Introduction
Alkaloids and glycosides are the active ingredients of the herb Dendrobium nobile, which is used in traditional Chinese medicine. The pharmacological effects of alkaloids include ...neuroprotective effects and regulatory effects on glucose and lipid metabolism, while glycosides improve the immune system. The pharmacological activities of the above chemical components are significantly different. In practice, the stems of 3‐year‐old D. nobile are usually used as the main source of Dendrobii Caulis. However, it has not been reported whether this harvesting time is appropriate.
Objective
The aim of this study was to compare the chemical characteristics of D. nobile in different growth years (1–3 years).
Methods
In this study, ultra‐high‐performance liquid chromatography coupled with quadrupole time‐of‐flight tandem mass spectrometry (UPLC‐Q/TOF‐MS) was employed to analyze the constituents of D. nobile. The relative abundance of each constituent was analyzed with multivariate statistical analyses to screen the characteristic constituents that contributed to the characterization and classification of D. nobile. Dendrobine, a component of D. nobile that is used for quality control according to the Chinese Pharmacopoeia, was assayed by gas chromatography.
Results
As a result, 34 characteristic constituents (VIP > 2) were identified or tentatively identified as alkaloids and glycosides based on MS/MS data. Moreover, the content of alkaloids decreased over time, whereas the content of glycosides showed the opposite trend. The absolute quantification of dendrobine was consistent with the metabolomics results.
Conclusion
Our findings provide valuable information to optimize the harvest period and a reference for the clinical application of D. nobile.
In this work, the chemical characteristics of D. nobile with different growth years were determined using UPLC‐Q/TOF‐MS coupled with multivariate statistical analyses. The results showed the opposite accumulation trends of glycosides and alkaloids in D. nobile with different growth years. The above results may have been caused by an underlying mechanism. In summary, the new findings could provide valuable information for the optimum harvest period and provide reference for clinical drug therapeutics.
Background and Purpose
New remedies are required for the treatment of diabetic neuropathic pain (DNP) due to insufficient efficacy of available therapies. Here, we used chemogenetic approaches ...combined with in vivo pharmacology to elucidate the role of basolateral amygdala (BLA) astrocytes in DNP pathogenesis and provide new insights into therapeutic strategies for DNP.
Experimental Approach
A streptozotocin‐induced DNP model was established. Designer receptors exclusively activated by designer drugs (DREADDs) were used to regulate astrocyte activity. Mechanical hyperalgesia was assessed using the electronic von Frey test. Anxiety‐like behaviours were detected using open field and elevated plus maze tests. Astrocytic activity was detected by immunofluorescence, and cytokine content was determined by ELISA.
Key Results
BLA astrocytes were regulated by DREADDs, and inhibition of BLA astrocytes attenuated mechanical allodynia and pain‐related negative emotions in DNP rats. In contrast, temporary activation of BLA astrocytes induced allodynia without anxious behaviours in naive rats. In addition, koumine (KM) alleviated mechanical allodynia and anxiety‐like behaviours in DNP rats, inhibited the activation of BLA astrocytes and suppressed the inflammatory response. Furthermore, persistent activation of BLA astrocytes through chemogenetics mimicked chronic pain, and KM alleviated the pain hypersensitivity and anxiety‐like behaviours.
Conclusion and Implications
DREADDs bidirectionally regulate the activity of BLA astrocytes, which proves for the first time the role of BLA astrocyte activation in the pathogenesis of DNP and represents a novel therapeutic strategy for DNP. KM ameliorates DNP, perhaps by inhibiting the activation of BLA astrocytes and reveal KM as a potential candidate for treating DNP.
Oxytocin is a well-known neurohypophysial hormone that plays an important role in behavioral anxiety and nociception. Two major forms of long-term potentiation, presynaptic LTP (pre-LTP) and ...postsynaptic LTP (post-LTP), have been characterized in the anterior cingulate cortex (ACC). Both pre-LTP and post-LTP contribute to chronic-pain-related anxiety and behavioral sensitization. The roles of oxytocin in the ACC have not been studied. Here, we find that microinjections of oxytocin into the ACC attenuate nociceptive responses and anxiety-like behavioral responses in animals with neuropathic pain. Application of oxytocin selectively blocks the maintenance of pre-LTP but not post-LTP. In addition, oxytocin enhances inhibitory transmission and excites ACC interneurons. Similar results are obtained by using selective optical stimulation of oxytocin-containing projecting terminals in the ACC in animals with neuropathic pain. Our results demonstrate that oxytocin acts on central synapses and reduces chronic-pain-induced anxiety by reducing pre-LTP.
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•Oxytocin microinjected into ACC attenuates injury-related pain and anxiety responses•Oxytocin blocks the maintenance of pre-LTP, but not post-LTP•Oxytocin depolarizes the interneurons and decreases the ratio of E/I transmission•Activation of PVN-ACC pathway blocks pre-LTP and has analgesic and anxiolytic effects
Li et al. report that microinjection of oxytocin into the ACC attenuates nerve-injury-induced nociceptive and anxiety behavioral responses. They show that oxytocin blocks the maintenance of pre-LTP and potentiates inhibitory transmission. Optical activation of endogenous oxytocin release in the ACC blocks pre-LTP and produces analgesic and anxiolytic effects.
Summary
Aims
Axonal degeneration is a pathological symbol in the early stage of Alzheimer's disease (AD), which can be triggered by amyloid‐β (Aβ) peptide deposition. Growing evidence indicates that ...deficit of autophagy eventually leads to the axonal degeneration. Our previous studies have shown that Dendrobium nobile Lindl alkaloid (DNLA) had protective effect on neuron impairment in vivo and in vitro; however, the underlying mechanisms is still unclear.
Methods
We exposed cultured hippocampus neurons to Aβ25‐35 to investigate the effect of DNLA in vitro. Axonal degeneration was evaluated by immunofluorescence staining and MTT assay. Neurons overexpressing GFP‐LC3B were used to measure the formation of autophagosome. Autophagosome‐lysosome fusion, the lysosomal pH, and cathepsin activity were assessed to reflect autophagy process. Proteins of interest were analyzed by Western blot.
Results
DNLA pretreatment significantly inhibited axonal degeneration induced by Aβ25‐35 peptide in vitro. Further studies revealed DNLA treatment increased autophagic flux through promoting formation and degradation of autophagosome in hippocampus neurons. Moreover, enhancement of autophagic flux was responsible for the protective effects of DNLA on axonal degeneration.
Conclusions
DNLA prevents Aβ25‐35‐induced axonal degeneration via activation of autophagy process and could be a novel therapeutic target.
In 2009, a mysterious illness associated with fever, thrombocytopenia, gastrointestinal symptoms, and leucopenia was seen in rural areas in central China, with an initial case fatality rate of 30%. ...After extensive investigation, a novel bunyavirus was identified.
Between late March and mid-July 2009, an emerging infectious disease, which was identified as the severe fever with thrombocytopenia syndrome (SFTS), was reported in rural areas of Hubei and Henan provinces in Central China. The cause of the illness was unknown. The major clinical symptoms included fever, thrombocytopenia, gastrointestinal symptoms, and leukocytopenia, and there was an unusually high initial case fatality rate of 30%. In June 2009, an investigation was performed to identify whether the disease was caused by
Anaplasma phagocytophilum
or other pathogens. Although the clinical symptoms were considered to resemble those of human anaplasmosis,
1
neither bacterial DNA nor . . .
Objectives
In our previous studies, Dendrobium nobile Lindl. alkaloids (DNLA) has been shown to have glucose‐lowering and antihyperlipidaemia effects in diabetic rats, in rats fed with high‐fat ...diets, and in mice challenged with adrenaline. This study aimed to examine the effects of DNLA on the expression of glucose and lipid metabolism genes in livers of mice.
Methods
Mice were given DNLA at doses of 10–80 mg/kg, po for 8 days, and livers were removed for total RNA and protein isolation to perform real‐time RT‐PCR and Western blot analysis.
Key findings
Dendrobium nobile Lindl. alkaloids increased PGC1α at mRNA and protein levels and increased glucose metabolism gene Glut2 and FoxO1 expression. DNLA also increased the expression of fatty acid β‐oxidation genes Acox1 and Cpt1a. The lipid synthesis regulator Srebp1 (sterol regulatory element‐binding protein‐1) was decreased, while the lipolysis gene ATGL was increased. Interestingly, DNLA increased the expression of antioxidant gene metallothionein‐1 and NADPH quinone oxidoreductase‐1 (Nqo1) in livers of mice. Western blot on selected proteins confirmed these changes including the increased expression of GLUT4 and PPARα.
Conclusions
DNLA has beneficial effects on liver glucose and lipid metabolism gene expressions, and enhances the Nrf2‐antioxidant pathway gene expressions, which could play integrated roles in regulating metabolic disorders.
As the major degradation pathway for long-lived proteins and organelles, macroautophagy is a decisive factor for the survival and longevity of cells. The existing evidence indicates that the ...disruption of substrate proteolysis in autolysosomes is the main mechanism underlying autophagy failure in Alzheimer's disease (AD). Thus, the restoration of normal lysosomal proteolysis and autophagy efficiency is a novel therapeutic strategy in the treatment of AD. In this study, 9-month-old APPswe/PS1ΔE9 transgenic (APP/PS1) mice were administered Dendrobium nobile Lindl. alkaloids (DNLA, 40 and 80 mg/kg) or Metformin (80 mg/kg), and age-matched wild-type mice were administered an isovolumic vehicle orally once a day for 4 months. The results demonstrated that DNLA significantly improved learning and memory function in APP/PS1 transgenic mice in the Morris water maze. Furthermore, DNLA could increase the expression of the v-ATPase A1 subunit to facilitate lysosomal acidification, prompt the dissociation of the cation independent-mannose-phosphate receptor from cathepsin (cat) D, promote the proteolytic maturation of cat D, increase the degradation of accumulated autophagic vacuoles (AVs) and β-amyloid (Aβ) contained in the AVs, and alleviate neuronal and synaptic injury. These findings demonstrate that DNLA improves learning and memory function in APP/PS1 mice, and the mechanisms appear to be due to the promotion of intracellular Aβ degradation by increasing the protein level of v-ATPase A1 and then improving autolysosomal acidification and proteolysis.
Cortical areas including the anterior cingulate cortex (ACC) play critical roles in different types of chronic pain. Most of previous studies focus on the sensory inputs from somatic areas, and less ...information about plastic changes in the cortex for visceral pain. In this study, chronic visceral pain animal model was established by injection with zymosan into the colon of adult male C57/BL6 mice. Whole cell patch‐clamp recording, behavioral tests, western blot, and Cannulation and ACC microinjection were employed to explore the role of adenylyl cyclase 1 (AC1) in the ACC of C57/BL6 and AC1 knock out mice. Integrative approaches were used to investigate possible changes of neuronal AC1 in the ACC after the injury. We found that AC1, a key enzyme for pain‐related cortical plasticity, was significantly increased in the ACC in an animal model of irritable bowel syndrome. Inhibiting AC1 activity by a selective AC1 inhibitor NB001 significantly reduced the up‐regulation of AC1 protein in the ACC. Furthermore, we found that AC1 is required for NMDA GluN2B receptor up‐regulation and increases of NMDA receptor‐mediated currents. These results suggest that AC1 may form a positive regulation in the cortex during chronic visceral pain. Our findings demonstrate that the up‐regulation of AC1 protein in the cortex may underlie the pathology of chronic visceral pain; and inhibiting AC1 activity may be beneficial for the treatment of visceral pain.
Anterior cingulate cortex (ACC) plays critical roles in different types of chronic pain. Calcium‐stimulated, neuronal selective adenylyl cyclase subtype 1 (AC1) is critical for injury‐triggered cortical plasticity and chronic pain. We demonstrate that AC1 protein was up‐regulated in the ACC for a long‐period of time in a mouse model of chronic visceral pain. AC1 activity is required for the up‐regulation of AC1 protein, suggesting that AC1 may form a positive feedback in the cortex during chronic visceral pain. This is the first time to demonstrate that AC1 protein can undergo long‐term increases in central neurons after peripheral injuries.
The present study was undertaken to investigate the neuroprotective effects of resveratrol on 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease in rats. 6-OHDA-induced Parkinson's disease rat ...model involves chronic inflammation, mitochondrial dysfunction, and oxidative stress, and the loss of the dopaminergic neurons in the substantia nigra is the predominant lesion. Resveratrol has been shown to have anti-inflammatory actions, and thus was tested for its beneficial effects using 6-OHDA-induced Parkinson's disease rat model. Adult Sprague–Dawley (SD) rats were unilaterally injected with 6-OHDA (5 µg/2 µl) into the right striatum, and the striatum damage was assessed by rotational test, ultrahistopathology, and molecular alterations. Resveratrol (10, 20 and 40 mg/kg) was then given orally to Parkinson's disease rats, daily for 10 weeks to examine the protective effects. Rotational test (turns of rats) showed that resveratrol significantly attenuated apomorphine-induced turns of rats in 6-OHDA-injuried Parkinson's disease rat model as early as two weeks of administration. Ultrastructural analysis showed that resveratrol alleviated 6-OHDA-induced chromatin condensation, mitochondrial tumefaction and vacuolization of dopaminergic neurons in rat substantia nigra. Furthermore, resveratrol treatment also significantly decreased the levels of COX-2 and TNF-α mRNA in the substantia nigra as detected by real-time RT-PCR. COX-2 protein expression in the substantia nigra was also decreased as evidenced by Western blotting. These results demonstrate that resveratrol exerts a neuroprotective effect on 6-OHDA-induced Parkinson's disease rat model, and this protection is related to the reduced inflammatory reaction.
Remdesivir (RDV) exerts anti-severe acute respiratory coronavirus 2 activity following metabolic activation in the target tissues. However, the pharmacokinetics and tissue distributions of the parent ...drug and its active metabolites have been poorly characterized to date. Blood and tissue levels were evaluated in the current study. After intravenous administration of 20 mg/kg RDV in mice, the concentrations of the parent drug, nucleotide monophosphate (RMP) and triphosphate (RTP), as well as nucleoside (RN), in the blood, heart, liver, lung, kidney, testis, and small intestine were quantified. In blood, RDV was rapidly and completely metabolized and was barely detected at 0.5 h, similar to RTP, while its metabolites RMP and RN exhibited higher blood levels with increased residence times. The area under the concentration versus time curve up to the last measured point in time (AUC0-t) values of RMP and RN were 4558 and 136,572 h∙nM, respectively. The maximum plasma concentration (Cmax) values of RMP and RN were 2896 nM and 35,819 nM, respectively. Moreover, RDV presented an extensive distribution, and the lung, liver and kidney showed high levels of the parent drug and metabolites. The metabolic stabilities of RDV and RMP were also evaluated using lung, liver, and kidney microsomes. RDV showed higher clearances in the liver and kidney than in the lung, with intrinsic clearance (CLint) values of 1740, 1253, and 127 mL/(min∙g microsomal protein), respectively.
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