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Objectives Despite of strenuous research in the past decades, the etiology of schizophrenia (SCZ) still remains incredibly controversial. Previous genetic analysis has uncovered a close association of Unc-51 like kinase 4 (ULK4), a family member of Unc-51-like serine/threonine kinase, with SCZ. However, animal behavior data which may connect Ulk4 deficiency with psychiatric disorders, particularly SCZ are still missing. Methods We generated Emx1-Cre:Ulk4flox/flox conditional knockout (CKO) mice, in which Ulk4 was deleted in the excitatory neurons of cerebral cortex and hippocampus. Results The cerebral cellular architecture was maintained but the spine density of pyramidal neurons was reduced in Ulk4 CKO mice. CKO mice showed deficits in the spatial and working memories and sensorimotor gating. Levels of p-Akt and p-GSK-3α/β were markedly reduced in the CKO mice indicating an elevation of GSK-3 signaling. Mechanistically, Ulk4 may regulate the GSK-3 signaling via putative protein complex comprising of two phosphatases, protein phosphatase 2A (PP2A) and 1α (PP1α). Indeed, the reduction of p-Akt and p-GSK-3α/β was rescued by administration of inhibitor acting on PP2A and PP1α in CKO mice. Conclusions Our data identified potential downstream signaling pathway of Ulk4, which plays important roles in the cognitive functions and when defective, may promote SCZ-like pathogenesis and behavioral phenotypes in mice. [ABSTRACT FROM AUTHOR]

Benzene (BZ) is an important occupational and environmental pollutant. Exposure to BZ may cause aplastic anemia which is characterized as bone marrow hematopoietic failure. In order to reduce the harmful effects of this pollutant, it is necessary to identify additional preventative measures. In this study, we investigated the protective effects of epimedium polysaccharide (EPS), a natural compound with antioxidant and immune-enhancing potency, on aplastic anemia induced by benzene exposure in mice. Male CD-1 mice were randomly divided into five groups including control, BZ (880 mg/kg), LE (EPS low-dose, 20 mg/kg + BZ), ME (EPS middle-dose, 100 mg/kg + BZ), and HE (EPS high-dose, 200 mg/kg + BZ) groups. Animals were exposed to BZ by subcutaneous injection in the presence or absence of EPS via oral administration. All mice were treated 3 times a week for 8 consecutive weeks to develop a mouse model of benzene-induced aplastic anemia (BIAA). Results showed that BZ induced a significant decrease in both white and red blood cells, platelet counts, and hemoglobin level compared with that in the control group (p < 0.01). Treatment of EPS led to a protective effect against these changes particularly in the highest-dose group (HE, p < 0.01). EPS also recovered the decreased number of nucleated cells in peripheral blood cell smears and femur biopsies by BZ exposure. The increased level of reactive oxygen species (ROS) in bone marrow mononuclear cells (BMMNCs) in mice from the BZ group was significantly lower (p < 0.01) in the mice from the highest concentration of EPS (HE) group when compared with that from the control group. In addition, BZ exposure led to a significant increase in the apoptosis rate in BMMNCs which was prevented by EPS in a dose-dependent manner (p < 0.01). The antiapoptosis effect of EPS was through reversing apoptotic proteins such as BAX, Caspase-9 and Caspase-3, and Bcl-2. Finally, EPS treatment partially restored the levels of T cells and the different subtypes except CD80+ and CD86+ compared with the BZ group (HE, p < 0.05). These results suggest that EPS has protective effects against BIAA via antioxidative stress, immune modulation, and antiapoptosis mechanisms. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication of cisplatin, which is characterized by intolerable paresthesia, burning, and hyperalgesia, and severely impacts the life quality of patients. However, no clearly potent drug has been found for clinical medication due to its undefined mechanism. Corydalis Saxicola Bunting, a traditional Chinese medicine, has been proven to work well in anti-inflammation, blood circulations improvement, hemostasis, and analgesia. This study was designed to observe the effects of Corydalis saxicola Bunting total alkaloids (CSBTA) on cisplatin-induced neuropathic pain and to explore its potential mechanisms. In this study, the rats received intraperitoneal injection of 2 mg/kg cisplatin twice a week for five weeks. Meanwhile, oral administration of low (30 mg/kg)-, medium (60 mg/kg)- and high (120 mg/kg)-dose CSBTA were given daily for five weeks. By using Von-frey hair, heat radiant and − 8 0 ∘ C cold acetone, we found that CSBTA could obviously relieve cisplatin-induced mechanical, heat, and cold hyperalgesia. It has been verified that cisplatin-induced peripheral neuropathy is related to intraepidermal nerve fibers loss and activation of inflammation downstream. Our research found that Tumor necrosis factor-alpha (TNF- α), Interleukin-1beta (IL-1 β), and Prostaglandin E2 (PGE2) were significantly increased by 10 intraperitoneal injections of cisplatin, and such pro-inflammation cytokines could be reduced via CSBTA administration. Besides, in the cisplatin model group, the neuronal structures of dorsal root ganglia (DRG) were severely damaged and the loss of intraepidermal nerve fibers occurred; but in the CSBTA administration groups, all above pathological changes were improved. Moreover, CSBTA could normalize the overexpression levels of p-p38 and Transient receptor potential vanilloid receptor (TRPV1) induced by cisplatin in DRG, trigeminal ganglion (TG), spinal cord, and foot of rats. In summary, we considered that CSBTA exerted its therapeutic effects by ameliorating neuronal damages, improving intraepidermal nerve fiber (IENF) loss, and inhibiting inflammation-induced p38 phosphorylation to block TRPV1 activation. These findings were the first to confirm the analgesic effect of CSBTA on CIPN and suggested a novel strategy for treating CIPN in clinic. [ABSTRACT FROM AUTHOR]

The flower bud of Daphne genkwa ( Genkwa Flos) is a commonly used herbal medicine in Asian countries. Luteolin and apigenin are two recognized active flavonoids in Genkwa Flos. The aim of this study was to investigate the intestinal absorption mechanisms of Genkwa Flos flavonoids using in situ single-pass intestinal perfusion rat model. Using HPLC, we determined its major effective flavonoids luteolin, apigenin, as well as, hydroxygenkwanin and genkwanin in biological samples. The intestinal absorption mechanisms of the total flavonoids in Genkwa Flos (TFG) were investigated using in situ single-pass intestinal perfusion rat model. Comparing the TFG absorption rate in different intestinal segments, data showed that the small intestine absorption was significantly higher than that of the colon (). Compared with duodenum and ileum, the jejunum was the best small intestinal site for TFG absorption. The high TFG concentration (61.48g/ml) yielded the highest permeability (). Subsequently, three membrane protein inhibitors (verapamil, pantoprazole and probenecid) were used to explore the TFG absorption pathways. Data showed probenecid, a multidrug resistance protein (or MRP) inhibitor, effectively enhanced the TFG absorption (). Furthermore, by comparing commonly used natural absorption enhancers on TFG, it was observed that camphor was the most effective. In Situ single-pass intestinal perfusion experiment shows that TFG absorption is much higher in the small intestine than in the colon, and the TFG is absorbed mainly via an active transport pathway with MRP-mediated efflux mechanism. Camphor obviously enhanced the TFG absorption, and this could be an effective TFG formulation preparation method to increase clinical effectiveness after Genkwa Flos administration. Our study elucidated the TFG absorption mechanisms, and provided new information for its formulation preparation. [ABSTRACT FROM AUTHOR]

Background: Transient receptor potential melastatin 2 is a Ca-permeable cation channel abundantly expressed in macrophages. Trpm2 mice showed exacerbated infection and mortality during polymicrobial sepsis, which is associated with inefficient bacterial killing in macrophages. However, the mechanism of transient receptor potential melastatin 2 regulating bacterial killing remains unknown.Methods: Trpm2 mice were intraperitoneally injected with Escherichia coli. The survival rate (n = 21) and bacterial burden (n = 5) were assessed. The processes of phagosome maturation and phagosome-lysosome fusion in peritoneal macrophages were extensively studied. The impact of increasing intracellular Ca concentration on bacterial clearance in macrophages (n = 3) and on survival rate of Trpm2 mice infected with E. coli (n = 21) was investigated.Results: Trpm2 mice exhibited increased mortality (85% vs. 54%; P < 0.01) and aggravated bacterial burden during E. coli sepsis. Trpm2 peritoneal macrophages infected with E. coli showed dampened recruitment of lysosomal-associated membrane protein 1 and impaired phagosome maturation evidenced by a decrease in the accumulation of early endosome antigen 1, whereas a normal acquisition of Ras-related protein in brain 5. Increasing the cytosolic Ca concentration in Trpm2 peritoneal macrophages via ionomycin treatment facilitated early endosome antigen 1 recruitment to Ras-related protein in brain 5 and phagosomal localization of lysosomal-associated membrane protein 1 and consequently enhanced bactericidal activity. Adoptive transfer of ionomycin-treated Trpm2 peritoneal macrophages improved bacterial clearance and survival (67% vs. 29%; P < 0.01) in Trpm2 mice challenged with E. coli.Conclusions: Transient receptor potential melastatin 2 plays a critical role in host defense against invading bacteria via promoting phagosome maturation through facilitation of early endosome antigen 1 recruitment. [ABSTRACT FROM AUTHOR]

To investigate the absorptive transport behavior of genkwanin and the beneficial effects of monoterpene enhancers with different functional groups, the single-pass intestinal perfusion (SPIP) of rats was used. The results showed that genkwanin was segmentally-dependent and the best absorptive site was the duodenum. The effective permeability coefficient (Peff) was 1.97 × 10-4 cm/s and the absorption rate constant (Ka) was 0.62 × 10-2 s-1. Transepithelial transportation descended with increasing concentrations of genkwanin. This was a 1.4-fold increase in Peff by probenecid, whereas a 1.4-fold or 1.6-fold decrease was observed by verapamil and pantoprazole, respectively. Furthermore, among the absorption enhancers, the enhancement with carbonyl (camphor and menthone) was higher than that with hydroxyl (borneol and menthol). The concentration-independent permeability and enhancement by coperfusion of probenecid indicated that genkwanin was transported by both passive diffusion and multidrug resistance protein (MDR)-mediated efflux mechanisms. [ABSTRACT FROM AUTHOR]

Objective: It has been widely acknowledged that early treadmill training plays an important role in rewiring neurons in a functionally meaningful manner in spinal cord injury (SCI) treatment. However, it is still unclear how early to start treadmill training to obtain the most efficacious results after SCI. The purpose of this study was to find the earliest time point when treadmill training was most effective in rewiring neurons. Methods: The rats were randomly divided into five groups: a sham group, control group, and three treadmill groups based on training start time post-injury: a 24 h group, 48 h group, and 72 h group. Results: The results revealed that in the 72 h group, Basso, Beattie, and Bresnaham scores increased and apoptotic cells decreased significantly compared to the other groups. There were no statistically differences in neuron counting and 5-bromo-2V-deoxyuridine assays between the groups. Conclusion: These results indicated that the best start time for treadmill training is 72 h after SCI. [ABSTRACT FROM AUTHOR]

Oxidative stress is well known to play a pivotal role in cerebral ischemia–reperfusion injury. On the basis of this fact, antioxidative agents have been demonstrated to be neuroprotective. Neohesperidin (NH) is abundant in citrus flavonoids and possesses reactive oxygen species scavenging activity and neuroprotective effectsin vitro. However, little is known about its effects on cerebral ischemia–reperfusion injury and the underlying mechanisms. In this study, we use a rat model of middle cerebral artery occlusion (MCAO) to investigate the neuroprotective effects of NH. NH significantly improved neurological functions and attenuated MCAO-induced infarct volume, pathological changes, and neuronal loss. Moreover, it enhanced antioxidant capacity and suppressed oxidative stress in the brain. NH inhibited the MCAO-induced upregulation of Bax, cytochromec, and cleaved caspase-9 and -3, as well as the downregulation of Bcl-2. Interestingly, NH treatment upregulated heme oxygenase-1 (HO-1) in a concentration-dependent manner, which was due to the NH-mediated activation of the protein kinase B (Akt)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. NH also abolished the MCAO-induced inhibition of the Akt/Nrf2 pathway. In conclusion, NH attenuates cerebral ischemia–reperfusion injury via the inhibition of neuronal apoptosis and oxidative stress through the regulation of the apoptotic pathway and the Akt/Nrf2/HO-1 pathway. NH might be a promising preventive agent for ischemic stroke. [ABSTRACT FROM PUBLISHER]

Abstract: Ethnopharmacological relevance: Swertia kouitchensis has long been used as a folk medicine to treat hepatitis and diabetes in central-western China. Therefore, this study was aimed to evaluate the anti-diabetic activity of the plant ethanol extract. Materials and methods: Firstly, the extract was tested for its inhibitory activity on α-amylase and α-glucosidase in vitro. Following that, insulin secretion test in NIT-1cell was performed. Then, oral sucrose or starch tolerance test of the extract were carried out in normal mice. After that, acute effect of the extract was executed in normal and streptozotocin-induced (60mg/kg) diabetic mice. Eventually, long term effect of the extract was performed in diabetic mice for 4 weeks. Oral glucose tolerance test and biochemical parameters were estimated at the end of the study. Results: Swertia kouitchensis extract could remarkably inhibit the activity of α-amylase and α-glucosidase and stimulate insulin secretion in vitro. And also the extract displayed anti-hyperglycemic activity, improved antioxidant capacity, ameliorated the hyperlipidemia and carbohydrate metabolism in diabetic mice. Conclusions: Swertia kouitchensis exhibits considerable anti-diabetic activity and metabolic alterations in diabetic mice. These results provide a rationale for the use of Swertia kouitchensis to treat diabetes mellitus. [Copyright &y& Elsevier]

Toxicokinetic characteristics of naringin and its metabolite naringenin were investigated in beagle dogs after oral administration of naringin at the doses of 20, 100, or 500 mg/kg/day in a repeated-dose study for 1, 30, 90, and 180 days. Plasma concentrations of naringin and naringenin were determined by a rapid resolution liquid chromatography/electrospray ionization/tandem mass spectrometric method. The results showed that no differences in systemic exposure were observed between male and female beagle dogs. Systematic exposure exhibited dose-dependent increase for both naringin and naringenin. No significant accumulations were observed. Results would be taken into consideration for the interpretation of toxicology findings and provide a reference for clinical safety assessment. [ABSTRACT FROM PUBLISHER]

Obesity has become a public burden worldwide due to its booming incidence and various complications, and browning of white adipose tissue (WAT) is recognized as a hopeful strategy to combat it. Blossom of Citrus aurantium L. var. amara Engl. (CAVA) is a popular folk medicine and dietary supplement used for relieving dyspepsia, which is recorded in the Chinese Materia Medica. Our previous study showed that blossom of CAVA had anti-obesity potential, while its role in browning of WAT was still unclear. This study aimed to characterize the constituents in flavonoids from blossom of CAVA (CAVAF) and to clarify the anti-obesity capacities especially the effects on browning of WAT. Gradient ethanol eluents from blossom of CAVA were obtained by AB-8 macroporous resin. 3T3-L1 cells and pancreatic lipase inhibition assay were employed to investigate the potential anti-obesity effects in vitro. HPLC and UPLC/MS assays were performed to characterize the chemical profiles of different eluents. Network pharmacology and molecular docking assays were used to reveal potential anti-obesity targets. Furthermore, high-fat diet (HFD)-induced mice were constructed to explore the anti-obesity actions and mechanisms in vivo. 30% ethanol eluents with high flavonoid content and great inhibition on proliferation of 3T3-L1 preadipocytes and pancreatic lipase activity were regarded as CAVAF. 19 compounds were identified in CAVAF. Network pharmacology analysis demonstrated that AMPK and PPARα were potential targets for CAVAF in alleviating obesity. Animal studies demonstrated that CAVAF intervention significantly decreased the body weight, WAT weight, serum TG, TC and LDL-C levels in HFD-fed obese mice. HFD-induced insulin resistance and morphological changes in WAT and brown adipose tissue were also markedly attenuated by CAVAF treatment. CAVAF supplementation potently inhibited iWAT inflammation by regulating IL-6, IL-1β, TNF-α and IL-10 mRNA expression in iWAT of mice. Furthermore, the gene expression levels of thermogenic markers including Cyto C, ATP synthesis, Cidea, Cox8b and especially UCP1 in iWAT of mice were significantly up-regulated by CAVAF administration. CAVAF intervention also markedly increased the expression levels of PRDM16, PGC-1α, SIRT1, AMPK-α1, PPARα and PPARγ mRNA in iWAT of mice. CAVAF treatment significantly promoted browning of WAT in HFD-fed mice. These results suggested that flavonoid extracts from blossom of CAVA were probably promising candidates for the treatment of obesity. CAVAF was a flavonoid-rich extract from blossom of CAVA. CAVAF treatment not only significantly inhibited pancreatic lipase activity and 3T3-L1 cells proliferation, but also potently promoted browning of WAT in HFD-fed mice. [Display omitted] [ABSTRACT FROM AUTHOR]

Sepsis is a leading cause of death in critical illness, and its pathophysiology varies depending on preexisting medical conditions. Here we identified nonalcoholic fatty liver disease (NAFLD) as an independent risk factor for sepsis in a large clinical cohort and showed a link between mortality in NAFLD-associated sepsis and hepatic mitochondrial and energetic metabolism dysfunction. Using in vivo and in vitro models of liver lipid overload, we discovered a metabolic coordination between hepatocyte mitochondria and liver macrophages that express triggering receptor expressed on myeloid cells-2 (TREM2). Trem2-deficient macrophages released exosomes that impaired hepatocytic mitochondrial structure and energy supply because of their high content of miR-106b-5p, which blocks Mitofusin 2 (Mfn2). In a mouse model of NAFLD-associated sepsis, TREM2 deficiency accelerated the initial progression of NAFLD and subsequent susceptibility to sepsis. Conversely, overexpression of TREM2 in liver macrophages improved hepatic energy supply and sepsis outcome. This study demonstrates that NAFLD is a risk factor for sepsis, providing a basis for precision treatment, and identifies hepatocyte-macrophage metabolic coordination and TREM2 as potential targets for future clinical trials. [ABSTRACT FROM AUTHOR]

What We Already Know About This Topic: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Pyroptosis, a type of proinflammatory programmed cell death, drives cytokine storm. Caspase-11-dependent macrophage pyroptosis contributes to mortality during sepsis. Sphingosine-1-phosphate receptor 2 (S1PR2) signaling can amplify interleukin-1β secretion in endotoxin-induced inflammation. Here, we hypothesized that S1PR2 signaling increases caspase-11-dependent macrophage pyroptosis and worsens Gram-negative sepsis outcome.Methods: A Gram-negative sepsis model was induced through intraperitoneal injection of Escherichia coli. Primary peritoneal macrophages isolated from wild-type, S1pr2-deficient (S1pr2), or nucleotide-binding oligomerization domain-like receptor protein-3-deficient mice were treated with E. coli. Caspase-11 activation, macrophage pyroptosis, and Ras homolog gene family, member A-guanosine triphosphate levels were assessed in those cells. Additionally, monocyte caspase-4 (an analog of caspase-11) expression and its correlation with S1PR2 expression were determined in patients with Gram-negative sepsis (n = 11).Results: Genetic deficiency of S1PR2 significantly improved survival rate (2/10 [20%] in wild-type vs. 7/10 [70%] in S1pr2, P = 0.004) and decreased peritoneal macrophage pyroptosis (pyroptosis rate: 35 ± 3% in wild-type vs. 10 ± 3% in S1pr2, P < 0.001). Decreased caspase-11 activation in S1PR2 deficiency cells contributed to the reduced macrophage pyroptosis. In addition, RhoA inhibitor abrogated the amplified caspase-11 activation in wild-type or S1PR2-overexpressing cells. In patients with Gram-negative sepsis, caspase-4 increased significantly in monocytes compared to nonseptic controls and was positively correlated with S1PR2 (r = 0.636, P = 0.035).Conclusions: S1PR2 deficiency decreased macrophage pyroptosis and improved survival in E. coli sepsis. These beneficial effects were attributed to the decreased caspase-11 activation of S1PR2-deficient macrophages. S1PR2 and caspase-11 may be promising new targets for treatment of sepsis. [ABSTRACT FROM AUTHOR]

Objectives: Basal forebrain cholinergic neurons are proposed as a major neuromodulatory system in inflammatory modulation. However, the function of basal forebrain cholinergic neurons in sepsis is unknown, and the neural pathways underlying cholinergic anti-inflammation remain unexplored.Design: Animal research.Setting: University research laboratory.Subjects: Male wild-type C57BL/6 mice and ChAT-ChR2-EYFP (ChAT) transgenic mice.Interventions: The cholinergic neuronal activity of the basal forebrain was manipulated optogenetically. Cecal ligation and puncture was produced to induce sepsis. Left cervical vagotomy and 6-hydroxydopamine injection to the spleen were used.Measurements and Main Results: Photostimulation of basal forebrain cholinergic neurons induced a significant decrease in the levels of tumor necrosis factor-α and interleukin-6 in the serum and spleen. When cecal ligation and puncture was combined with left cervical vagotomy in photostimulated ChAT mice, these reductions in tumor necrosis factor-α and interleukin-6 were partly reversed. Furthermore, photostimulating basal forebrain cholinergic neurons induced a large increase in c-Fos expression in the basal forebrain, the dorsal motor nucleus of the vagus, and the ventral part of the solitary nucleus. Among them, 35.2% were tyrosine hydroxylase positive neurons. Furthermore, chemical denervation showed that dopaminergic neurotransmission to the spleen is indispensable for the anti-inflammation.Conclusions: These results are the first to demonstrate that selectively activating basal forebrain cholinergic neurons is sufficient to attenuate systemic inflammation in sepsis. Specifically, photostimulation of basal forebrain cholinergic neurons activated dopaminergic neurons in dorsal motor nucleus of the vagus/ventral part of the solitary nucleus, and this dopaminergic efferent signal was further transmitted by the vagus nerve to the spleen. This cholinergic-to-dopaminergic neural circuitry, connecting central cholinergic neurons to the peripheral organ, might have mediated the anti-inflammatory effect in sepsis. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Genkwa flos (Daphne genkwa Sieb. et Zucc.), a Chinese herbal medicine, has been traditionally used for over two thousand years in China for inflammation related symptoms, including joint pain. To evaluate the antioxidative effects of flavonoid aglycones (FA) isolated from Genkwa flos on adjuvant arthritis in rats and to identify the relationship between antioxidant potential and whole blood viscosity (WBV). Materials and methods: FA compounds were identified using LC–MS and the content was assayed by HPLC. Arthritis was induced by an intradermal injection of Freund?s complete adjuvant in the footpad. The effects of FA on paw volumes, secondary arthritis scores, histopathology of joints, and body and organ weights were measured. The antioxidant effects of FA and WBV were determined. Results: LC–MS analysis showed that the FA contained four major compounds: luteolin, apigenin, hydroxygenkwanin and genkwanin. FA significantly decreased paw edema, arthritis scores, and weight loss. These observations were consistent with the reduction of oxidative stress and the improvement of the WBV. Conclusion: FA significantly decreased arthritis in a rat model through antioxidant and hemorheological modulatory mechanisms. The Genkwa flos flavonoids may have clinical potential for the treatment of rheumatoid arthritis. [Copyright &y& Elsevier]