Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that deteriorates cognitive function. Patients with AD generally exhibit neuroinflammation, elevated beta-amyloid (Aβ), tau phosphorylation (p-tau), and other pathological changes in the brain. The kynurenine pathway (KP) and several of its metabolites, especially quinolinic acid (QA), are considered to be involved in the neuropathogenesis of AD. The important metabolites and key enzymes show significant importance in neuroinflammation and AD. Meanwhile, the discovery of changed levels of KP metabolites in patients with AD suggests that KP metabolites may have a prominent role in the pathogenesis of AD. Further, some KP metabolites exhibit other effects on the brain, such as oxidative stress regulation and neurotoxicity. Both analogs of the neuroprotective and antineuroinflammation metabolites and small molecule enzyme inhibitors preventing the formation of neurotoxic and neuroinflammation compounds may have potential therapeutic significance. This review focused on the KP metabolites through the relationship of neuroinflammation in AD, significant KP metabolites, and associated molecular mechanisms as well as the utility of these metabolites as biomarkers and therapeutic targets for AD. The objective is to provide references to find biomarkers and therapeutic targets for patients with AD.
Patients with neuropathic pain often experience exaggerated pain and anxiety. Central sensitization has been linked with the maintenance of neuropathic pain and may become an autonomous pain generator. Conversely, emerging evidence accumulated that central sensitization is initiated and maintained by ongoing nociceptive primary afferent inputs. However, it remains elusive what mechanisms underlie this phenomenon and which peripheral candidate contributes to central sensitization that accounts for pain hypersensitivity and pain-related anxiety. Previous studies have implicated peripherally localized cGMP-dependent protein kinase I (PKG-I) in plasticity of nociceptors and spinal synaptic transmission as well as inflammatory hyperalgesia. However, whether peripheral PKG-I contributes to cortical plasticity and hence maintains nerve injury–induced pain hypersensitivity and anxiety is unknown. Here, we demonstrated significant upregulation of PKG-I in ipsilateral L3 dorsal root ganglia (DRG), no change in L4 DRG, and downregulation in L5 DRG upon spared nerve injury. Genetic ablation of PKG-I specifically in nociceptors or post-treatment with intervertebral foramen injection of PKG-I antagonist, KT5823, attenuated the development and maintenance of spared nerve injury–induced bilateral pain hypersensitivity and anxiety. Mechanistic analysis revealed that activation of PKG-I in nociceptors is responsible for synaptic potentiation in the anterior cingulate cortex upon peripheral neuropathy through presynaptic mechanisms involving brain-derived neurotropic factor signaling. Our results revealed that PKG-I expressed in nociceptors is a key determinant for cingulate synaptic plasticity after nerve injury, which contributes to the maintenance of pain hypersensitivity and anxiety. Thereby, this study presents a strong basis for opening up a novel therapeutic target, PKG-I, in nociceptors for treatment of comorbidity of neuropathic pain and anxiety with least side effects.
Previous studies have shown that CCL2 may cause chronic pain, but the exact mechanism of central sensitization is unclear. In this article, we further explore the presynaptic role of CCL2. Behavioral experiments show that intervertebral foramen injection CCR2 antagonists into dorsal root ganglion (DRG) can inhibit the inflammatory pain caused by CCL2 in spinal cord. We raised the question of the role of presynaptic CCR2 in the spinal dorsal horn. Subsequent electron microscopy experiments showed that CCR2 was expressed in the presynaptic CGRP terminal in the spinal dorsal horn. CCL2 can enhance presynaptic calcium signal. Whole-cell patch-clamp recordings showed that CCL2 can enhance NMDAR-eEPSCs through presynaptic effects, and further application of glutamate sensor method proved that CCL2 can act on presynaptic CCR2 to increase the release of presynaptic glutamate. In conclusion, we suggest that CCL2 can directly act on the CCR2 on presynaptic terminals of sensory neurons in the spinal dorsal horn, leading to an increase in the release of presynaptic glutamate and participate in the formation of central sensitization.
Background. Idiopathic pulmonary fibrosis (IPF) is a major global health problem. The prevalence of the disease appears to be increasing. There is no curative therapy for IPF except lung transplantation. Chinese herbal medicines (CHMs) are showing promise for treatment of IPF. However, their effectiveness and safety are still unclear and deserve further investigation. The aim of this systematic review is to access the efficacy and safety of CHMs in treating IPF. Methods. The protocol of this review is registered at PROSPERO. We searched seven main databases for randomized clinical trials (RCTs) on CHMs for IPF from their inception to June 4, 2018. The methodological quality of RCTs was assessed using the Cochrane risk of bias tool. All trials included were analyzed according to the criteria of the Cochrane Handbook. Review Manager 5.3, R-3.5.2 software, and Grade pro GDT web solution were used for data synthesis and analysis. Results. Thirteen randomized clinical trials enrolling 733 patients were included. All trials included had clear outcome indicators. The methodological quality of included trials was generally “poor.” Few trials reported methods of randomization. One trial on Xuefu-zhuyu capsule assessed rate of acute exacerbation and mortality after treatment for 72 weeks and found no statistically significant difference between two groups. This meta-analysis demonstrated a significant improvement in QOL of IPF patients when CHMs was applied or combined with conventional medicine treatment. 6MWT was significantly improved in IPF patients after using CHMs or combined with conventional medicine treatment. CHMs treatment also had a certain improvement in TLC and DLCO, but the effect on FVC was not significant. Besides, CHMs failed to provide benefits in terms of PaO2. The reported adverse events were not obvious and severe. Conclusions. Some CHMs seem effective and safe as alternative remedies for patients with IPF, suggesting that further study of CHMs in the treatment of IPF is warranted. Although this systematic review suggests that CHMs may have positive effect on quality of life, 6-minute walk test distance, and lung function (TLC, DLOC%) and seem to be relatively safe during the course of treatment, the results must be treated with great caution because of the methodological flaws of the included trials. Long-term and high-quality trials are needed in the future to provide clear evidence for the use of CHMs.
T ransjugular intrahepatic portosystemic shunt (TIPS) is a well-established treatment for complications arising from portal hypertension. 1 However, hepatic encephalopathy (HE) is a common complication after TIPS insertion. The incidence rate of HE after TIPS insertion is 15%-48%.2 TIPS implantation with or without gastroesophageal variceal embolization remains questionable in general, 2,3 but it is particularly questionable when TIPS is used in patients with splenorenal shunt (SRS). SRS is a spontaneous portosystemic shunt (SPSS) that persists in 14%-21% of patients with cirrhosis. 4 A previous study suggested that SPSS embolization alone is an effective and safe treatment for chronic HE.5 However, combining TIPS implantation with SPSS embolization for patients who present with variceal bleeding (VB) remains an issue. We report on a case of improved post-TIPS HE after embolizing the coexisting SRS in a patient with cirrhosis with VB. Case ReportA 34-year-old man who had experienced repeated melena and hematemesis three times (total, 600 mL) for 13 days with post-hepatitis B cirrhosis required hospitalization on March 16, 2012. The Child-Pugh score was B/8 (total bilirubin level: 0.92 mg/dL; serum albumin: 3.17 g/dL; mild ascites, no encephalopathy), and the hemoglobin level was 9.2 g/dL. An upper endoscopy revealed significant gastroesophageal varices (GEV), and a large SRS (11 mm in diameter) was observed by angiography (Fig. 1A). Hematemesis and melena disappeared after pharmacological treatment. To further decrease the portal pressure and prevent variceal rebleeding, we implanted a TIPS using an 8-mm Bard polytetrafluoroethylene-covered stent. The portosystemic pressure gradient decreased from 36 to 15 mmHg. Diagnostic endoscopy showed improved GEV 2 days later, and ascites disappeared a few days after TIPS implantation. Given the lack of evidence in the literature regarding the role of embolotherapy during the TIPS procedure, SRS was not embolized at that time (Fig. 1B).The patient developed lethargy and disorientation 5 days after TIPS insertion, and a diagnosis of grade II HE was made. HE occurred repeatedly in the following days, despite a continuous treatment of branched-chain amino acids and lactulose. To treat the post-TIPS encephalopathy effectively, we embolized the SRS using an Amplatzer plugging device (18 mm in diameter) from the femoral vein through the left renal vein to the SRS 37 days after TIPS placement (Fig. 1C,D). After embolization, the HE symptoms gradually disappeared in approximately 6 hours. The Child-Pugh score changed to A/5 (total bilirubin level: 1.15 mg/dL; serum albumin: 3.95 g/dL), and the hemoglobin level was 9.3 g/dL 1 year later. There was no recurrence of HE or any significant increase in the aggravation of preexisting varices at the 2-year follow-up. DiscussionRecently, SPSS has received increasing attention because it appears in 46%-70% of patients with refractory HE. 5 In TIPS patients, the large SRS diverts portal flow, resulting in the diversion of portal venous flow ...
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