Orexins alleviate motor deficits via increasing firing activity of pallidal neurons in a mouse model of Parkinson's disease.

Orexin is a peptide neurotransmitter released in the globus pallidus. Morphological evidence reveals that both orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R) exist in the globus pallidus. Here we showed that bilateral microinjection of both orexin-A and orexin-B into the globus pallidus alleviated motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian mice. Further in vivo extracellular single-unit recording revealed that the basal spontaneous firing rate of the globus pallidus neurons in MPTP parkinsonian mice was slower than that of normal mice. Application of orexin-A or orexin-B significantly increased the spontaneous firing rate of pallidal neurons. The influx of Ca2+ through the L-type Ca2+ channel is the major mechanism involved in orexin-induced excitation in the globus pallidus. Orexin-A-induced increase in firing rate of pallidal neurons in MPTP parkinsonian mice was stronger than that of normal mice. Orexin-A exerted both electrophysiological and behavioral effects mainly via OX1R, and orexin-B exerted the effects via OX2R. Endogenous orexins modulated the excitability of globus pallidus neurons mainly through OX1R. The present behavioral and electrophysiological results suggest that orexins ameliorate parkinsonian motor deficits through increasing the spontaneous firing of globus pallidus neurons.

Strictosamide promotes wound healing through activation of the PI3K/AKT pathway.

Nauclea officinalis, as a Chinese medicine in Hainan province, had the effect of treating lower limb ulcers, burn infections. In this paper, we studied the effect of Strictosamide (STR), the main bioactive compound in Nauclea officinals, on wound healing and explored its internal mechanism. Firstly, the wound healing potential of STR was evaluated in a rat model, demonstrating its ability to expedite wound healing, mitigate inflammatory infiltration, and enhance collagen deposition. Additionally, immunofluorescence analysis revealed that STR up-regulated the expression of CD31 and PCNA. Subsequently, target prediction, protein-protein interaction (PPI), gene ontology (GO), and pathway enrichment analyses were used to obtain potential targets, specific biological processes, and molecular mechanisms of STR for the potential treatment of wound healing. Furthermore, molecular docking was conducted to predict the binding affinity between STR and its associated targets. Additionally, in vivo and in vitro experiments confirmed that STR could increase the expression of P-PI3K, P-AKT and P-mTOR by activating the PI3K/AKT signaling pathway. In summary, this study provided a new explanation for the mechanism by which STR promotes wound healing through network pharmacology, suggesting that STR may be a new candidate for treating wound.

Diagnostic Value of Color Doppler Ultrasound and Contrast-Enhanced Ultrasound in the Artery Steal Syndrome After Orthotopic Liver Transplantation.

Purpose: This study aimed to investigate the application of color Doppler ultrasound (CDU) and contrast-enhanced ultrasound (CEU) in the early diagnosis of arterial steal syndrome (ASS) after orthotopic liver transplantation (OLT). Patients and Methods: A total of 1827 patients received OLT in our department between January 2007 and December 2021, and CDU and CEU were performed after surgery. Ultrasonographic data were collected and further analyzed. ASS was confirmed by digital subtraction angiography (DSA), and the use of splenic artery embolization was dependent on the DSA findings and clinical conditions. The ultrasonographic data were collected before and after embolization. Results: ASS was found in 23 patients (23/1827; 1.26%). CDU: the portal vein velocity was higher than normal in 17 patients (52.83±21.74 cm/s); the hepatic artery flow signals disappeared in 7 patients; the hepatic artery velocity was 13.57±5.85 cm/s in 16 patients. In 23 patients, the spleen artery velocity was 170.12±32.04 cm/s. CEU: the hepatic artery was observed in 7 patients without hepatic artery flow signals on CDU; in 23 patients, the contrast agent reached the portal vein at the presence of contrast in the hepatic artery or earlier (difference: 2.21±1.09 s). Splenic artery embolization was done in 17 of 23 patients with ASS. The hepatic artery flow velocity, hepatic artery resistance index, splenic artery velocity and time to the presence of contrast were significantly improved after embolization (P<0.05). Conclusion: CDU and CEU are the preferred, effective tools in the diagnosis of ASS. Reduced peak hepatic artery velocity, increased spleen artery velocity and reduced time difference in the contrast reaching the portal vein and hepatic artery are indicative of ASS.

A diarylheptanoid compound from Alpinia officinarum Hance ameliorates high glucose-induced insulin resistance by regulating PI3K/AKT-Nrf2-GSK3ß signaling pathways in HepG2 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Alpinia officinarum Hance, a perennial natural medicine-food herb, has been traditionally used to treat colds, stomachache, and diabetes for thousands of years. 1,7-Diphenyl-4E-en-3-heptanone (DPH5), a diarylheptanoid isolated from the rhizome of A. officinarum has been reported to be safe and to have antioxidant and hypoglycemic effects, suggesting its potential in the treatment of insulin resistance (IR). AIM OF THE STUDY: Aim of to investigate the protective effect of DPH5 on IR and elucidate its underlying mechanism of action. MATERIALS AND METHODS: HepG2 cells were used as the research objects. Glucose uptake and reactive oxygen species (ROS) levels in high glucose-induced insulin-resistant HepG2 cells were assessed using flow cytometry. Glucose consumption and the levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were analyzed using the corresponding assay kits. The expression of mRNA and proteins related to insulin signaling, glucose metabolism, and antioxidant factor, including insulin receptor substrate-1 (IRS1), phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), translocation of glucose transporter-4, glycogen synthase kinase-3ß (GSK3ß), glucokinase (GCK), pyruvate kinase (PK), phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), nuclear factor-erythroid 2 related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NADPH quinoneoxidoreductase (NQO1), and glutathione peroxidase (GSH-Px) was determined using real-time quantitative polymerase chain reaction and western blotting. Furthermore, molecular docking was performed to determine the spatial mechanism of DPH5 on the key targets PI3K, AKT, Nrf2, and GSK3ß. RESULTS: DPH5 could improve IR that manifested as increased glucose uptake and glucose consumption in insulin-resistant HepG2 cells. Moreover, DPH5 could enhance antioxidant capacity by activating Nrf2/HO-1 elements, including increasing Nrf2, HO-1, SOD, NQO1, and GSH-Px expression and reducing MDA, ROS, and JNK levels, thereby improving oxidative stress and ultimately alleviating IR. Additionally, DPH5 could promote the expression of IRS1, PI3K, AKT, GSK3ß, GCK, and PK, and downregulate the expression of PEPCK and G6pase, thereby accelerating glucose utilization and enhancing insulin sensitivity. The mechanism underlying the effect of DPH5 in alleviating IR was related to the PI3K/AKT- and Nrf2/HO-1-mediated regulation of the GSK3ß signaling pathway, and the results were further confirmed using the specific inhibitors LY294002 and ML385. Results from molecular docking indicated that there were different regulatory sites and interacting forces between DPH5 and PI3K, AKT, Nrf2, and GSK3ß; however, the binding force was relatively strong. CONCLUSIONS: DPH5 improved oxidative stress and glucose metabolism via modulating the PI3K/AKT-Nrf2-GSK3ß pathway, thereby ameliorating IR. Overall, our findings suggest the potential of DPH5 as a natural medicine to treat type-2 diabetes mellitus.

Involvement of orexin-A in the regulation of neuronal activity and emotional behaviors in central amygdala in rats.

The amygdala is a complex structure involved in the regulation of emotional behaviors including fear and anxiety. The central amygdala is the main output of the amygdala and plays an important role in emotional processing. Recent studies indicate that orexin, a kind of neuropeptides responsible for maintaining wakefulness, is also associated with emotion-related behaviors, such as depression- and anxiety-like behaviors. Central amygdala receives orexinergic fibers originating from the lateral hypothalamus and expresses OX1 receptors in rats. To test the electrophysiological and behavioral effects of orexins in the central amygdala, single unit in vivo extracellular recordings, open field and elevated plus maze tests were performed in rats. Micro-pressure administration of orexin-A (0.01 mmol/L) increased the firing rate in 18 out of the 31 central amygdala neurons, while the other 13 neurons were not excited by orexin-A. The excitatory effects of orexin-A on central amygdala neurons were mainly mediated by OX1 receptors rather than OX2 receptors. Orexin-B (0.01 mmol/L) did not change the firing activity in all recorded central amygdala neurons. Selectively blocking OX1 receptors by SB-334867 (0.01 mmol/L) significantly decreased the spontaneous firing rate in 14 out of the 33 central amygdala neurons, leaving the remaining 19 neurons were not affected. However, blocking OX2 receptors by TCS-OX2-29 (0.01 mmol/L) did not change the firing activity. Finally, both open field test and elevated plus maze test showed that bilateral microinjection of orexin-A into the central amygdala induced significantly anxiolytic-like behaviors. The specific OX1 receptor antagonist tended to produce opposite effects although there was no statistical difference. The present electrophysiological and behavioral studies suggested that orexin-A participates in anxiety-like behaviors by modulating the spontaneous firing activity of central amygdala neurons.

Real-world cost-effectiveness associated with infliximab maintenance therapy for moderate to severe Crohn's disease in China.

BACKGROUND: Infliximab was the first approved biologic treatment for moderate to severe Crohn's disease (MS-CD) in China. However, the cost-effectiveness of infliximab maintenance therapy (IMT) for MS-CD relative to conventional maintenance therapy remained unclarified. AIM: To assess the cost-effectiveness of IMT for MS-CD in Chinese patients from the perspective of Chinese public insurance payer. METHODS: A cohort of MS-CD patients managed in a Chinese tertiary care hospital was created to compare IMT with conventional maintenance therapy (CMT) for clinical outcomes and direct medical costs over a 1-year observation time using conventional regression analyses. A decision-analytic model with the generated evidence was constructed to assess the cost-effectiveness of IMT relative to CMT using reimbursed medical costs. RESULTS: Based on the included 389 patients, IMT was associated with significantly higher disease remission chance [odds ratio: 4.060, P = 0.003], lower risk of developing new complications (odds ratio: 0.527, P = 0.010), higher utility value for quality of life (coefficient 0.822, P = 0.008), and lower total hospital costs related to disease management (coefficient -0.378, P = 0.008) than CMT. Base-case cost-effectiveness analysis estimated that IMT could cost Chinese health insurance payers ¥55260 to gain one quality-adjusted life year (QALY). The cost-effectiveness of IMT was mainly driven by the estimate of quality of life, treatment efficacy of maintenance therapy, mortality risk associated with active disease, and unit price of infliximab. The probability that IMT was cost-effective at a willingness-to-pay threshold of three times gross domestic product [2018 Chinese gross domestic product per capita (GDPPC)] was 86.4%. CONCLUSION: IMT significantly improved real-world health outcomes and cost the Chinese public health insurance payers less than one GDPPC to gain one QALY in Chinese MS-CD patients.

Orexin-A Exerts Neuroprotective Effects via OX1R in Parkinson's Disease.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by progressive and selective death of dopaminergic neurons. Orexin-A is involved in many biological effects of the body. It has been reported that orexin-A has protective effects in cellular models of PD. However, little is known about the protective effects of orexin-A in animal parkinsonian models and the cellular mechanism has not yet been fully clarified. The aim of this study was to evaluate the effects of orexin-A in MPTP mice model of PD as well as the possible neuroprotective mechanisms of orexin-A on dopaminergic neurons. The results from animal experiments demonstrated that orexin-A attenuated the loss of dopaminergic neurons and the decrease of tyrosine hydroxylase (TH) expression in the substantia nigra, normalized the striatal dopaminergic fibers, and prevented the depletion of dopamine and its metabolites in the striatum. MPTP-treated mice showed cognitive impairments accompanied with significant motor deficiency. Orexin-A improved MPTP-induced impairments in both motor activity and spatial memory. Importantly, orexin-A increased the protein level of brain-derived neurotrophic factor (BDNF) in dopaminergic neurons of the substantia nigra. Furthermore, the protective effects of orexin-A on MPTP parkinsonian mice could be blocked by orexinergic receptor 1 (OX1R) antagonist, SB334867. In another set of experiments with SH-SY5Y dopaminergic cells, orexin-A significantly induced the expression of BDNF in a dose and time-dependent manner. The upregulation of BDNF is mainly concerned with PI3K and PKC signaling pathways via OX1R. The present study demonstrated that orexin-A exerted neuroprotective effects on MPTP parkinsonian mice, which may imply orexin-A as a potential therapeutic target for PD.