Ginsenoside Rg1 mitigates cerebral ischaemia/reperfusion injury in mice by inhibiting autophagy through activation of mTOR signalling.

Reperfusion injury, which is distinct from ischaemic injury, occurs when blood flow is restored in previously ischaemic brain tissue, further compromising neurons and other cells and worsening the injury. There is currently a lack of pharmaceutical agents and therapeutic interventions that specifically mitigate cerebral ischaemia/reperfusion (I/R) injury. Ginsenoside Rg1 (Rg1), a protopanaxatriol-type saponin isolated from Panax ginseng C. A. Meyer, has been found to protect against cerebral I/R injury, but its intricate protective mechanisms remain to be elucidated. Numerous studies have shown that autophagy plays a crucial role in protecting brain tissue during the I/R process and is emerging as a promising therapeutic strategy for effective treatment. In this study, we investigated whether Rg1 protected against I/R damage in vitro and in vivo by regulating autophagy. Both MCAO and OGD/R models were established. SK-N-AS and SH-SY5Y cells were subjected to OGD followed by reperfusion with Rg1 (4-32 µM). MCAO mice were injected with Rg1 (30 mg·kg-1·d-1. i.p.) for 3 days before and on the day of surgery. Rg1 treatment significantly mitigated ischaemia/reperfusion injury both in vitro and in vivo. Furthermore, we demonstrated that the induction of autophagy contributed to I/R injury, which was effectively inhibited by Rg1 in both in vitro and in vivo models of cerebral I/R injury. Rg1 inhibited autophagy through multiple steps, including impeding autophagy initiation, inducing lysosomal dysfunction and inhibiting cathepsin enzyme activities. We revealed that mTOR activation was pivotal in mediating the inhibitory effect of Rg1 on autophagy. Treatment with Torin-1, an autophagy inducer and mTOR-specific inhibitor, significantly reversed the impact of Rg1 on autophagy, decreasing its protective efficacy against I/R injury both in vitro and in vivo. In conclusion, our results suggest that Rg1 may serve as a promising drug candidate against cerebral I/R injury by inhibiting autophagy through activation of mTOR signalling.

Malignant tumor increases the risk of all causes in-hospital mortality in critically ill patients with ischemic stroke: analysis of the MIMIC-IV database.

BACKGROUND: Ischemic stroke (IS) and malignant tumor (MT) have high morbidity and mortality rates worldwide, and several associations exist between them. This study aimed to determine the effect of MT on hospital mortality in patients with IS. METHODS: Based on their MT status, participants with IS in the Medical Information Mart for Intensive Care IV (MIMIC-IV) were divided into two groups. The primary outcome was in-hospital all causes mortality. Kaplan-Meier survival analysis was performed to evaluate the intergroup in-hospital mortality, and three Cox regression models were used to determine the association between MT and in-hospital mortality. RESULTS: A total of 1605 participants (749 males and 856 females) were included in the study. The mean age was 72.030 ± 15.463 years. Of these, 257 (16%) patients died in the hospital. Kaplan-Meier analysis showed that the MT group had a significantly lower possibility of in-hospital survival than the non-MT group. In the unadjusted model, in-hospital mortality among MT patients had a higher odds ratio (OR) of 1.905 (95% CI, 1.320-2.748; P < 0.001) than the non-MT group. After adjusting for basic information, vital signs, and laboratory data, MT was also associated with increased in-hospital mortality (OR = 1.844, 95% CI: 1.255-2.708; P = 0.002). CONCLUSIONS: Among the patients with IS, the risk of all causes in-hospital mortality was higher for MT than for patients non-MT. This finding can assist clinicians in more accurately assessing prognosis and making informed treatment decisions.

Treating reverse osmosis brine of petrochemical wastewater using preparative vertical-flow electrophoresis (PVFE) with multi-objective optimization by response surface method.

Electrochemical desalination is an effective method for recovering salts from reverse osmosis (RO) brine. However, traditional technologies like bipolar membrane technology often face challenges related to membrane blockage. To overcome this issue, a preparative vertical-flow electrophoresis (PVFE) system was used for the first time to treat RO brine of petrochemical wastewater. In order to optimize the PVFE operation and maximize acids and bases production while minimizing energy consumption, the response surface method was employed. The independent variables selected were the electric field intensity (E) and flow rate (v), while the dependent variables were the acid-base concentration and energy consumption (EC) for acid-base production. Using the central composite design methodology, the operation parameters were optimized to be E = 154.311 V/m and v = 0.83 mL/min. Under these conditions, the base concentrations of the produced bases and acids reached 3183.06 and 2231.63 mg/L, respectively. The corresponding base EC and acid EC were calculated to be 12.57 and 11.62 kW·h/kg. In terms of the acid-base concentration and energy consumption during the PVFE process, the electric field intensity was found to have a greater influence than the flow rate. These findings provide a practical and targeted solution for recycling waste salt resources from RO brine.

Rolipram Ameliorates Memory Deficits and Depression-Like Behavior in APP/PS1/tau Triple Transgenic Mice: Involvement of Neuroinflammation and Apoptosis via cAMP Signaling.

BACKGROUND: Alzheimer disease (AD) and depression often cooccur, and inhibition of phosphodiesterase-4 (PDE4) has been shown to ameliorate neurodegenerative illness. Therefore, we explored whether PDE4 inhibitor rolipram might also improve the symptoms of comorbid AD and depression. METHODS: APP/PS1/tau mice (10 months old) were treated with or without daily i.p. injections of rolipram for 10 days. The animal groups were compared in behavioral tests related to learning, memory, anxiety, and depression. Neurochemical measures were conducted to explore the underlying mechanism of rolipram. RESULTS: Rolipram attenuated cognitive decline as well as anxiety- and depression-like behaviors. These benefits were attributed at least partly to the downregulation of amyloid-ß, Amyloid precursor protein (APP), and Presenilin 1 (PS1); lower tau phosphorylation; greater neuronal survival; and normalized glial cell function following rolipram treatment. In addition, rolipram upregulated B-cell lymphoma-2 (Bcl-2) and downregulated Bcl-2-associated X protein (Bax) to reduce apoptosis; it also downregulated interleukin-1ß, interleukin-6, and tumor necrosis factor-α to restrain neuroinflammation. Furthermore, rolipram increased cAMP, PKA, 26S proteasome, EPAC2, and phosphorylation of ERK1/2 while decreasing EPAC1. CONCLUSIONS: Rolipram may mitigate cognitive deficits and depression-like behavior by reducing amyloid-ß pathology, tau phosphorylation, neuroinflammation, and apoptosis. These effects may be mediated by stimulating cAMP/PKA/26S and cAMP/exchange protein directly activated by cAMP (EPAC)/ERK signaling pathways. This study suggests that PDE4 inhibitor rolipram can be an effective target for treatment of comorbid AD and depression.

Effects of Danggui-Shaoyao-San on central neuroendocrine and pharmacokinetics in female ovariectomized rats.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese medicine formula Danggui-Shaoyao-San (DSS) has been reported to have estrogen-like effects and therapeutic effects on the symptoms of Alzheimer's disease (AD). AIM OF THE STUDY: To explore whether the central oxytocin and neuroendocrine system is involved in the modulating effects of DSS on the cognition and neuropsychiatric hebaviors in female AD rats, and to investigate the pharmacokinetics of paeoniflorin and ferulic acid in female AD rats with DSS treatment. MATERIAL AND METHODS: DSS (1.2, 3.2, 8.6 g/kg/day) was orally administered to ovariectomized (OVX) rats, and saline was orally administered to sham operation rats as control group. The Morris water maze test, novel object recognition test, and passive avoidance test were conducted for evaluation of learning and memory abilities, while elevated plus maze test and forced swim test were performed to assess anxiety- and depressive-like behaviors. ELISA kits were used to detect the levels of estrogen (E), estrogen receptor α (ERα), oxytocin (OT), oxytocin receptor (OTR), acetylcholine (Ach), acetylcholin esterase (AchE), and choline acetyl transferase (ChAT) in the cortex. The concentrations of Ach, glutamate (Glu), γ-aminobutyric acid (GABA), 5-hydroxytryptamine (5-HT), norepinephrine (NE) and dopamine (DA) in the hippocampus were assessed by HPLC-MS. The changes of neuronal morphology in the hippocampus were observed by Nissl staining. The pharmacokinetics of paeoniflorin and ferulic acid in OVX rats with DSS treatment were studied by HPLC. RESULTS: In the Morris water maze test, novel object recognition test, and passive avoidance test, OVX rats showed cognitive impairment. In the elevated plus maze test and forced swim test, the anxiety- and depressive-like behaviors of OVX rats were significant as compared to the control group. Treatment of DSS significantly imporved the cognitive deficits, and ameliorated anxiety- and depressive-like behaviors of OVX rats. The expression of E, ERα, OT, OTR, AchE and ChAT in the cortex of model group were significantly decreased, and DSS significantly reversed these changes. The concentrations of Ach, Glu, GABA, 5-HT and NE in the hippocampus of OVX rats were significantly decreased, whereas DSS significantly increased the levels of Ach, Glu, GABA, 5-HT and NE. There was no significant difference in the concentration of DA in the hippocampus among groups. Degenerating neurons in the hippocampal CA3 region were observed in OVX rats, and the number of neurons was decreased. DSS treatment reduced the degenerating neurons, and incresed the number of neurons. The MRT (0 - ∞), AUC (0 - ∞), Cmax and t1/2z values of paeoniflorin, and the AUC 0-∞ and Cmax value of ferulic acid were higher in DSS-treated OVX rats than those in the DSS-treated control rats. CONCLUSIONS: DSS improves the learning and memory ability, and attenuates anxiety- and depressive-like behaviors of OVX rats. The mechanism may be through increasing estrogen, reducing cholinergic damage, and modulating neurotransmitters. The increase in absorption and elimination time of paeoniflorin and ferulic acid in OVX rats may enhance the efficacy of DSS.

Chimonanthus nitens Oliv. essential oil mitigates lipopolysaccharide-induced acute lung injury in rats.

This study aimed to evaluate the effect of Chimonanthus nitens Oliv. essential oil (named CEO) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats. In the present study, 21 compounds were characterized in CEO by gas chromatography-mass spectrometry analysis. Furthermore, animal data suggested that CEO could protect rats against ALI, as evidence by increasing white blood cell count, reducing immune organ index and improving lung histopathological changes in rats subjected to LPS. Reduction of the levels of IL-1ß was also shown during CEO-triggering lung protection in rats. Meanwhile, these protective effects of CEO were accompanied by the attenuation of lipid oxidation, and elevation of antioxidant enzymes, suggesting that enhancement of antioxidant defense was linked to its lung protection. Moreover, a combination with CEO and LPS significantly elevated short-chain fatty acids (SCFAs) compared with LPS alone via increasing propionic, i-butyric, butyric and i-valeric acid on LPS-induced ALI in rats. Therefore, our findings indicated that CEO could alleviate LPS-caused ALI in rats by controlling aberrant inflammation, correcting the redox system, and modulating SCFAs in rats.

A Novel Clinical Nomogram to Predict Transient Symptomatic Associated with Infarction: The ABCD3-SLOPE Score.

BACKGROUND: It is hard to differentiate transient symptoms associated with infarction (TSI) from transient ischemic stroke (TIA) without MRI in the early onset. However, they have distinct clinical outcomes and respond differently to therapeutics. Therefore, we aimed to develop a risk prediction model based on the clinical features to identify TSI. METHODS: We enrolled 230 consecutive patients with transient neurologic deficit in the Department of Neurology, Tongji University Affiliated Tenth People's Hospital from March 2014 to October 2019. All the patients were assigned into TIA group (DWI-negative) or TSI group (DWI-positive) based on MRI conducted within five days of onset. We summarized the clinical characteristics of TSI by univariate and multivariate analyses. And then, we developed and validated a nomogram to identify TSI by the logistic regression equation. RESULTS: Of the 230 patients, 41.3% were diagnosed with TSI. According to the multivariate analysis, four independent risk factors, including smoking history, low-density lipoprotein cholesterol, brain natriuretic peptide precursor, and ABCD3 score, were incorporated into a nomogram. We developed a predictive model named ABCD3-SLOPE. The calibration curve showed good agreement between nomogram prediction and observation. The concordance index (C-index) of the nomogram for TSI prediction was 0.77 (95% confidence interval, 0.70-0.83), and it was well-calibrated. CONCLUSIONS: Smoking history, low-density lipoprotein cholesterol, brain natriuretic peptide precursor, and ABCD3 score were reliable risk factors for TSI. ABCD3-SLOPE was a potential tool to quantify the likelihood of TSI.

Intraoperative ultrasonography assistance for minimally invasive repair of the acute Achilles tendon rupture.

BACKGROUND: Minimally invasive repair is a better option for Achilles tendon rupture with low re-rupture and wound-related complications than conservative treatment or traditional open repair. The major problem is sural nerve injury. The purpose of this study was to evaluate the effect and advantage of the intraoperative ultrasonography assistance for minimally invasive repair of the acute Achilles tendon rupture. METHODS: A retrospective study was performed on 36 cases of acute Achilles tendon rupture treated with minimally invasive repair assisted with intraoperative ultrasonography from January 2015 to December 2017. The relationship of the sural nerve and small saphenous vein was confirmed on the preoperative MRI. The course of the small saphenous vein and the sural nerve was identified and marked by intraoperative ultrasonography. The ruptured Achilles tendon was repaired with minimally invasive Bunnell suture on the medial side of the small saphenous vein (SSV). RESULTS: All patients were followed up for at least 12 months. No sural nerve injury or other complications was found intraoperatively and postoperatively. All the patients returned to work and light sporting activities at a mean of 12.78 ± 1.40 weeks and 17.28 ± 2.34 weeks, respectively. The Mean American Orthopaedic Foot & Ankle Society (AOFAS) scores improved from 59.17 ± 5.31 preoperatively to 98.92 ± 1.63 at the time of 12 months follow-up. There was a statistically significant difference (P < 0.001). No patient complained of a negative effect on their life. CONCLUSIONS: The minimally invasive repair assisted with intraoperative ultrasonography can yield good clinical outcomes, less surgical time, and less complications, especially sural nerve injury. It is an efficient, reliable, and safe method for acute Achilles tendon (AT) rupture.

[Enrichment characteristics and source apportionment of polycyclic aromatic hydrocarbons (PAHs) in pine (Pinus massoniana lamb) needles from parks in Nanjing City, China].

The concentrations of 15 polycyclic aromatic hydrocarbons (PAHs) in pine (Pinus massoniana Lamb) needles from 8 urban parks in Nanjing City (China) were determined using High Performance Liquid Chromatography, and the source apportionment of PAHs in pine needles was studied using diagnostic ratios. The results show that the total PAHs concentrations (sigma PAHs) accumulated in needles from different parks ranged from 909.8 (Linggu Temple) to 2 129.6 ng x g(-1) (Mochou Lake), with an average of 1438.0 ng x g(-1). The PAHs in pine needles mainly associates with 2,3-ring PAHs and 4-ring PAHs, accounting for 66.4% and 29.6% of the sigma PAHs, respectively, while 5,6-ring PAHs only accounts for 4% of the sigma PAHs. Phenanthrene is the dominant PAH with an average concentration of 591.4 ng x g(-1). The average concentration of Benzo (a) pyrene, the most carcinogenic PAH, is 5.1 ng x g(-1). The source apportionment indicates that vehicle emission is the predominant source for PAHs in the pine needles.

Study of the insulin signaling pathways in the regulation of ACAT1 expression in cultured macrophages.

OBJECTIVE: To determine the signaling pathways and components involved in insulin-mediated regulation of Acyl-CoA: cholesterol acyltransferase1 (ACAT1). METHODS: THP-1 cells were cultured in RPMI 1640 medium and were induced into macrophages in the presence of 160 nM phorbol 12-myristate 13-acetate (PMA). Before insulin was added in, macrophages were preincubated with the inhibitors of the insulin signaling pathway, including wortmannin, phosphatidylinositol 3-kinase (PI3K) inhibitor; PD98059, extracellular signal-regulated kinase (ERK) inhibitor; SB203580, p38 mitogen-activated protein kinase (p38MAPK) inhibitor; SP600125, c-Jun N-terminal kinase (JNK) inhibitor and U73122, phospholipase C-gamma (PLC-gamma) inhibitor. ACAT1 mRNA and protein expression level in macrophages were determined by real-time quantitative polymerase chain reaction and western blotting, respectively. RESULTS: Real-time quantitative polymerase chain reaction and western blotting demonstrated that PD98059, SB203580 or SP600125 down-regulated the expression of ACAT1 in a dose-dependent manner. However, no obvious alteration was found in wortmannin and U73122 groups. CONCLUSION: These results suggest that the ERK, p38MAPK and JNK signaling pathways may be involved in insulin-mediated regulation of ACAT1, but no PI3K and PLC-gamma signaling pathways were involved in the present study.

Purification of recombinant human interferon-epsilon and oligonucleotide microarray analysis of interferon-epsilon-regulated genes.

Recently identified interferon-epsilon (IFN-epsilon) belongs to type I interferons. IFN-epsilon is highly and constitutively expressed in the brain, but its biochemical and biological characteristics are poorly understood. In this study, full-length IFN-epsilon cDNA was cloned from human peripheral blood lymphocyte by RT-PCR, and was expressed in Escherichia coli (E. coli). Reverse phase high pressure liquid chromatography was used to purify recombinant human IFN-epsilon (rhIFN-epsilon) and to facilitate refolding of the protein. About 0.8mg of highly purified rhIFN-epsilon protein was obtained from 100ml of E. coli culture. Functional study of rhIFN-epsilon demonstrated that the antiviral activity of rhIFN-epsilon was 6+/-0.5x10(5)IU/mg, which was lower than that of rhIFN-alpha-2b in the WISH-VSV (WISH cells infected with vesicular stomatitis virus) assay system. As for the activity to promote NK cytotoxicity and antiproliferation activities, rhIFN-epsilon was about 60 times less potent than rhIFN-alpha-2b. However, oligonucleotide microarray analyses revealed dramatic differences in gene expression profiles of cultured human cells treated with IFN-epsilon and IFN-alpha-2b. Particularly, differential regulation of genes related to central nervous system by rhIFN-epsilon suggests a role for IFN-epsilon in maintenance of the structure and function of brain.