HMGB1 Mediates Inflammation-Induced DMT1 Increase and Dopaminergic Neurodegeneration in the Early Stage of Parkinsonism.

Both neuroinflammation and iron accumulation play roles in the pathogenesis of Parkinson's disease (PD). However, whether inflammation induces iron dyshomeostasis in dopaminergic neurons at an early stage of PD, at which no quantifiable dopaminergic neuron loss can be observed, is still unknown. As for the inflammation mediators, although several cytokines have been reported to increase in PD, the functions of these cytokines in the SN are double-edged and controversial. In this study, whether inflammation could induce iron dyshomeostasis in dopaminergic neurons through high mobility group protein B1 (HMGB1) in the early stage of PD is explored. Lipopolysaccharide (LPS), a toxin that primarily activates glia cells, and 6-hydroxydopamine (6-OHDA), the neurotoxin that firstly impacts dopaminergic neurons, were utilized to mimic PD in rats. We found a common and exceedingly early over-production of HMGB1, followed by an increase of divalent metal transporter 1 with iron responsive element (DMT1+) in the dopaminergic neurons before quantifiable neuronal loss. HMGB1 neutralizing antibody suppressed inflammation in the SN, DMT1+ elevation in dopaminergic neurons, and dopaminergic neuronal loss in both LPS and 6-OHDA administration- induced PD models. On the contrary, interleukin-1ß inhibitor diacerein failed to suppress these outcomes induced by 6-OHDA. Our findings not only demonstrate that inflammation could be one of the causes of DMT1+ increase in dopaminergic neurons, but also highlight HMGB1 as a pivotal early mediator of inflammation-induced iron increase and subsequent neurodegeneration, thereby HMGB1 could serve as a potential target for early-stage PD treatment.

Baicalein attenuates rotenone-induced SH-SY5Y cell apoptosis through binding to SUR1 and activating ATP-sensitive potassium channels.

Dopaminergic neurons in the substantia nigra (SN) expressing SUR1/Kir6.2 type ATP-sensitive potassium channels (K-ATP) are more vulnerable to rotenone or metabolic stress, which may be an important reason for the selective degeneration of neurons in Parkinson's disease (PD). Baicalein has shown neuroprotective effects in PD animal models. In this study, we investigated the effect of baicalein on K-ATP channels and the underlying mechanisms in rotenone-induced apoptosis of SH-SY5Y cells. K-ATP currents were recorded from SH-SY5Y cells using whole-cell voltage-clamp recording. Drugs dissolved in the external solution at the final concentration were directly pipetted onto the cells. We showed that rotenone and baicalein opened K-ATP channels and increased the current amplitudes with EC50 values of 0.438 µM and 6.159 µM, respectively. K-ATP channel blockers glibenclamide (50 µM) or 5-hydroxydecanoate (5-HD, 250 µM) attenuated the protective effects of baicalein in reducing reactive oxygen species (ROS) content and increasing mitochondrial membrane potential and ATP levels in rotenone-injured SH-SY5Y cells, suggesting that baicalein protected against the apoptosis of SH-SY5Y cells by regulating the effect of rotenone on opening K-ATP channels. Administration of baicalein (150, 300 mg·kg-1·d-1, i.g.) significantly inhibited rotenone-induced overexpression of SUR1 in SN and striatum of rats. We conducted surface plasmon resonance assay and molecular docking, and found that baicalein had a higher affinity with SUR1 protein (KD = 10.39 µM) than glibenclamide (KD = 24.32 µM), thus reducing the sensitivity of K-ATP channels to rotenone. Knockdown of SUR1 subunit reduced rotenone-induced apoptosis and damage of SH-SY5Y cells, confirming that SUR1 was an important target for slowing dopaminergic neuronal degeneration in PD. Taken together, we demonstrate for the first time that baicalein attenuates rotenone-induced SH-SY5Y cell apoptosis through binding to SUR1 and activating K-ATP channels.

Cp*Rh(III)-catalyzed regioselective cyclization of aromatic amides with allenes.

A new Cp*Rh(III)-catalyzed regioselective cyclization reaction of aromatic amides with allenes is reported. The use of allenyl derivatives bearing a directing-group assistant as a reaction promoter was the key to the success of this protocol. In this catalytic system, N-(pivaloyloxy)benzamide substrates react with allenes via Rh-σ-alkenyl intermediates, while N-(pivaloyloxy) indol substrates react via Rh-π-allyl intermediates. These reactions were characterized by mild reaction conditions, a broad substrate scope, and high functional-group compatibility to yield several high-value isoquinolinone and pyrimido[1,6-a]indol-1(2H)-one skeleton-containing compounds. The synthetic applications and primary mechanisms were also investigated.

Melatonin-related dysfunction in chronic restraint stress triggers sleep disorders in mice.

Stress may trigger sleep disorders and are also risk factors for depression. The study explored the melatonin-related mechanisms of stress-associated sleep disorders on a mouse model of chronic stress by exploring the alteration in sleep architecture, melatonin, and related small molecule levels, transcription and expression of melatonin-related genes as well as proteins. Mice undergoing chronic restraint stress modeling for 28 days showed body weight loss and reduced locomotor activity. Sleep fragmentation, circadian rhythm disorders, and insomnia exhibited in CRS-treated mice formed sleep disorders. Tryptophan and 5-hydroxytryptamine levels were increased in the hypothalamus, while melatonin level was decreased. The transcription and expression of melatonin receptors were reduced, and circadian rhythm related genes were altered. Expression of downstream effectors to melatonin receptors was also affected. These results identified sleep disorders in a mice model of chronic stress. The alteration of melatonin-related pathways was shown to trigger sleep disorders.

Salvianolic acid A improve mitochondrial respiration and cardiac function via inhibiting apoptosis pathway through CRYAB in diabetic cardiomyopathy.

Salvianolic acid A (SAA) is a traditional Chinese medicine that has a good therapeutic effect on cardiovascular disease. However, the underlying mechanisms by which SAA improves mitochondrial respiration and cardiac function in diabetic cardiomyopathy (DCM) remain unknown. This study aims to elucidate whether SAA had any cardiovascular protection on the pathophysiology of DCM and explored the potential mechanisms. Diabetes was induced in rats by 30 mg/kg of streptozotocin (STZ) treatment. After a week of stability, 5 mg/kg isoprenaline (ISO) was injected into the rats subcutaneously. 3 mg/kg SAA was orally administered for six weeks and 150 mg/kg Metformin was selected as a positive group. At the end of this period, cardiac function was assessed by ultrasound, electrocardiogram, and relevant cardiac injury biomarkers testing. Treatment with SAA improved cardiac function, glucose, and lipid levels, mitochondrial respiration, and suppressed myocardial inflammation and apoptosis. Furthermore, SAA treatment inhibits the apoptosis pathway through CRYAB in diabetic cardiomyopathy rats. As a result, this study not only provides new insights into the mechanism of SAA against DCM but also provides new therapeutic ideas for the discovery of anti-DCM compounds in the clinic.

Targeting the dysfunction of glutamate receptors for the development of novel antidepressants.

Increasing evidence indicates that dysfunction of glutamate receptors is involved in the pathophysiology of major depressive disorder (MDD). Although accumulating efforts have been made to elucidate the applications and mechanisms underlying antidepressant-like effects of ketamine, a non-selective antagonist of N-methyl-d-aspartate receptor (NMDAR), the role of specific glutamate receptor subunit in regulating depression is not completely clear. The current review aims to discuss the relationships between glutamate receptor subunits and depressive-like behaviors. Research literatures were searched from inception to July 2020. We summarized the alterations of glutamate receptor subunits in patients with MDD and animal models of depression. Animal behaviors in response to dysfunction of glutamate receptor subunits were also surveyed. To fully understand mechanisms underlying antidepressant-like effects of modulators targeting glutamate receptors, we discussed effects of each glutamate receptor subunit on serotonin system, synaptic plasticity, neurogenesis and neuroinflammation. Finally, we collected most recent clinical applications of glutamate receptor modulators and pointed out the limitations of these candidates in the treatment of MDD.

The Potential of Traditional Chinese Medicine in the Treatment and Modulation of Pain.

Pain is an unpleasant sensory and emotional experience associated with various diseases. Extensive research has been conducted to find appropriate methods of relieving pain and improving the quality of life. However, the most commonly used pain-relieving agents such as opioid therapeutics are often associated with harmful side effects; moreover, users are prone to become addicted to these agents and may develop tolerance. Often, nonopioid therapeutics is only marginally effective, thus leading to a significant unmet medical need. Scientists have studied herbal medicines, finding more than 800 kinds of traditional Chinese medicine (TCM) to be effective in relieving pain while also creating several monomeric compounds to develop novel analgesic drugs. In this review, we summarize the representative TCM currently available for the treatment and modulation of pain. Ten different natural products, mainly herbs, used in Chinese medicine to relieve pain are discussed in light of the theories of TCM and modern pharmacology. We hope that this review will provide valuable information for future studies on the potential of TCM in alleviating pain.

Antagonism of quercetin against tremor induced by unilateral striatal lesion of 6-OHDA in rats.

Quercetin, a flavonoid present in many plants, is reported to be effective in models of neurodegenerative diseases. The aim of the present study was to evaluate the anti-tremor effects of quercetin in 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson's disease. In rats, quercetin had no effect on apomorphine-induced rotations, but it could significantly attenuate muscle tremor of 6-OHDA lesioned rats. Interestingly, quercetin could decrease the burst frequency in a dose- and time-dependent manner. These results suggest that quercetin may have a protective effect on models to mimic muscle tremors of Parkinson's disease. This effect of quercetin may be associated with serotonergic system, but further study is needed.

Critical Role of Endoplasmic Reticulum Stress in Chronic Intermittent Hypoxia-Induced Deficits in Synaptic Plasticity and Long-Term Memory.

AIMS: This study examined the role of endoplasmic reticulum (ER) stress in mediating chronic intermittent hypoxia (IH)-induced neurocognitive deficits. We designed experiments to demonstrate that ER stress is initiated in the hippocampus under chronic IH and determined its role in apoptotic cell death, impaired synaptic structure and plasticity, and memory deficits. RESULTS: Two weeks of IH disrupted ER fine structure and upregulated ER stress markers, glucose-regulated protein 78, caspase-12, and C/EBP homologous protein, in the hippocampus, which could be suppressed by ER stress inhibitors, tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid. Meanwhile, ER stress induced apoptosis via decreased Bcl-2, promoted reactive oxygen species production, and increased malondialdehyde formation and protein carbonyl, as well as suppressed mitochondrial function. These effects were largely prevented by ER stress inhibitors. On the other hand, suppression of oxidative stress could reduce ER stress. In addition, the length of the synaptic active zone and number of mature spines were reduced by IH. Long-term recognition memory and spatial memory were also impaired, which was accompanied by reduced long-term potentiation in the Schaffer collateral pathway. These effects were prevented by coadministration of the TUDCA. INNOVATION AND CONCLUSION: These results show that ER stress plays a critical role in underlying memory deficits in obstructive sleep apnea (OSA)-associated IH. Attenuators of ER stress may serve as novel adjunct therapeutic agents for ameliorating OSA-induced neurocognitive impairment.