillus cereus NL1, Ralstonia NLG26, and Delftia NLG11) could degrade nicotine when grown in a nicotine-containing medium, with the highest degradation (71%) observed in Delftia NLG11. RT-qPCR and ELISA analysis revealed an increased expression level of CYP6AY1 and P450 enzyme activities in Delftia NLG11, respectively. CYP6AY1 increased by 20% under the action of Delftia and nicotine, while P450 enzyme activity increased by 18.1%. After CYP6AY1 interference, nicotine tolerance decreased, and the mortality rate reached 76.65% on the first day and 100% on the third day. Moreover, Delftia NLG11 helped axenic BPHs to increase their survival rate when fed nicotine in the liquid-diet sac (LDS) feeding system. Compared with axenic BPHs, the survival rate improved by 25.11% on day 2% and 6.67% on day 3. These results revealed an altered gut microbiota and a cooperative relationship between Delftia NLG11 and CYP6AY1 in nicotine-treated BPH, suggesting that insects can adapt to a hostile environment by interacting with their symbionts and providing a new idea for integrated pest management strategies.

Design and synthesis of ligustrazine derivatives as potential anti-Alzheimer's agents.

A novel series of ligustrazine derivatives was designed, synthesized, and evaluated as acetylcholinesterase (AChE) and butylcholinesterase (BuChE) inhibitors for the treatment of Alzheimer's disease (AD). In vitro studies displayed that some of the synthesized compounds revealed promising AChE and BuChE inhibitory effects. Particularly, compounds E12 and E27, indicated highly AChE inhibitory activity with IC50 values of 1.85 µM and 0.98 µM, respectively and showed noteworthy protective effects against on glutamate-induced SH-SY5Y cells damage at 1 µM and 10 µM concentrations. Furthermore, molecular simulation docking elucidates compounds E12 and E27 interacting with residues in the binding site of AChE (PDB code: 4EY7) and BuChE (PDB code: 1P0I), emphasizing the protein residues that participate in the main interactions with the two targets. Taken together, these results revealed that compounds E12 and E27 might be potential lead compounds for further structure optimization in the drug-discovery process against AD.

USP18 overexpression protects against spinal cord ischemia/reperfusion injury via regulating autophagy.

BACKGROUND: Spinal cord ischemia-reperfusion injury (SCII) is usually caused by spinal surgery, often leading to severe neurological deficits. The ubiquitin-specific protease 18 (USP18) plays a significant role in neurological diseases. OBJECTIVE: The present study was designed to assess the effects and mechanisms of USP18 on SCII. METHODS: By inducing transient aortic occlusion and subsequent reperfusion, a rat model of SCII was successfully established. The Basso-Beattie-Bresnahan scores, the inclined plane test, and hematoxylin and eosin (HE) were used to measure locomotor activity and histological changes in the injured spinal cords. Moreover, the SCII cell model was established using PC12 cells under oxygen-glucose deprivation and reoxygenation (OGD/R). Proinflammatory factors (TNF-α, IL-6, and INF-α) were examined using an ELISA kit. Cell apoptosis was assessed by Annexin V-FITC/PI double-staining and TUNEL assays. Western blot was used to detect the expression levels of proteins related to apoptosis and autophagy. RESULTS: USP18 expression was decreasedin vivo and in vitro SCII models. The upregulation of USP18 ameliorated hind limbs' motor function, inhibiting inflammation and apoptosis after SCII in rats. USP18 overexpression in vitro may protect PC12 cells from OGD/R-induced damage by modulating inflammatory responses and apoptosis. Moreover, Overexpression of USP18 enhanced autophagy to inhibit cell apoptosis induced by SCII in vivo and in vitro. CONCLUSIONS: In summary, USP18 overexpression protects against SCII via regulating autophagy.

Effect of Repeated Intranasal Administration of Different Doses of Insulin on Postoperative Delirium, Serum τ and Aß Protein in Elderly Patients Undergoing Radical Esophageal Cancer Surgery.

Objective: Postoperative delirium is common after general anesthesia in older patients. However, there are currently no effective preventive measures. This study investigated the effect of repeated intranasal administration of different insulin doses before surgery on postoperative delirium in older patients with esophageal cancer, and the possible mechanism for its efficacy. Methods: In this randomized, placebo-controlled, double-blind, parallel-group study, 90 older patients were randomly assigned to either a Control (normal saline), Insulin 1 (20 U/0.5 mL intranasal insulin), or Insulin 2 (30 U/0.75 mL intranasal insulin) group. Delirium was assessed on postoperative days 1 (T2), 2 (T3), and 3 (T4) using the Confusion Assessment Method for the Intensive Care Unit. Serum τ and Aß protein levels were measured at T0 (before insulin/saline administration), T1 (end of surgery), T2, T3 and T4. Results: The Insulin 2 group had a significantly lower prevalence of delirium compared to the Control and Insulin 1 groups three days after surgery. Compared to baseline, τ and Aß protein levels increased significantly at T1-T4. Compared to the Control group, the Insulin 1 and 2 groups had significantly lower τ and Aß protein levels at T1-T4, and the Insulin 2 group had significantly lower levels than the Insulin 1 group at T1-T2. Conclusion: The administration of 30 U of intranasal insulin twice daily, from 2 days preoperatively until 10 minutes preanesthesia on the day of surgery, can significantly reduce postoperative delirium in older patients undergoing radical esophagectomy. It can also decrease postoperative τ and Aß protein expression without causing hypoglycemia. Clinical Trial Registration: This study was registered at the Chinese Clinical Trial Registry (www.chictr.org.cn, with the unique identifier: ChiCTR2100054245; December 11, 2021).

Administration of combined spinal epidural anesthesia with ultrasound-assisted positioning in obese patients undergoing open hysterectomy: A randomized controlled trial.

BACKGROUND: Administration of combined spinal epidural anesthesia (CSEA) with traditional landmark-guided positioning can be challenging in patients with high body mass index (BMI). The popularization of ultrasound technology may effectively solve these problems. However, reports on the administration of CSEA ultrasound-assisted positioning in obese populations are relatively limited and have made inconsistent conclusions. We aimed to investigate the ability of ultrasound-assisted positioning to improve the success rate of CSEA in obese patients. METHODS: Overall, 118 adult women with a BMI ≥ 30 kg/m2 who scheduled to undergo open hysterectomy and received CSEA were recruited. Finally, 108 patients were enrolled and randomly assigned to 2 groups: the ultrasound-assisted positioning group (group A) and traditional landmark-guided positioning group (group B). Ultrasound-assisted or landmark-guided positioning was employed to locate the puncture interspace before anesthesia. The primary outcomes were the success rate of first attempt and number of attempts. The secondary outcomes were the patient positioning accuracy, positioning time, CSEA operation time, patient-satisfaction scores, anesthesia characteristics, and complications of CSEA. RESULTS: The success rate of patient first puncture attempt in group A was significantly higher than that in group B (78.4% vs 52.9%, P = .007). The total number of punctures was lower in group A than that in groups B (average rank 44.54 vs 58.46, P = .005). Using ultrasound positioning as the gold standard, the accuracy of landmark-guided location was only 67%. Positioning time in croup A was longer in group A than that in group B (P = .004), while CSEA operation time spent in Group A was less than that in Group B (P < .001). Patient satisfaction score in group A was significantly higher than that in group B (P = .002). The successful puncture interspace in group A were more likely at L3-4 than that in group B (P = .02). CONCLUSION: The success rate of first puncture attempt and positioning accuracy in CSEA with ultrasound-assisted is significantly higher than those based on landmark-guided location in obese patients.

Research progress in brain-targeted nasal drug delivery.

The unique anatomical and physiological connections between the nasal cavity and brain provide a pathway for bypassing the blood-brain barrier to allow for direct brain-targeted drug delivery through nasal administration. There are several advantages of nasal administration compared with other routes; for example, the first-pass effect that leads to the metabolism of orally administered drugs can be bypassed, and the poor compliance associated with injections can be minimized. Nasal administration can also help maximize brain-targeted drug delivery, allowing for high pharmacological activity at lower drug dosages, thereby minimizing the likelihood of adverse effects and providing a highly promising drug delivery pathway for the treatment of central nervous system diseases. The aim of this review article was to briefly describe the physiological structures of the nasal cavity and brain, the pathways through which drugs can enter the brain through the nose, the factors affecting brain-targeted nasal drug delivery, methods to improve brain-targeted nasal drug delivery systems through the application of related biomaterials, common experimental methods used in intranasal drug delivery research, and the current limitations of such approaches, providing a solid foundation for further in-depth research on intranasal brain-targeted drug delivery systems (see Graphical Abstract).

Salidroside attenuates HALI via IL-17A-mediated ferroptosis of alveolar epithelial cells by regulating Act1-TRAF6-p38 MAPK pathway.

BACKGROUND AND PURPOSE: Hyperoxia-induced acute lung injury (HALI) is a critical life-threatening disorder characterized by severe infiltration immune cells and death of type II alveolar epithelial cells (AECII). However, little is known about the relations between immune cells and AECII in HALI. IL-17A is a pro-inflammatory cytokine mainly secreted by Th17 cells, contributing to the pathogenesis of various inflammatory diseases. The present study investigated the role of IL-17A in cell-cell communication between immune cells and AECII in HALI, and explored the therapeutic effect of salidroside (Sal, a natural anti-inflammatory agents) on HALI. METHODS: Mice with HALI were induced by exposure to hyperoxia over 90% for 12 h, 24 h, 48 h or 72 h, and the optimal timing was detected by H&E and Masson staining. Ferroptosis was confirmed by detecting the levels of MDA, Fe2+ and GPX4, and the morphological alterations of AECII under transmission electron microscopy. The expression of pro-inflammatory cytokine, including IL-6, TGF-ß1, IL-17A and IL-17A receptor (IL-17RA) were measured by Western blotting and immunohistochemical stanning. The ferroptosis-related Act1/TRAF6/p38 MAPK pathway was detected by Western blotting. The role of pro-inflammatory cytokine IL-17A for AECII ferroptosis, and the effect of Sal on HALI were investigated by administration of Y-320 (IL-17 inhibitor) and Sal respectively 3 days before mice exposed to hyperoxia. RESULTS: Mice exposed to hyperoxia for 24 h suffered sufficient HALI with inflammatory cell infiltration and collagen deposition, and exhibited features of ferroptosis under TME. Meanwhile, compared with sham mice, mice exposed to hyperoxia showed down-regulation of GPX4, and up-regulation of IL-6, TGF-ß1, IL-17A, IL-17RA, Act1, TRAF6, p38 MAPK and p-p38 MAPK. Moreover, inhibition of IL-17A with Y-320 or administration with Sal could reverse the effect caused by hyperoxia respectively. CONCLUSIONS: IL-17A is associated with immune cells infiltration in HALI, and contributes to ferroptosis of AECII that related to Act1/TRAF6/p38 MAPK pathway. Additionally, Sal protects against HALI throughout the whole pathogenic process. Video Abstract.

Oxygen inhalation has been widely used in the treatment of some diseases caused by hypoxia. This often leads people to mistakenly believe that oxygen inhalation is beneficial without harm. However, long-term high concentration oxygen inhalation will cause serious harm to the human body, sometimes even fatal. Hyperoxia causes lung cells to secrete proinflammatory factors, which promote the differentiation of infiltrated immune cells. The differentiated immune cells in turn act on lung cells and lead to their death. In short, this process is a vicious circle. Our research explores this process and is committed to finding a drug to reduce the damage of hyperoxia to the lungs when oxygen must be inhaled.

Solanum nigrum Linn.: An Insight into Current Research on Traditional Uses, Phytochemistry, and Pharmacology.

Solanum nigrum Linn., is a common edible medicinal herb of the Solanaceae family which is native to Southeast Asia and is now widely distributed in temperate to tropical regions of Europe, Asia, and America. Traditionally, it has been used to treat various cancers, acute nephritis, urethritis, leucorrhea, sore throat, toothache, dermatitis, eczema, carbuncles, and furuncles. Up to now, 188 chemical constituents have been identified from S. nigrum. Among them, steroidal saponins, alkaloids, phenols, and polysaccharides are the major bioactive constituents. Investigations of pharmacological activities of S. nigrum revealed that this edible medicinal herb exhibits a wide range of therapeutic potential, including antitumor, anti-inflammatory, antioxidant, antibacterial, and neuroprotective activities both in vivo and in vitro. This article presents a comprehensive and systematic overview of the botanical, traditional uses, phytochemical compositions, pharmacological properties, clinical trials, and toxicity of S. nigrum to provide the latest information for further exploitation and applications of S. nigrum in functional foods and medicines.

Preventing nausea and vomiting after gynecological laparoscopic surgery by patient-controlled intravenous analgesia with a naloxone admixture: A randomized controlled trial.

BACKGROUND: Opioid-induced nausea and vomiting are common side effects of patient-controlled intravenous analgesia (PCIA). This study aimed to explore the inhibitory effect of a naloxone admixture on the incidence of sufentanil-induced postoperative nausea and vomiting (PONV). METHODS: A total of 132 Uyghur American Society of Anesthesiologists I and II patients scheduled to undergo elective gynecological laparoscopic surgery were recruited; among these, 120 patients were enrolled and randomly allocated into 4 groups: patients receiving PCIA but no naloxone were included in the control group (group A); patients receiving PCIA with a low-dose naloxone admixture at 0.2 µg·kg-1·h-1 were included in group B; patients receiving PCIA with naloxone admixture at 0.4 µg·kg-1·h-1 were included in group C; patients receiving PCIA with naloxone admixture at 0.6 µg·kg-1·h-1 were included in group D. All patients were administered sufentanil at 0.04 kg-1·h-1, butorphanol at 2 kg-1·h-1, and dexmedetomidine at 0.08 kg-1·h-1 using a PCIA device within 2 days of surgery. The occurrence of nausea and vomiting, visual analogue scores for pain intensity, mean arterial pressure, heart rate, oxygen saturation, pruritus, lethargy, respiratory depression, etc, was recorded at 2, 8, 12, 24, and 48 hours postoperatively. RESULTS: There was a significant difference in the PONV scores between the groups at 8, 12, and 24 hours after surgery (P < 0.01). At 8 and 12 hours, the score of group C/D was significantly lower than that of group A/B (P < 0.01). At 24 hours after surgery, the PONV score of group B/C/D was significantly lower than that of group A (P < 0.01). No significant difference was observed in the general data and visual analogue scores for postoperative pain between the 4 groups. CONCLUSION: Naloxone admixture administered at 0.4 to 0.6 µg·kg-1·h-1 can exert an effective inhibitory effect on the incidence and intensity of PONV in gynecological laparoscopic surgery.

Hypoxia Acclimation Protects against Heart Failure Postacute Myocardial Infarction via Fundc1-Mediated Mitophagy.

Mitochondrial dysfunction is the main cause of heart failure (HF) postacute myocardial infarction (AMI). Hypoxia acclimation (HA) reduces efficiently the area of AMI caused by ischemia and/or reperfusion and delays HF. Here, we examined whether HA improves mitochondrial structure and function through the hypoxic autophagy receptor FUNDC1 to prevent HF post-AMI. Male adult mice were acclimated in a low-pressure hypoxic animal chamber (11% oxygen (O2)) for 8 h/day for 28 days, and then, an induced HF post-AMI model via left anterior descending (LAD) artery ligation was structured to explore the efficacy and mechanism of HA. Our results showed that HA exposure can improve cardiac structure and function in mice with HF post-AMI and protected myocardial mitochondrial morphology and function. Further studies showed that HA increased the expression of Fundc1 protein and its associated mitophagy protein LC3 in myocardial tissue after infarction. We then established a cellular model of oxygen glucose deprivation (OGD) in vitro, and knockdown of FUNDC1 attenuated the protective effect of HA exposed on cardiomyocyte mitochondria and increased cardiomyocyte apoptosis. In conclusion, the protective effect of HA on HF post-AMI is achieved by regulating Fundc1-mediated mitophagy in myocardial tissue. FUNDC1-mediated mitophagy could be a promising strategy to treat cardiovascular diseases, including HF.

Isodon rubescens (Hemls.) Hara.: A Comprehensive Review on Traditional Uses, Phytochemistry, and Pharmacological Activities.

Isodon rubescens is a medicinal and food plant, often eaten as a wild vegetable in ancient China, and has been widely used for decades to treat sore throats, tonsillitis, colds and headaches, bronchitis, chronic hepatitis, joint rheumatism, snake and insect bites, and various cancers. This comprehensive and systematic review of the ethnomedicinal uses, phytochemical composition, pharmacological activity, quality control and toxicology of I. rubescens provides updated information for the further development and application in the fields of functional foods and new drugs research. To date, a total of 324 substances have been isolated and identified from the plant, including terpenoids, flavonoids, polyphenols, alkaloids, amino acids, and volatile oils. Among these substances, diterpenoids are the most important and abundant bioactive components. In the past decades pharmacological studies have shown that I. rubescens has significant biological activities, especially in the modulation of antitumor and multidrug resistance. However, most of these studies have been conducted in vitro. In-depth in vivo studies on the quality control of its crude extracts and active ingredients, as well as on metabolite identification are still very limited. Therefore, more well-designed preclinical and clinical studies are needed to confirm the reported therapeutic potential of I. rubescens.

Salivary protein 7 of the brown planthopper functions as an effector for mediating tricin metabolism in rice plants.

The brown planthopper (BPH), Nilaparvata lugens, is an important pest that affects rice (Oryza sativa) production in Asia. The flavone tricin (5,7,4'-trihydroxy-3',5'-dimethoxy flavone) is a valuable secondary metabolite commonly found in rice plants that can defend rice plants against infestation by BPH. BPH damage can reduce the metabolic level of tricin in rice. Our preliminary transcriptome research results showed that BPH salivary protein 7 (NlSP7), is highly responsive to tricin stimuli. However, the function of NlSP7 in mediating the interaction between the rice plant and the BPH is unknown. In this study, we cloned the NlSP7 gene in N. lugens and found that its mRNA level was greater in the presence of high tricin content than low tricin content, regardless of whether the BPHs were fed a rice plant diet or an artificial diet containing 100 mg/L tricin. Knocking down NlSP7 resulted in BPH individuals spending more time in the non-penetration and pathway phase, and less time feeding on the phloem of rice plants. These changes decreased BPH food intake, feeding behavior, and fitness, as well as the tricin content of the rice plants. These findings demonstrate that the salivary protein 7 of BPH functions as an effector for tricin metabolism in rice.

Organocatalytic cycloaddition of alkynylindoles with azonaphthalenes for atroposelective construction of indole-based biaryls.

The axially chiral indole-aryl motifs are present in natural products and biologically active compounds as well as in chiral ligands. Atroposelective indole formation is an efficient method to construct indole-based biaryls. We report herein the result of a chiral phosphoric acid catalyzed asymmetric cycloaddition of 3-alkynylindoles with azonaphthalenes. A class of indole-based biaryls were prepared efficiently with excellent yields and enantioselectivities (up to 98% yield, 99% ee). Control experiment and DFT calculations illustrate a possible mechanism in which the reaction proceeds via a dearomatization of indole to generate an allene-iminium intermediate, followed by an intramolecular aza-Michael addition. This approach provides a convergent synthetic strategy for enantioselective construction of axially chiral heterobiaryl backbones.

Nicotiana tabacum as a dead-end trap for adult Diaphorina citri: A potential biological tactic for protecting citrus orchards.

The Asian citrus psyllid, Diaphorina citri Kuwayama (Hemiptera: Liviidae), is a key vector of the causal agents of Huanglongbing (HLB), a devastating disease affecting citrus almost worldwide. Nicotiana tabacum L. is an important commercial crop in China. Field observations suggested that D. citri adults die on N. tabacum leaves when grown nearby citrus orchards. In this study, the preference for and survivorship of D. citri adults on N. tabacum and their feeding behavior were investigated. The results showed that D. citri adults were attracted to N. tabacum and to the green leaf volatiles (GLVs) (Z)-3-hexenol and (E)-2-hexenol. The survival of D. citri adults on N. tabacum was less than 30 h, which was shorter than that for adults without food (35 h) and on a suitable host Murraya exotica L. (29 days). Electrical penetration graph (EPG) recordings revealed that the pathway phase of D. citri on N. tabacum leaves consisted of four waveforms-the non-probing phase (NP), the pathway phase (PP, including intercellular probing of activity in the phloem (C) and phloem penetration (D)), phloem salivation (E1), and phloem ingestion (E2). Diaphorina citri only secreted saliva and ingested sap from phloem on N. tabacum leaves and spent the longest duration in phloem sap ingestion (E2). Moreover, L-nicotine, an important defense compound against insects in N. tabacum plants, was highly toxic to D. citri. These results suggested that N. tabacum plants could help to sustainably control the spread of D. citri and HLB when growing in and around citrus orchards.

Phenylboronic Acid-Modified Polyamidoamine Mediated the Transfection of Polo-Like Kinase-1 siRNA to Achieve an Anti-Tumor Efficacy.

BACKGROUND: The construction of tumor-targeting carriers with favorable transfection efficiency was of great significance to achieve the tumor gene therapy. The phenylboronic acid-modified polyamidoamine (namely PP) was employed as a carrier for the delivery of Polo-like kinase-1 siRNA (siPlk-1), inducing an obvious anti-tumor response. MATERIALS AND METHODS: The interaction between PP and siPlk-1 was evaluated by gel retardation assay. The transfection efficiency and tumor-targeting ability were analyzed by flow cytometry and confocal laser scanning microscopy, using hepatocarcinoma cell line HepG2 as a model. The anti-proliferation effect of PP/siPlk-1 and related mechanism were studied using the strategies of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell apoptosis and cell cycle arrest. The anti-migration effect induced by PP/siPlk-1 delivery was assayed by wound healing and Transwell migration techniques. Finally, quantitative real-time PCR and Western blotting were performed to measure the expression level of Plk-1 and other key targets. RESULTS: The derivative PP could achieve the condensation of siPlk-1 into stable nanoparticles at nitrogen/phosphate groups ratio (N/P ratio) of >3.0, and it could facilitate the transfection of siPk-1 in a phenylboronic acid-dependent manner. The PP/siPlk-1 nanoparticles exhibited obvious anti-proliferation effect owing to the gene silence of Plk-1, which was identified to be associated with the cell apoptosis and cell cycle arrest at G2 phase. Meanwhile, PP/siPlk-1 transfection could efficiently suppress the migration and invasion of tumor cells. CONCLUSION: The derivative PP has been demonstrated to be an ideal tumor-targeting carrier for the delivery of Plk-1 siRNA, exhibiting great potential in the gene therapy of malignant tumors.

Repeated Preoperative Intranasal Administration of Insulin Decreases the Incidence of Postoperative Delirium in Elderly Patients Undergoing Laparoscopic Radical Gastrointestinal Surgery: A Randomized, Placebo-Controlled, Double-Blinded Clinical Study.

STUDY OBJECTIVES: This study aimed to investigate the effects of repeated preoperative intranasal administration of insulin on the incidence of postoperative delirium (POD) and the levels of serum pro-inflammatory markers in elderly patients undergoing laparoscopic radical gastrointestinal surgery. DESIGN: Prospective, randomized, double-blinded, placebo-controlled clinical study. SETTING: General Hospital of Western Theater Command from August 2019 to December 2019. PATIENTS: Ninety elderly patients underwent laparoscopic radical gastrointestinal tumor resections under general anesthesia. INTERVENTIONS: Patients were randomly divided into a control group (0.5 mL saline administered intranasally) or an insulin group (20 U/0.5 mL insulin administered intranasally) for 2 days prior to surgery, with 45 patients in each group. MEASUREMENTS: The incidence of delirium was measured at postoperative day 1 (T2), day 3 (T3), and day 5 (T4) using the Confusion Assessment Method for the intensive care unit (CAM-ICU). Plasma levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α were measured at T0 (before insulin or saline administration), T1 (at the end of surgery), T2, T3, and T4 by enzyme-linked immunosorbent assay. MAIN RESULTS: Compared with the control group, the insulin group demonstrated a decreased POD incidence (12.5% vs. 47.5%, p = 0.001) within 5 days after surgery. The incidence of POD was significantly lower in the Ins group than in the Con group at T2 (12.5% vs. 32.5%, p = 0.032) and at T3 (2.5% vs. 20%, p = 0.034). The incidence of POD decreased in both groups over time and was similar at T4 (0% vs 10%, p = 0.116). Compared with the baseline value at T0, serum TNF-α, IL-6 and IL-1ß concentrations increased significantly at T1-4 (p <0.05). Compared with the control group at the same time point, the expression levels of TNF-α, IL-6 and IL-1ß in group I at T2 and T3 were significantly reduced (p <0.05). The incidence rates of adverse events were similar in the two groups. CONCLUSIONS: Repeated preoperative intranasal administration of insulin prevented the occurrence of delirium after laparoscopic radical gastrointestinal surgery in elderly patients and reduced TNF-α, IL-1ß, and IL-6 levels.

Silencing hsa_circRNA_0008035 exerted repressive function on osteosarcoma cell growth and migration by upregulating microRNA-375.

Traditionally, circular RAN hsa_circ_0008035 was proven to function as a tumor inhibitor in gastric cancer. Nevertheless, much less was known about hsa_circ_0008035 in osteosarcoma (OSA). This project was undertaken to assess the role of hsa_circ_0008035 in OSA. Hsa_circ_0008035 level in serum of OSA patients, OSA tissues and cell lines were measured by reverse transcription-quantitative PCR. After downregulation or overexpression of hsa_circ_0008035, cell proliferation, apoptosis and migration were tested in MG63, SAOS-2 or hFOB1.19 cells. Meanwhile, the expression level of miR-375 was analyzed. The binding between hsa_circ_0008035 and miR-375 was confirmed using bioinformatics and luciferase assay. Subsequently, the effects of miR-375 inhibition on MG63 cell growth and migratory potential were reevaluated. Eventually, the activating status of Notch pathway was assessed by Western blot. Our results demonstrated that hsa_circ_0008035 was overexpressed in serum of OSA patients, OSA tissues and cells. Silencing hsa_circRNA_0008035 impeded OSA cell growth and migration, while hsa_circ_0008035 facilitated cell behaviors of hFOB1.19 cells. Additionally, hsa_circ_0008035 negatively modulated miR-375 expression. Meanwhile, miR-375 inhibition overturned the suppressive effects of silencing hsa_circRNA_0008035 on OSA cell behaviors. Furthermore, silencing hsa_circ_0008035 perturbed Notch pathway by adjusting miR-375 expression. In conclusion, silencing hsa_circRNA_0008035 exerted repressive function on OSA cell growth and migration and Notch pathway by accelerating miR-375.