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"Gong, Yan-ling"
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Gut microbiota-derived propionate mediates the neuroprotective effect of osteocalcin in a mouse model of Parkinson’s disease
Background
Parkinson’s disease (PD) is a neurodegenerative disorder with no absolute cure. The evidence of the involvement of gut microbiota in PD pathogenesis suggests the need to identify certain molecule(s) derived from the gut microbiota, which has the potential to manage PD. Osteocalcin (OCN), an osteoblast-secreted protein, has been shown to modulate brain function. Thus, it is of interest to investigate whether OCN could exert protective effect on PD and, if yes, whether the underlying mechanism lies in the subsequent changes in gut microbiota.
Results
The intraperitoneal injection of OCN can effectively ameliorate the motor deficits and dopaminergic neuronal loss in a 6-hydroxydopamine-induced PD mouse model. The further antibiotics treatment and fecal microbiota transplantation experiments confirmed that the gut microbiota was required for OCN-induced protection in PD mice. OCN elevated
Bacteroidetes
and depleted
Firmicutes
phyla in the gut microbiota of PD mice with elevated potential of microbial propionate production and was confirmed by fecal propionate levels. Two months of orally administered propionate successfully rescued motor deficits and dopaminergic neuronal loss in PD mice. Furthermore, AR420626, the agonist of FFAR3, which is the receptor of propionate, mimicked the neuroprotective effects of propionate and the ablation of enteric neurons blocked the prevention of dopaminergic neuronal loss by propionate in PD mice.
Conclusions
Together, our results demonstrate that OCN ameliorates motor deficits and dopaminergic neuronal loss in PD mice, modulating gut microbiome and increasing propionate level might be an underlying mechanism responsible for the neuroprotective effects of OCN on PD, and the FFAR3, expressed in enteric nervous system, might be the main action site of propionate.
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Video abstract
Journal Article
Osteocalcin ameliorates cognitive dysfunctions in a mouse model of Alzheimer’s Disease by reducing amyloid β burden and upregulating glycolysis in neuroglia
Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized by the accumulation of amyloid β peptides (Aβ) and impaired glucose metabolism in the brain. Osteocalcin (OCN), an osteoblast-derived protein, has been shown to modulate brain functions but whether it has any effect on AD is undetermined. In this study, daily intraperitoneal injection of OCN for 4 weeks ameliorated the anxiety-like behaviors and cognitive dysfunctions in the APP/PS1 transgenic AD mice model, as shown in the increased entries into the central area in open field test, the increased time and entries into open arms in elevated plus maze test, the increased time spent in the light chamber in light-dark transition test, as well as the reduced escape latency and the increased preference for target quadrant in Morris water maze test. Aβ burden in the hippocampus and cortex of AD mice was ameliorated by OCN. Besides, OCN improved the neural network function of the brain, mainly in the enhanced power of high gamma band in the medial prefrontal cortex of AD mice. The proliferation of astrocytes in the hippocampus in AD mice was also inhibited by OCN as demonstrated by immunofluorescence. Furthermore, OCN enhanced glycolysis in astrocytes and microglia, as evidenced by elevated glucose consumption, lactate production, and increased extracellular acidification rate. Such an effect was abolished when the receptor of OCN – Gpr158 was knockdown in astrocytes. Our study revealed OCN as a novel therapeutic factor for AD potentially through reducing Aβ burden and upregulation of glycolysis in neuroglia.
Journal Article
Salsola collina ethyl acetate extract alleviates diabetic gastroparesis possibly through oxidative stress inhibition
Objective: To investigate the therapeutic significance of ethyl acetate extract of Salsola collina (EES) on diabetic gastroparesis (DGP) and its underlying mechanisms. Methods: The composition of EES was analyzed by HPLC and LC/MS. A DGP model was established by streptozotocin injection and irregularly feeding a high-sugar, high-fat (HSHF) diet. Serum nitric oxide (NO), total cholesterol (TC), and triglyceride (TG) and the gastric superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), and glutathione peroxidase (GSH-Px) concentrations were measured by colorimetry and ELISA. The expression of neuronal nitric oxide synthase (nNOS) and protein gene product 9.5 (PGP9.5) in the gastric tissue were examined by Western blot and immunohistochemistry. Results: EES promoted gastric emptying delayed by DGP, which was mainly composed of 10 organic acids. Furthermore, EES increased serum NO, decreased glucose, TC and TG, increased gastric SOD, CAT, and GSH-Px, while decreased MDA, increased nNOS and PGP9.5 expression in the gastric tissue, and showed a concentration dependence. Conclusion: EES promoted gastric emptying in the DGP rats, which might be related to its inhibition of oxidative stress and the associated increase in the gastric neuron population, as well as its hypoglycemic and lipid-lowering activities. These findings suggest that Salsola may have potential benefits in the treatment of DGP.
Journal Article
ROS generated by CYP450, especially CYP2E1, mediate mitochondrial dysfunction induced by tetrandrine in rat hepatocytes
Aim： Tetrandrine, an alkaloid with a remarkable pharmacological profile, induces oxidative stress and mitochondrial dysfunction in hepatocytes; however, mitochondria are not the direct target of tetrandrine, which prompts us to elucidate the role of oxidative stress in tetrandrine-induced mitochondrial dysfunction and the sources of oxidative stress.
Methods： Rat primary hepatocytes were isolated by two-step collagenase perfusion. Mitochondrial function was evaluated by analyzing ATP content, mitochondrial membrane potential （MMP） and the mitochondrial permeability transition. The oxidative stress was evaluated by examining changes in the levels of reactive oxygen species （ROS） and glutathione （GSH）.
Results： ROS scavengers largely attenuated the cytotoxicity induced by tetrandrine in rat hepatocytes, indicating the important role of ROS in the hepatotoxicity of tetrandrine. Of the multiple ROS inhibitors that were tested, only inhibitors of CYP450 （SKF-525A and others） reduced the ROS levels and ameliorated the depletion of GSH. Mitochondrial function assays showed that the mitochondrial permeability transition （MPT） induced by tetrandrine was inhibited by SKF-525A and vitamin C （VC）, both of which also rescued the depletion of ATP levels and the mitochondrial membrane potential. Upon inhibiting specific CYP450 isoforms, we observed that the inhibitors of CYP2D, CYP2C, and CYP2E1 attenuated the ATP depletion that occurred following tetrandrine exposure, whereas the inhibitors of CYP2D and CYP2E1 reduced the ROS induced by tetrandrine. Overexpression of CYP2E1 enhanced the tetrandrine-induced cytotoxicity.
Conclusion： We demonstrated that CYP450 plays an important role in the mitochondrial dysfunction induced by the administration of tetrandrine. ROS generated by CYP450, especially CYP2E1, may contribute to the mitochondrial dysfunction induced by tetrandrine.
Journal Article
Pharmacological mechanisms underlying the antinociceptive and tolerance effects of the 6,14-bridged oripavine compound 030418
Aim： To investigate possible pharmacological mechanisms underlying the antinociceptive effect of and tolerance to N-methyl-7α-[（R）-i- hydroxy-i-methyl-3-（thien-3-yl）-propyl]-6,14-endo-ethanotetrahydronororipavine （030418）, a derivative of thienorphine. Methods： The binding affinity and efficacy of 030418 were determined using receptor binding and guanosine 5＇-O-（3-[^35S]thio）triphos- phate （[^35S]GTPyS） assays in CHO-μ, CHO-K, CHO-（3, and CHO-ORLi cell membranes. The analgesic activity of and tolerance to 0304i8 were evaluated in thermal nociceptive tests in mice. The effects of 030418 on opioid receptors were further investigated using in vivo pharmacological antagonist blockade and in vitro tissue preparations. Results： The compound 030418 displayed high binding affinity to all subtypes of opioid receptors with Ki values in the nanomolar range. In [^35S]GTPyS binding assay, the maximal stimulation of 030418 to μ-, K-, σ-receptors and the ORLi receptor was 89%, 86%, 67% and 91%, respectively. In hot-plate test, the antinociceptive effect of 030418 was more potent and longer than morphine. The nonselective opioid receptor antagonist naloxone could completely block 030418-induced antinociception, while both the μ-opioid receptor antagonist β-FNA and the K-opioid receptor antagonist nor-BNI attenuated 030418-induced antinociception. In contrast, the ORL1 receptor antagonist J-ii3397 enhanced the antinociceptive effect of 030418. Additionally, chronic treatment with 030418 resulted in a dramatic development of tolerance that could not be effectively prevented by J-113397. In guinea pig ileum preparation, the existing action of 030418 could be removed with difficulty after prolonged washing. Conclusion： The compound 030418 is a novel agonist of opioid receptors with high efficiency, long-lasting effect and liability to tolerance, which may be closely correlated with the methyl group at the N17 position and the high hydrophobicity of the C7-thiophene group in its chemical structure.
Journal Article
Expression of phosphatidylinositol-3 kinase and effects of inhibitor Wortmannin on expression of tumor necrosis factor-α in severe acute pancreatitis associated with acute lung injury
BACKGROUND: Acute lung injury(ALI) is a common and serious complication of severe acute pancreatitis(SAP). The study aimed to investigate the protective effect and mechanism of phosphatidylinositol-3 kinase(PI3K) inhibitor Wortmannin in SAP associated with ALI.METHODS: Ninety rats were randomly divided into three groups: sham operation(SO) group(n=30), SAP group(n=30), and SAP+Wortmannin(SAP+W) group(n=30). SAP model was induced by retrograde injection of 4% sodium taurocholate into the biliopancreatic duct of rats. The rate of lung water content, myeloperoxidase(MPO), matrix metalloproteinase 9(MMP-9), protein kinase B(PKB), abdphosphorylation of protein kinase B(P-PKB) activity in the lung tissue were evaluated.RESULTS: In the SAP group, the p-PKB expression in the lung tissue began to rise at 3 hours after modeling, and peaked at 12 hours(P<0.05); the rate of lung water content, MPO and TNF-α activity were also gradually increased, and the degree of lung lesion gradually increased(P<0.05). In the SAP+Wortmannin group, the p-PKB expression in the lung tissue began to rise at 3 hours after modeling, and peaked at 12 hours; it was higher than that in the SO group(P<0.05), but significantly lower than that in the SAP group(P<0.05). The rest indicators in the SAP+Wortmannin group were also significantly decreased as compared with the SAP group(P<0.05).CONCLUSIONS: The expression of phosphatidylinositol-3 kinase/protein kinase B was elevated in severe pancreatitis rats with lung injury. This suggested that PI3 K signal transduction pathway is involved in the control and release of proinfl ammatory cytokines TNF-α, which may play an important role in the pathogenesis of severe acute pancreatitis associated with lung injury. This finding indicated that Wortmannin can block the PI3 K signal transduction pathway, and inhibit the release of infl ammatory factor TNF-α.
Journal Article
Polypeptide from Chlamys farreri attenuates murine thymocytes damage induced by ultraviolet B
Aim： Polypeptide from Chlamysfarreri （PCF, molecular mass is 879） is a new marine polypeptide compound isolated from Chlamysfarreri. This study investigates the possible protective roles and the mechanism of PCF against ultraviolet B （UVB）-induced apoptosis in murine thymocytes. Methods： The rate of apoptosis and caspase-3 activation was measured by flow cytometry. The expression of stress-response genes c-fos and c-jun was observed by RT-PCR. Western blot analysis was performed to determine the release of cytochrome c. Results： It was found that UVB induced murine thymocyte death. The cells treated with UVB showed an increase in cytochrome c release, caspase-3 activity, as well as in the expression of c-fos and c-jun. In addition, all were involved in UVB-induced cell apoptosis. Conclusion： Our present observations pointed to the ability of PCF to avert UVB-induced apoptosis in thymocytes by modulating c-fos and c-jun expression, cytochrome c release, and the consequent activation of caspase-3, which were essential components of the UV-induced cell apoptotic pathway. The results suggested that PCF is a promising protective substance against UV radiation.
Journal Article
The value of L3 skeletal muscle index in evaluating preoperative nutritional risk and long-term prognosis in colorectal cancer patients
L3 skeletal muscle index (L3SMI) was reportedly related to postoperative outcomes. We aimed to investigate the value of L3SMI in evaluating preoperative nutritional risk and long-term prognosis in colorectal cancer (CRC) patients. We retrospectively enrolled 400 CRC patients who underwent surgery from January 2012 to December 2014. The L3SMI was calculated by preoperative computed tomography (CT) and classified into two groups by gender quartile method. We found that the CT diagnostic criteria of sarcopenia in South China population was: male ≤38.89cm
2
/m
2
, female ≤33.28cm
2
/m
2
. Multivariate logistic regression analysis showed that low L3SMI was an independent risk factor for preoperative nutritional risk (p < 0.001). Kaplan-Meier survival curves showed that low status group had significantly lower disease-free survival (p = 0.004) and overall survival (p = 0.001), especially in TNM II stage. Multivariate Cox regression analysis revealed preoperative low L3SMI adversely affected disease-free survival (p < 0.001, HR 1.894 (95% CI: 1.330–2.698)), and overall survival (p < 0.001, HR 2.030 (95% CI: 1.420–2.902)). In conclusion, L3SMI is a useful supplement for screening preoperative nutritional risk and diagnosing sarcopenia, and a potential clinical indicator that can be used to predict the prognosis of CRC patients, especially TNM stage II patients.
Journal Article