Brain Activity in Age-Related Macular Degeneration Patients From the Perspective of Regional Homogeneity: A Resting-State Functional Magnetic Resonance Imaging Study.

Objective: In this study, the regional homogeneity (ReHo) method was used to investigate levels of cerebral homogeneity in individuals with age-related macular degeneration (AMD), with the aim of exploring whether these measures are associated with clinical characteristics. Materials and Methods: Patients with AMD and healthy controls attending the First Affiliated Hospital of Nanchang University were invited to participate. Resting state functional magnetic resonance images were recorded in each participant and levels of synchronous neural activity were evaluated using ReHo. Receiver operating characteristic (ROC) curves were used to evaluate the sensitivity and specificity of this method. Results: Eighteen patients with AMD (9 males and 9 females) and 15 healthy controls (HCs) were recruited. The two groups were approximately matched in age, gender and weight. Compared with controls, the ReHo values were significantly higher in the AMD group at the limbic lobe and parahippocampal gyrus, and were significantly reduced at the cingulate gyrus, superior frontal gyrus, middle frontal gyrus, inferior parietal lobule, and precentral gyrus. Mean ReHo values at the cingulate gyrus and the superior frontal gyrus were negatively correlated with clinical symptoms. Conclusion: Brain neural homogeneity dysfunction is a manifestation of visual pathways in AMD patients, and may be one of the pathological mechanisms of chronic vision loss, anxiety and depression in AMD patients. In addition, the ReHo data may be useful for early screening for AMD.

Vitrectomy alone or Vitrectomy Combined with Scleral Buckle in the Management of Giant Retinal Tears.

The aim of this study was to compare as to which treatment achieves better outcomes in the management of giant retinal tears (GRTs) - pars plana vitrectomy (PPV) alone or combined with scleral buckle (SB)? The Web of Science, PubMed, and Cochrane Library databases were searched from January 1, 1950 to October 1, 2020. Pooled odds ratios (ORs), 95% confidence intervals (CIs), heterogeneity, and publication bias were determined with Review Manager software. PPV combined with SB significantly decreased the risk of recurrent retinal detachment (RRD, OR = 0.39, 95% CI = 0.20-0.77, I2 = 35%, p = 0.006) in GRT management compared with PPV alone. However, the final anatomical success (OR = 0.74, 95% CI = 0.23-2.39, I2 = 0%, p = 0.61), final visual acuity (OR = 1.11, 95% CI = 0.48-2.58, I2=13%, p = 0.81), and risk factors of GRT ≥180° (OR = 0.43, 95% CI = 0.15-1.22, I2 = 0%, p = 0.11) were not significantly different between the two approaches. According to the final anatomical success, final visual acuity, and risk factors of GRT ≥180°, there were no significant differences between PPV combined with SB and PPV alone for the management of GRT in the current study, except in decreasing the risk of RRD. Key Words: Giant retinal tear, Pars plana vitrectomy, Scleral buckling, Recurrent retinal detachment.

Quercetin regulates fibrogenic responses of endometrial stromal cell by upregulating miR-145 and inhibiting the TGF-ß1/Smad2/Smad3 pathway.

OBJECTIVES: Aim of this study is to explore whether quercetin can inhibit the enlarged fibrogenic responses of endometrial stromal cells by increasing the level of microRNA-145 (miR-145) and mediating the TGFß1/Smad2/Smad3 signaling pathway, and to discuss the mechanism of signal transduction, further to provide experimental basis for revealing the pathophysiological mechanism and seeking new strategies for effective prevention and treatment of endometrial fibrosis. METHODS: The expression levels of miR-145 and TGF-ß receptor 2 (TGFBR2) were detected by RT-qPCR analysis. Expressions of α-smooth muscle actin (α-SMA) and vimentin were examined by immunofluorescence staining. Cell viability was measured by MTT assay. The protein expression of collagen type 1 alpha 1 (Col1a1), α-SMA, fibronectin (FN), TGFBR2, transforming growth factor (TGF-ß1), Smad2/3, phospho-Smad2/3 (p-Smad2/3) were detected by western blot analysis. The interaction between miR-145 and TGFBR2 was confirmed by dual-luciferase reporter gene assay. RESULTS: The expression level of miR-145 was decreased, whereas TGFBR2 was increased in intrauterine adhesion tissue. The expression levels of COL1A1, α-SMA, FN, TGFBR2, and p-Smad2/3 were increased, whereas miR-145 and cell proliferation were decreased in human endometrial stromal cells (hESCs) in response to TGF-ß1 stimulation in a time and dose-dependent manner, which could be reversed by quercetin. Furthermore, quercetin regulates cell fibrogenic responses of endometrial stromal cells via miR-145/TGF-ß1/Smad2/Smad3 pathway. CONCLUSIONS: These findings indicated that quercetin have a significant anti-fibrotic effect and could upregulate miR-145 and inhibit activation of TGF-ß1/Smad2/Smad3 pathway to regulate TGF-ß1 induced fibrogenic responses of endometrial stromal cells, which may serve as a potential therapeutic agent for endometrial fibrosis.

Role of S-adenosylmethionine, folate, and betaine in the treatment of alcoholic liver disease: summary of a symposium.

This report is a summary of a symposium on the role of S-adenosylmethionine (SAM), betaine, and folate in the treatment of alcoholic liver disease (ALD), which was organized by the National Institute on Alcohol Abuse and Alcoholism in collaboration with the Office of Dietary Supplements and the National Center for Complementary and Alternative Medicine of the National Institutes of Health (Bethesda, MD) and held on 3 October 2005. SAM supplementation may attenuate ALD by decreasing oxidative stress through the up-regulation of glutathione synthesis, reducing inflammation via the down-regulation of tumor necrosis factor-alpha and the up-regulation of interleukin-10 synthesis, increasing the ratio of SAM to S-adenosylhomocysteine (SAH), and inhibiting the apoptosis of normal hepatocytes and stimulating the apoptosis of liver cancer cells. Folate deficiency may accelerate or promote ALD by increasing hepatic homocysteine and SAH concentrations; decreasing hepatic SAM and glutathione concentrations and the SAM-SAH ratio; increasing cytochrome P4502E1 activation and lipid peroxidation; up-regulating endoplasmic reticulum stress markers, including sterol regulatory element-binding protein-1, and proapoptotic gene caspase-12; and decreasing global DNA methylation. Betaine may attenuate ALD by increasing the synthesis of SAM and, eventually, glutathione, decreasing the hepatic concentrations of homocysteine and SAH, and increasing the SAM-SAH ratio, which can trigger a cascade of events that lead to the activation of phosphatidylethanolamine methyltransferase, increased phosphatidylcholine synthesis, and formation of VLDL for the export of triacylglycerol from the liver to the circulation. Additionally, decreased concentrations of homocysteine can down-regulate endoplasmic reticulum stress, which leads to the attenuation of apoptosis and fatty acid synthesis.

Cholesterol-enriched diet affects spatial learning and synaptic function in hippocampal synapses.

The aim of the present study was to determine the effect of a cholesterol-rich diet on learning performance and monitor possible related changes in synaptic function. To this purpose, we compared controls with rats fed with a cholesterol-enriched diet (CD). By using a Morris water-maze paradigm, we found that CD rats learned a water-maze task more quickly than rats fed with a regular diet (RD). A longer period of this diet tended to alter the retention of memory without affecting the improvement in the acquisition of the task. Because of the importance of the hippocampus in spatial learning, we hypothesized that these behavioral effects of cholesterol would involve synaptic changes at the hippocampal level. We used whole-cell patch-clamp recording in the CA1 area of a hippocampal rat slice preparation to test the influence of the CD on pre- and postsynaptic function. CD rats displayed an increase in paired-pulse ratio in both glutamatergic synapses (+48 +/- 9%) and GABAergic synapses (+41 +/- 8%), suggesting that the CD induces long-lasting changes in presynaptic function. Furthermore, by recording NMDA-receptor-mediated currents (I(NMDA)) and AMPA-receptor-mediated currents (I(AMPA)) in the same set of cells we found that CD rats display a lower I(NMDA)/I(AMPA) ratio (I(NMDA)/I(AMPA) = 0.75 +/- 0.32 in RD versus 0.10 +/- 0.03 in CD), demonstrating that cholesterol regulates also postsynaptic function. We conclude that a cholesterol-rich diet affects learning speed and performance, and that these behavioral changes occur together with robust, long-lasting, synaptic changes at both the pre- and postsynaptic level.

The complete mitochondrial genome of white-tufted-ear marmoset, Callithrix jacchus (Primates: Callitrichinae).

The white-tufted-ear marmoset (Callithrix jacchus) is a New World primate that inhabits the coastal rainforests of eastern Brazil. In the present work, we report the complete mitochondrial genome sequence of white-tufted-ear marmoset for the first time. The total length of this mitogenome is 16,499 bp long, containing 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes, and 1 non-coding region (D-loop region). The gene organization and arrangement is identical to typical vertebrates. The overall base composition is 32.75% of A, 26.95% of T, 26.91% C, and 13.39% G, with a slight A + T bias of 59.7%. All the genes are encoded on H-strand, except for the ND6 subunit gene and 8 tRNA genes. The complete mitochondrial genome sequence reported here will be useful for comparative genomics studies in primates.

Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C.

Silymarin, derived from the milk thistle plant Silybum marianum, is widely used for self-treatment of liver diseases, including hepatitis C virus (HCV), and its antiviral activity has been demonstrated in vitro and in HCV patients administered an intravenous formulation of the major silymarin flavonolignans, silybin A and silybin B. The safety and dose-exposure relationships of higher than customary oral doses of silymarin and its acute effects on serum HCV RNA were evaluated in noncirrhotic HCV patients. Four cohorts of 8 patients with well-compensated, chronic noncirrhotic HCV who failed interferon-based therapy were randomized 3:1 to silymarin or placebo. Oral doses of 140, 280, 560, or 700 mg silymarin were administered every 8 hours for 7 days. Steady-state exposures for silybin A and silybin B increased 11-fold and 38-fold, respectively, with a 5-fold increase in dose, suggesting nonlinear pharmacokinetics. No drug-related adverse events were reported, and no clinically meaningful reductions from baseline serum transaminases or HCV RNA titer were observed. Oral doses of silymarin up to 2.1 g per day were safe and well tolerated. The nonlinear pharmacokinetics of silybin A and silybin B suggests low bioavailability associated with customary doses of silymarin may be overcome with doses above 700 mg.

Enhancement of long-term memory retention and short-term synaptic plasticity in cbl-b null mice.

The cbl-b gene is a member of the cbl protooncogene family. It encodes a protein with multiple domains, which can interact with other proteins in a variety of signaling pathways. The functions of cbl family genes in the brain are unknown. In this report, we used genetic, immunohistochemical, behavioral, and electrophysiological approaches to study the role of cbl-b in learning and memory. Cbl-b null mice developed normally and had no abnormalities in their locomotor performance. In spatial learning and memory studies, cbl-b null and WT mice performed similarly during training. To test memory retention, two probe trials were used. cbl-b null mice performed slightly better 1 day after training. However, in the probe trial 45 days after training, the cbl-b null group showed significantly higher memory retention than WT mice, suggesting an enhancement of long-term memory. Using electrophysiological approaches, we found there was enhanced paired-pulse facilitation in the Schaffer Collateral-CA1 glutamatergic synapses of the cbl-b null mice. On the other hand, there was no difference in long-term potentiation between the two groups of mice. In summary, we provide evidence that (i) cbl-b protein is concentrated in the synaptic regions of CA1, CA3, and the dentate gyrus of the hippocampus; (ii) cbl-b null mice have enhanced long-term memory; and (iii) cbl-b null mice show an enhancement in short-term plasticity. These results indicate that cbl-b is a negative regulator of long-term memory, and its neuronal mechanism regulates synaptic transmission in the hippocampus.

Allopregnanolone activates GABA(A) receptor/Cl(-) channels in a multiphasic manner in embryonic rat hippocampal neurons.

Although 3alpha-substituted metabolites of progesterone are well established to interact with GABA(A) receptor/Cl(-) channels, the nature of the interaction(s) remains uncertain. We used patch-clamp recording to study the interaction with GABA(A) receptor/Cl(-) channels expressed by embryonic hippocampal neurons differentiating in culture and nonneuronal cells transfected with GABA(A) receptor subunits. Allopregnanolone primarily induced multiphasic current responses in neurons, which were eliminated by bicuculline, an antagonist of GABA at GABA(A) receptor/Cl(-) channels. Similar multiphasic responses blocked by bicuculline were induced by allopregnanollone in nonneuronal cells transfected with alpha(1) and gamma(2) subunits, indicating that the steroid activation of GABA(A) receptor/Cl(-) channels occurred independently of GABA. Fluctuation analyses of current responses to allopregnanolone and GABA revealed underlying channel activities with similar estimated unitary properties. However, although both agonists activated Cl(-) channels with similar estimated short and long burst-length durations, most of those stimulated by the steroid were short, while most of those opened by GABA were long. Allopregnanolone potentiated GABA-evoked Cl(-) currents in nonneuronal cells transfected with alpha(1) and beta(2) or beta(3) subunits, which did not exhibit multiphasic responses to the steroid, indicating another, independent action of the steroid at activated receptors. Pertussis toxin treatment eliminated the low-amplitude current and attenuated the high-amplitude current induced by allopregnanolone in a reversible manner. Mastoparan, which activates G proteins directly, triggered a high-amplitude current after a delay, which was blocked by bicuculline. The results indicate that allopregnanolone interacts with GABA(A) receptor/Cl(-) channels expressed by embryonic hippocampal neurons in multiple ways, some of which are mediated by G proteins.