Cytosolic DNA initiates a vicious circle of aging-related endothelial inflammation and mitochondrial dysfunction via STING: the inhibitory effect of Cilostazol.

Endothelial senescence, aging-related inflammation, and mitochondrial dysfunction are prominent features of vascular aging and contribute to the development of aging-associated vascular disease. Accumulating evidence indicates that DNA damage occurs in aging vascular cells, especially in endothelial cells (ECs). However, the mechanism of EC senescence has not been completely elucidated, and so far, there is no specific drug in the clinic to treat EC senescence and vascular aging. Here we show that various aging stimuli induce nuclear DNA and mitochondrial damage in ECs, thus facilitating the release of cytoplasmic free DNA (cfDNA), which activates the DNA-sensing adapter protein STING. STING activation led to a senescence-associated secretory phenotype (SASP), thereby releasing pro-aging cytokines and cfDNA to further exacerbate mitochondrial damage and EC senescence, thus forming a vicious circle, all of which can be suppressed by STING knockdown or inhibition. Using next-generation RNA sequencing, we demonstrate that STING activation stimulates, whereas STING inhibition disrupts pathways associated with cell senescence and SASP. In vivo studies unravel that endothelial-specific Sting deficiency alleviates aging-related endothelial inflammation and mitochondrial dysfunction and prevents the development of atherosclerosis in mice. By screening FDA-approved vasoprotective drugs, we identified Cilostazol as a new STING inhibitor that attenuates aging-related endothelial inflammation both in vitro and in vivo. We demonstrated that Cilostazol significantly inhibited STING translocation from the ER to the Golgi apparatus during STING activation by targeting S162 and S243 residues of STING. These results disclose the deleterious effects of a cfDNA-STING-SASP-cfDNA vicious circle on EC senescence and atherogenesis and suggest that the STING pathway is a promising therapeutic target for vascular aging-related diseases. A proposed model illustrates the central role of STING in mediating a vicious circle of cfDNA-STING-SASP-cfDNA to aggravate age-related endothelial inflammation and mitochondrial damage.

Sarcopenia is associated with non-motor symptoms in Han Chinese patients with Parkinson's Disease: a cross-sectional study.

BACKGROUND: Sarcopenia is commonly seen in the older adults and increases in incidence with age, also in Parkinson's disease (PD). Although research has indicated that the development of sarcopenia in patients with PD may be related to both motor symptoms and non-motor symptoms (NMS), the precise relationship between the two conditions remains unclear. Therefore, we aimed to investigate the incidence of sarcopenia in patients with PD and its association with NMS. METHODS: The study included 123 patients with PD and 38 age- and sex-matched healthy controls (HC). All participants were evaluated for sarcopenia using the 2019 Asian Sarcopenia Diagnostic Criteria, and patients with PD underwent standard assessments of motor symptoms and NMS. Multiple logistic regression and receiver operating characteristic (ROC) curve analyses were used to examine the association between sarcopenia and NMS in patients with PD. RESULTS: The incidence of sarcopenia was significantly higher in patients with PD than in HC (26.8% vs. 10.4%, p = 0.046). Multiple logistic regression analysis revealed that poorer sleep quality (odds ratio [OR]: 1.245; 95% confidence interval [CI]: 1.011-1.533; p = 0.040) and fatigue (OR: 1.085, 95% CI: 1.006-1.170, p = 0.034) were independently associated with sarcopenia. ROC analysis indicated that the optimal cut-off value for Pittsburgh Sleep Quality Index (PSQI) scores was 10, with 72.7% sensitivity and 74.4% specificity (area under the curve [AUC] = 0.776, 95% CI: 0.683-0.868, p < 0.001). The optimal cut-off value for Fatigue Severity Scale (FSS) scores was 39, with 87% sensitivity and 50% specificity (AUC = 0.725, 95% CI: 0.629 -0.820, p < 0.001). Joint use of FSS and PSQI scores increased the predictive value for sarcopenia(AUC = 0.804, 95% CI: 0.724-0.885, p < 0.001). CONCLUSION: Patients with PD are more susceptible to sarcopenia than healthy older adults, and fatigue and poorer sleep are positively associated with sarcopenia. Further longitudinal studies are needed to clarify the causal relationships.

Design, Synthesis, and Biological Activity of Chalcone Analogs Containing 4-Phenylquinolin and Benzohydrazide.

A series of chalcone derivatives (3a-3m) containing 4-phenylquinoline and benzohydrazide were designed and synthesized, and their anti-inflammatory, analgesic, and antidepressant activities were evaluated. Using the classic antidepressant model, except for compounds 3a and 3d, 11 compounds all showed certain antidepressant activity at a dose of 100 mg/kg, among which compounds 3f, 3h, and 3m showed good antidepressant activity (inhibition rate, respectively 63.0 %, 73.2 %, and 76.4 %), which was equivalent to the positive control fluoxetine (inhibition rate of 70.0 %). Secondly, the inhibitory activity of these compounds on mouse MAOA was evaluated. At 10 mM, compounds 3f and 3j showed a certain selective inhibitory effect on mouse MAOA , while compounds 3b, 3d, 3g, 3i, and 3m had a good inhibitory effect on mouse MAOA (inhibition rate is 42.3-71.4 %). The mouse ear edema model was used to evaluate the anti-inflammatory activity of compounds 3a-3m. At 30 mg/kg, compounds 3b, 3c, 3e, 3f, 3g, and 3m showed certain anti-inflammatory effects (inhibition rate of 51.5-99.9 %), which was equivalent to the positive control indomethacin (inhibition rate of 69.7 %). Results of the acetic acid-induced abdominal writhing test showed that, at 30 mg/kg, excepted for compounds 3a, 3b and 3d, all the other 10 compounds can show certain analgesic activity (inhibition rate 67-99.9 %). The use of Auto dock Vina (simina) to simulate molecular target docking shows that the development of quinoline and benzohydrazide groups is of great significance to MAOA inhibitors.

Luteolin inhibits the proliferation, adhesion, migration and invasion of choroidal melanoma cells in vitro.

Choroidal melanoma is a devastating disease that causes visual loss and a high mortality rate due to metastasis. Luteolin, a potential anticancer compound, is widely found in natural plants. The aim of this study was to evaluate the antiproliferative, antiadhesive, antimigratory and anti-invasive effects of luteolin on choroidal melanoma cells in vitro and to explore its potential mechanism. Cell counting kit-8 (CCK-8) assays, 5-ethynyl-2'-deoxyuridine (EdU) assays, Cell adhesion, migration, and invasion assays were performed to examine the inhibitory effects of luteolin on cell cell viability, proliferation, adhesion, migration and invasion capacities, respectively. Considering the correlation between Matrix metalloenzymes and tumor metastasis, Enzyme-linked immunosorbent assays (ELISAs) were used to assess matrix metalloproteases MMP-2 and MMP-9 secretion. Western blotting was performed to detect p-PI3K P85, Akt, and p-Akt protein expression. The cytoskeletal proteins vimentin were observed with cell immunofluorescence staining. Luteolin can inhibit OCM-1 cell proliferation, migration, invasion and adhesion and C918 cell proliferation, migration, and invasion through the PI3K/Akt signaling pathway. Therefore, Luteolin may have potential as a therapeutic medication for Choroidal melanoma.

Interaction of WBP2 with ERα increases doxorubicin resistance of breast cancer cells by modulating MDR1 transcription.

BACKGROUND: Surgery combined with new adjuvant chemotherapy is the primary treatment for early stage invasive and advanced stage breast cancer. Growing evidence indicates that patients with ERα-positive breast cancer show poor response to chemotherapeutics. However, ERα-mediated drug-resistant mechanisms remain unclear. METHODS: Levels of WW domain-binding protein 2 (WBP2) and drug-resistant gene were determined by western blotting and RT-PCR, respectively. Cell viability was measured by preforming MTT assay. CD243 expression and apoptosis rate were evaluated by flow cytometry. Interactions of WBP2/ERα and ERα/MDR1 were detected by co-immunoprecipitation and chromatin immunoprecipitation (ChIP) assay, respectively. RESULTS: There was an intrinsic link between WBP2 and ERα in drug-resistant cancer cells. Upregulation of WBP2 in MCF7 cells increased the chemoresistance to doxorubicin, while RNAi-mediated knockdown of WBP2 in MCF7/ADR cells sensitised the cancer cells to doxorubicin. Further investigation in in vitro and in vivo models demonstrated that WBP2 expression was directly correlated with MDR1, and WBP2 could directly modulate MDR1 transcription through binding to ERα, resulting in increased chemotherapy drug resistance. CONCLUSIONS: Our finding provides a new mechanism for the chemotherapy response of ERα-positive breast tumours, and WBP2 might be a key molecule for developing new therapeutic strategies to treat chemoresistance in breast cancer patients.

The Wnt-ß-catenin pathway represses let-7 microRNA expression through transactivation of Lin28 to augment breast cancer stem cell expansion.

Wnt signalling through ß-catenin and the lymphoid-enhancing factor 1/T-cell factor (LEF1/TCF) family of transcription factors maintains stem cell properties in both normal and malignant tissues; however, the underlying molecular pathway involved in this process has not been completely defined. Using a microRNA microarray screening assay, we identified let-7 miRNAs as downstream targets of the Wnt-ß-catenin pathway. Expression studies indicated that the Wnt-ß-catenin pathway suppresses mature let-7 miRNAs but not the primary transcripts, which suggests a post-transcriptional regulation of repression. Furthermore, we identified Lin28, a negative let-7 biogenesis regulator, as a novel direct downstream target of the Wnt-ß-catenin pathway. Loss of function of Lin28 impairs Wnt-ß-catenin-pathway-mediated let-7 inhibition and breast cancer stem cell expansion; enforced expression of let-7 blocks the Wnt-ß-catenin pathway-stimulated breast cancer stem cell phenotype. Finally, we demonstrated that the Wnt-ß-catenin pathway induces Lin28 upregulation and let-7 downregulation in both cancer samples and mouse tumour models. Moreover, the delivery of a modified lin28 siRNA or a let-7a agomir into the premalignant mammary tissues of MMTV-wnt-1 mice resulted in a complete rescue of the stem cell phenotype driven by the Wnt-ß-catenin pathway. These findings highlight a pivotal role for Lin28/let-7 in Wnt-ß-catenin-pathway-mediated cellular phenotypes. Thus, the Wnt-ß-catenin pathway, Lin28 and let-7 miRNAs, three of the most crucial stem cell regulators, connect in one signal cascade.

Agrin-Lrp4 pathway in hippocampal astrocytes restrains development of temporal lobe epilepsy through adenosine signaling.

BACKGROUND: Human patients often experience an episode of serious seizure activity, such as status epilepticus (SE), prior to the onset of temporal lobe epilepsy (TLE), suggesting that SE can trigger the development of epilepsy. Yet, the underlying mechanisms are not fully understood. The low-density lipoprotein receptor related protein (Lrp4), a receptor for proteoglycan-agrin, has been indicated to modulate seizure susceptibility. However, whether agrin-Lrp4 pathway also plays a role in the development of SE-induced TLE is not clear. METHODS: Lrp4f/f mice were crossed with hGFAP-Cre and Nex-Cre mice to generate brain conditional Lrp4 knockout mice (hGFAP-Lrp4-/-) and pyramidal neuron specific knockout mice (Nex-Lrp4-/-). Lrp4 was specifically knocked down in hippocampal astrocytes by injecting AAV virus carrying hGFAP-Cre into the hippocampus. The effects of agrin-Lrp4 pathway on the development of SE-induced TLE were evaluated on the chronic seizure model generated by injecting kainic acid (KA) into the amygdala. The spontaneous recurrent seizures (SRS) in mice were video monitored. RESULTS: We found that Lrp4 deletion from the brain but not from the pyramidal neurons elevated the seizure threshold and reduced SRS numbers, with no change in the stage or duration of SRS. More importantly, knockdown of Lrp4 in the hippocampal astrocytes after SE induction decreased SRS numbers. In accord, direct injection of agrin into the lateral ventricle of control mice but not mice with Lrp4 deletion in hippocampal astrocytes also increased the SRS numbers. These results indicate a promoting effect of agrin-Lrp4 signaling in hippocampal astrocytes on the development of SE-induced TLE. Last, we observed that knockdown of Lrp4 in hippocampal astrocytes increased the extracellular adenosine levels in the hippocampus 2 weeks after SE induction. Blockade of adenosine A1 receptor in the hippocampus by DPCPX after SE induction diminished the effects of Lrp4 on the development of SE-induced TLE. CONCLUSION: These results demonstrate a promoting role of agrin-Lrp4 signaling in hippocampal astrocytes in the development of SE-induced development of epilepsy through elevating adenosine levels. Targeting agrin-Lrp4 signaling may serve as a potential therapeutic intervention strategy to treat TLE.

NRG1-ErbB4 signaling in the medial amygdala controls mating motivation in adult male mice.

Motivation-driven mating is a basic affair for the maintenance of species. However, the underlying molecular mechanisms that control mating motivation are not fully understood. Here, we report that NRG1-ErbB4 signaling in the medial amygdala (MeA) is pivotal in regulating mating motivation. NRG1 expression in the MeA negatively correlates with the mating motivation levels in adult male mice. Local injection and knockdown of MeA NRG1 reduce and promote mating motivation, respectively. Consistently, knockdown of MeA ErbB4, a major receptor for NRG1, and genetic inactivation of its kinase both promote mating motivation. ErbB4 deletion decreases neuronal excitability, whereas chemogenetic manipulations of ErbB4-positive neuronal activities bidirectionally modulate mating motivation. We also identify that the effects of NRG1-ErbB4 signaling on neuronal excitability and mating motivation rely on hyperpolarization-activated cyclic nucleotide-gated channel 3. This study reveals a critical molecular mechanism for regulating mating motivation in adult male mice.

Research Progress on Gene Synthesis and Anticancer and Lipid-lowering Mechanism of Monacolin K.

Monacolin K (MK), also known as lovastatin (LOV), is a secondary metabolite synthesized by Monascus in the later stage of fermentation and is the main component of functional red yeast rice (RYR). The structure of MK is similar to 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), and it can competitively bind to 3-hydroxy-3- methylglutaryl coenzyme A reductase (HMGCR), thus reducing the level of blood lipids. MK can affect the expression of MAPK, PI3K/AKT, and NF-κB pathway, prepare conjugates with other compounds, and enhance the sensitivity of cancer cells to chemotherapeutic drugs so as to induce apoptosis of acute myeloid leukemia, prostate cancer, breast cancer, lung cancer, gastric cancer, and liver cancer. Combined with the synthetic route of MK, this paper summarizes the latest lipid-lowering and anticancer mechanism of MK, and provides a reference for the application of MK in medicine.

New striatal neurons form projections to substantia nigra in adult rat brain after stroke.

Previous studies have demonstrated that newborn striatal neurons can functionally integrate with local neural networks in adult rat brain after injury. In the present study, we determined whether these newly generated striatal neurons can develop projections to the substantia nigra, a target of striatal projection neurons. We used 5'-bromodeoxyuridine (BrdU) and a retroviral vector expressing green fluorescent protein (GFP) combined with multiple immunostaining labels of newborn striatal neurons, and nigral microinjection of fluorogold (FG) to trace the striatonigral projection in adult rat brain at different weeks following a transient middle cerebral artery occlusion (MCAO). We found that FG positive (FG(+)) cells could be detected in newly generated neurons (BrdU(+)-NeuN(+) and GFP(+)-NeuN(+)) in ipsilateral striatum clearly at 12, but not 2 weeks after MCAO. The data suggest that ischemia-induced newborn striatal projection neurons could form long axons that targeted the substantia nigra (striatonigral projection pathway) and that have intact axonal transport from the nerve terminal to cell body. These new striatal neurons express glutamate NR2 and dopamine D2L receptors, which form the molecular basis for responding to the inputs from cortical glutamatergic and nigral dopaminergic projection neurons. Our data provide the first morphological evidence that newborn neurons in the striatum, a non-neurogenic region, can establish new striatonigral neural circuits, important pathways for the maintenance of motor function. These results help us to understand endogenous cellular mechanisms of brain repair, and suggest that increasing adult neurogenesis could be a practical strategy for enhancing the efficacy of rehabilitative therapy in stroke patients.

Expression and clinical significance of extracellular matrix protein 1 and vascular endothelial growth factor-C in lymphatic metastasis of human breast cancer.

BACKGROUND: Extracellular matrix protein 1 (ECM1) and vascular endothelial growth factor-C (VEGF-C) are secretory glycoproteins that are associated with lymphangiogenesis; these proteins could, therefore, play important roles in the lymphatic dissemination of tumors. However, very little is known about their potential roles in lymphangiogenesis. The aim of this study was to investigate whether correlations exist between ECM1 and VEGF-C in human breast cancer, lymphangiogenesis, and the clinicopathological characteristics of the disease. METHODS: ECM1 and VEGF-C mRNA and protein expression levels in 41 patients were investigated using real-time reverse transcriptase polymerase chain reaction (RT-PCR), or immunohistochemical (IHC) staining of breast cancer tissue, matched noncancerous breast epithelial tissues, and suspicious metastatic axillary lymph nodes. D2-40 labelled lymph vessels and lymphatic microvessel density (LMVD) were counted. Correlations between ECM1 or VEGF-C protein expression levels, LMVD, and clinicopathological parameters were statistically tested. RESULTS: The rate of ECM1 positive staining in breast cancer tissues was higher (31/41, 75.6%) than that in the corresponding epithelial tissues (4/41, 9.8%, P < 0.001) and lymph nodes (13/41, 31.7%, P < 0.001). Similarly, the VEGF-C expression rate in cancer specimens was higher (33/41, 80.5%) than in epithelial tissues (19/41, 46.3%, P < 0.01) or lymph nodes (15/41, 36.6%, P < 0.01). Higher ECM1 and VEGF-C mRNA expression levels were also detected in the tumor tissues, compared to the non-cancerous tissue types or lymph nodes (P < 0.05). ECM1 protein expression was positively correlated with the estrogen receptor status (P < 0.05) and LMVD (P < 0.05). LMVD in the ECM1- and VEGF-C-positive tumor specimens was higher than that in the tissue types with negative staining (P < 0.05). CONCLUSIONS: Both ECM1 and VEGF-C were overexpressed in breast cancer tissue samples. ECM1 expression was positively correlated with estrogen responsiveness and the metastatic properties of breast cancer. We conclude, therefore, that ECM1 and VEGF-C may have a synergistic effect on lymphangiogenesis to facilitate lymphatic metastasis of breast cancer.

A new method of spermatic cord mobilization in herniorrhaphy.

Spermatic cord mobilization is a routine part of inguinal hernia repair, but the method of cord mobilization varies among surgeons. This study establishes an anatomic plane for spermatic cord mobilization. We studied the anatomy of the superficial cremasteric fascia in 105 male patients during herniorrhaphy for primary inguinal hernias. The mean patient age was 44.8 (18-71) years and mean body mass index was 24.1 kg/m(2) (21.5-27.1 kg/m(2)). The two layers of the superficial cremasteric fascia between the spermatic cord and the inguinal falx were incised to mobilize the cord. We found that spermatic cord mobilization during herniorrhaphy can be easily approached through an anatomic plane between the spermatic cord and the conjoined tendon with subsequent division of the superficial cremasteric fascia. None of the patients experienced any hemorrhage or nerve injury during cord mobilization. We found this method to be both safe and easy to learn.

A pH-activated fluorescent probe via transformation of azo and hydrazone forms for lysosomal pH imaging.

We developed a fluorescent probe Sth-NH by introducing a 6-hydroxypyridone skeleton. The presence of an active proton enables the probe to transform from a deprotonated azo form to a hydrazone form in a strongly acidic environment to realize fluorescence light-up behavior, thus monitoring the lower lysosomal pH of cancer cells and distinguishing them from normal cells.

Rational design of a fluorescent probe for specific sensing of hydrogen peroxide/glucose and intracellular imaging applications.

A new type of dye with advantages of high selectivity and sensitivity is formed by using the strategy of hybridization between the luminescent unit and recognition unit. Based on this strategy, we exploit a novel dye bonding the benzopyrylium salt as a luminescent unit and phenylboronate group as a response site, which is served as a fluorescent probe 1 for specific recognition of hydrogen peroxide in biological application. Probe 1 employs a unique recognition switch, phenylboronate unit, to"turn-on"a highly specific and rapid fluorescence response toward hydrogen peroxide combined with the 1,6-rearrangement elimination reaction strategy. Meanwhile, probe 1 has the ability to glucose assay by taking advantage of glucose oxidase/glucose enzymatic reaction. What's more, the probe 1 is capable of tracking endogenous hydrogen peroxide in living cells and intracellular imaging. Therefore, the newly developed bioprobe 1 is expected to be used to monitor hydrogen peroxide and glucose levels in complex organisms.

Antioxidant, Anti-inflammatory, Antibacterial, and Analgesic Activities and Mechanisms of Quinolines, Indoles and Related Derivatives.

Quinoline, isoquinoline, and indoles are common heterocyclic compounds. They have many biological activities, such as antioxidant, anti-inflammatory, antibacterial, antitumor, anti-virus, anti-rheumatism, immunity regulation, expectorant, and analgesic. Over the past few centuries, traditional natural products have made great contributions to the discovery and development of new therapeutic agents. Many important drugs have been found from these three classes of compounds. In this mini-review, we mainly cover the research progress on antioxidant, anti-inflammatory, antibacterial, analgesic activities of quinoline, isoquinoline, and indole compounds over the past 20 years (2000- 2019). We aim to explore new characteristic groups or structures in the search for active lead compounds and provide a basis for rational drug design.

Hepatitis C virus induces oxidative stress, DNA damage and modulates the DNA repair enzyme NEIL1.

BACKGROUND AND AIMS: Hepatitis C virus (HCV)-induced chronic inflammation may induce oxidative stress which could compromise the repair of damaged DNA, rendering cells more susceptible to spontaneous or mutagen-induced alterations, the underlying cause of liver cirrhosis and hepatocellular carcinoma. In the current study we examined the induction of reactive oxygen species (ROS) resulting from HCV infection and evaluated its effect on the host DNA damage and repair machinery. METHODS: HCV infected human hepatoma cells were analyzed to determine (i) ROS, (ii) 8-oxoG and (iii) DNA glycosylases NEIL1, NEIL2, OGG1. Liver biopsies were analyzed for NEIL1. RESULTS: Human hepatoma cells infected with HCV JFH-1 showed 30-60-fold increases in ROS levels compared to uninfected cells. Levels of the oxidatively modified guanosine base 8-oxoguanine (8-oxoG) were significantly increased sixfold in the HCV-infected cells. Because DNA glycosylases are the enzymes that remove oxidized nucleotides, their expression in HCV-infected cells was analyzed. NEIL1 but not OGG1 or NEIL2 gene expression was impaired in HCV-infected cells. In accordance, we found reduced glycosylase (NEIL1-specific) activity in HCV-infected cells. The antioxidant N-acetyl cystein (NAC) efficiently reversed the NEIL1 repression by inhibiting ROS induction by HCV. NEIL1 expression was also partly restored when virus-infected cells were treated with interferon (IFN). HCV core and to a lesser extent NS3-4a and NS5A induced ROS, and downregulated NEIL1 expression. Liver biopsy specimens showed significant impairment of NEIL1 levels in HCV-infected patients with advanced liver disease compared to patients with no disease. CONCLUSION: Collectively, the data indicate that HCV induction of ROS and perturbation of NEIL1 expression may be mechanistically involved in progression of liver disease and suggest that antioxidant and antiviral therapies can reverse these deleterious effects of HCV in part by restoring function of the DNA repair enzyme/s.

Laparoscopic versus open appendectomy: a prospective randomized comparison.

BACKGROUND: Whether laparoscopy offers a benefit over open surgery in the management of acute appendicitis or not remains a subject of controversy despite the publication of numerous randomized studies. This study aimed to compare laparoscopic appendectomy (LA) with open appendectomy (OA) and to ascertain its therapeutic benefit. METHODS: Adult patients older than 14 years presenting with signs and symptoms suggestive of acute appendicitis were randomized to undergo either LA or OA from January 2006 to December 2007. Comparisons were based on operating time, time until return to a general diet, time until return to normal activity and work, length of hospital stay, billed charges, and postoperative complications. RESULTS: The study enrolled 220 patients: 108 to undergo OA and 112 to undergo LA. The groups were similar in terms of clinicopathologic characteristics. The operating time seemed to be shorter for the OA patients than for the LA patients, but the difference was not significant (LA, 30 +/- 15.2 min vs. OA, 28.7 +/- 16.3 min; p > 0.05). The hospital stay of 4.1 +/- 1.5 days for the LA group and 7.2 +/- 1.7 days for the OA group, and the difference was statistically significant (p < 0.05). Laparoscopic appendectomy remained associated with a shorter time until return to a general diet (LA, 20.2 +/- 12.4 h vs. OA, 36.5 +/- 10 h; p < 0.05), to normal activity (LA, 9.1 +/- 4.2 days vs. OA, 13.7 +/- 5.8 days; p < 0.05), and to work (LA, 21.2 +/- 3.5 days vs. OA, 27.7 +/- 4.9 days; p < 0.05). The billed charges appeared to be higher for LA (LA, 5,720.3 +/- 115.7 yuan vs. OA, 5,310 +/- 575.4 yuan), but this difference failed to be clinically important or statistically significant (p > 0.05). Wound infections were more common after OA (n = 14) than after LA (n = 0) (p < 0.05). Intraabdominal abscesses occurred for two patients in the LA group and nine patients in the OA group (p < 0.05). Postoperative ileus occurred with frequencies of 0% in the LA group and 7.4% in the OA group (p < 0.05). The rate for overall complications was significantly lower in the LA group. CONCLUSION: Laparoscopic appendectomy is a useful tool in the treatment of acute appendicitis. Its advantages lie in its minimal invasiveness, its better cosmetic outcome, its lower rate of complications based on surgical expertise and state-of-the-art equipment. It can be recommended as an adoptable method for the routine patient with appendicitis.

Bioinformatics analysis revealed hub genes and pathways involved in sorafenib resistance in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is increasingly known as a serious, worldwide public health concern. Sorafenib resistance is the main challenge faced by many advanced HCC patients. The specific mechanisms of sorafenib resistance remind unclear. In the current study, GEO2R was conducted to identify differentially expressed genes (DEGs) between sorafenib-resistant samples and the control group by using RNA-sequence analysis and analyzing dataset GSE109211. Next, protein-protein interaction (PPI) network was built to explore key targets proteins in sorafenib-resistant HCC. Furthermore, gene ontology (GO) analysis was used to research the underlying roles of key proteins. Moreover, the Kaplan-Meier survival analysis was performed to display the effect of key proteins on overall survival in HCC. Western blotting was performed to detected resistance-related proteins and CCK-8 assay was employed to measured cell viability. In the present research, 164 sorafenib resistance-related DEGs in HCC were identified by using RNA-sequence analysis and analyzing the dataset GSE109211. GO analysis revealed DEGs were involved in regulating multiple biological processes and molecular functions. DYNLL2, H2AFJ, SHANK2, ZWILCH, CDC14A, IFT20, MTA3, SERPINA1 and TCF4 were confirmed as key genes in this process. Moreover, our study showed Akt signaling was aberrantly activated and inhibition of Akt signaling enhanced anti-tumor capacity of sorafenib in sorafenib-resistant HCC cells. Identification of the DEGs in sorafenib resistant HCC cells may further provide the new insights of underlying sorafenib-resistant mechanisms and offer latent targets for early diagnosis and new therapies to improve clinical efficacy for sorafenib-resistant HCC patients.

[Effects of different disturbance patterns on stand structure of infected pure Pinus massoniana plantation]. / 不同干扰模式对受害马尾松人工纯林林分结构的影响.

To explore the effects of different disturbance patterns on restoring the health of an infected stand, concentrated disturbance of not cutting trees before 10 years after infection, mode-rate disturbance of cutting infected pine trees, and strong distrubance of cutting infected pine trees, the neighboring trees and poorly growing pine trees were compared in a pure Pinus massomiana plantation infected by Bursaphelenchus xylophlius in Anji, Zhejiang, China. After 16 years, the importance values of P. massoniana in the three treatments were: concentrated disturbance > mode-rate disturbance > strong disturbance. However, the importance values of broad-leaved trees showed the opposite trend. Compared with the concentrated disturbance, the average DBH of P. massoniana in the moderate and strong disturbance treatments were 1.2 and 1.7 times higher, respectively, and those of broad-leaved species were 1.3 and 1.9 times higher, respectively. The average height of pine trees in the moderate and strong disturbance treatments increased 1.5 and 2.0 times, respectively, and those of broad-leaved species 1.2 and 1.8 times, respectively. The tree volume per hectare in moderate and strong disturbance treatments were 5.2 and 3.8 times that of concentrated disturbance treatment, respectively. In the moderate and strong disturbance treatments, the number of trees in each diameter class was greater than in the concentrated disturbance treatment. The stand diameter distribution in the multi-storied moderate and strong disturbance treatments followed an inverse J-shaped curve. The species richness and biodiversity were significantly higher in the mode-rate and strong disturbance treatments than in the concentrated disturbance treatment. The individual size inequality and structural complexity indices followed the order of moderate disturbance > strong disturbance > concentrated disturbance. Under moderate and strong disturbance treatments, the single-storied and evenly aged pure P. massoniana plantation became multi-storied and unevenly aged mixed stands. All the three disturbance patterns promoted the succession of broad-leaved trees, with the pace of succession in the order of strong disturbance > moderate disturbance > concentrated disturbance. In conclusion, moderate disturbance achieved better restoration. Thinning pure P. massoniana plantation could accelerate the succession of a mixed stand to enhance resistance against Bursaphelenchus xylophlius invasion.

Gene polymorphisms and circulating levels of the TNF-alpha are associated with ischemic stroke: A meta-analysis based on 19,873 individuals.

OBJECTIVE: Numerous studies have investigated associations of gene polymorphisms and circulating levels of TNF-α with ischemic stroke (IS), but the results were controversial. The aims of this study were to systematically evaluate these associations. METHODS: Relevant publications were retrieved by searching databases. Odds ratios (ORs) and standard mean differences (SMDs) with 95% confidence intervals (95% CIs) were used to assess the association of the TNF-α gene and cytokine with IS, respectively. The Cochrane Q test and I2 statistic were used to test heterogeneity. Subgroup analysis and publication bias were performed. RESULTS: 25 and 9 articles examined the association of polymorphisms and levels of the TNF-α with IS risk, respectively. Rs1800629 polymorphism was associated with IS susceptibility (OR (95% CI) =0.82 (0.72, 0.95)), especially in Asians (OR (95% CI) =0.75 (0.63, 0.89)); and rs1800610 was associated with IS susceptibility in Asians patients (OR (95% CI) =1.54 (1.31, 1.80)). While rs361525, rs1799964 and rs1799724 polymorphisms were not associated with IS susceptibility. The TNF-α level was elevated in IS patients (SMD (95% CI) =0.65 (0.29, 1.01)) including Asians (SMD (95% CI) =1.26 (0.49, 2.03)) and Caucasians (SMD (95% CI) =0.26 (0.03, 0.49)). In addition, increased level occurred in patients' serum (SMD (95% CI) =0.54 (0.08, 1.01)). CONCLUSIONS: Rs1800629 and rs1800610 polymorphisms were elucidated to be a protective factor for IS (especially in Asians) and a risk factor for Asians patients, respectively. The TNF-α level was elevated in IS, indicating that TNF-α plays an important role in the pathogenesis of IS and is a promising therapeutic target for IS.