Dihydroquercetin alleviates dopamine neuron loss via regulating TREM2 activation.

BACKGROUND: Parkinson's disease (PD) is a prevalent neurodegenerative disorder, marked by the degeneration of dopamine (DA) neurons in the substantia nigra (SN). Current evidence strongly suggests that neuroinflammation, primarily mediated by microglia, contributes to PD pathogenesis. Triggering receptor expressed on myeloid cells 2 (TREM2) might serve as a promising therapeutic target for PD due to its ability to suppress neuroinflammation. Dihydroquercetin (DHQ) is an important natural dihydroflavone and confers apparent anti-inflammatory, antioxidant and anti-fibrotic effects. Recently, DHQ-mediated neuroprotection was exhibited. However, the specific mechanisms of its neuroprotective effects remain incompletely elucidated. METHODS: In this study, rat models were utilized to induce damage to DA neurons using lipopolysaccharide (LPS) and 6-hydroxydopamine (6-OHDA) to assess the impacts of DHQ on the loss of DA neurons. Furthermore, DA neuronal MN9D cells and microglial BV2 cells were employed to investigate the function of TREM2 in DHQ-mediated DA neuroprotection. Finally, TREM2 knockout mice were used to investigate whether the neuroprotective effects mediated by DHQ through a mechanism dependent on TREM2. RESULTS: The main findings demonstrated that DHQ effectively protected DA neurons against neurotoxicity induced by LPS and 6-OHDA and inhibited microglia-elicited neuroinflammation. Meanwhile, DHQ promoted microglial TREM2 signaling activation. Notably, DHQ failed to reduce inflammatory cytokines release and further present neuroprotection from DA neurotoxicity upon TREM2 silencing. Similarly, DHQ didn't exert DA neuroprotection in TREM2 knockout mice. CONCLUSIONS: These findings suggest that DHQ exerted DA neuroprotection by regulating microglia TREM2 activation.

Resveratrol Alleviates Levodopa-Induced Dyskinesia in Rats.

Dyskinesia is a serious complication of Parkinson's disease during levodopa (L-DOPA) treatment. The pathophysiology of L-DOPA-induced dyskinesia (LID) is complex and not fully illuminated. At present, treatment of dyskinesia is quite limited. Recent studies demonstrated neuroinflammation plays an important role in development of LID. Thus, inhibition of neuroinflammation might open a new avenue for LID treatment. Resveratrol (RES) is the most well-known polyphenolic stilbenoid and verified to possess a large variety of biological activities. DA neurotoxicity was assessed via behavior test and DA neuronal quantification. The movement disorders of dyskinesia were detected by the abnormal involuntary movements scores analysis. Effects of RES on glial cells-elicited neuroinflammation were also explored. Data showed that RES attenuated dyskinesia induced by L-DOPA without affecting L-DOPA's anti-parkinsonian effects. Furthermore, RES generated neuroprotection against long term treatment of L-DOPA-induced DA neuronal damage. Meanwhile, RES reduced protein expression of dyskinesia molecular markers, ΔFOS B and ERK, in the striatum. Also, there was a strong negative correlation between DA system damage and ΔFOS B level in the striatum. In addition, RES inhibited microglia and astroglia activation in substantia nigra and subsequent inflammatory responses in the striatum during L-DOPA treatment. RES alleviates dyskinesia induced by L-DOPA and these beneficial effects are closely associated with protection against DA neuronal damage and inhibition of glial cells-mediated neuroinflammatory reactions.

Targeting TREM2 for Parkinson's Disease: Where to Go?

Parkinson's disease (PD) is one of most common neurodegenerative disorders caused by a combination of environmental and genetic risk factors. Currently, numerous population genetic studies have shown that polymorphisms in myeloid cell-triggered receptor II (TREM2) are associated with a variety of neurodegenerative disorders. Recently, TREM2 has been verified to represent a promising candidate gene for PD susceptibility and progression. For example, the expression of TREM2 was apparently increased in the prefrontal cortex of PD patients. Moreover, the rare missense mutations in TREM2 (rs75932628, p.R47H) was confirmed to be a risk factor of PD. In addition, overexpression of TREM2 reduced dopaminergic neurodegeneration in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine mouse model of PD. Due to the complex pathogenesis of PD, there is still no effective drug treatment. Thus, TREM2 has received increasing widespread attention as a potential therapeutic target. This review focused on the variation of TREM2 in PD and roles of TREM2 in PD pathogenesis, such as excessive-immune inflammatory response, α-Synuclein aggregation and oxidative stress, to further provide evidence for new immune-related biomarkers and therapies for PD.

Single-port laparoscopic intragastric surgery using SILS port: a feasibility study on a porcine model.

OBJECTIVE: The aim of this study was to evaluate the feasibility, safety, and efficiency of single-port laparoscopic intragastric surgery by using a single-port device. METHODS: The single-port device was introduced into the anterior wall of the stomach through 2.5-cm long abdominal and gastric incisions. Gastric mucosa resection and suturing (group 1) and mucosa resection by using staplers (group 2) were performed with 3 pigs in each group. RESULTS: The time for setting up the intragastric ports ranged from 8 to 40 minutes (average 16.2 ± 12.2 minutes). The total surgery times for the 3 pigs in group 1 were 75, 45, and 38 minutes and for the other 3 pigs in group 2 were 80, 85, 70 minutes, respectively. CONCLUSION: A simple and stable intragastric surgery platform can be set up by using the single-port device placed into the stomach. This seems to be safe and feasible and may be a suitable alternative for humans.

Environmental exposure and p53 mutations in esophageal cancer patients in areas of low and high incidence of esophageal cancer in China.

Esophageal cancer is the 6th most common cancer in the world, and genetic factors (p53 mutations) in addition to the environmental factors (food, nutrition, smoking, drinking, etc.) are involved in its development. In this study, the association between the both factors, environmental risk factors for esophageal cancer and p53 mutations, in tumor tissues was investigated in 77 patients living in a high-incidence area and 50 patients living in a low-incidence area in Hebei Province, China. Among these patients, p53 mutations were observed in about 50%, without regional differences in the respective frequencies. G:C>A:T (G to A or C to T) transition mutations were the major type of mutations observed in patients in the high-incidence area (19 patients, 50%), whereas G:C>A:T transitions and insertions were observed with equal frequency (8 patients, 33.3%) in the low-incidence area. As for the association with environmental factors, p53 mutations occurred with higher frequency in patients with a daily intake of spicy foods and in those who used unboiled well water in the low-incidence area. Logistic regression analysis showed no association between food intakes and p53 mutations in high- and low-incidence areas. Thus, higher frequency of spicy food intake and use of unboiled well water may be risk factors of esophageal cancer via p53 mutations in China.

Proapoptotic triterpene electrophiles (avicins) form channels in membranes: cholesterol dependence.

Avicins, a family of triterpenoid saponins from Acacia victoriae, can regulate the innate stress response in human cells. Their ability to induce apoptosis in transformed cells makes them potential anticancer agents. We report that avicins can form channels in membranes. The conductance reached a steady state after each addition, indicating a dynamic equilibrium between avicin in solution and in the membrane. The high power dependence (up to 10) of the membrane conductance on the avicin concentration indicates the formation of multimeric channels, consistent with the estimated pore radius of 1.1 nm. This radius is too small to allow protein flux across the mitochondrial outer membrane, a process known to initiate apoptosis. Channel formation is lost when avicin's amphipathic side chain is removed, implicating this as the channel-forming region. A small difference in this side chain results in strong cholesterol dependence of channel formation in avicin G that is not found in avicin D. In neutral membranes, avicin channels are nonselective, but negatively-charged lipids confer cation selectivity (5:1, K(+):Cl(-)), indicating that phospholipids form part of the permeation pathway. Avicin channels in the mitochondrial outer membrane may favor apoptosis by altering the potential across this membrane and the intermembrane space pH.

DHPLC is superior to SSCP in screening p53 mutations in esophageal cancer tissues.

Mutations of the p53 tumor-suppressor gene universally occur on exons 5-8 in human cancer. We analyzed these mutations in esophageal cancer tissue from 207 patients in China using 2 methods, single-strand conformation polymorphism (SSCP), one of the most frequently used methods, and the recently developed denaturing high-performance liquid chromatography (DHPLC), and compared their sensitivity and efficiency. Exons 5-8 of p53 were amplified from esophageal cancer tissue genomes, screened for fragments of mutations and polymorphisms by SSCP and DHPLC in a blind study and confirmed by direct sequencing to detect the mutations and polymorphisms. The numbers detected by DHPLC were greater than those detected by SSCP, though the rate of mutations and polymorphisms was lower in SSCP than in DHPLC, which appeared to detect smaller mutations (substitutions and 1 bp insertions/deletions). Of the mutations with substitutions detected by DHPLC but not by SSCP, 50% substituted adenosine for other nucleotides, suggesting that these mutations are often missed when SSCP is used. According to these data, the sensitivity of SSCP and DHPLC was 81% and 97%, respectively, and the specificity was 97% and 85%, respectively. Our results suggest that DHPLC may be recommended over SSCP when screening gene mutations. Thus, rates of p53 mutations and polymorphisms in esophageal cancer tissue in Chinese patients were 49% and 41% by DHPLC and SSCP, respectively.

Catalyzed insertion of proteins into phospholipid membranes: specificity of the process.

The process of insertion of intrinsic proteins into phospholipid membranes conjures up the thought of enormous energy barriers but is a routine occurrence in cells. Proteinaceous complexes responsible for protein targeting/translocation/insertion into membranes have been studied intensively. However, the mitochondrial voltage-dependent anion channel (VDAC), can insert into phospholipid membranes by an auto-catalytic process called "auto-directed insertion." This process results in an oriented insertion of VDAC channels and an increase in insertion rate per unit area of 10 orders of magnitude. Here we report that VDAC catalyzes the insertion of PorA/C1 and KcsA by increasing their calculated insertion rate per unit area by 9 orders of magnitude with no detectable effect on the insertion of alpha-hemolysin. This was measured as a reduction in the delay before the first insertion of these proteins. Gramicidin and PorA/C1 accelerate the calculated insertion rate per unit area of VDAC by 8 and 9 orders of magnitude, respectively. Only PorA/C1 increases the overall rate of VDAC insertion (50-fold) over the self-catalyzed rate. Our results indicate that catalyzed insertion of proteins into phospholipid membranes does not arise simply from disturbance of the phospholipid membrane because it shows strong specificity.

Electrostatics explains the shift in VDAC gating with salt activity gradient.

We have analyzed voltage-dependent anion-selective channel (VDAC) gating on the assumption that the states occupied by the channel are determined mainly by their electrostatic energy. The voltage dependence of VDAC gating both in the presence and in the absence of a salt activity gradient was explained just by invoking electrostatic interactions. A model describing this energy in the main VDAC states has been developed. On the basis of the model, we have considered how external factors cause the redistribution of the channels among their conformational states. We propose that there is a difference in the electrostatic interaction between the voltage sensor and fixed charge within the channel when the former is located in the cis side of membrane as opposed to the trans. This could be the main cause of the shift in the probability curve. The theory describes satisfactorily the experimental data (Zizi et al., Biophys. J. 1998. 75:704-713) and explains some peculiarities of VDAC gating. The asymmetry of the probability curve was related to the apparent location of the VDAC voltage sensor in the open state. By analyzing published experimental data, we concluded that this apparent location is influenced by the diffusion potential. Also discussed is the possibility that VDAC gating at high voltage may be better described by assuming that the mobile charge consists of two parts that have to overcome different energetic barriers in the channel-closing process.