Irisin attenuates ethanol-induced behavioral deficits in mice through activation of Nrf2 and inhibition of NF-κB pathways.

This study aims to investigate the effect of irisin on ethanol-induced behavioral deficits and explore the underlying mechanisms. A mouse model of ethanol addiction/withdrawal was constructed through chronic ethanol administration. Depressive-like behaviors were evaluated by the tail suspension test and forced swimming test, and anxiety-like behaviors were evaluated by the marble-burying test and elevated plus maze test. The expression of Nrf2 was measured by western blotting. Levels of inflammatory mediators (NF-κB, TNF-α, IL-1ß and IL-6) and oxidative stress factors (ROS, MDA, GSH and SOD) were detected by ELISA. The ethanol-induced PC12/BV2 cell injury model was used to elucidate whether the effect of irisin on ethanol-induced neurological injury was related to anti-inflammatory and antioxidant mechanisms. Ethanol-induced ethanol preference and emotional deficits were improved by chronic irisin treatment; however, these improvements were partly reversed by cotreatment with the Nrf2 inhibitor ML385. Further results implied that the improvement effect of irisin on behavioral abnormalities may be related to its anti-inflammatory and antioxidant effects. In detail, irisin inhibited ethanol-induced abnormal expression of ROS and MDA and upregulated the expression of GSH and SOD. Meanwhile, irisin treatment inhibited ethanol-induced overexpression of NF-κB, TNF-α, IL-1ß and IL-6 in the hippocampus and cerebral cortex. The regulation of oxidative stress factors by irisin was reversed after ML385 treatment. In the in vitro study, overexpression of oxidative stress factors in ethanol-treated PC12 cells was inhibited by irisin treatment; however, the prevention was reversed after the knockdown of Nrf2 siRNA. Moreover, ethanol-induced overexpression of inflammatory mediators in BV2 cells was also inhibited by irisin treatment. Irisin improved depressive and anxiety-like behaviors induced by ethanol addiction/withdrawal in mice, and this protection was greatly associated with the NF-κB-mediated anti-inflammatory signaling pathway and Nrf2-mediated antioxidative stress signaling pathway.

Engineering Design of an Active-Passive Combined Thermal Control Technology for an Aerial Optoelectronic Platform.

: In order to ensure the imaging performance of the aerial optoelectronic platform system in low temperature environment, an active-passive combined thermal control technology was studied. A thermal control finite element model of the aerial optoelectronic platform was established. Additionally, thermal control simulation analysis and experiments under extreme conditions were carried out respectively. The simulation and experimental results showed that the temperature level of the primary mirror is improved above 25 ℃ by the proposed thermal control technology effectively, meanwhile the temperature gradient of the primary and secondary mirrors are less than 5 ℃. The successful implementation of this active-passive combined thermal control technology provides a technical support for the precision thermal control of aerial optoelectronic platforms.

Impact of Thermal Control Measures on the Imaging Quality of an Aerial Optoelectronic Sensor.

The image resolution is the most important performance parameter for an aerial optoelectronic sensor. Existing thermal control methods cannot eliminate the sensor's temperature gradient, making the image resolution difficult to further improve. This article analyzes the different impacts of temperature changes on the imaging resolution and proposes modifications. Firstly, the sensor was subjected to thermo-optical simulation by means of finite element analysis, and the different impacts of temperature changes on the imaging quality were analyzed. According to the simulation results, an active thermal control method is suggested to enhance the temperature uniformity of the sensor. Considering the impacts of active and passive thermal control measures, thermal optical analysis was carried out to predict the performance of the sensor. The results of the analysis show that the imaging quality of the sensor has been significantly improved. The experimental results show that the image resolution of the optoelectronic sensor improved from 47 to 59 lp/mm, which demonstrates that the sensor can produce a high image quality in a low-temperature environment.

Role of the indoleamine-2,3-dioxygenase/kynurenine pathway of tryptophan metabolism in behavioral alterations in a hepatic encephalopathy rat model.

BACKGROUND: This study aims to explore the role of indoleamine-2,3-dioxygenase (IDO)/kynurenine (KYN) pathway of tryptophan (TRY) metabolism in behavioral alterations observed in hepatic encephalopathy (HE) rats. METHODS: Expression levels of proinflammatory cytokines were tested by QT-PCR and ELISA, levels of IDOs were tested by QT-PCR and Western blot, and levels of 5-hydroxytryptamine (5-HT), KYN, TRY, 3-hydroxykynurenine (3-HK), and kynurenic acid (KA) in different brain regions were estimated using HPLC. Effects of the IDO direct inhibitor 1-methyl-L-tryptophan (1-MT) on cognitive, anxiety, and depressive-like behavior were evaluated in bile duct ligation (BDL) rats. RESULTS: Increased serum TNF-α, IL-1ß, and IL-6 levels were shown in rats 7 days after BDL, and these increases were observed earlier than those in the brain, indicating peripheral immune activation may result in central upregulation of proinflammatory cytokines. Moreover, BDL rats showed a progressive decline in memory formation, as well as anxiety and depressive-like behavior. Further study revealed that IDO expression increased after BDL, accompanied by a decrease of 5-HT and an increase of KYN, as well as abnormal expression of 3-HK and KA. The above results affected by BDL surgery were reversed by IDO inhibitor 1-MT treatment. CONCLUSION: Taken together, these findings indicate that (1) behavioral impairment in BDL rats is correlated with proinflammatory cytokines; (2) TRY pathway of KYN metabolism, activated by inflammation, may play an important role in HE development; and (3) 1-MT may serve as a therapeutic agent for HE.

Anti-ICAM-1 antibody-modified nanostructured lipid carriers: a pulmonary vascular endothelium-targeted device for acute lung injury therapy.

BACKGROUND: Acute lung injury (ALI) is a life-threatening clinical syndrome without effective treatment. Targeting delivery of glucocorticoid to lung shows potential efficacy for ALI based on their anti-inflammatory and anti-fibrotic properties, breaking through their clinical application limitation due to systemic side effects. This work was aimed to establish lung-targeted dexamethasone (DEX) loaded nanostructured lipid carriers (NLCs) with opposite surface charge and investigate their therapeutic effects on lipopolysaccharide (LPS)-induced ALI mice. RESULTS: The diameter of anionic anti-intercellular adhesion molecule 1 (anti-ICAM-1) antibody-conjugated DEX-loaded NLCs (ICAM/DEX/NLCs) and the cationic ones with octadecylamine (ODA) modification (ICAM/DEX/ODA-NLCs) was about 249.9 and 235.9 nm. The zeta potential of ICAM/DEX/NLCs and ICAM/DEX/ODA-NLCs was about - 30.3 and 37.4 mV, respectively. Relative to the non-targeted control and ICAM/DEX/ODA-NLCs, ICAM/DEX/NLCs exhibited higher in vitro cellular uptake in LPS-activated human vascular endothelial cell line EAhy926 after CAM-mediated endocytosis, and stronger in vivo pulmonary distribution in the ALI model mice. In vivo i.v. administration of ICAM/DEX/NLCs significantly attenuated pulmonary inflammatory cells infiltration, and the production of pro-inflammatory cytokine TNF-α and IL-6 in ALI mice. H&E stain also revealed positive histological improvements by ICAM/DEX/NLCs. CONCLUSIONS: ICAM/DEX/NLCs may represent a potential pulmonary endothelium targeted device, which facilitate translation of DEX into clinical ALI treatment.

Administration of Curcumin Protects Kidney Tubules Against Renal Ischemia-Reperfusion Injury (RIRI) by Modulating Nitric Oxide (NO) Signaling Pathway.

BACKGROUND/AIMS: To explore the protective effect of curcumin on renal ischemia-reperfusion injury (RIRI) in rats, and its influence on nephridial tissue's NO and cGMP levels as well as downstream signaling pathway, to elucidate the possible mechanism of curcumin on RIRI. METHODS: 36 Sprague Dawley rats (SD rats) were randomly divided into Sham group, Model group, curcumin (CUR +) Model group, 12 rats per group. They were all given RIRI model preparation by unilateral artery occlusion method. All groups' ß2-MG in urine in 24h, serum Cr and BUN were compared, and UAER were calculated. Nitric oxide synthase (NOS), cGMP-dependent protein kinase (PKG), Caspase-3 expression were all determined by western blot. Nitric oxide (NO), NOS and cGMP levels were also examined by using ELISA. All groups' nephridial histomorphology and kidney tubules score were evaluated and compared. RESULTS: ß2-MG and UAER in urine, serum Cr and BUN, in renal tissue were all elevated in Model of RIRI, indicating the success of animal model of RIRI establishment, and above index in CUR + Model group were all lower than those in Model group. Furthermore, iNOS, NO, cGMP, PKG and Caspase-3 in renal tissue were all increased in Model of RIRI, indicating the NO signaling pathway was activated, which is one of the pathogenesis of RIRI, and above index in CUR + Model group were all lower than those in Model group, suggesting that inactivation of iNOS/NO/cGMP/PKG signaling pathway is one of the reasons that explain the protective effect of curcumin in RIRI. CONCLUSION: The activation of iNOS/NO/cGMP/PKG signaling pathway and the consequent promoted apoptosis of renal tubules are significantly involved in the pathogenesis of development of RIRI, and curcumin treatment could protect renal tubules against RIRI, at least partially, by suppressing the activated iNOS/NO/cGMP/PKG signaling pathway.

Fasudil alleviates alcohol-induced cognitive deficits and hippocampal morphology injury partly by altering the assembly of the actin cytoskeleton and microtubules.

Alcohol-Related Brain Damage (ARBD) manifests predominantly as cognitive impairment and brain atrophy with the hippocampus showing particular vulnerability. Fasudil, a Rho kinase (ROCK) inhibitor, has established neuroprotective properties; however, its impact on alcohol-induced cognitive dysfunction and hippocampal structural damage remains unelucidated. This study probes Fasudil's neuroprotective potential and identifies its mechanism of action in an in vivo context. Male C57BL/6 J mice were exposed to 30% (v/v, 6.0 g/kg) ethanol by intragastric administration for four weeks. Concurrently, these mice received a co-treatment with Fasudil through intraperitoneal injections at a dosage of 10 mg/kg/day. Fasudil was found to mitigate alcohol-induced spatial and recognition memory deficits, which were quantified using Y maze, Morris water maze, and novel object recognition tests. Concurrently, Fasudil attenuated hippocampal structural damage prompted by chronic alcohol exposure. Notably, Fasudil moderated alcohol-induced disassembly of the actin cytoskeleton and microtubules-mechanisms central to the maintenance of hippocampal synaptic integrity. Collectively, our findings indicate that Fasudil partially reverses alcohol-induced cognitive and morphological detriments by modulating cytoskeletal dynamics, offering insights into potential therapeutic strategies for ARBD.

[Effects of Short-term Nitrogen Addition on Soil Organic Carbon Components in Robinia pseudoacacia L. Plantation].

Nitrogen (N) deposition in the context of human activities continuously affects the carbon cycle of ecosystems. The effect of N deposition on soil organic carbon is related to the differential responses of different carbon fractions. To investigate the changes in soil organic carbon fraction and its influencing factors in the context of short-term N deposition, four N addition gradients:0 (CK), 1.5 (N1), 3 (N2), and 6 (N3) g·(m2·a)-1 were set up in acacia plantations based on field N addition experiments, and the soil physicochemical properties, microbial biomass, and enzyme activities were measured in June and September. The results showed that:① exogenous N input reduced soil pH, promoted the increase in soluble organic carbon content, and increased soil nitrogen effectiveness. ② Short-term N addition significantly reduced soil organic carbon content, and the response of each component of organic carbon to N addition was different. Among them, the content of easily oxidized organic carbon was significantly reduced and reached the lowest value under the N2 treatment, with 54.4% and 48.2% reduction compared with that of the control, respectively, and the content of inert organic carbon increased, although the increase was not significant. Nitrogen addition reduced the soil carbon pool activity and improved the stability of the soil carbon pool. Soil carbon pool activity reached its lowest under the N3 and N2 treatments, with a decrease of 53.3% and 52.80%, respectively, compared to that of the control. ③Random forest modeling indicated that the soil microbial biomass stoichiometry ratio, microbial biomass carbon, and AP were the key factors driving the changes in soil organic carbon activity under short-term N addition, explaining 65.96% and 66.68% of the changes in oxidizable organic carbon and inert organic carbon, respectively. Structural equation modeling validated the results of the random forest modeling, and soil microbial biomass stoichiometric ratios significantly influenced carbon pool activity. Short-term nitrogen addition changed soil microbial biomass and its stoichiometric ratio in the acacia plantation forest mainly through two pathways, i.e., increasing soil nitrogen effectiveness and promoting soil acidification and inhibiting extracellular carbon hydrolase activity, thus changing the soil carbon fraction ratio and participating in the soil organic carbon cycling process.

Design, synthesis, and evaluation of 8-aminoquinoline-melatonin derivatives as effective multifunctional agents for Alzheimer's disease.

Background: Alzheimer's disease (AD) is thought to be a complex, multifactorial syndrome with many related molecular lesions contributing to its pathogenesis. Thus, multi-target-directed ligands are considered an effective way of treating AD. This study sought to evaluate 8-aminoquinoline-melatonin derivatives as effective multifunctional agents for AD. Methods: Thioflavin-T fluorescence assays were used to detect the inhibitory potency of 8-aminoquinoline-melatonin hybrids (a1-a5, b1-b5, and c1-c5) on self- and acetylcholinesterase (AChE)-induced amyloid-ß (Aß) aggregation. The AChE and butyrylcholinesterase (BuChE) inhibitory potency within the compounds was evaluated by Ellman's assays. Methyl thiazolyl tetrazolium (MTT) assays were performed to evaluate the cytotoxicity of the compounds to C17.2 cells. MTT assay was used to detect the cell viability of HT22 cells to evaluate the antioxidant effect of the compounds. Metal chelation property was measured by ultraviolet-visible spectrophotometry. Results: Compounds c3 and c5 had superior inhibitory activity against self-induced Aß aggregation (with inhibitory rates of 41.4±2.1 and 25.5±3.2 at 10 µM, respectively) compared to the other compounds. Compounds in the carbamate group (i.e., a4, a5, b4, b5, c4, and c5) showed significant BuChE inhibitory activity and excellent selectivity over AChE. Most of the compounds exhibited low cytotoxicity in the C17.2 cells. Notably, a2, a3, b2, and b3 and series c (c1-c5) exhibited strong protective effects. Additionally, a3 and c1 specifically chelated with copper ions. Conclusions: Taking all of the promising results together, 8-aminoquinoline-melatonin hybrids can serve as lead molecules in the further development of new multi-functional anti-AD agents.

Application Perspectives of Nanomedicine in Cancer Treatment.

Cancer is a disease that seriously threatens human health. Based on the improvement of traditional treatment methods and the development of new treatment modes, the pattern of cancer treatment is constantly being optimized. Nanomedicine plays an important role in these evolving tumor treatment modalities. In this article, we outline the applications of nanomedicine in three important tumor-related fields: chemotherapy, gene therapy, and immunotherapy. According to the current common problems, such as poor targeting of first-line chemotherapy drugs, easy destruction of nucleic acid drugs, and common immune-related adverse events in immunotherapy, we discuss how nanomedicine can be combined with these treatment modalities, provide typical examples, and summarize the advantages brought by the application of nanomedicine.

Lipopolysaccharide-induced depression is associated with estrogen receptor-α/SIRT1/NF-κB signaling pathway in old female mice.

The present study aims to investigate the influence of sex/age on depressive-like behaviors in lipopolysaccharide (LPS)-challenged mice model, and explore the underlying mechanisms. Tail suspension test and forced swimming test were used to evaluate the depressive-like behaviors. SIRT1 mRNA expression was assessed by PCR. Levels of 17ß-estradiol (E2), SIRT1, NF-κB, tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß) and interleukin 6 (IL-6) were detected by enzyme linked immunosorbent assay (ELISA). In the behavior tests, under the same LPS stimulation, significant depressive-like behavior was observed in young male mice but not in young female mice, however, female mice were more likely to be depressed than male mice in the old age. Moreover, we found age-related depression difference existed only in female mice. In the experiments of mechanism exploration in old female mice, E2 improved LPS-induced depressive-like behavior, and simultaneously elevated SIRT1 levels and downregulated expressions of NF-κB and inflammatory cytokines in the hippocampus and frontal cortex. Interestingly, ERα inhibition, not ERß inhibition, abolished E2's function. Additionally, SIRT1 antagonist also reversed E2's effects on depressive-like behavior and the expressions of NF-κB and inflammatory cytokines. These results suggested that E2 could protect the old female mice from depression via E2/ERα/SIRT1/NF-κB signaling pathway. In other words, LPS-induced depression was associated with ER-α/SIRT1/NF-κB signaling pathway in old female mice. By comparing the results of mechanism exploration in old male mice and old female mice and the different expression levels of E2, SIRT1, NF-κB and inflammatory cytokines in young female mice and old female mice, we speculate that the age or gender-related depression difference may be associated with the different activation levels of the ERα/SIRT1/NF-κB signaling pathway.

Ferulic acid improves motor function induced by spinal cord injury in rats via inhibiting neuroinflammation and apoptosis.

PURPOSE: To investigate the effect of ferulic acid (FA) on spinal cord injury (SCI)-induced motor dysfunction and to explore the possible pharmacological mechanisms. METHODS: Adult male Wistar rats were used in our study. SCI was achieved by clipping the spinal cord T9 of the rat by a vascular clip for 2 minutes. The motor function of the rat was evaluated by Basso, Beattie, and Bresnahan scoring method (BBB) and inclined plane test. Hematoxylin and eosin (HE) staining, NISSL staining, and transmission electron microscopic examination were used to evaluate alterations at the histological level. Polymerase chain reaction (PCR), Western blots, and enzyme-linked immunosorbent assays (ELISA) were employed in biochemical analysis. RESULTS: The BBB score and inclined plane test score significantly decreased after SCI surgery, whereas chronic FA treatment (dose of 90 mg/kg, i.g.) for 28 days improved SCI-induced motor dysfunction. HE staining showed that SCI surgery induced internal spinal cord edema, but the structural changes of the spinal cord could be reversed by FA treatment. NISSL staining and transmission electron microscopic examination confirmed the improvement of the effect of FA on the injury site. In the biochemical analysis, it could be found that FA inhibitedSCI-induced mRNA and protein overexpression of pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α), as well as iNOS and COX-2 via the modulation of NF-κB level in the spinal cord of SCI rat. Moreover, the SCI-induced decrease of Bcl-2/Bax ratio was also reversed by FA treatment. However, the effect of FA on the expression of Beclin-1 was not statistically significant. CONCLUSIONS: FA showed a therapeutic effect on SCI, which may be associated with the regulation of neuroinflammation and apoptosis.

Irisin protects female mice with LPS-induced endometritis through the AMPK/NF-κB pathway.

OBJECTIVES: This research was designed to determine the role of irisin in lipopolysaccharide (LPS)-induced endometritis in female mice. MATERIALS AND METHODS: Animals were randomly assigned into sham, sham + irisin, LPS, LPS + irisin (0.1, 1, 10 µg/kg), and LPS + irisin + compound C groups. Histological features and expression of AMPK, NF-κB, inflammatory mediators, and oxidative stress markers were compared among different groups. RESULTS: The results showed that LPS resulted in obvious uterus damage, meanwhile, the inflammatory mediators (COX-2, iNOS, IL-1ß, IL-6, and TNF-α), as well as NF-κB in the uterine tissue, were significantly increased and the level of adenosine monophosphate-activated protein kinase (AMPK) was reduced. Nevertheless, pretreatment with irisin reversed the phenomena caused by LPS. Interestingly, compound C (AMPK inhibitor) abolished irisin's effects on the uterus, which suggested that irisin's beneficial function was achieved through regulating the AMPK-NF-κB pathway. Moreover, LPS-induced alterations of oxidative factors (MnSOD, GSH, and MDA) were reversed significantly by pretreatment with irisin. This data indicated irisin's beneficial function was also related to antioxidation besides anti-inflammation. CONCLUSION: Our study implies that irisin is a potential therapeutic agent for endometritis.

Withdrawal Notice: Renoprotective Effect of Curcumin Labelled on Mesoscale Nanoparticles (MNPs) in Renal Ischemia-Reperfusion Injury (RIRI) via the miR-146a/nNOS/NO/cGMP/PKG Signaling Pathway

The article has been withdrawn by the Editorial office of the journal Current Pharmaceutical Biotechnology, due to some inconsistencies in the figures provided by the first author that have come to light, and after a thorough investigation we would like to withdraw this paper. Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused. The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policies-main.php Bentham Science Disclaimer: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript, the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

Chronic trans-astaxanthin treatment exerts antihyperalgesic effect and corrects co-morbid depressive like behaviors in mice with chronic pain.

Patients suffering from chronic neuropathic pain are at high risk of co-morbid depression, which burdens healthcare. Trans-astaxanthin has been shown in our previous studies to exert antidepressant-like effect. This work aimed to investigate the effects of trans-astaxanthin on pain-related depressive-like behaviors in mice and explored the mechanism(s). Chronic constriction injury (CCI) model was used in this research. Chronic pain was evaluated by thermal hyperalgesia in Hargreaves test and mechanical allodynia in von Frey test, depressive-like behaviors were evaluated by immobility time in forced swim test and tail suspension test. Chronic trans-astaxanthin treatment ameliorated mechanical allodynia and thermal hyperalgesia, as well as decreasing immobility time in forced swim test and tail suspension test in CCI mice, and these actions were abolished by co-treatment with P-Chlorophenylalanine (PCPA). Subsequent study indicated that indoleamine 2,3-dioxygenase (IDO) expression increased after CCI surgery in hippocampus and spinal cord, accompanied by increase of kynurenine (KYN)/tryptophan (TRY) ratio, decrease of serotonin (5-HT)/TRY ratio and decrease of 5-HT/5-HIAA ratio. The above results affected by CCI surgery were reversed by trans-astaxanthin treatment. Moreover, trans-astaxanthin at 80mg/kg was demonstrated to effectively antagonize IL-1ß, IL-6 and TNF-α expression in hippocampus and spinal cord of CCI mice. Taken together, chronic trans-astaxanthin administration exerts therapeutic effects on thermal hyperalgesia and co-morbid depressive-like behaviors in CCI mice. These effects of trans-astaxanthin involves the serotonergic system, and also may be owing to its potent anti-inflammatory property.

Ferulic acid improves motor function induced by spinal cord injury in rats via inhibiting neuroinflammation and apoptosis

ABSTRACT Purpose To investigate the effect of ferulic acid (FA) on spinal cord injury (SCI)-induced motor dysfunction and to explore the possible pharmacological mechanisms. Methods Adult male Wistar rats were used in our study. SCI was achieved by clipping the spinal cord T9 of the rat by a vascular clip for 2 minutes. The motor function of the rat was evaluated by Basso, Beattie, and Bresnahan scoring method (BBB) and inclined plane test. Hematoxylin and eosin (HE) staining, NISSL staining, and transmission electron microscopic examination were used to evaluate alterations at the histological level. Polymerase chain reaction (PCR), Western blots, and enzyme-linked immunosorbent assays (ELISA) were employed in biochemical analysis. Results The BBB score and inclined plane test score significantly decreased after SCI surgery, whereas chronic FA treatment (dose of 90 mg/kg, i.g.) for 28 days improved SCI-induced motor dysfunction. HE staining showed that SCI surgery induced internal spinal cord edema, but the structural changes of the spinal cord could be reversed by FA treatment. NISSL staining and transmission electron microscopic examination confirmed the improvement of the effect of FA on the injury site. In the biochemical analysis, it could be found that FA inhibitedSCI-induced mRNA and protein overexpression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), as well as iNOS and COX-2 via the modulation of NF-κB level in the spinal cord of SCI rat. Moreover, the SCI-induced decrease of Bcl-2/Bax ratio was also reversed by FA treatment. However, the effect of FA on the expression of Beclin-1 was not statistically significant. Conclusions FA showed a therapeutic effect on SCI, which may be associated with the regulation of neuroinflammation and apoptosis.