Antinociceptive role of the thalamic dopamine D3 receptor in descending modulation of intramuscular formalin-induced muscle nociception in a rat model of Parkinson's disease.

Pain in Parkinson's disease (PD) has been validated as one of the major non-motor dysfunctions affecting the quality of life and subsequent rehabilitation. In the present study, we investigated the role of the dopamine D3 receptor in the thalamic mediodorsal (MD) and ventromedial (VM) nuclei mediated descending control of nociception and intramuscular (i.m.) 2.5% formalin-induced persistent muscle nociception. Paw withdrawal reflexes were measured in naive rats and rats subjected to PD induced by unilateral microinjection of 6 µg 6-OHDA into the rat striatum. Formalin-induced muscle nociception in phase 1, inter-phase, and phase 2 was significantly greater in PD rats compared to naive and vehicle-treated rats (P ˂ 0.001). PD rats exhibited bilaterally mechanical hyperalgesia and heat hypoalgesia in formalin-induced muscle nociception. Microinjection of SK609, a dopamine D3 receptor agonist, at various doses (2.5-7.5 nmol/0.5 µl) into the thalamic VM nucleus dose-dependently prolonged heat-evoked paw withdrawal latencies in both naive and PD rats. Administration of SK609 to either the MD or VM nuclei had no effect on noxious mechanically evoked paw withdrawal reflexes. Pre-treatment of the thalamic MD nucleus with SK609 significantly attenuated formalin-induced nociception, and reversed mechanical hyperalgesia, but not heat hypoalgesia. Pre-treatment of the thalamic VM nucleus with SK609 inhibited formalin-induced nociception in the late phase of phase 2 (30-75 min) and heat hypoalgesia, but not mechanical hyperalgesia (P < 0.05). It is suggested that the dopamine D3 receptors in the thalamus play an antinociceptive role in the descending modulation of nociception. Activation of D3 receptors within the thalamic MD and VM nuclei attenuates descending facilitation and enhances descending inhibition in rats during PD.

Pathological pain: Non-motor manifestations in Parkinson disease and its treatment.

In addition to motor symptoms, non-motor manifestations of Parkinson's disease (PD), i.e. pain, depression, sleep disturbance, and autonomic disorders, have received increasing attention. As one of the non-motor symptoms, pain has a high prevalence and is considered an early pre-motor symptom in the development of PD. In relation to pathological pain and its management in PD, particularly in the early stages, it is hypothesized that the loss of dopaminergic neurons causes a functional deficit in supraspinal structures, leading to an imbalance in endogenous descending modulation. Deficits in dopaminergic-dependent pathways also affect non-dopaminergic neurotransmitter systems that contribute to the pathological processing of nociceptive input, the integration, and modulation of pain in PD. This review examines the onset and progression of pain in PD, with a particular focus on alterations in the central modulation of nociception. The discussion highlights the importance of abnormal endogenous descending facilitation and inhibition in PD pain, which may provide potential clues to a better understanding of the nature of pathological pain and its effective clinical management.

[Progress on the mechanism and treatment of Parkinson's disease-related pathological pain].

Parkinson's disease (PD) is a common neurodegenerative disease characterized by motor symptoms, including bradykinesia, resting tremor, and progressive rigidity. More recently, non-motor symptoms of PD, such as pain, depression and anxiety, and autonomic dysfunction, have attracted increasing attention from scientists and clinicians. As one of non-motor symptoms, pain has high prevalence and early onset feature. Because the mechanism of PD-related pathological pain is unclear, the clinical therapy for treating PD-related pathological pain is very limited, with a focus on relieving the symptoms. This paper reviewed the clinical features, pathogenesis, and therapeutic strategies of PD-related pathological pain and discussed the mechanism of the chronicity of PD-related pathological pain, hoping to provide useful data for the study of drugs and clinical intervention for PD-related pathological pain.

Identification of natural product inhibitors of PTP1B based on high-throughput virtual screening strategy: In silico, in vitro and in vivo studies.

Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of the insulin signaling pathway, which is a potential therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). In this study, we identified several PTP1B inhibitors with high activity by using high-throughput virtual screening and in vitro enzyme inhibition activity verification strategies. Among them, baicalin was first reported as a selective mixed inhibitor of PTP1B, with IC50 value of 3.87 ± 0.45 µM, and its inhibitory activity against homologous proteins TCPTP, SHP2, and SHP1 exceeded 50 µM. Molecular docking study found that baicalin and PTP1B could bind stably, and revealed that baicalin had a dual inhibitory effect. Cell experiments showed that baicalin was almost non-toxic and could significantly enhance the phosphorylation of IRS-1 in C2C12 myotube cells. Animal experiments showed that baicalin could significantly reduce the blood sugar of STZ-induced diabetic mice models, and had a liver protective effect. In conclusion, this study can provide new ideas for the development of PTP1B selective inhibitors.

[The effects of DNA methylation on the homeostasis in vascular diseases].

Homeostasis is fundamental to maintain normal physiological functions in our body. Internal and external physical, chemical and biologial changes can cause dysregulation of vascular homeostasis, which is closely associated with the homeostasis of oxygen supply, blood transportation and lipid metabolism. Subsequent epigenetic modifications are able to lead to abnormal structures and function of vessels. DNA methylation has been shown to play a vital role in the development of vascular diseases. In addition, 5-hydroxymethylcytosine (5hmC) and N(6)-methyladenine (m(6)A), as new epigenetic modifications, provide additional clues for vascular diseases. In this review, we summarize the effects of DNA methylation on the homeostasis dysregulation in the vascular diseases.

[The effect of environmental factors and DNA methylation on type 2 diabetes mellitus].

Type 2 diabetes mellitus (T2DM) is a glucose metabolic disorder driven by both genetic and environmental factors. Recent DNA methylation studies have established that T2DM may be contributed by environmental factors through the regulation of DNA methylation. Human and animal model studies have made much progress on the interaction between DNA methylation of T2DM genes and environmental factors in multiple tissues. Current studies on DNA methylation of T2DM genes mainly focus on glucose and energy metabolism, inflammation, and so on. This review comprehensively introduces the DNA methylation studies for the genes involved in T2DM and its related environmental factors.

Mammogram-based discriminant fusion analysis for breast cancer diagnosis.

Mammogram-based classification is an important and effective way for computer-aided diagnosis (CAD)-based breast cancer diagnosis. In this paper, we present a novel discriminant fusing analysis (DFA)-based mammogram classification CAD-based breast cancer diagnosis. The discriminative breast tissue features are exacted and fused by DFA, and DFA achieves the optimal fusion coefficients. The largest class discriminant in the fused feature space is achieved by DFA for classification. Beside the detailed theory derivation, many experimental evaluations are implemented on Mammography Image Analysis Society mammogram database for breast cancer diagnosis.

Breast tissue image classification based on Semi-supervised Locality Discriminant Projection with Kernels.

Breast tissue classification is an important and effective way for computer aided diagnosis of breast cancer. We present Semi-supervised Locality Discriminant Projections with Kernels for breast cancer classification. The contributions of this work lie in: 1) Semi-supervised learning is used into Locality Preserving Projections (LPP) to enhance its performance using side-information together with the unlabelled training samples, while current algorithms only consider the side-information but ignoring the unlabeled training samples. 2) Kernel trick is applied into Semi-supervised LPP to improve its ability in the nonlinear classification. 3) The framework of breast cancer classification with Semi-supervised LPP with kernels is presented. Many experiments are implemented on four breast tissue databases to testify and evaluate the feasibility and affectivity of the proposed scheme.

Study on acetylcholinesterase inhibition induced by endogenous neurotoxin with an enzyme-semiconductor photoelectrochemical system.

The integration of Au-doped TiO(2) nanotubes with biomolecule acetylcholinesterase (AChE) yields a novel AChE-Au-TiO(2) hybrid system, which provides a new rapid and valid photoelectrochemical approach to the determination of AChE inhibition induced by endogenous neurotoxin.

2-Bromo-4,4-dimethyl-1-(2,4,5-trimethoxy-phen-yl)pentan-3-one.

The three meth-oxy groups of the title compound, C(16)H(23)BrO(4), are almost coplanar with the attached aromatic ring, forming dihedral angles of 7.19 (13), 2.48 (13) and 7.24 (12)°. The crystal structure shows an intra-molecular and an inter-molecular C-H⋯O inter-action.

[Effects of different donor cells on the development of nuclear-transferred porcine embryos].

This study was undertaken to systematically examine the effects of different donor cells and numbers of passages on the development of nuclear-transferred porcine embryos, so as to establish a preliminary procedure for porcine cloning. Porcine oocytes obtained at slaughter were matured in vitro for 40-44 h and then enucleated in manipulation medium containing 5 micro g/mL cytochalasin B. Fibroblast cells (FC), oviduct epithelial cells (OEC), granulosa cells (GC) and cumulus cells (CC) after 3-9 passages in 10% FBS-supplemented culture medium were either treated by serum starvation (0.5% FBS for 2-9 days), 0.1 micro g/mL aphidiconlin (APD) for 1 day and 0.5% FBS for 2-9 days or left untreated in complete medium for 2-9 days. They were transferred into enucleated oocytes by microinjection or electric fusion (100 V/mm, 30 ms and 1 pulse). Reconstituted embryos were activated with a combination of calcium ionophore A23187 or electric pulse and 6-DMAP, and cultured for 6 days, to evaluate their cleavage and embryonic development. The cleavage rate of embryos reconstructed with FC and GC pretreated with 0.1 micro g/mL APD + 0.5% FBS were significantly higher than that of serum starvation group and control group (P<0.01). There was a significant difference in the cleavage rate and embryonic development among embryos derived from GC, CC and FC, OEC pretreated with 0.1 micro g/mL APD + 0.5% FBS. The cleavage rate of embryos reconstructed with GC by electrofusion was significantly higher than that by microinjection (P<0.05), but no difference was found in the proportion of embryos that developed to blastocysts. About 75% to 85% of GC at 3 and 6 passages, and FC at 6 and 10 passages had a normal karyotype, and resulted in similar cleavage rate and blastocyst development. These results indicate that: (1) FC and GC can be cultured up to 9 passages and maintain a relatively stable karyotype; (2) Treatment of donor cells with 0.1 micro g/mL APD prior to nuclear transfer can improve the efficiency of somatic cell nuclear transfer in buffalo but serum starvation is inefficient in our system; (3) Both FC and GC cells can be used as the donor karyoplasts for nuclear transfer, and their efficiency is not influenced by the culture passages. (4) The development of reconstructed embryos by electrofusion is higher than that by microinjection, but there is no difference in the overall efficiency between the two methods.

[Effects of different donor cells and passages on the development of nuclear transfer porcine embryos].

This study was undertaken to systematically examine effects of different donor cells and passages on the development of nuclear transfer porcine embryos, so as to establish a preliminary procedure for porcine cloning. Porcine oocytes obtained from ovaries at slaughter were matured in vitro for 40-44h and then enucleated in manipulation medium containing 5 microg/mL cytochalasin B. Fibroblast cells (FC), oviduct epithelial cells (OEC), granulosa cells (GC) and cumulus cells(CC) after 3-9 passages in TCM + 10% FBS were treated by serum starvation (0.5% FBS for 2-9 days), 0.1 microg/mL aphidiconlin (APD) for 1 day and 0.5% FBS for 2-9 days or continue culturing in 10% FBS for 2-9 days, then, were transferred into enucleated oocytes by microinjection or electronic fusion (100 V/mm, 30 micros and 1 pulses). Reconstituted embryos were activated with a combination of calcium ionophore A23187 or electric pulse and 6-DMAP, and cultured for 6 days, to evaluate their cleavage and embryonic development. The cleavage rate of embryos reconstructed with FC and GC pretreated with 0.1 microg/mL APD + 0.5% FBS were significantly higher than that of serum starvation group and control group (P<0.01). There was significantly difference in the cleavage rate and embryonic development among embryos derived from GC, CC and FC, OEC pretreated with 0.1 microg/mL APD + 0.5% FBS. The cleavage rate of embryos reconstructed with GC by electrofusion was significantly higher than that by microinjection (P<0.05), but no difference was found in their proportion developing to blastocysts. 75% to 85% of GC at 3 and 6 passages, and FC at 6 and 10 passages had normal karyotype, which did not show significant difference among them (P>0.05). When GC at G3, G4, G5 and G6 of passages were used as donor cells, the cleavage rate and blastocyst rate was similar, moreover, FC at G6, G7, G8 and G9 of passages also resulted in a similar cleavage rate and blastocyst development. These results indicate that: (1) FC and GC can be cultured up to 9 passages and keep relatively stable karyotepe; (2) Using 0.1 microg/mL APD to treat donor cells prior to nuclear transfer can improve the efficiency of somatic cell nuclear transfer in buffalo but serum starvation is inefficient in our system; (3) Both of FC and GC cells can be used as the donor karyoplasts for nuclear transfer, and their efficiency are not influenced by the culture passages; (4) The development of reconstructed embryos by electrofusion is higher than that by microinjection, but there is no difference in the total efficiency between the two methods.