Targeting GPR65 alleviates hepatic inflammation and fibrosis by suppressing the JNK and NF-κB pathways.

BACKGROUND: G-protein coupled receptors (GPCRs) are recognized as attractive targets for drug therapy. However, it remains poorly understood how GPCRs, except for a few chemokine receptors, regulate the progression of liver fibrosis. Here, we aimed to reveal the role of GPR65, a proton-sensing receptor, in liver fibrosis and to elucidate the underlying mechanism. METHODS: The expression level of GPR65 was evaluated in both human and mouse fibrotic livers. Furthermore, Gpr65-deficient mice were treated with either bile duct ligation (BDL) for 21 d or carbon tetrachloride (CCl4) for 8 weeks to investigate the role of GPR65 in liver fibrosis. A combination of experimental approaches, including Western blotting, quantitative real-time reverse transcription­polymerase chain reaction (qRT-PCR), and enzyme-linked immunosorbent assay (ELISA), confocal microscopy and rescue studies, were used to explore the underlying mechanisms of GPR65's action in liver fibrosis. Additionally, the therapeutic potential of GPR65 inhibitor in the development of liver fibrosis was investigated. RESULTS: We found that hepatic macrophages (HMs)-enriched GPR65 was upregulated in both human and mouse fibrotic livers. Moreover, knockout of Gpr65 significantly alleviated BDL- and CCl4-induced liver inflammation, injury and fibrosis in vivo, and mouse bone marrow transplantation (BMT) experiments further demonstrated that the protective effect of Gpr65 knockout is primarily mediated by bone marrow-derived macrophages (BMMs). Additionally, in vitro data demonstrated that Gpr65 silencing and GPR65 antagonist inhibited, while GPR65 overexpression and application of GPR65 endogenous and exogenous agonists enhanced the expression and release of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and transforming growth factor-ß (TGF-ß), all of which subsequently promoted the activation of hepatic stellate cells (HSCs) and the damage of hepatocytes (HCs). Mechanistically, GPR65 overexpression, the acidic pH and GPR65 exogenous agonist induced up-regulation of TNF-α and IL-6 via the Gαq-Ca2+-JNK/NF-κB pathways, while promoted the expression of TGF-ß through the Gαq-Ca2+-MLK3-MKK7-JNK pathway. Notably, pharmacological GPR65 inhibition retarded the development of inflammation, HCs injury and fibrosis in vivo. CONCLUSIONS: GPR65 is a major regulator that modulates the progression of liver fibrosis. Thus, targeting GPR65 could be an effective therapeutic strategy for the prevention of liver fibrosis.

Bibliometric analysis of post-traumatic growth after childbirth.

AIM: To make a bibliometric analysis on post-traumatic growth (PTG) after childbirth. METHODS: The topic advanced search strategy extracted the information from the Web of Science Core Collection. Descriptive statistics were performed using Excel, and bibliometric analysis was performed using VOSviewer. RESULTS: A total of 362 publications were published in 199 journals were obtained in the WoSCC from 1999 to 2022. Postpartum post-traumatic growth is in a trend of fluctuating growth, and the United States (N = 156) and Bar-Ilan University (N = 22) were the top contributing countries and institutions, respectively. Research hotspots mainly focus on theoretical models of PTG, postpartum post-traumatic stress disorder (PTSD) as a predictor of PTG, facilitators of PTG, and the relationship between mother-infant attachment and PTG. CONCLUSION: This bibliometric study provides a comprehensive overview of the current state of research on PTG after childbirth, an area that has received considerable scholarly attention in recent years. However, research on post-traumatic growth after childbirth is lacking, and further research is needed.

The satisfaction of the undergraduate nursing classroom teaching quality based on the Kano model in China.

Objectives: To investigate the satisfaction of the undergraduate nursing classroom teaching quality based on the Kano model and provide a reference for improving the overall quality of educational services. Methods: A total of 621 sophomores and juniors of nursing at Hubei University of Medicine were selected to conduct questionnaires based on the Kano model using convenient sampling. Results: The 16 items are all a one-dimensional factor. The satisfaction and importance are 0.77 to 0.86 and -0.58 to -0.80, respectively. In the quadrant analysis chart, there are four items in the dominant area, three items for improvement, three in the observation area, and six in the retention area. Conclusion: Analyzing the satisfaction of nursing undergraduates' classroom teaching quality can help us effectively understand the intrinsic needs of students and improve the overall quality of nursing undergraduates' curriculum teaching services.

Two Structurally Similar Co5 Cluster-Based Metal-Organic Frameworks Containing Open Metal Sites for Efficient C2H2/CO2 Separation.

To reasonably design and synthesize metal-organic frameworks (MOFs) with high stability and excellent adsorption/separation performance, the pore configuration and functional sites are very important. Here, we report two structurally similar cluster-based MOFs using a pyridine-modified low-symmetry ligand [H4L = 2,6-bis(2',5'-dicarboxyphenyl)pyridine], [(NH2Me2)2][Co5(L)2(OCH3)2(µ3-OH)2·2DMF]·2DMF·2H2O (1) and [Co5(L)2(µ3-OH)2(H2O)2]·2H2O·4DMF (2). The structures of 1 and 2 are built from Co5 clusters, which have one-dimensional open channels, but their microporous environments are different due to the different ways in which ligands bind to the metals. Both MOFs have extremely high chemical stabilities over a wide pH range (2-12). The two MOFs have similar adsorption capacities of C2H2 (144.0 cm3 g-1 for 1 and 141.3 cm3 g-1 for 2), but 1 has a higher C2H2/CO2 selectivity of 3.5 under ambient conditions. The difference in gas adsorption and separation between the two MOFs has been compared by a breakthrough experiment and theoretical calculation, and the influence of the microporous environment on the gas adsorption and separation performance of MOFs has been further studied.

Influencing Factors of Horizontal Movement Distance of Bodies in High Falling Deaths.

OBJECTIVES: To explore the influencing factors of the horizontal distance of bodies in the high falling scene and the feasibility of inferring the falling mode based on it. METHODS: A total of 614 high falling deaths and 15 cases of corpse dumping from high altitudes were collected. The relationship between the horizontal distance and the falling height, as well as the sex, age and manner of death (suicide, accident and corpse dumping) were observed. RESULTS: The horizontal distance increased with the increase of falling height, and the difference among the height groups was statistically significant. The horizontal distance decreased with the increase of the age of the deceased, in each height group, the difference between the group over 60 years old and other age groups was statistically significant (P<0.05). The horizontal distance of male deceased was (1.99±0.27) m, which was greater than that of female deceased (1.88±0.19) m, and the difference was statistically significant in partial height groups (P<0.05). Roof falls had a greater horizontal movement distance than window falls. Except for the >20-30 m group, there was no significant difference in horizontal distance between suicide high falls and accidental high falls in other height groups. CONCLUSIONS: The horizontal distance is affected by the falling height, the sex and age of the victim, and the spatial characteristics of the falling starting point.

An anionic Zn-MOF composed of 1D columnar SBUs for highly C2H2/CH4 selective adsorption, dye adsorption and fluorescence sensing.

An anionic three-dimensional framework {(Me2NH2)2[Zn8(L)6(ad)4(µ4-O)]·10DMF·11H2O}(Zn-MOF, L2- = 4,4'-(3-aminopyridine-2,5-diyl)dibenzoic acid; ad- = adeninate) with a column-layered structure was synthesized. Structural studies show that the Zn-MOF has octahedral cages [Zn8(ad)4(µ4-O)], the adjacent cages are connected by O atoms to form 1D columnar SBUs, and every four SBUs are connected by L2- to form a square channel 3D framework. Gas adsorption studies show that the BET and Langmuir surface areas of Zn-MOF are 1370.31 and 1478.04 m2 g-1, respectively, and the total pore volume for single-point adsorption is 0.528 cm3 g-1. The surface of the pores of the Zn-MOF is occupied by open metal sites and uncoordinated carboxyl groups, showing good capture ability for C2H2 and good adsorption selectivity for C2H2/CH4. More importantly, the free (CH3)2NH2+ ions present in the pores of the columnar layered Zn-MOF can cation-exchange with MB, MV, and RhB ions in aqueous solution. Therefore, Zn-MOF can not only effectively adsorb the cationic dyes MB, MV, and RhB, but also exhibit particularly selective sorption towards the mixed anion and cation dyes MB/MO and MV/MO. In addition, a series of fluorescence experiments show that Zn-MOF has good fluorescence properties, exhibiting highly selective and sensitive fluorescence detection and recognition performance for Fe3+ ions in aqueous solution with a low detection limit.

Structural Tuning and Pore Modulation of Three Cu(II)-Organic Frameworks: Enhancement of Stability and Functionality.

Through use of an irregular pentacarboxylate ligand, 2,2'-(pyridine-2,6-diyl)diterephthalic acid (H4L), two Cu(II)-based metal-organic frameworks, {[(Me2NH2)0.5][Cu0.75(L)0.5(DMA)0.375]·H2O}n (1) and {[Cu4(L)2(H2O)4]·4DMF·8H2O}n (2), have been synthesized. A structural analysis demonstrates that 1 is a 2D layer and 2 shows a 3D framework, which exhibit hopeful possibilities for the selective separations of C2H2/CH4 and CO2/CH4. To enhance the adsorption properties, 5-amino-1H-tetrazole (HAT) has been introduced in the synthesis system, and a new framework, {[Cu4(L)2(ATZ)2(H2O)]·5DMF·5H2O}n (3), has been obtained. 3 is a 3D framework. Especially, 3 is constructed from multiple SBUs and displays an unusual (3,4,6)-connected topology. Furthermore, especially 3 performs better than 1 and 2 in terms of uptake capacity as well as adsorption selectivity, which might be ascribed to the more proper pore space of 3.

Fenretinide attenuates lipopolysaccharide (LPS)-induced blood-brain barrier (BBB) and depressive-like behavior in mice by targeting Nrf-2 signaling.

The transcription factor nuclear factor erythroid-2 related factor 2 (Nrf2) is a dominant manager to inhibit oxidative and inflammatory damage. Fenretinide (Fen) is a novel agent, showing significant role in regulating oxidative stress and inflammatory response. However, its effects on lipopolysaccharide (LPS)-induced brain injury are still unclear. In the present study, we explored the regulatory role of Fen in LPS-triggered neuroinflammation, and the underlying molecular mechanisms. Results here indicated that Fen treatment markedly improved Nrf2 expression and nuclear translocation in mouse brain endothelial cell line bEnd.3 cells, and promoted Nrf2-antioxidant responsive element (ARE) transcription activity, as well as its down-streaming signals, which was Nrf2-dependent. Fen also exhibited cytoprotective role in LPS-stimulated bEnd.3 cells through improving anti-oxidant capacity and inhibiting inflammation by the blockage of nuclear factor-kappa B (NF-κB) signaling. Mouse model with brain injury induced by LPS, Fen administration markedly attenuated the behavior impairments, blood-brain-barrier (BBB) and the histological changes in hippocampus samples. Additionally, Fen attenuated oxidative stress and blunted inflammation in hippocampus of LPS-challenged mice. Therefore, results in the study highlighted the protective role of Fen against LPS-elicited brain injury.

Expression of CCL2 and CCR2 in the hippocampus and the interventional roles of propofol in rat cerebral ischemia/reperfusion.

The aim of the present study was to determine the roles of the chemotactic factor, chemokine ligand 2 (CCL2), and its receptor, chemokine receptor type 2 (CCR2), in the hippocampus of rats with cerebral ischemia/reperfusion injury. In total, 24 Sprague-Dawley rats, weighting 250-300 g, were randomly divided into three groups (n=8): Sham-operated (C group), cerebral ischemia/reperfusion injury (I/R group) and propofol-intervention (P group) groups. The rats were sacrificed at 6 h after the ischemia/reperfusion surgery, and the brains were obtained to isolate the hippocampus. The mRNA expression levels of CCL2 and CCR2 in the hippocampus were analyzed by quantitative polymerase chain reaction, while the protein expression levels of CCL2 and CCR2 were determined by western blot analysis. The expression levels of CCL2 and CCR2 in the procerebrum were markedly elevated in the I/R and P groups at 6 h after the ischemia/reperfusion surgery when compared with the C group (P<0.05). In addition, the mRNA expression levels of CCL2 and CCR2 decreased significantly in the P group as compared with that in the I/R group (P<0.05). Therefore, CCL2 and CCR2 may be involved in the mechanisms underlying cerebral ischemia/reperfusion injury, and propofol may protect the brain through regulating the expression of CCL2 and CCR2.

[Effects of repetitive transcranial magnetic stimulation with different paradigms on the cognitive function and psychotic symptoms of schizophrenia patients].

OBJECTIVE: To evaluate the effect of different paradigms of repetitive transcranial magnetic stimulation (rTMS) on the treatment of schizophrenia through assessing cognitive function and psychotic symptoms. METHODS: Eighty patients diagnosed with schizophrenia were randomly assigned to four groups, which were sham intervention group, theta burst stimulation (TBS) group, 10 Hz group and 20 Hz group. All the subjects were exposed to 5 daily treatments at 80% of motor threshold over the left dorsolateral prefrontal cortex with a total stimuli of 1 200 per day, while being maintained on their former antipsychotic treatment. Visual spatial working memory test and verbal fluency test were applied to evaluate the cognitive function, while Positive and Negative Symptom Scale (PANSS) was used to assess the psychotic symptoms. RESULTS: 20 Hz of rTMS could improve the visual spatial working memory of schizophrenia patients (t=-2.469,P=0.024). Only patients in TBS group showed significant improvement of verbal fluency test after rTMS treatment (t=-4.538,P=0.000). The negative symptoms were alleviated significantly both in TBS and 10 Hz groups (TBS: t=5.373,P=0.000; 10 Hz: t=2.272,P=0.036). General psychopathology symptoms were improved significantly both in 10 Hz and 20 Hz groups (10 Hz:t=2.725,P=0.014;20 Hz:t=3.632,P=0.002). CONCLUSION: The effects of rTMS on the cognitive function and psychotic symptoms of schizophrenia vary according to the changes in stimulus parameters, suggesting that rTMS could provide a new way for the individual therapy of schizophrenia.

Mapping IgE binding epitopes of major shrimp (Penaeus monodon) allergen with immunoinformatics tools.

Tropomyosin, a myofibrillar protein, was described as the major allergen in crustaceans. The objective of this study was to screen and identify the linear IgE epitopes of tropomyosin in Penaeus monodon. Three immunoinformatics tools were used to predict the potential epitopes and the resultant epitopes were confirmed by dot-blot inhibition with sera from shrimp allergic subjects. As the result, 10 peptides were predicted and assembled by solid-phase synthesis. Eight epitopes were identified by dot-blot inhibition test, among which peptide 4 and 8 had not been reported by previous researches. Moreover, peptide 6 and 10 had IgE binding capability with all sera, while peptide 5, 8 and 9 could bind with 80% of the sera. Amino acid analysis demonstrated that Y, E, R, F and S presented more frequently in epitopes. Although further research should be done, it seems that immunoinformatics-driven epitope prediction can benefit epitope identification with high accuracy and efficiency.

CB1 cannabinoid receptor participates in the vascular hyporeactivity resulting from hemorrhagic shock in rats.

BACKGROUND: Vascular hyporeactivity, which occurs in the terminal stage of hemorrhagic shock, is believed to be critical for treating hemorrhagic shock. The present study was designed to examine whether the CB1 cannabinoid receptor (CB1R) was involved in the development of vascular hyporeactivity in rats suffering from hemorrhagic shock. METHODS: Sixteen animals were randomly divided into two groups (n = 8 in each group): sham-operated (Sham) and hemorrhagic shock (HS) groups. Hemorrhagic shock was induced by bleeding. The mean arterial pressure (MAP) was reduced to and stabilized at (25 +/- 5) mmHg for 2 hours. The vascular reactivity was determined by the response of MAP to norepinephrine (NE). In later experiments another twelve animals were used in which the changes of CB1R mRNA and protein in aorta and superior mesenteric artery (SMA) were analyzed by RT-PCR and Western blotting. In addition, we investigated the effects of a CB1R antagonist on the vascular hyporeactivity and survival rates in rats with hemorrhagic shock. Survival rates were analyzed by the Fisher's exact probability test. The MAP response was analyzed by one-way analysis of variance (ANOVA). RESULTS: Vascular hyporeactivity developed in all animals suffering from hemorrhagic shock. The expression of CB1R mRNA and protein in aorta and 2 - 3 branches of the SMA were significantly increased in the HS group after the development of vascular hyporeactivity when compared to those in Sham group. When SR141716A or AM251 was administered, the MAP response to NE was (41.75 +/- 4.08) mmHg or (44.78 +/- 1.80) mmHg respectively, which was higher than that in saline groups with (4.31 +/- 0.36) mmHg (P < 0.01). We also showed an increased 4-hour survival rate in the SR141716A or AM251-treated group with 20% or 30%, but with a statistically significant difference present between the AM251-treated and saline groups (P < 0.05). CONCLUSIONS: CB1R is involved in vascular hyporeactivity resulting from hemorrhagic shock in rats, and CB1R antagonist may be useful in treating patients with traumatic, hemorrhagic shock who need field-rescue or initial treatment.

Severity of sepsis is correlated with the elevation of serum high-mobility group box 1 in rats.

BACKGROUND: Sepsis is a leading cause of death in the intensive care units. The late inflammatory cytokine, high-mobility group box 1 (HMGB1), plays a critical role in sepsis. In the present study, we investigated the association between the serum HMGB1 levels and the severity of organ injury in the lipopolysaccharide-induced sepsis in rats. METHODS: To produce an animal model of sepsis with different degree of organ injury, animals were treated with three different doses of lipopolysaccharide (4, 8 and 16 mg/kg), and the animals in control group were treated with the same volume of the vehicle (saline). The levels of serum HMGB1 were measured at 0, 2, 4, 8, 16, 24, 32 and 48 hours after lipopolysaccharide (LPS) or vehicle injection, meanwhile the biochemical and histopathological indicators for the severity of organ injury were assessed. RESULTS: The level of HMGB1 had a positive, high correlation with the abnormal changes of serum cardiac troponin I, alanine aminotransferase, aspartate aminotransferase, creatinine and blood urea nitrogen, as well as the pathologic scores of heart, lung, liver and kidney. CONCLUSIONS: The level of serum HMGB1 is highly correlated with the severity of sepsis in rats, suggesting that HMGB1 could serve as a valuable adjunct in the diagnosis and management of sepsis.

[Biological flocculants used for turbidity elimination during coagulation in water treatment].

Research was investigated about bioflocculants (BFs) used for turbidity removal from kaolin clay solution and raw water based on jar tests. The results show that the elimination efficiency to turbidity from kaolin clay solution by BFs is 84%, over 5-19 mg/L, which is lower than 93% for Al2(SO4)3 and 94% for Fe2(SO4)3. From the variation of Zeta potential and pH, it was demonstrated that coagulation with BFs was governed by bridging flocculation. It was also observed that the addition of a small amount of inorganic salts (Fe or Al) could substantially enhance the coagulation efficiency. It appeared likely that the combined applications of inorganic salts and BFs resulted in an enhancement of charge neutralization and bridging flocculation. The case study shows that the combination of Fe and BFs can effectively eliminate turbidity from raw water at low dosage and neutral pH (by 94.6%). For biodegradable nature of produced sludge and reducing the health risk related to aluminum accumulation, BFs are considered to be a new type of environmental-friendly flocculants.

A modified single-prolonged stress model for post-traumatic stress disorder.

In the rat, single-prolonged stress (SPS) model produces a core symptom of post-traumatic stress disorder (PTSD), the enhanced fear response to the traumatic cue (conditioned fear response). This investigative tool is typically used for PTSD studies. However, whether SPS can produce another core symptom of PTSD, hyperarousal (the sensitized fear response in animal models), has not been evaluated. It is also not clear whether SPS can enhance both conditioned and sensitized fear responses after different incubation times. In this study, a single inescapable electric foot shock was given to rats immediately after SPS procedures (SPS&S). After different incubation times (1, 7 or 14 days), the conditioned or sensitized fear response was measured by re-exposing the stressed rats to the shock context or a neutral tone in a novel environment. Additionally, paroxetine, a selective serotonin reuptake inhibitor (SSRI) was administered after SPS&S for 14 days to test its potential preventive effect on PTSD-like symptoms. We observed that conditioned fear persisted and sensitized fear increased with ongoing incubation times after SPS&S. Early rapid intervention with paroxetine after SPS&S ameliorated PTSD-like symptoms in both fear responses and anxiety behaviors. Our data suggests that this modified SPS&S model may be both novel and predictably mimic the clinical characteristics of PTSD better than other investigative paradigms.