Pygo-F773W Mutation Reveals Novel Functions beyond Wnt Signaling in Drosophila.

Pygopus (Pygo) has been identified as a specific nuclear co-activator of the canonical Wingless (Wg)/Wnt signaling pathway in Drosophila melanogaster. Pygo proteins consist of two conserved domains: an N-terminal homologous domain (NHD) and a C-terminal plant homologous domain (PHD). The PHD's ability to bind to di- and trimethylated lysine 4 of histone H3 (H3K4me2/3) appears to be independent of Wnt signaling. There is ongoing debate regarding the significance of Pygo's histone-binding capacity. Drosophila Pygo orthologs have a tryptophan (W) > phenylalanine (F) substitution in their histone pocket-divider compared to vertebrates, leading to reduced histone affinity. In this research, we utilized CRISPR/Cas9 technology to introduce the Pygo-F773W point mutation in Drosophila, successfully establishing a viable homozygous Pygo mutant line for the first time. Adult mutant flies displayed noticeable abnormalities in reproduction, locomotion, heart function, and lifespan. RNA-seq and cluster analysis indicated that the mutation primarily affected pathways related to immunity, metabolism, and posttranslational modification in adult flies rather than the Wnt signaling pathway. Additionally, a reduction in H3K9 acetylation levels during the embryonic stage was observed in the mutant strains. These findings support the notion that Pygo plays a wider role in chromatin remodeling, with its involvement in Wnt signaling representing only a specific aspect of its chromatin-related functions.

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We analyzed soil quality based on soil microbial characteristics of three different vegetation types in the wetlands of East Dongting Lake, including Carex tristachya wetland (CTW), Phragmites australis wetland (PAW), and Salix babylonica wetland (SBW). The soil microbial biomass carbon (MBC), nitrogen (MBN) and enzyme activities were measured and the key influen-cing factors were analyzed during the normal, flood, and dry periods. The results showed that: 1) The amounts of MBC, MBN, and the activities of invertase and cellulase (except cellulase of dry season) in 0-10 cm were higher than those in 10-20 cm for all wetlands, while the catalase activity showed an opposite pattern. 2) The amounts of MBC and MBN and the values of MBC/TOC and MBN/TN for the 0-20 cm soil layer of each vegetation type wetland were the lowest in flood period. 3) Soil invertase activity for each vegetation type wetland in the 0-20 cm soil layer peaked in the dry period, while soil cellulase activity peaked in the normal period. The seasonal fluctuation of soil catalase activities in all wetlands were small, with activities being slightly higher in flood period than the other two periods. 4) Among different vegetation types, soil invertase activity of PAW was significantly higher than that of other vegetation types, and cellulase activity of which was the lowest in both normal and flood periods. There was no difference in these two enzymes activities among wetlands during the dry period. The highest soil catalase activity was found in CTW during normal period and in SBW during dry period, respectively, while its lowest value was in PAW during flood period. 5) Soil MBC, MBN and invertase activity were correlated positively with soil TOC, TN and TP, and negatively correlated with soil pH. The activities of soil cellulase and catalase were significantly negatively correlated with TOC, TN, TP and positively correlated with pH. It suggested that the seasonal fluctuation of water level affected soil C, N, P contents and pH values, with consequences on soil MBC, MBN and enzyme activities.

Dental Pulp Mesenchymal Stem Cells Attenuate Limb Ischemia via Promoting Capillary Proliferation and Collateral Development in a Preclinical Model.

Critical limb ischemia (CLI), an end-stage manifestation of peripheral artery disease (PAD), still lacks effective therapeutic strategies. Recently, dental pulp-derived mesenchymal stem cells (DP-MSCs) have been attracting more and more attentions in therapeutic applications due to their high proliferation ability, powerful osteogenic differentiation potential, and effective anti-inflammatory effects. In this study, we compared the therapeutic effects of MSCs derived from different sources in a femoral artery-ligated preclinical ischemic model. We found that treatments with MSCs, including bone marrow- (BM-), adipose- (AD-), dental pulp- (DP-), and umbilical cord- (UC-) derived MSCs, improved limb functions, reduced inflammatory responses, increased angiogenesis, and promoted regeneration of muscle fiber. Among them, DP-MSCs and BM-MSCs produced much more impressive effects in restoring limb functions and promoting angiogenesis. The flow velocity restored to nearly 20% of the normal level at 3 weeks after treatments with DP-MSCs and BM-MSCs, and obvious capillary proliferation and collateral development could be observed. Although neovascularization was induced in the ischemic limb after ligation, MSCs, especially DP-MSCs, significantly enhanced the angiogenesis. In vitro experiments showed that serum deprivation improved the expression of angiogenic factors, growth factors, and chemokines in DP-MSCs and UC-MSCs, but not in BM-MSCs and AD-MSCs. However, DP-MSCs produced stronger therapeutic responses than UC-MSCs, which might be due to the higher expression of hepatocyte growth factor (HGF) and hypoxia-inducible factor-1 α (HIF-1α). We speculated that DP-MSCs might stimulate angiogenesis and promote tissue repair via expressing and secreting angiogenic factors, growth factors, and chemokines, especially HGF and HIF-1α. In conclusion, DP-MSCs might be a promising approach for treating CLI.

The Association Between Serum Apelin-13 and the Prognosis of Acute Ischemic Stroke.

While a number of studies have reported an association between apelin-13 and ischemic stroke, few have verified its clinical effect. We investigated the prognostic value of serum apelin-13 levels in patients with acute ischemic stroke (AIS). We prospectively recruited 244 AIS patients within 24 h after stroke onset, and 167 healthy controls. We assessed the serum apelin-13 levels using ELISA, and the severity of AIS using the National Institutes of Health Stroke Scale (NIHSS). The primary outcomes included death or major disability (modified Rankin Scale score, 3-6) and major disability (modified Rankin Scale score, 3-5). Secondary outcomes included recurrent stroke and combined events (all-cause death, or cardiovascular and cerebrovascular events). We found that the serum apelin-13 levels in the patients (38.63 ng/mL (interquartile range [IQR], 29.86-50.99)) were lower than those in the healthy controls (42.50 ng/mL [IQR, 31.25-59.17]) (P = 0.017). Patients with a NIHSS score ≤ 3 had higher apelin-13 levels than those with a NIHSS score > 3 (P = 0.048). At the 3-month follow-up, multivariate logistic regression analysis indicated an association between apelin-13 and death or major disability (OR 0.31; 95% CI 0.11-0.86; P = 0.024) and major disability (OR 0.32; 95% CI 0.11-0.90; P = 0.030). At the 1-year follow-up, the patients with high apelin-13 levels showed a lower incidence of stroke and combined events (Log-rank test P < 0.05). Our findings indicate that serum apelin-13 may be a potential prognostic biomarker for AIS.

The Hemoglobin, Albumin, Lymphocyte, and Platelet (HALP) Score Is Associated With Poor Outcome of Acute Ischemic Stroke.

Background: The combined index of hemoglobin, albumin, lymphocyte, and platelet (HALP) is considered a novel score to reflect systemic inflammation and nutritional status. This study aimed to investigate the association between HALP score and poor outcome in patients with acute ischemic stroke (AIS). Methods: Consecutive AIS patients within 24 h after onset were prospectively enrolled. Poor outcome was a combination of a new stroke event (ischemic and hemorrhagic) and all-cause death within 90 days and 1 year. The association between HALP score and poor outcome was analyzed using Cox proportional hazards. Results: A total of 1,337 patients were included. Overall, 60 (4.5%) and 118 (8.8%) patients experienced poor outcome within 90 days and 1 year, respectively. Patients in the highest tertile of HALP score had a lower risk of poor outcome within 90 days and 1 year (hazard ratio: 0.25 and 0.42; 95% confidence intervals: 0.11-0.57 and 0.25-0.69, P for trend <0.01 for all) compared with those in the lowest tertile after adjusting relevant confounding factors. Adding HALP score to the conventional risk factors improved prediction of poor outcome in patients with AIS within 90 days and 1 year (net reclassification index, 48.38 and 28.95%; integrated discrimination improvement, 1.51 and 1.51%; P < 0.05 for all). Conclusions: Increased HALP score was associated with a decreased risk of recurrent stroke and death within 90 days and 1 year after stroke onset, suggesting that HALP score may serve as a powerful indicator for AIS.

Heterogeneous photocatalytic performances of CO2 reduction based on the [Emim]BF4 + TEOA + H2O system.

The photochemical reduction of CO2 was studied in a 1-ethyl-3-methylimidazolium tetrafluoroborate, triethanolamine and water ([Emim]BF4 + TEOA + H2O) system under visible light irradiation. The integration of CdS and the Co-bpy complex, which acted as a photocatalyst and cocatalyst, respectively, was employed as an efficient catalytic system for the CO2-to-CO conversion. The utilization of [Emim]BF4 and water took advantage of their green properties. The amount of CO production showed that the test medium containing 10 vol% H2O was favourable for the catalytic performance of the CO2 reduction. In order to further study the factors that influenced the current system, the physical and spectroscopy properties were characterized by altering the composition ratio of the ingredients. Relevant parameters, including the viscosity, conductivity, solubility and coordination, were adjusted using the ratio of the H2O/[Emim]BF4 addition, resulting in a different catalytic performance. All of these attempts led to an optimal reaction condition for the CO2 reduction process.

Multi-disciplinary team for early gastric cancer diagnosis improves the detection rate of early gastric cancer.

BACKGROUND: Gastric cancer is a frequent malignant tumor worldwide and its early detection is crucial for curing the disease and enhancing patients' survival rate. This study aimed to assess whether the multi-disciplinary team (MDT) can improve the detection rate of early gastric cancer (EGC). METHODS: The detection rate of EGC at the Digestive Endoscopy Center, Affiliated Hospital, Zunyi Medical College, China between September 2013 and September 2015 was analyzed. MDT for the diagnosis of EGC in the hospital was established in September 2014. The study was divided into 2 time periods: September 1, 2013 to August 31, 2014 (period 1) and September 1, 2014 to September 1, 2015 (period 2). RESULTS: A total of 60,800 patients' gastroscopies were performed during the two years. 61 of these patients (0.1%) were diagnosed as EGC, accounting for 16.44% (61/371) of total patients with gastric cancer. The EGC detection rate before MDT (period 1) was 0.05% (16/29403), accounting for 9.09% (16/176) of total patients with gastric cancer during this period. In comparison, the EGC detection rate during MDT (period 2) was 0.15% (45/31397), accounting for 23% (45/195) of total patients with gastric cancer during this period (P < 0.05). Univariate and multivariate logistic analyses showed that intensive gastroscopy for high risk patients of gastric cancer enhanced the detection rate of EGC in cooperation with Department of Pathology (OR = 10.1, 95% CI 2.39-43.3, P < 0.05). CONCLUSION: MDT could improve the endoscopic detection rate of EGC.

A modified endoscopic submucosal dissection for a superficial hypopharyngeal cancer: a case report and technical discussion.

BACKGROUND: Adequate working space and a clear view for the dissected lesion are crucial for endoscopic submucosal dissection (ESD). Pharyngeal ESD requires that an otorhinolaryngologist creates working space by lifting the larynx with a curved laryngoscope. However, many countries do not have this kind of curved laryngoscope, and the devices could interfere with endoscope because of the narrow space of the pharynx. To overcome these issues, we used a transparent hood (Elastic Touch, slit and hole type, M (long), Top company, Tokyo Japan) instead of the curved laryngoscope to create adequate working space by pushing the larynx, and pharyngeal ESD could be done by gastroenterologists. CASE PRESENTATION: A 64-year-old male patient was admitted to our hospital because of chronic persistent swallowing dysfunction for 2 years. Oesophagogastroduodenoscopy showed a superficial hypopharyngeal cancer in the right pyriform sinus. We used a transparent hood (Elastic Touch, slit and hole type, M (long), Top company, Tokyo Japan) instead of the curved laryngoscope to create adequate working space by pushing the larynx, and dental floss tied to a haemoclip was applied to create counter traction during ESD. The lesion was pathologically confirmed as superficial squamous cell carcinoma and resected completely. CONCLUSIONS: This is the first report of modified ESD for a superficial hypopharyngeal cancer. The modified ESD enables early pharyngeal superficial cancer to be removed completely under endoscope by gastroenterologist.

AMP-activated protein kinase suppresses the in vitro and in vivo proliferation of hepatocellular carcinoma.

AMP-activated protein kinase (AMPK) is a central metabolic sensor and plays an important role in regulating glucose, lipid and cholesterol metabolism. Therefore, AMPK is a key therapeutic target in diabetes. Recent pilot studies have suggested that diabetes drugs may reduce the risk of cancer by affecting the AMPK pathway. However, the association between AMPK and the proliferation of hepatocellular carcinoma (HCC) is unknown. In this study, we investigated the relationship between AMPK activity and the proliferation of HCC in cell lines, nude mice and human clinic samples. We first investigated the relationship between AMPK activity and cell proliferation in two HCC cell lines, PLC/PRF/5 and HepG2, by two AMPK activators, 5-aminoimidazole-4-carboxamide-1-h-D-ribofuranoside (AICAR) and metformain. AICAR and metformin treatment significantly inhibited the proliferation of HCC cells and induced cell cycle arrest at G1-S checkpoint. We then observed that metformin abrogated the growth of HCC xenografts in nude mice. The clinical pathology of AMPK activity in HCC, including cell proliferation, differential grade, tumor size and microvessel density, was studied by using 30 clinical tissue samples. In HCC tissue samples, phosphorylated AMPK was expressed mainly in cytoplasm. AMPK activity decreased significantly in HCC in comparison with paracancerous liver tissues (P<0.05). AMPK activity was negatively correlated with the level of Ki-67 (a marker of cell proliferation), differential degradation and tumor size (P<0.05), but not with microvessel density, hemorrhage or necrosis in HCC. Our findings suggest that AMPK activity inhibits the proliferation of HCC and AMPK might be an effective target for prevention and treatment of HCC.

Metformin suppresses hepatocellular carcinoma cell growth through induction of cell cycle G1/G0 phase arrest and p21CIP and p27KIP expression and downregulation of cyclin D1 in vitro and in vivo.

Metformin is used as a first-line therapy for type 2 diabetes, with reports of its usefulness for the prevention and control of several types of cancers. This study investigated the effects of metformin on hepatocellular carcinoma (HCC). The human HCC cell lines HepG2 and PLC/PRF/5 were cultured and treated with metformin or 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), an activator of adenosine monophosphate (AMP)-activated protein kinase. Changes in cell viability and cell cycle distribution were evaluated by MTT and flow cytometry, respectively. Apoptosis was assessed by fluorescent-dye staining. An HCC model was established in 6- to 8-week-old BALB/c-nu mice by subcutaneous injection of PLC/PRF/5 cells. After 1 week, mice were treated intragastrically with metformin or vehicle. Tumor xenograft tissues were examined using immunohistochemistry for evaluation of the the expression of cyclin D1, p21CIP and p27KIP. HCC cells and tissues from the in vitro and in vivo experiments, respectively, were subjected to protein extraction and western blotting. We found that metformin treatment reduced HCC cell viability in a dose-dependent manner similar to AICAR treatment. In addition, metformin treatment induced HCC cell cycle arrest at G1/G0 phase and apoptosis. Intragastric treatment of the mouse PLC/PRF/5 cell xenograft model with metformin showed that metformin not only blocked tumor progression, but also reduced tumor morbidity. Treatment with metformin upregulated the expression of p21CIP and p27KIP, but downregulated cyclin D1 levels, both in vitro and in vivo. Metformin treatment also upregulated the expression of phosphorylated AMPK protein in xenograft tissues. These findings indicate that metformin warrants further evaluation as a novel therapeutic and preventive strategy against HCC.

Uric acid induces oxidative stress and growth inhibition by activating adenosine monophosphate-activated protein kinase and extracellular signal-regulated kinase signal pathways in pancreatic ß cells.

Hyperuricaemia is a disorder of purine metabolism, and is strongly associated with insulin resistance and abnormal glucose metabolism. As the producer of insulin, pancreatic ß cells might be affected by elevated serum uric acid levels and contribute to the disregulated glucose metabolism. In this study, we investigated the effect of high uric acid on rat pancreatic ß cell function. Under high uric acid condition, proliferation of pancreatic ß cells was inhibited, production of reactive oxygen species increased, and glucose stimulated insulin secretion was also compromised. Further examination on signal transduction pathways revealed that uric acid-induced ROS is involved in the activation of adenosine monophosphate-activated protein kinase (AMPK), and extracellular signal-regulated kinase (ERK). Pharmacological inhibition of ERK activation rescued ß cells from growth inhibition. More importantly, activation of ERK induced by uric acid is significantly diminished by AMPK inhibitor, indicating ERK as a downstream target of AMPK in response to high uric acid condition. We also investigated the transportation channel for uric acid into pancreatic ß cells. While major urate transporter URAT1 is not expressed in ß cells, organic anion transporter (OAT) inhibitor successfully blocked the activation of ERK by uric acid. Our data indicate that high uric acid levels induce oxidative damage and inhibit growth of rat pancreatic ß cells by activating the AMPK and ERK signal pathways. Hyperuricemia may contribute to abnormal glucose metabolism by causing oxidative damage and function inhibition of pancreatic ß cells.

Significance of nitric oxide on the pathogenesis of steroid induced femoral head necrosis.

Steroid-induced femoral head necrosis is claimed to be an ischemic femoral head disease. But there is no discussion on the role of nitric oxide (NO) in the idiopathic disease. The concentration of NO indirectly in serum with steroid induced avascular necrosis of femoral head (ANFH) and in controls are studied in this article.