Improve the Charge Carrier Transporting in Two-Dimensional Ruddlesden-Popper Perovskite Solar Cells.

Conventional 3D organic-inorganic halide perovskite materials have shown substantial potential in the field of optoelectronics, enabling the power conversation efficiency of solar cells beyond 26%. A key challenge limiting the further commercial application of 3D perovskite solar cells is their inherent instability over outer oxygen, humidity, light, and heat. By contrast, 2D Ruddlesden-Popper (2DRP) perovskites with bulky organic cations can effectively stabilize the inorganic slabs, yielding excellent environmental stability. However, the efficiencies of 2DRP perovskite solar cells are much lower than those of the 3D counterparts due to poor charge carrier transporting property of insulating bulky organic cations. Their inner structural, dielectric, optical, and excitonic properties remain to be primarily studied. In this review, the main reasons for the low efficiency of 2DRP perovskite solar cells are first analyzed. Next, a detailed description of various strategies for improving the charge carrier transporting of 2DRP perovskites is provided, such as bandgap regulation, perovskite crystal phase orientation and distribution, energy level matching, interfacial modification, etc. Finally, a summary is given, and the possible future research directions and methods to achieve high-efficiency and stable 2DRP perovskite solar cells are rationalized.

The endoplasmic reticulum stress protein GRP94 modulates cathepsin L activity in M2 macrophages in conditions of obesity-associated inflammation and contributes to their pro-inflammatory profile.

BACKGROUND/OBJECTIVES: Adipose tissue macrophages (ATM) are key actors in the pathophysiology of obesity-related diseases. They have a unique intermediate M2-M1 phenotype which has been linked to endoplasmic reticulum (ER) stress. We previously reported that human M2 macrophages treated with the ER stress inducer thapsigargin switched to a pro-inflammatory phenotype that depended on the stress protein GRP94. In these conditions, GRP94 promoted cathepsin L secretion and was co-secreted with complement C3. As cathepsin L and complement C3 have been reported to play a role in the pathophysiology of obesity, in this work we studied the involvement of GRP94 in the pro-inflammatory phenotype of ATM. METHODS: GRP94, cathepsin L and C3 expression were analyzed in CD206 + ATM from mice, WT or obesity-resistant transgenic fat-1, fed a high-fat diet (HFD) or a standard diet. GRP94 colocalization with cathepsin L and C3 and its effects were analyzed in human primary macrophages using thapsigargin as a control to induce ER stress and palmitic acid (PA) as a driver of metabolic activation. RESULTS: In WT, but not in fat-1 mice, fed a HFD, we observed an increase in crown-like structures consisting of CD206 + pSTAT1+ macrophages showing high expression of GRP94 that colocalized with cathepsin L and C3. In vitro experiments showed that PA favored a M2-M1 switch depending on GRP94. This switch was prevented by omega-3 fatty acids. PA-induced GRP94-cathepsin L colocalization and a decrease in cathepsin L enzymatic activity within the cells (while the enzymatic activity in the extracellular medium was increased). These effects were prevented by the GRP94 inhibitor PU-WS13. CONCLUSIONS: GRP94 is overexpressed in macrophages both in in vivo and in vitro conditions of obesity-associated inflammation and is involved in changing their profile towards a more pro-inflammatory profile. It colocalizes with complement C3 and cathepsin L and modulates cathepsin L activity.

Promoting Ruddlesden-Popper Perovskite Formation by Tailoring Spacer Intramolecular Interaction for Efficient and Stable Solar Cells.

Low-dimensional Ruddlesden-Popper phase (LDRP) perovskites are widely studied in the field of photovoltaics due to their tunable energy-band properties, enhanced photostability, and improved environmental stability compared to the 3D perovskites. However, the insulating spacers with weak intramolecular interaction used in LDRP materials limit the out-of-plane charge transport, leading to poor device performance of LDRP perovskite solar cells (PSCs). Here, a functional ligand, 3-guanidinopropanoic acid (GPA), which is capable of forming strong intramolecular hydrogen bonds through the carboxylic acid group, is employed as an organic spacer for LDRP PSCs. Owing to the strong interaction between GPA molecules, high-quality LDRP (GPA)2 (MA)n-1 Pbn I3n+1 film with promoted formation of n = 5 phase, improved crystallinity, preferential vertical growth orientations, reduced trap-state density, and prolonged carrier lifetime is achieved using GPAI as the dimensionality regulator compared to butylamine hydroiodide (BAI). As a result, GPA-based LDRP PSC exhibits a champion power conversion efficiency of 18.16% that is much superior to the BA-based LDRP PSC (15.43%). Importantly, the optimized GPA-based LDRP PSCs without encapsulation show enhanced illumination, thermal, storage, and humidity stability compared to BA-based ones. This work provides new insights into producing high n value LDRP films and their efficient and stable PSCs.

Tetrahedral Bonding Structure (Ni3 -Se) Induced by Lattice-Distortion of Ni to Achieve High Catalytic Activity in Na-Se Battery.

Fabrication of transition-metal catalytic materials is regarded as a promising strategy for developing high-performance sodium-selenium (Na-Se) batteries. However, more systematic explorations are further demanded to find out how their bonding interactions and electronic structures can affect the Na storage process. This study finds that lattice-distorted nickel (Ni) structure can form different bonding structures with Na2 Se4 , providing high activity to catalyze the electrochemical reactions in Na-Se batteries. Using this Ni structure to prepare electrode (Se@NiSe2 /Ni/CTs) can realize rapid charge transfer and high cycle stability of the battery. The electrode exhibits high storage performance of Na+ ; i.e., 345 mAh g⁻1 at 1 C after 400 cycles, and 286.4 mAh g⁻1 at 10 C in rate performance test. Further results reveal the existence of a regulated electronic structure with upshifts of the d-band center in the distorted Ni structure. This regulation changes the interaction between Ni and Na2 Se4 to form a Ni3 -Se tetrahedral bonding structure. This bonding structure can provide higher adsorption energy of Ni to Na2 Se4 to facilitate the redox reaction of Na2 Se4 during the electrochemical process. This study can inspire the design of bonding structure with high performance in conversion-reaction-based batteries.

Cognitive Enhancer Donepezil Attenuates Heroin-Seeking Behavior Induced by Cues in Rats.

PURPOSE: Opioid use disorder is a significant global problem. Chronic heroin use is associated with impairment of cognitive function and conscious control ability. The cholinergic system can be disrupted following heroin administration, indicating that activation of the cholinergic system may prevent chronic heroin misuse. Donepezil as an inhibitor of cholinesterase has been reported to clinically improve cognition and attention. In this study, the inhibition of heroin self-administration and heroin-seeking behaviours by donepezil were evaluated in rats. METHODS: Rats were trained to self-administer heroin every four hours for 14 consecutive days under a fixed ratio 1 (FR1) reinforcement schedule, then underwent withdrawal for two weeks. A progressive ratio schedule was then used to evaluate the relative motivational value of heroin reinforcement. After withdrawal, a conditioned cue was introduced for the reinstatement of heroin-seeking behaviour. Donepezil (0.3-3 mg/kg, i.p.) was used during both the FR1 heroin self-administration and progressive ratio schedules. Immunohistochemistry was used to investigate the mechanism of action of donepezil in the rat brain. RESULTS: Pre-treatment with high dose donepezil (3 mg/kg) but not low doses (0.3-1 mg/kg) significantly inhibited heroin self-administration under the FR1 schedule. Donepezil decreased motivation values under the progressive ratio schedule in a dose-dependent manner. All doses of donepezil (1-3 mg/kg) decreased the reinstatement of heroin seeking induced by cues. Correlation analysis indicated that the inhibition of donepezil on heroin-seeking behaviour was positively correlated with an increased expression of dopamine receptor 1 (D1R) and dopamine receptor 2 (D2R) in the nucleus accumbens (NAc) and increased expression of choline acetyltransferase (ChAT) in the ventral tegmental area (VTA). CONCLUSIONS: The present study demonstrated that donepezil could inhibit heroin intake and heroin-seeking behaviour. Further, donepezil could regulate dopamine receptors in the NAc via an increase of acetylcholine. These results suggested that donepezil could be developed as a potential approach for the treatment of heroin misuse.

Polypyrimidine tract binding protein knockdown reverses depression-like behaviors and cognition impairment in mice with lesioned cholinergic neurons.

Background and objectives: Depression is a common comorbidity of dementia and may be a risk factor for dementia. Accumulating evidence has suggested that the cholinergic system plays a central role in dementia and depression, and the loss of cholinergic neurons is associated with memory decline in aging and Alzheimer's patients. A specific loss of cholinergic neurons in the horizontal limb of the diagonal band of Broca (HDB) is correlated with depression and dysfunction of cognition in mice. In this study, we examined the potential regenerative mechanisms of knockdown the RNA-binding protein polypyrimidine tract binding protein (PTB) in reversing depression-like behaviors and cognition impairment in mice with lesioned cholinergic neurons. Methods: We lesioned cholinergic neurons in mice induced by injection of 192 IgG-saporin into HDB; then, we injected either antisense oligonucleotides or adeno-associated virus-shRNA (GFAP promoter) into the injured area of HDB to deplete PTB followed by a broad range of methodologies including behavioral examinations, Western blot, RT-qPCR and immunofluorescence. Results: We found that the conversion of astrocytes to newborn neurons by using antisense oligonucleotides on PTB in vitro, and depletion of PTB using either antisense oligonucleotides or adeno-associated virus-shRNA into the injured area of HDB could specifically transform astrocytes into cholinergic neurons. Meanwhile, knockdown of PTB by both approaches could relieve the depression-like behaviors shown by sucrose preference, forced swimming or tail-suspension tests, and alleviate cognitive impairment such as fear conditioning and novel object recognition in mice with lesioned cholinergic neurons. Conclusion: These findings suggest that supplementing cholinergic neurons after PTB knockdown may be a promising therapeutic strategy to revert depression-like behaviors and cognitive impairment.

Fatty acids and their sn-2 positional distribution in breast milk and their association with edible oils in maternal diet: a study of five regions in China.

This study analyzed total fatty acids (FAs) and their sn-2 positional distribution in triacylglycerol (TAG) in breast milk (n = 300) from three lactational stages in five regions of China, and further investigated their association with the effect of the type of edible oil consumed by lactating mothers. A total of 33 FAs including 12 saturated fatty acids (SFAs), 8 monounsaturated fatty acids (MUFAs), and 13 polyunsaturated fatty acids (PUFAs) were determined using GC. Breast milk from different regions showed significant differences in MUFAs, sn-2 MUFAs, and PUFAs (P < 0.01, P < 0.001, and P < 0.001). The results showed that 10 : 0, 18 : 0, 18 : 1 n-9, 18 : 2 n-6 (LA), and 18 : 3 n-3 (ALA) were mainly esterified at the sn-1 and sn-3 positions; 20 : 4 n-6 (ARA) seemed homogeneously esterified at all sn-positions in TAG, while 14 : 0, 16 : 0, and 22 : 6 n-3 (DHA) were primarily esterified at the sn-2 position. In breast milk, major FAs (16 : 0, 18 : 1 n-9, LA, and ALA) and the ratio of PUFAs (LA/ALA and n-6/n-3) were obviously influenced by maternal edible oils. Breast milk from mothers consuming rapeseed oil had the lowest LA (∼19%) and the highest ALA (∼1.9%). The MUFAs, especially 18 : 1 n-9, in breast milk from mothers consuming high oleic acid oils were significantly higher than those in breast milk from mothers consuming other types of edible oils. These results provide a potential nutritional strategy for better breastfeeding by specifically adjusting maternal edible oils despite other fat sources being part of the diet of lactating women.

Buprenorphine reduces methamphetamine intake and drug seeking behavior via activating nociceptin/orphanin FQ peptide receptor in rats.

Buprenorphine, which has been approved for the treatment of opioid dependence, reduces cocaine consumption by co-activating µ-opioid receptors and nociceptin/orphanin FQ peptide (NOP) receptors. However, the role of buprenorphine in methamphetamine (METH) reinforcement and drug-seeking behavior remains unclear. This study investigated the effects of buprenorphine on METH self-administration and reinstatement of METH-seeking behavior in rats. We found that buprenorphine pretreatment had an inhibitory effect on METH self-administration behavior, and that buprenorphine at a dose of 0.3 mg/kg could inhibit motivation to respond for METH. Pretreatment with the NOP receptor antagonist thienorphine (0.5 mg/kg) or SB-612111 (1 mg/kg) could reverse the inhibitory effect of buprenorphine (0.1 mg/kg) on the METH self-administration. Moreover, treatment with buprenorphine (0.1 mg/kg and 0.3 mg/kg) significantly reduced the drug-seeking behavior induced by context or by METH priming but failed to reduce the drug-seeking behavior induced by conditional cues. Additionally, the NOP receptor antagonist SB-612111 reversed the inhibitory action of buprenorphine on the drug-seeking behavior induced by METH priming. The results demonstrated that buprenorphine reduced either METH intake or the drug-seeking behavior by activating NOP receptors, providing empirical evidence for the clinical use of buprenorphine in the treatment of METH relapse and addiction.

A comparison of reinforcing effectiveness and drug-seeking reinstatement of 2-fluorodeschloroketamine and ketamine in self-administered rats.

2-Fluorodeschloroketamine (2F-DCK), a structural analog of ketamine, has been reported to cause impaired consciousness, agitation, and hallucination in abuse cases. It has similar reinforcing and discriminative effects as ketamine. However, the reinforcing efficacy and drug-seeking reinstatement of this analog have not been clarified to date. In this study, the effectiveness of 2F-DCK and ketamine was compared using a behavioral economics demand curve. The reinstatement of 2F-DCK- and ketamine-seeking behaviors induced by either conditioned cues or self-priming was also analyzed. Rats were intravenously self-administered 2F-DCK and ketamine at a dose of 0.5 mg/kg/infusion under a reinforcing schedule of fixed ratio 1 (FR1) with 4 h of daily training for at least 10 consecutive days. The elasticity coefficient parameter α and the essential value of the demand curve in the two groups were similar. Both groups of rats showed significant drug-seeking behavior induced either by conditional cues or by 2F-DCK and ketamine priming. Moreover, the α parameter was inversely related to the degree of reinstatement induced by cues or drug priming in both groups. In total, the expression levels of brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP response element-binding protein (p-CREB) in the nucleus accumbens in both extinguished and reinstated rats were significantly lower than those in the control. The expression of total Akt, glycogen synthase kinase (GSK)-3ß, mammalian target of rapamycin (mTOR), and extracellular signal-related kinase (ERK) also decreased, but p-Akt, p-GSK-3ß, p-mTOR, and p-ERK levels increased in both extinguished and reinstated rats. This is the first study to demonstrate that 2F-DCK has similar reinforcing efficacy, effectiveness, and post-withdrawal cravings as ketamine after repeated use. These data suggest that the downregulation of CREB/BDNF and the upregulation of the Akt/mTOR/GSK-3ß signaling pathway in the nucleus accumbens may be involved in ketamine or 2F-DCK relapse.

Uterine fibroids increase the risk of preterm birth and other adverse birth events: a systematic review and meta-analysis.

Background: Uterine fibroids may cause preterm birth. This meta-analysis evaluates the effect of uterine fibroids on the risk of preterm birth and other obstetric outcomes. Methods: Using the literature review method, the databases PubMed, Medline, Embase and Central were retrieved to obtain relevant research literature. The selected studies were analyzed and evaluated. The literature was a cohort study or a case-control study of pregnant women as the research object and uterine fibroids as the exposure factor to observe adverse events during pregnancy. The chi-square test was used to test for heterogeneity. Subgroup analyses were used to explore sources of heterogeneity. Publication bias was assessed using Egger's test. Enumeration data were described by odds ratio (OR). Measurement data were described by mean difference (MD). Calculate the confidence interval (CI). Results: A total of 11 studies were included in this study, including 7 cohort studies and 4 case-control studies, with a total of 313,913 women. The probability of uterine fibroids among women was 3.99%. The results of meta-analysis showed that women with uterine fibroids experienced preterm birth <37 weeks (OR =1.43, 95% CI: 1.25 to 1.64, P<0.00001), preterm birth <34 weeks (OR =1.73, 95% CI: 1.34 to 2.25, P<0.0001), premature rupture of membranes (OR =1.38, 95% CI: 1.08 to 1.75, P=0.009), placental abruption (OR =1.60, 95% CI: 1.20 to 2.14, P=0.001), cesarean section (OR =2.09, 95% CI: 1.69 to 2.58, P<0.00001), and postpartum hemorrhage (OR =2.95, 95% CI: 1.86 to 4.66, P<0.00001) were all at higher risk, and the mean gestational age at delivery [mean difference (MD) =-0.58, 95% CI: -0.66 to -0.51, P<0.00001] and birth weight (MD =-117.82, 95% CI: -155.19 to -80.45, P<0.00001) were lower. Egger's test indicated that there was no publication bias among the included studies (P>0.05). Conclusions: Pregnant women with uterine fibroids are at higher risk for preterm birth and other adverse obstetric outcomes and require closer monitoring.

Evaluation of total, sn-2 fatty acid, and triacylglycerol composition in commercial infant formulas on the Chinese market: A comparative study of preterm and term formulas.

Preterm infants with physiological immaturity require higher lipid provision than term infants. This study compared the lipid composition, including total, sn-2 fatty acid, and triacylglycerol (TAG) compositions in 14 preterm formulas and 25 term formulas in the Chinese market, in 2020-2021. Preterm formula had higher medium-chain fatty acid (MCFA) and comparable C22:6n-3 (DHA) contents than term formula. Notably, significantly lower C16:0 and C18:0 (p < 0.001) were distributed on the sn-2 position in preterm formula. Two hundred and thirteen kinds of TAG molecular species were identified using UPLC-Q-TOF-MS. In preterm formula, significantly higher Ca-Ca-Cy and Ca-Ca-Ca (p < 0.001) existed. These clear distinctions showed the challenge of the progress in preterm formula, such as DHA status, MCFA pattern, and TAG esterified with palmitic acid on the sn-2 position.

Elevated Th17 cell frequencies and Th17/Treg ratio are associated with airway hyperresponsiveness in asthmatic children.

Introduction: The elevation of T helper (Th)17 cell frequencies and the imbalance of Th17/regulatory T (Treg) cells occur in asthma pathogenesis. Airway hyperresponsiveness (AHR) is a cardinal feature of asthma, and Th17 responses can promote AHR. We hypothesized that changes in Th17 cells and the Th17/Treg ratio correlate with AHR in asthmatic children.Methods: Twenty asthmatic children and twenty healthy children were included in the study. The peak expiratory flow (PEF) % pred, forced expiratory volume in 1 s (FEV1) % pred and the FEV1/forced vital capacity (FVC) ratio were measured in all subjects. Methacholine challenge test (MCT) was performed in asthmatic children. Flow cytometric analysis was used to determine the proportions of Th17 and Treg cells in peripheral blood mononuclear cells. ELISA was used to assess serum levels of interleukin (IL)-17A and IL-10.Results: Th17 cell frequencies (2.272 ± 0.207% in asthmatics, 1.193 ± 0.131% in controls, P < 0.01) and Th17/Treg ratios (0.371 ± 0.0387 in asthmatics, 0.183 ± 0.020 in controls, P < 0.01) were significantly increased in asthmatic children compared to controls. In asthmatic children, the MCT grade had positive correlations with the Th17 cell frequencies [r = 0.718, P < 0.01], serum IL-17A level [r = 0.753, P < 0.01] and Th17/Treg ratio [r = 0.721, P < 0.01], while the log10PD20-FEV1 value was negatively correlated with the Th17 cell frequencies [r = -0.654, P < 0.01], serum IL-17A level [r = -0.652, P < 0.01] and Th17/Treg ratio [r = -0.625, P < 0.01].Conclusion: Th17 cell, IL-17A and Th17/Treg ratio were positively correlated with AHR in asthmatic children. It may be helpful to monitor Th17 cells and the Th17/Treg ratio as indicators of AHR in clinical practice.

Reciprocal Substitution Between Methamphetamine and Heroin in Terms of Reinforcement Effects in Rats.

Heroin and methamphetamine are both popular illicit drugs in China. Previous clinical data showed that habitual users of either heroin or methamphetamine abuse the other drug for substitution in case of unavailability of their preferred drug. The present study aimed to observe whether heroin can substitute the methamphetamine reinforcement effect in rats, and vice versa. Rats were trained to self-administer heroin or methamphetamine (both 50 µg/kg/infusion) under an FR1 reinforcing schedule for 10 days. After having extracted the dose-effect curve of the two drugs, we administered methamphetamine at different doses (12.5-200 µg/kg/infusion) to replace heroin during the period of self-administration, and vice versa. The heroin dose-effect curve showed an inverted U-shaped trend, and the total intake dose of heroin significantly increased when the training dose increased from 50 to 100 or 200 µg/kg/infusion. Following replacement with methamphetamine, the total dose-effect curve shifted leftwards and upwards. By contrast, although the dose-effect curve of methamphetamine also showed an inverted U-shaped trend, the total dose of methamphetamine significantly decreased when the training dose decreased from 50 to 25 µg/kg/infusion; conversely, when the methamphetamine training dose increased, the total dose did not change significantly. The total dose-effect curve shifted rightwards after heroin was substituted with methamphetamine. Although heroin and methamphetamine had their own independent reward effects, low doses of methamphetamine can replace the heroin reward effect, while high doses of heroin can replace the methamphetamine reward effect. These results demonstrated that heroin and methamphetamine can substitute each other in terms of reinforcement effects in rats.

Huperzine A inhibits heroin-seeking behaviors induced by cue or heroin priming in rats.

Cholinergic systems modulate dopaminergic function in brain pathways are thought to mediate heroin addiction. This study investigated whether huperzine A, an acetylcholinesterase inhibitor, has beneficial effects on heroin reward and heroin-seeking behavior. Rats were trained to self-administer heroin (50 µg/kg/infusion) under the fixed ratio 1 schedule for 14 days and then drug-seeking was extinguished for 10 days, after which reinstatement of drug-seeking was induced by conditioned cues or heroin priming. Acute treatment with huperzine A at dose from 0.05 to 0.2 mg/kg potently and dose-dependently suppressed the cue- and heroin-induced reinstatement of heroin-seeking behavior following extinction. Huperzine A at these doses failed to alter either heroin rewarding effect or spontaneous locomotion activity. The study demonstrated that acute treatment with huperzine A inhibited heroin-seeking behavior, suggesting that huperzine A may be used as an adjuvant treatment for heroin relapse and addiction.

An epidemiological investigation of food allergy among children aged 3 to 6 in an urban area of Wenzhou, China.

BACKGROUND: The prevalence of food allergy (FA) has increased worldwide. In China, the prevalence of FA in infants and school-aged children is well known, but the prevalence in preschool children is unknown. METHODS: A total of 4151 preschool children aged 3 to 6 years in urban Wenzhou, China, were recruited for this cross-sectional study. Their parents completed a preliminary screening questionnaire, and a detailed FA questionnaire was given to parents whose children had suspected FA according to the preliminary screening. According to the results of the detailed FA questionnaires, some children underwent a skin prick test (SPT) and specific IgE (sIgE) measurement. Children with abnormal SPT and/or sIgE results who did not meet the diagnostic criteria and those with negative SPT and sIgE results whose histories strongly supported FA underwent an oral food challenge (OFC). RESULTS: Of the 4151 children's parents who completed the surveys, 534 (12.86%) indicated a positive medical history of FA. Among the 40 children who underwent an OFC, 24 were positive. According to SPT and sIgE measurements, 11 children were diagnosed with FA. The prevalence of FA was at least 0.84%; children who dropped out during the study were considered FA-negative. Among the 35 children with FA, the most common allergic manifestation was skin symptoms. The most common allergic foods were egg, fish and shrimp. CONCLUSIONS: The parent-reported rate of FA in preschool children in urban Wenzhou was 12.86%. The prevalence of FA was at least 0.84%. Among all cases, the most common allergic food was eggs, and the most common allergic manifestation was skin symptoms. TRIAL REGISTRATION: NCT03974555, registered on 30 May 2019 (www.clinicaltrials.gov).

Absolute phase synchronization over optical fiber.

An absolute phase synchronization method based on phase-conjugation scheme is demonstrated. A repeatable phase difference regardless of restart operation and fiber route changing between the phase standard at local site and the recovered signal at the intermediate-access node is achieved. This indicates that absolute phase synchronization to arbitrary nodes along the fiber link is feasible. At the intermediate-access node, this phase difference is highly stable with a fluctuation of ±0.014 rad over 10000s. And this phase difference shows consistency within 2% of the full cycle under different situations such as restart operation and fiber route changing.

Cognitive enhancers as a treatment for heroin relapse and addiction.

Heroin addiction is a disorder that stems from maladaptive plasticity within neural circuits and produces broad cognitive deficits. Despite considerable advances in psychotherapy and pharmacotherapy for heroin relapse and addiction, effective treatments for heroin use disorder are still lacking. Increasing preclinical evidence indicates that heroin seeking behavior is persistent after withdrawal, while cognitive dysfunctions associated with chronic heroin use are an important contributing factor to risk of heroin relapse and addiction. Cognitive enhancers may be used to stimulate treatment success and enhance treatment efficacy. The purpose of this review is to outline the literature that demonstrates the cognitive deficits during the development of heroin addiction and withdrawal process, and several factors that underline the efficacy of cognitive enhancers for heroin use disorders. The review, then, examines the potential use and pharmacological mechanisms of cognitive enhancers that act on cholinergic, glutamatergic, dopaminergic or adrenergic pathways. It also examines the effects of compounds that alter CREB signaling and epigenetic mechanisms in animal model of heroin relapse. The current body of research reveals the new insights into the pharmacological mechanisms underlying heroin addiction and holds a significant promise for cognitive enhancers as an improved approach to treat heroin use disorder in a more efficient and persistent way.

Identification of candidate target genes for endometrial cancer, such as ANO1, using weighted gene co-expression network analysis.

Network-based systems biology has become an important method for analysis of high-throughput gene expression data and gene function mining. The aim of the present study was to implement a weighted gene co-expression network analysis to screen genes that were significantly correlated with the clinical phenotype of endometrial cancer based on data from The Cancer Genome Atlas. By using the function 'pickSoftThreshold' in R software, the optimum soft thresholding power was determined to be 4. Subsequently, a total of 2,414 expressed genes were identified among 19,791 genes from 506 samples, which were divided into 24 modules according to the different expression patterns. After analyzing the correlation between the gene expression in these 24 modules and the clinical phenotype of endometrial cancer, the anoctamin 1 (ANO1) gene was selected for further analysis. The Chi-squared test indicated that ANO1 was significantly associated with age (P=0.047), histological type (P<0.001), clinical stage (P<0.001), pathological grade (P<0.001) and positive peritoneal washing (P=0.001) of endometrial carcinoma. Kaplan-Meier survival analysis revealed that a high level of ANO1 was significantly associated with a good prognosis for endometrial cancer patients. Univariate and multivariate Cox regression analysis indicated that ANO1 is an independent prognostic factor in endometrial cancer. Further characterization of the most relevant module containing ANO1 with the database for annotation, visualization and integrated discovery tool suggested that ANO1 is involved in various pathways, including metabolic pathways. The present study suggests that ANO1 may be a potential marker for good prognosis in endometrial cancer.

Vibsanin A sensitizes human acute myeloid leukemia cells to tyrosine kinase inhibitor-induced myeloid differentiation via activation of PKC and upregulation of Lyn.

Differentiation therapies have been proposed to overcome the impaired cell differentiation in acute myeloid leukemia (AML). However, thus far the all-trans retinoic acid-based differentiation therapy has been the only successful modality in treating acute promyelocytic leukemia. Here, we showed that vibsanin A, a novel protein kinase C (PKC) activator, sensitized AML cells to tyrosine kinase inhibitor (TKI)-induced differentiation. Vibsanin A augmented the ability of TKIs to induce growth inhibition and G1 cell cycle arrest of AML cells. Mechanistically, PKC activation was involved in the differentiation-inducing effects of combining vibsanin A with TKIs. Moreover, we found that vibsanin A enhanced TKI-induced Lyn expression and suppression of Lyn interfered with AML cell differentiation, indicating an essential role for Lyn expression in the combination-induced differentiation. Finally, combining vibsanin A and TKIs enhanced the activation of the Raf/MEK/ERK cascade. Together, this is the first study to evaluate the synergy of vibsanin A and TKIs in AML cell differentiation. Our study lays the foundation in assessing new opportunities for the combination of vibsanin A and TKIs as a promising approach for future differentiation therapy.

Vibsanol A induces differentiation of acute myeloid leukemia cells via activation of the PKC signaling pathway and induction of ROS.

Identifying novel differentiating agents to promote leukemia-cell differentiation is a pressing need. Here, we demonstrated that vibsanol A, a vibsane-type diterpenoid, inhibited the growth of acute myeloid leukemia (AML) cells via induction of cell differentiation, which was characterized by G1 cell cycle arrest. The differentiation-inducing effects of vibsanol A were dependent upon protein kinase C (PKC) activation, and subsequent activation of the extracellular signal-regulated kinase (ERK) pathway. Furthermore, vibsanol A treatment increased reactive oxygen species (ROS) levels, and the ROS scavenger NAC reversed the vibsanol A-induced cell differentiation, indicating an important role for ROS in the action of vibsanol A. Finally, vibsanol A exhibited a differentiation-enhancing effect when used in combination with all-trans retinoic acid in AML cells. Overall results suggested that vibsanol A induces AML cell differentiation via activation of the PKC/ERK signaling and induction of ROS. Vibsanol A may prove to be an effective differentiating agent against AML.