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.

N-Isopropylbenzylamine-induced conditioned place preference, sensitization behaviour and self-administration in rodents.

N-Isopropylbenzylamine (N-ipb), a chain isomer of methamphetamine (METH) with similar physical properties, has been used as a substitute for METH in seized drug samples. However, the abuse potential of N-ipb remains unclear. Therefore, this study aimed to evaluate the abuse potential of N-ipb in comparison to METH, by using conditioned place preference (CPP), locomotor sensitization and intravenous self-administration tests. The results showed that N-ipb at a dose of 3 mg·kg-1 significantly induced CPP in mice, which was comparable to the effect of METH at 1 mg·kg-1 . Either acute or repeated N-ipb injections (1 or 3 mg·kg-1 ) failed to raise the locomotor activity. However, acute treatment with 10 mg·kg-1 N-ipb elevated the locomotor activity compared with saline, while chronic injection of 10 mg·kg-1 N-ipb induced a delayed and attenuated sensitization compared with 1 mg·kg-1 METH. Rats could acquire N-ipb self-administration at a dose of 1 mg·kg-1 ·infusion-1 , and a typical inverted U-shaped dose-response curve was obtained for N-ipb. The mean dose of N-ipb that maintained the maximum response was greater than that of METH, indicating that N-ipb is less potent for reinforcement than METH. In the economic behavioural analysis, comparison of essential values derived from the demand elasticity revealed that N-ipb is less efficacy as a reinforcer than METH. The present data demonstrate that N-ipb functions as a reinforcer and has a potential for abuse. However, the potency of psychomotor stimulation and the reinforcing effectiveness of N-ipb are lower than those of METH.

Biodegradable FePS3 nanoplatform for efficient treatment of osteosarcoma by combination of gene and NIR-II photothermal therapy.

As a common tumor with high incidence, osteosarcoma possesses extremely poor prognosis and high mortality. Improving the survival of osteosarcoma patients is still a great challenge due to the precipice of advancement in treatment. In this study, a combination strategy of gene therapy and photothermal therapy (PTT) is developed for efficient treatment of osteosarcoma. Two-dimensional (2D) FePS3 nanosheets are synthesized and functionalized by poly-L-lysine-PEG-folic acid (PPF) to fabricate a multifunctional nanoplatform (FePS@PPF) for further loading microRNAs inhibitor, miR-19a inhibitor (anti-miR-19a). The photothermal conversion efficiency of FePS@PPF is up to 47.1% under irradiation by 1064 nm laser. In vitro study shows that anti-miR-19a can be efficiently internalized into osteosarcoma cells through the protection and delivery of FePS@PPF nanaocarrier, which induces up-regulation of PTEN protein and down-regulation p-AKT protein. After intravenous injection, the FePS@PPF nanoplatform specifically accumulates to tumor site of osteosarcoma-bearing mice. The in vitro and in vivo investigations reveal that the combined PTT-gene therapy displays most significant tumor ablation compared with monotherapy. More importantly, the good biodegradability promotes FePS@PPF to be cleared from body avoiding potential toxicity of long-term retention. Our work not only develops a combined strategy of NIR-II PTT and gene therapy mediated by anti-miR-19a/FePS@PPF but also provides insights into the design and applications of other nanotherapeutic platforms.

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.

Evaluation of Different Processes Impact on Flavor of Camellia Seed Oil Using HS-SPME-GC/MS.

In this study, the flavor compounds of Camellia seed oils obtained by four processes were characterized by headspace solid phase microextraction/gas chromatography/mass spectrometry (HS-SPME/GC/MS). A variety of about 76 volatile flavor compounds were identified from all the oil samples. Of the four processing processes, the pressing process can retain a lot of volatile components. Among these, compounds nonanal and 2-undecenal were predominantly in the majority of the samples. Meanwhile, other compounds such as octyl ester formic acid, octanal and 2-nonenal (E), 3-acetyldihydro 2(3H)-furanone, (E)-2-decenal, dihydro-5-penty 2(3H)-furanone, nonanoic acid, and dodecane were also among the most consistently found compounds among the oil samples analyzed. The principal component analysis carried out to categorize the data produced seven clusters of the total oil samples based on the number of flavor compounds obtained in each sample. This categorization would lead to understanding the components which highly contributed to the characteristic volatile flavor and build up the flavor profile of Camellia seed oil.

Property-Activity Relationship of Black Phosphorus at the Nano-Bio Interface: From Molecules to Organisms.

As a novel member of the two-dimensional nanomaterial family, mono- or few-layer black phosphorus (BP) with direct bandgap and high charge carrier mobility is promising in many applications such as microelectronic devices, photoelectronic devices, energy technologies, and catalysis agents. Due to its benign elemental composition (phosphorus), large surface area, electronic/photonic performances, and chemical/biological activities, BP has also demonstrated a great potential in biomedical applications including biosensing, photothermal/photodynamic therapies, controlled drug releases, and antibacterial uses. The nature of the BP-bio interface is comprised of dynamic contacts between nanomaterials (NMs) and biological systems, where BP and the biological system interact. The physicochemical interactions at the nano-bio interface play a critical role in the biological effects of NMs. In this review, we discuss the interface in the context of BP as a nanomaterial and its unique physicochemical properties that may affect its biological effects. Herein, we comprehensively reviewed the recent studies on the interactions between BP and biomolecules, cells, and animals and summarized various cellular responses, inflammatory/immunological effects, as well as other biological outcomes of BP depending on its own physical properties, exposure routes, and biodistribution. In addition, we also discussed the environmental behaviors and potential risks on environmental organisms of BP. Based on accumulating knowledge on the BP-bio interfaces, this review also summarizes various safer-by-design strategies to change the physicochemical properties including chemical stability and nano-bio interactions, which are critical in tuning the biological behaviors of BP. The better understanding of the biological activity of BP at BP-bio interfaces and corresponding methods to overcome the challenges would promote its future exploration in terms of bringing this new nanomaterial to practical applications.

The Value of Comprehensive Nursing Intervention on Anxiety in Patients with Acute Heart Failure and Diabetes via Expression of Stress-related Genes.

Many patients with acute heart failure and diabetes experience varying degrees of anxiety upon entering the cardiac intensive care unit, which has adverse effects on the recovery process of these patients. Anxiety syndrome in these patients increases the risk of death up to three times. This study aimed to determine the effect of comprehensive nursing intervention on anxiety in patients with acute heart failure and diabetes by evaluating the expression of stress-related genes, i.e. COMT and BDNF genes. In this clinical trial study, 74 patients with acute heart failure and diabetes hospitalized in the cardiac intensive care unit were selected by convenience sampling method and randomly assigned to intervention and control groups. The control group received routine ward care, and the intervention group received nursing support program-based interventions in three informational, emotional, and physical dimensions in addition to regular care. Beck Anxiety Inventory was completed before and after the intervention in both groups. The expression of COMT and BDNF genes was evaluated by the qRT-PCR technique. Data were analyzed by Mann-Whitney U and independent T-test in SPSS software version 16. Before the intervention, no significant difference was observed between patients' anxiety scores in the intervention and control groups (p = 0.162). While, after the intervention, the anxiety score of the intervention group was lower than the control group (p = 0.02). The expression of COMT gene results showed that this gene expression was no statistical difference between the control group and intervention group, before intervention (p = 0.83). But, after the intervention, the expression of this gene was statistically decreased in the intervention group in comparison with the control group (p = 0.006). The BDNF gene expression results demonstrated that there was no difference between the two groups, before intervention (p = 0.46). After intervention, statistical increase was observed in control group (p = 0.042) and intervention group (p = 0.007). According to the results of this study, the comprehensive nursing intervention reduced patients' anxiety in the intervention group compared to the control group. This result was also confirmed by evaluating the expression of stress-related genes. Therefore, it is suggested that this intervention method be used to reduce anxiety in these patients.

2-Fluorodeschloroketamine has similar abuse potential as ketamine.

2-Fluorodeschloroketamine (2-FDCK) as a substitute for ketamine has emerged among drug abusers in recent years. However, 2-FDCK has not been controlled or regulated in many countries, which may be partly related to the lack of evidence on its abuse potential. In this study, we evaluated the abuse potential of 2-FDCK via the tests of the conditioned place preference (CPP), locomotor sensitization, drug self-administration and drug discrimination using ketamine as a reference. 2-FDCK induced significant CPP at a minimum dose of 3 mg/kg in mice, an effect comparable with that of ketamine (3 mg/kg). Acute injections of 2-FDCK or ketamine at 30 mg/kg enhanced locomotor activity. Repeated treatments with this dose of 2-FDCK and ketamine induced locomotor sensitization after withdrawal. 2-FDCK readily induced self-administration with 0.5 mg/kg/infusion, the same dose for ketamine, and induced the highest seeking response at 1 mg/kg. Drug discrimination test showed that 2-FDCK dose-dependently substitute for ketamine with comparable ED50 to ketamine in substitution testing. Taken together, these results strongly suggested that 2-FDCK has an abuse potential comparable with ketamine.

Association between rs1799971 in the mu opioid receptor gene and methadone maintenance treatment response.

OBJECTIVE: Genetic variations can affect individual response to methadone maintenance treatment (MMT) for heroin addiction. The A118G variant (rs1799971) in the mu opioid receptor gene (OPRM1) is a potential candidate single nucleotide polymorphism (SNP) for personalized MMT. This study determined whether rs1799971 is related to MMT response or dose. METHODS: We recruited 286 MMT patients from a Han Chinese population. The rs1799971 genotype was determined via TaqMan genotyping assay. The genetic effect of this SNP on MMT response or dose was evaluated using logistic regression. A meta-analysis was performed to merge all available data to evaluate the role of rs1799971 in MMT using RevMan 5.3 software. RESULTS: No statistical significance was observed in the association between the OPRM1 rs1799971 and MMT response or dose in our Chinese cohort. Meta-analysis indicated that the OPRM1 A118G variation was not significantly associated with MMT response or dose requirement. CONCLUSION: The results suggest that rs1799971 in OPRM1 might not play a critical role alone in influencing MMT response or dose.

Cellular transport of uranium and its cytotoxicity effects on CHO-k1 cells.

Uranium is a radioactive heavy metal and a significant public health concern; however, its associated underlying toxicological mechanisms remain largely unknown. In this work, the uptake and efflux processes of uranium in CHO-k1 cells were studied and the cytotoxicity effects were explored. It was found that both the uptake and efflux processes took place rapidly and half of the internalized uranium was expelled within 8 h. The uranium exposure caused a decrease of cell viability and adhesion ability in a dose-dependent manner and blocked the cell cycle at the G1 stage. In addition, gene expression analysis revealed relative changes in the transcription of metabolism related genes. Further studies revealed that the cytotoxicity of uranium could be alleviated by exposing cells to a lower temperature or by the addition of amantadine-HCl, an endocytosis inhibitor. Interestingly, after uranium exposure, needle-like precipitates were observed in both intracellular and extracellular regions. These findings collectively suggest that the cellular transport of uranium is a rapid process that disturbs cell metabolism and induces cytotoxicity, and this impact could be reduced by slowing down endocytic processes.

Feasibility of a break-in period of less than 24 hours for urgent start peritoneal dialysis: a multicenter study.

PURPOSE: Urgent start peritoneal dialysis (USPD) is an effective therapeutic method for end-stage renal disease (ESRD). However, whether it is safe to initiate peritoneal dialysis (PD) within 24 h unclear. We examined the short-term outcomes of a break-in period (BI) of 24 h for patients undergoing USPD. METHODS: This real-world, multicenter, retrospective cohort study evaluated USPD patients from five centers from January 2013 to August 2020. Patients were divided into BI ≤ 24 h or BI > 24 h groups. The Primary outcomes included incidence of mechanical and infectious complications. The secondary outcome was technique failure. Moreover, we presented a subgroup analysis for patients who did not receive temporary hemodialysis (HD). RESULTS: A total of 871 USPD patients were included: 470 in the BI ≤ 24 h and 401 in the BI > 24 h groups. Mechanical and infectious complications did not differ between the two groups across the follow-up timepoints (2 weeks, 1 month, 3 months, and 6 months) (p > 0.05). Multiple logistic regression analysis revealed that BI ≤ 24 h was not an independent risk factor for mechanical complications, catheter migration, or infectious complications (p > 0.05). A BI ≤ 24 h was not an independent significant risk factor for technique failure by multivariate Cox regression analysis (p > 0.05). The subgroup analysis of patients who did not receive temporary HD returned the same results. CONCLUSION: Initiating PD within 24 h of catheter insertion was not associated with increased mechanical complications, infectious complications, or technique failures.

Detection of coronavirus in environmental surveillance and risk monitoring for pandemic control.

The novel human infectious coronaviruses (CoVs) responsible for severe respiratory syndromes have raised concerns owing to the global public health emergencies they have caused repeatedly over the past two decades. However, the ongoing coronavirus disease 2019 (COVID-19) pandemic induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has received unprecedented attention internationally. Monitoring pathogenic CoVs in environmental compartments has been proposed as a promising strategy in preventing the environmental spread and tracing of infectious diseases, but a lack of reliable and efficient detection techniques is still a significant challenge. Moreover, the lack of information regarding the monitoring methodology may pose a barrier to primary researchers. Here, we provide a systematic introduction focused on the detection of CoVs in various environmental matrices, comprehensively involving methods and techniques of sampling, pretreatment, and analysis. Furthermore, the review addresses the challenges and potential improvements in virus detection techniques for environmental surveillance.

[Clinical Characteristics and Treatment Outcome of Pseudomonas Peritoneal Dialysis-associated Peritonitis].

Objective To explore the clinical characteristics and treatment of Pseudomonas peritoneal dialysis-associated peritonitis(PsP). Methods The data of patients receiving peritoneal dialysis in four tertiary hospitals in Jilin province from 2015 to 2019 were retrospectively analyzed.According to the etiological classification,the patients with peritoneal dialysis-associated peritonitis(PDAP)were classified into PsP group and non-PsP group.The incidence of PsP was calculated,and the clinical characteristics and treatment outcomes of the two groups were compared.Kaplan-Meier method was used to draw the survival curve,and Cox regression was performed to analyze the risk factors affecting the technical failure of PsP.The treatment options of Pseudomonas aeruginosa-caused PDAP and the drug sensitivity of PsP were summarized. Results A total of 1530 peritoneal dialysis patients with complete data were included in this study,among which 439 patients had 664 times of PDAP.The incidence of PsP was 0.007 episodes/patient-year.PsP group had higher proportion of refractory peritonitis(41.38% vs.19.69%,P=0.005),lower cure rate(55.17% vs.80.79%, P=0.001),and higher extubation rate(24.14% vs.7.09%,P=0.003)than non-PsP group.The technical survival rate of PsP group was lower than that of non-PsP group(P<0.001).Multivariate Cox regression analysis showed that Pseudomonas aeruginosa was an independent risk factor for technical failure in patients with PsP(HR=9.020,95%CI=1.141-71.279,P=0.037).Pseudomonas was highly sensitive to amikacin,meropenem,and piperacillin-tazobactam while highly resistant to compound sulfamethoxazole,cefazolin,and ampicillin. Conclusion The treatment outcome of PsP is worse than that of non-PsP,and Pseudomonas aeruginosa is an independent risk factor for technical failure of PsP.

Akt and its phosphorylation in nucleus accumbens mediate heroin-seeking behavior induced by cues in rats.

Akt is initially identified as one of the downstream targets of phosphatidylinositol-3 kinase (PI3K) and is involved in morphine reward and tolerance. However, whether phospholyration of Akt (p-Akt) mediates heroin relapse remains unclear. Here, we aimed to explore the role of p-Akt in the nucleus accumbens (NAc) in cue-induced heroin-seeking behaviors after withdrawal. First, rats were trained to self-administer heroin for 14 days, after which we assessed heroin-seeking behaviors induced by a context cue (CC) or by discrete conditioned cues (CS) after 1 day or 14 days of withdrawal. We found that the active responses induced by CC or CS after 14 days of withdrawal were higher than those after 1 day of withdrawal. Meanwhile, the expression of p-Akt in the NAc was also greatest when rats were exposed to the CS after 14 days of withdrawal. Additionally, a microinjection of LY294002, an inhibitor of PI3K, into the NAc inhibited the CS-induced heroin-seeking behaviors after 14 days of withdrawal, paralleling the decreased levels of p-Akt in the NAc. Finally, Akt1 or ß-arrestin 2 was downregulated via a lentiviral injection to assess the effect on heroin seeking after 14 days of withdrawal. CS-induced heroin-seeking behavior was inhibited by downregulation of Akt1, but not ß-arrestin 2, in the NAc. These data demonstrate that Akt phosphorylation in the NAc may play an important role in the incubation of heroin-seeking behavior, suggesting that the PI3K/Akt pathways may be involved in the process of heroin relapse and addiction.

Night sleep duration and risk of each lipid profile abnormality in a Chinese population: a prospective cohort study.

BACKGROUND: To explore the associations between sleep duration and abnormalities in serum lipid levels in a Chinese population. METHODS: A prospective study was conducted with 34,260 participants from the general Chinese population. Sleep duration was categorized as ≤5, 6, 7, 8 or ≥ 9 h. Each lipid profile abnormality was defined according to the Chinese Guidelines for the Prevention and Treatment of Dyslipidemia in Adults (2016). The Cox proportional hazards model was used to assess the association between sleep duration and dyslipidemia. RESULTS: Compared with a 7 h sleep duration, long sleep duration (≥9 h) was significantly associated with low high-density lipoprotein cholesterol (HDL-C) levels (hazard ratio (HR): 1.24; 95% CI: 1.12-1.38). In subgroup analyses, the positive association between long sleep duration and low HDL-C level in men and in the different age groups was more pronounced than the association in women. No significant interactions were observed in the association between sleep duration and each abnormal serum lipid level by sex/age in the study population (P-interaction> 0.05). CONCLUSIONS: These findings suggest that long sleep duration is associated with low HDL-C level among the Kailuan community population.

Increased expression of plasma hsa-miR-181a in male patients with heroin addiction use disorder.

BACKGROUND: Drug addiction is an uncontrolled, chronic, and recurrent encephalopathy that presently lacks specific and characteristic biomarkers for diagnosis and treatment. As regulators of gene expression, microRNAs (miRNAs) are increasingly used for diagnostic and prognostic purposes in various disease states. Previous studies indicated that miRNAs play important roles in the development and progression of drug addictions, including addiction to methamphetamine, cocaine, alcohol, and heroin. METHODS: We identified significant miRNAs using the microarray method and then validated the hsa-miR-181a expression levels in 53 heroin addiction patients and 49 normal controls using quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Finally, the potential associations between transcriptional levels in heroin addiction patients and their clinicopathological features were analyzed. RESULTS: A total of 2006 miRNAs were differentially expressed between heroin addiction patients and normal controls. The top 10 up-regulated miRNAs in patients were hsa-miR-21a, hsa-miR-181a, hsa-miR-4459, hsa-miR-4430, hsa-miR-4306, hsa-miR-22-3P, hsa-miR-486-5P, hsa-miR-371b-5P, hsa-miR-92a-3P, and hsa-miR-5001-5P. The top 10 down-regulated miRNAs in patients were hsa-miR-3195, hsa-miR-4767, hsa-miR-3135b, hsa-miR-6087, hsa-miR-1181, hsa-miR-4785, hsa-miR-718, hsa-miR-3141, hsa-miR-652-5P, and hsa-miR-6126. The expression level of hsa-miR-181a in heroin addiction patients was significantly increased compared with that in normal controls (P < .001). The area under the receiver operating characteristic curve of hsa-miR-181a was 0.783, the sensitivity was 0.867, and the specificity was 0.551. CONCLUSIONS: The increased expression of hsa-miR-181a in the plasma of heroin patients may be a consequence of the pathological process of heroin abuse. This study highlights the potential of hsa-miR-181a as a novel biomarker for the diagnosis of heroin addiction.

Evaluation of the Genotoxic and Oxidative Damage Potential of Silver Nanoparticles in Human NCM460 and HCT116 Cells.

Nano Ag has excellent antibacterial properties and is widely used in various antibacterial materials, such as antibacterial medicine and medical devices, food packaging materials and antibacterial textiles. Despite the many benefits of nano-Ag, more and more research indicates that it may have potential biotoxic effects. Studies have shown that people who ingest nanoparticles by mouth have the highest uptake in the intestinal tract, and that the colon area is the most vulnerable to damage and causes the disease. In this study, we examined the toxic effects of different concentrations of Ag-NPs on normal human colon cells (NCM460) and human colon cancer cells (HCT116). As the concentration of nanoparticles increased, the activity of the two colon cells decreased and intracellular reactive oxygen species (ROS) increased. RT-qPCR and Western-blot analyses showed that Ag NPs can promote the increase in P38 protein phosphorylation levels in two colon cells and promote the expression of P53 and Bax. The analysis also showed that Ag NPs can promote the down-regulation of Bcl-2, leading to an increased Bax / Bcl-2 ratio and activation of P21, further accelerating cell death .This study showed that a low concentration of nano Ag has no obvious toxic effect on colon cells, while nano Ag with concentrations higher than 15 µg/mL will cause oxidative damage to colon cells.

Adeno-associated virus-mediated over-expression of CREB-regulated transcription coactivator 1 in the hippocampal dentate gyrus ameliorates lipopolysaccharide-induced depression-like behaviour in mice.

Depression is a highly complex global disabling psychiatric disorder. Unfortunately, the currently available antidepressants are not effective in a significant percentage of patients. Therefore, the underlying mechanisms of depression must be explored at the molecular level to discover new candidate molecular targets for depression treatment. Behavioural and molecular depression-like endophenotypes have been observed in cyclic AMP response element-binding protein-regulated transcription coactivator 1 (Crtc1) knockout mice; however, the underlying mechanism for these endophenotypes remains unclear. This work investigated the role of hippocampal CREB-regulated transcription coactivator 1 (CRTC1) in depression using a recombinant adeno-associated virus (AAV) system to alter Crtc1 gene expression and explore its potential mechanism. We found that shRNA-mediated Crtc1 gene knockdown (AAV-shCRTC1) in the dentate gyrus regions of the ventral hippocampus directly resulted in depression-like behaviours and down-regulation of brain-derived neurotrophic factor and neuropeptide VGF levels. A widely used depression model induced by lipopolysaccharide administration (0.5 mg/kg, i.p.) was applied in our study and was validated by increased immobility time in the tail-suspension and forced swim tests and decreased sucrose consumption in the sucrose preference test. Importantly, CRTC1 over-expression mediated by AAV-CRTC1 in the ventral dentate gyrus regions prevented lipopolysaccharide-induced depressive-like behaviours, the down-regulation of brain-derived neurotrophic factor and VGF, and the accumulation of pro-inflammatory cytokines such as interleukin-6, interleukin 1-ß and tumour necrosis factor α in mice. Together, our findings indicate that CRTC1 is a key factor in depression-like behaviour and provide an important reference for finding a novel drug target in the neuroinflammatory and neurotrophic pathways for curing depressive disorders. Cover Image for this issue: doi: 10.1111/jnc.14500.

Inhibition of Methamphetamine Self-Administration and Reinstatement by Central Blockade of Angiotensin II Receptor in Rats.

The molecular mechanism and treatment of methamphetamine (METH) use disorder remain unclear. The current study aimed to investigate the role of central angiotensin II receptor (ATR) in drug taking and seeking behavior associated with METH use disorder. The effect of an ATR type 1 (AT1R) antagonist, candesartan cilexetil, on the reinforcing and motivational effects of METH was first assessed using the animal model of METH self-administration (SA) and reinstatement. The levels of dopamine D2 receptor (D2R) and AT1R were subsequently examined. Furthermore, the present study determined the expression of microRNAs (miRNAs) by comparing METH SA, METH-yoked, and Saline-yoked groups. The target miRNAs were further overexpressed in the nucleus accumbens (NAc) via a lentivirus vector to investigate the effects of target miRNAs on METH SA maintained under a fixed ratio 1, progressive ratio, and cue/drug reinstatement of METH SA. The potential role of the AT1R-PLCß-CREB signaling pathway was finally investigated. The results suggest that AT1R blockade effectively reduced METH SA and reinstatement, in conjunction with the counter-regulation of D2R and AT1R. A total of 17 miRNAs targeting Ang II in NAc were found to be associated with the voluntary intake of METH. Furthermore, overexpression of specific miR-219a-5p targeting AT1R-regulated METH SA and reinstatement. The AT1R-PLCß-CREB signaling pathway was found to be associated with the effect of AT1R on the drug-taking and drug-seeking behavior involving METH use disorder.

Inherent Chemotherapeutic Anti-Cancer Effects of Low-Dimensional Nanomaterials.

Low-dimensional nanomaterials (LDNs) are receiving increasing attention in cancer therapy owing to their unique properties, especially the large surface area-to-volume ratio. LDNs such as metallic nanoparticles (NPs), hydroxyapatite NPs, graphene derivatives, and black phosphorus (BP) nanosheets have been proposed for drug delivery, photothermal/photodynamic therapies, and multimodal theranostic treatments. The therapeutic effectiveness is mainly based on the physical characteristics of LDNs, but their inherent bioactivity has not been fully capitalized. In this Minireview, recent advances in the anti-cancer effects of various types of LDNs with inherent chemotherapeutic bioactivity are described and the bioactivity mechanisms are discussed on the cellular and molecular levels. BP, one of the newest and exciting members of the LDN family, is highlighted owing to the excellent inherent bioactivity, selectivity, and biocompatibility in cancer therapy. LDNs and related derivatives possess inherent bioactivity and selective chemotherapeutic effects suggesting large potential as nanostructured anti-cancer agents in cancer therapy.