Modified transcrestal sinus floor elevation with concomitant implant placement in edentulous posterior maxillae with residual bone height of 5 mm or less: a non-controlled prospective study.

The aim of this study was to describe a modified transcrestal sinus floor elevation (mTSFE) technique and to evaluate its clinical effectiveness and reliability when residual bone height is severely reduced. Forty-three maxillary edentulous patients who met the inclusion criteria were enrolled. All patients underwent the mTSFE technique; 66 dental implants were inserted simultaneously. Patient-reported outcomes were assessed 2 weeks after surgery. Prosthetic crowns were placed 6 months after surgery. Radiographic analyses and clinical analyses were conducted to assess the clinical effectiveness and feasibility of mTSFE during a follow-up period of 2-8 years. The mean vertical bone increase after surgery was 8.09 mm, and it decreased to 6.56 mm at 6 months after surgery. Two cases of membrane perforation occurred during surgery and one implant was lost in the third year after surgery; the survival rate at the implant level was 98.48%. No severe postoperative complication was reported and the subjective feeling of patients was acceptable. This mTSFE technique could simplify the operative procedure and might be helpful to reduce intraoperative trauma, as well as to alleviate postoperative discomfort.

[Significance of molecular classification in fertility-sparing treatment of endometrial carcinoma and atypical endometrial hyperplasia].

Objective: To investigate the molecular classification of endometrial carcinoma (EC) and atypical endometrial hyperplasia (AEH) treated with fertility-sparing therapy, and to analyze its relationship with clinicopathological factors and treatment efficacy. Methods: A total of 46 EC and AEH patients who received fertility-sparing therapy and molecular classification tested by next generation sequencing in Peking University People's Hospital from June 2020 to December 2021, were retrospectively collected. The relationships between molecular classification and clinicopathological factors and treatment outcomes were analyzed. Results: (1) Of the 46 patients, including 40 EC and 6 AEH patients, 32 cases (71%, 32/45) had complete response (CR) after treatment, with median CR time of 8 months, 6 cases (13%, 6/45) had partial response, and 8 cases (25%, 8/32) had recurrence. (2) The cases were distributed as no specific molecular profile (NSMP) 34 cases (74%, 34/46) subtype mainly, high microsatellite instability (MSI-H) 7 cases (15%, 7/46), POLE ultra-mutated 3 cases (7%, 3/46), and copy number high (CNH) 2 cases (4%, 2/46). Patients with CNH had the hightest serum cancer antigen 125 (CA125) level [(34.3±35.2) kU/L]. MSI-H subtype had more family history of tumors (6/7), more with loss of mismatch repair (MMR) protein expression by immunohistochemical (7/7), and higher nuclear antigen associated with cell proliferation (Ki-67) expression level (3/3). (3) Patients in MSI-H subgroup had the lowest CR rate at 6 months (0/6; P=0.019), and survival analysis showed that they were less likely to achieve CR than those with NSMP subtype (P=0.022). Subgroup analysis of patients with NSMP showed that age ≥30 years related with longer treatment time to CR (P=0.010). In addition, CR was obtained after treatment in 2/3 POLE ultra-mutated cases and 2/2 CNH, respectively. Conclusions: Molecular classification relates with the treatment response in patients with EC and AEH treated with fertility-sparing therapy. Patients with MSI-H subtype have poor treatment efficacy, and patients with NSMP need to be further studied and predict treatment benefit. However, there are few cases in POLE ultra-mutated and CNH subtypes, which need further clinical research.

[Clinical outcomes of simultaneous bilateral endoscopic surgery for bilateral upper urinary tract calculi].

OBJECTIVE: To discuss the efficacy and safety of simultaneous bilateral endoscopic surgery (SBES) for bilateral upper urinary tract calculi, and to summarize the initial experience. METHODS: Patients diagnosed with bilateral upper urinary tract calculi who underwent SBES in the Department of Urology, Beijing Chao-Yang Hospital from January 2019 to January 2020 were enrolled retrospectively. The demographic and clinical data of the patients were recorded, and the operation status, stone free rate (SFR) and peri-operative complications were analyzed. The primary end point was SFR, and second end point was peri-operative complications. RESULTS: A total of 23 patients underwent SBES, of which SBES was completed in 19 patients (12 males, and 7 females). The mean age was (41.3±12.0) years. Fourteen patients underwent modified supine position surgery and 4 patients in prone split-leg position. There was no statistical difference in the demographic and baseline clinical data of the patients in different positions. One patient underwent right percutaneous nephrolithotomy (PCNL) and left endoscopic combined intra-renal surgery (ECIRS) in the prone split-leg position, while 18 patients received simul-taneous surgery with PCNL and contralateral retrograde intra-renal surgery (RIRS). The mean anesthesia and operation time was (128.7±26.5) min and (70.7±20.3) min, respectively, which was significantly longer in the patients with prone split-leg position than in the patients with modified supine position, anesthesia time in the patients with prone split-leg position and modified supine position: (148.4±20.4) min vs. (121.6±25.3) min, respectively, t=－2.121, P=0.049, while the operation time in the patients with prone split-leg position and modified supine position: (86.4±21.1) min vs. (65.1±17.4) min, respectively, t=－2.222, P=0.040. There was no significant difference between the two groups in indwelling of nephrostomy [prone split-leg position and modified supine position: (2.6±0.9) d vs. (2.1±1.0) d, respectively; t=－0.880, P=0.391] and the length of hospital stay [prone split-leg position and modified supine position: (6.0±2.7) d vs. (5.2±1.8) d, respectively; t=－0.731, P=0.475]. One month after the operation, the SFR was 78.9%, and 3 patients had minor peri-operative complications (Clavien-Dindo grades Ⅰ/Ⅱ) without any serious complications (Clavien-Dindo grades Ⅲ/Ⅳ/Ⅴ). CONCLUSION: The simultaneous bilateral endoscopic surgery would decrease the operation time and anesthesia exposure under the premise of ensuring the SFR, which is helpful to reduce the risk of peri-operative complications, especially to the patients who can not tolerate the second-stage or long-time operation.

[Endoscopic combined ultrasound-guided access vs. ultrasound-guided access in endoscopic combined intrarenal surgery].

OBJECTIVE: To compare the outcomes of endoscopic combined ultrasound-guided access (EUGA) with the conventional ultrasound-guided access (UGA) to achieve percutaneous renal access in endoscopic combined intrarenal surgery (ECIRS). METHODS: A retrospective review of 53 patients undergoing ECIRS to treat upper urinary tract calculi between January 2017 and October 2019 was con-ducted. All of the cases were of complex upper urinary tract stones larger than 2 cm in diameter. The com-plex stone situations, such as multiple renal calyces calculi or staghorn calculi necessitated ECIRS. Under general anesthesia, the patients were placed in the galdakao-modified supine valdivia (GMSV) position, thus allowing both antegrade and retrograde accesss. The patients were divided to UGA and EUGA groups according to the protocol of achieving percutaneous renal access. In 28 cases, endoscopic combined ultrasound-guided accesss were obtained. Puncture and dilation were performed under direct flexible ureteroscopic visualization, while percutaneous renal access of 25 cases were performed with the conventional technique employing ultrasound guidance. Demographic and perioperative information, such as stone burden, presence of hydronephrosis and number of calyces involved was compared. Primary outcomes included total operative time, renal access time, repeat puncture, hemoglobin level, perioperative complications, and stone-free rate. RESULTS: No major intra-operative complication was recorded in all the 53 ECRIS. No significant difference was observed between the groups in age and gender. There was no significant difference in body mass index[BMI (29.21±3.14) kg/m2 vs.(28.53±2.56) kg/m2], stone burden (37.68±6.89) mm vs. (35.53±6.52) mm, number of calyces involved 2.72±0.68 vs. 2.86±0.71, presence of hydronephrosis (56.0% vs. 46.4%), total operative time (93.0±12.2) min vs. (96.8±14.2) min, hemoglobin level reduction (6.56±2.16) g/L vs. 97.54±2.64) g/L, stone-free rate (92.0% vs. 92.8%), hospital stay (5.52±0.59) d vs. (5.64±0.62) d, perioperative complication rate (8.0% vs. 7.2%). Two patients in EUGA group experienced perioperative complications (one urinary tract infection and one hematuria) while two patients in UGA group experienced perioperative urinary tract infection. None in both groups received blood transfusion. The patients undergoing EUGA had shorter renal access time [(4.0±0.7) min vs. (6.8±2.6) min, P < 0.01] and less repeat puncture (0 vs. 4 cases, P < 0.05). CONCLUSION: EUGA is an optimal technique to establish percutaneous renal access in ECIRS, which minimizes access time and repeated procedures.

Down-regulation of long noncoding RNA PGM5-AS1 correlates with tumor progression and predicts poor prognosis in clear cell renal cell carcinoma.

OBJECTIVE: Growing studies have shown that long non-coding RNAs (lncRNAs) have critical regulatory roles in tumorigenesis. Recently, a newly identified lncRNA, Homo sapiens PGM5 antisense RNA 1 (PGM5-AS1), was found to be dysregulated in several tumors. However, its roles in clear cell renal cell carcinoma (ccRCC) have not been investigated. The aim of the present study was to clarify the clinical significance of PGM5-AS1 in ccRCC patients. PATIENTS AND METHODS: The PGM5-AS1 expression levels were evaluated in 182 primary ccRCC patients using quantitative real-time PCR assays. The associations between expression of PGM5-AS1, clinicopathological parameters, and prognosis of ccRCC were examined using Chi-square test, Kaplan-Meier assays, and multivariate assays. RESULTS: The expressions of PGM5-AS1 in cancer specimens were lower than those in matched non-tumor specimens from the ccRCC patient (p<0.05). Downregulation of PGM5-AS1 was closely associated with more advanced clinical features, including lymph nodes metastasis (p=0.007) and distant metastasis (p=0.037). A clinical study revealed that ccRCC patients with lower PGM5-AS1 expressions had substantially shorter overall survival (OS) and disease-free survival (DFS) than patients with higher PGM5-AS1 expressions. Further multivariate assays demonstrated that PGM5-AS1 was identified as an independent prognostic factor for patients with ccRCC. CONCLUSIONS: Down-regulation of PGM5-AS1 in ccRCC tissues had a strong association with unfavorable outcomes and PGM5-AS1 might be a potential tumor suppressor.

[Effects of occupational noise exposure on asymmetric hearing loss in automobile manufacturing workers].

Objective: To investigate the characteristics of asymmetric hearing loss in automobile manufacturing workers and the effect of occupational noise exposure on asymmetric hearing loss. Methods: A cross-sectional approach was used in this study. From March 2017 to February 2018, Subjects (7066) from four complete vehicle factories were given a pure tone audiometry (Hearing thresholds were measured at frequencies of 0.5, 1, 2, 3, 4 and 6 kHz in each ear) and were required to complete a health-related information questionnaire. According to the inclusion criteria, a total of 6339 workers were selected. The mean hearing thresholds for the left and right ears at overall frequencies were compared using the repeated means analysis of variance (ANOVA) test. The threshold differences at each frequency were compared using paired t tests. Results: The overall mean left minus right threshold difference across all frequencies was determined to be 0.58 dB, which met statistical significance (P<0.01) . Hearing threshold in the left ear was statistically significantly higher compared with the right ear at each frequency. The differences between binaural threshold shifts at each frequency among subjects with a asymmetry in terms of worse left ear and worse right ear were at the range of 6.17-9.87 dB and 6.39-10.92 dB, respectively. Hearing threshold in the left ear was statistically significantly higher compared with the right ear at only 2, 3 kHz of subjects with high-frequency hearing threshold shifts (HFHTs) more than 25 dB. Hearing threshold in the left ear was statistically significantly higher compared with the right ear at only 3 kHz of subjects with high-frequency hearing threshold shifts (HFHTs) more than 30 dB. With the increase of HFHTs, the proportion of subjects with a asymmetry at 2 and 3 kHz of more than 10 dB in terms of worse left ear and worse right ear increased. Conclusion: The average hearing threshold of the left ear across overall frequencies is higher compared with the right ear, the proportion of the cases with a higher left ear hearing threshold is higher that that of the cases with a higher right ear hearing threshold. As hearing loss caused by occupational noise exposure getting worse, the proportion of the cases with a higher left ear hearing threshold and the cases with a higher right ear hearing threshold may tent to be the same.

Drug efficacies on bone mineral density and fracture rate for the treatment of postmenopausal osteoporosis: a network meta-analysis.

OBJECTIVE: Globally, a great number of elderly suffer from osteoporosis, especially postmenopausal women. Osteoporosis results in low bone mineral density (BMD) and high risk of fragility fracture. However, there is no defined strategy to select the most suitable anti-osteoporotic drugs for osteoporosis patients. Therefore, this study aims to select the most effective anti-osteoporotic drug for postmenopausal women with osteoporosis. MATERIALS AND METHODS: Literature search was conducted in PubMed, EMBASE, and the Cochrane Library. Raw data from the related randomized clinical trials were extracted. A pairwise and network meta-analysis model was utilized to assess the efficacy of ten drugs on the percentage change of BMD in the lumbar spine and total hip from baseline to one year of treatment. Risks of vertebral fracture and non-vertebral fracture were evaluated as well. We reported the effect size with a weighted mean difference (WMD) for continuous outcomes and odds ratio (OR) for dichotomous outcomes. All the drugs were ranked based on the surface under the cumulative ranking curve (SUCRA) value. Furthermore, the heterogeneity, consistency and publication bias of enrolled literature were assessed. RESULTS: With regard to lumbar spine BMD, the ten selected drugs all showed significant efficacy compared with placebo. In regard to total hip BMD and vertebral fracture, with the exception of calcitonin, the remaining nine drugs all showed significant efficacy compared with placebo. Six drugs - abaloparatide, alendronate, risedronate, strontium ranelate, teriparatide, and zoledronate - were significantly more effective compared with placebo for the treatment of non-vertebral fractures. As the SUCRA values indicated, abaloparatide performed the best on improving lumbar spine BMD, vertebral fracture and non-vertebral fracture, while denosumab was the best choice to improve total hip BMD. CONCLUSIONS: To sum up, abaloparatide, denosumab, and teriparatide showed the best efficacy for the treatment of postmenopausal osteoporosis, especially abaloparatide.

Circ-VANGL1 promotes the progression of osteoporosis by absorbing miRNA-217 to regulate RUNX2 expression.

OBJECTIVE: This study aims to investigate whether circ-VANGL1 can promote the progression of osteoporosis (OP) by absorbing miRNA-217 to regulate RUNX2 expression. PATIENTS AND METHODS: The serum levels of circ-VANGL1, miRNA-217 and RUNX2 in OP patients and non-OP patients were detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Their expression levels in human bone marrow mesenchymal stem cells (hBMSCs) at different time points of osteogenesis differentiation were determined as well. The expression levels of RUNX2 and osteogenic proteins (BSP, OCN, OPN) in hBMSCs were detected by Western blot. Dual-Luciferase reporter gene assay was performed to verify the relationship among circ-VANGL1, miRNA-217 and RUNX2. Alkaline phosphatase (ALP) staining was conducted to evaluate the degree of osteogenic differentiation influenced by circ-VANGL1 and miRNA-217. RESULTS: OP patients presented a higher serum level of miRNA-217 and lower serum levels of circ-VANGL1 and RUNX2 relative to non-OP patients. Circ-VANGL1 accelerated osteogenic differentiation by absorbing miRNA-217 to regulate RUNX2 expression. Moreover, miRNA-217 inhibited osteogenic differentiation by degrading RUNX2 by targeting to RUNX2 3'UTR. The overexpression of circ-VANGL1 upregulated expressions of RUNX2, BSP, OCN, and OPN. Meanwhile, ALP activity increased in hBMSCs overexpressing circ-VANGL1. However, co-overexpression of circ-VANGL1 and miRNA-217 did not alter RUNX2 expression. ALP activity in hBMSCs co-overexpressing circ-VANGL1 and miRNA-217 slightly increased, but had no difference with controls. CONCLUSIONS: Circ-VANGL1 promotes the development of OP via binding to miRNA-217 to downregulate RUNX2 expression.

MiR-490-3p inhibited the proliferation and metastasis of esophageal squamous cell carcinoma by targeting HMGA2.

OBJECTIVE: To identify the potential role of miR-490-3p in the development of esophageal squamous cell carcinoma (ESCC), and to explore the possible underlying mechanism. PATIENTS AND METHODS: Human ESCC tissues and cancer-adjacent normal tissues were collected. The mRNA expression level of miR-490-3p was detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). On-line target gene prediction software was applied to screen high-mobility group AT-hook 2 (HMGA2). Subsequently, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide), qRT-PCR, Western blotting, transwell and scratch-wound assays were conducted to analyze the effect of miR-490-3p on the biological function of the ESCC cell line (EC-109). RESULTS: In our study, the mRNA expression level of miR-490-3p was remarkably reduced in ESCC tissues and cells. Molecular mechanism analysis confirmed that miR-490-3p could act on the 3'-UTR of HMGA2 and regulate its expression. Subsequent functional experiments indicated that decreased expression of HMGA2 resulting from the up-regulation of miR-490-3p could inhibit the proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) of ESCC cells. CONCLUSIONS: We discovered the inhibitory effect of miR-490-3p on ESCC by targeting HMGA2, and revealed that miR-490-3p could be a potential therapeutic target for ESCC.

[Topping-off surgery versus double-segment fusion for treatment of lumbar degenerative disease with mid-long term follow-up].

Objective: To compare the mid-long term clinical effect of Topping-off surgery and lumbar fusion surgery for two-segmental lumbar degenerative disease. Methods: From March 2009 to March 2012, one hundred and twenty-six consecutive patients (Topping-off surgery and two-segment PLIF surgery) were studied in Orthopedics Department, Beijing Chao-Yang Hospital, Capital Medical University.The VAS and ODI were used to assess clinical symptoms.All patients underwent flexion/extension radiographs examinations before surgery, 1, 2 years and last follow-up postoperatively.Lumbar lordosis, sacral slop, data of Coflex segment and adjacent segment (disc height index, range of motion, foraminal height, foraminal width and Pfirrmann classification of intervertebral disc in MRI) were recorded.The paired double-tailed t test was used to analyze the differences in the results from baseline to each postoperative time point.The paired double-tailed t test was used in both groups to analyze the differences in the results from baseline to each postoperative time point.The Chi-square test was used to evaluate the differences between the incidences of adjacent segment degeneration(ASD) in the groups. Logistic regression analysis was used to analyze risk factors for developing radiographic ASD. Results: In topping-off group, 60 patients, average operation time was (134.5±10.2) min. The average blood loss was (301.5±64.6) ml.In fusion group, 68 patients, average age (58.3±4.6) years.The average follow-up time was (47.5±5.1) months.The average operation time was (158.6±19.3) min (P=0.000). The average blood loss was (413.6±131.3) ml (P=0.000). Sex, age, body mass index and intervertebral disc grading were matched between the two groups.Better improvement in VAS back pain score was noted in the topping-off group over the fusion group (P=0.030). Both groups achieved good recovery in ODI and improvement in VAS leg pain and back pain scores at last follow-up postoperatively.In the Topping-off group, FH increased from 10.5 mm at baseline to 11.8 mm at 1 year after surgery (P=0.000) and then decreased mildly in the third postoperative year, while in the fusion group, showed no significant change at all postoperative time points.In the fusion group, the disc height and FW at the same segment were no significant change after first year follow-up, while ROM was significantly decreased after surgery (P=0.000). Foraminal height, foraminal width and intervertebral disc height of adjacent segment of Coflex implant level were found decreased at the end of the postoperative follow-up, while compared with preoperative data no significant difference (P>0.05). At last follow-up, eight patients (13.3%) in the Topping-off group and eighteen patients (26.5%) in the fusion group developed ASD (P=0.033). Conclusions: Topping-off surgery compared with two-segment lumbar fusion surgery can achieve a good result in cases with pre-existing mild or moderate adjacent segment degeneration, restrict the adjacent segment's range of motion and reduce the adjacent segment degeneration. Under strict indications, Topping-off surgery is an acceptable alternative to fusion surgery for the treatment of two-segment lumbar disease.

Insights into the potential use of microRNAs as a novel class of biomarkers in esophageal cancer.

MicroRNAs (abbreviated miRNAs) have been demonstrated to be involved in tumorigenesis and cancer development and proposed as promising biomarkers in cancer diagnosis. Numerous studies have observed the aberrant expression of miRNAs in esophageal cancer. However, there are some discrepant results. Thus, we conducted this meta-analysis to identify the overall accuracy of miRNAs in the diagnosis of esophageal cancer. A comprehensive literature search was conducted in PubMed and other databases using combinations of key words. The summary receiver operator characteristic curves were plotted to assess the overall diagnostic performance of miRNAs. Chi-squared and I(2) tests were used to assess the heterogeneity between studies. Additionally, we conducted subgroup and sensitivity analyses to analyze the potential sources of heterogeneity. In total, 33 studies from 12 articles were available in this meta-analysis. The pooled sensitivity, specificity, positive and negative likelihood ratio (PLR, NLR) diagnostic odds ratio, and area under the curve were 0.80, 0.80, 4.0, 0.25, 16, and 0.87, respectively. Subgroup analyses based on the sample types (saliva-, serum- and plasma-based) showed no differences in the diagnostic accuracy of each subgroup. An independent meta-analysis of eight articles was conducted to evaluate the diagnostic accuracy of miRNAs in patients with esophageal squamous cell carcinoma, with a pooled sensitivity of 0.77, specificity of 0.83, PLR of 4.4, NLR of 0.27, diagnostic odds ratio of 16, and area under the curve of 0.87. In conclusion, this meta-analysis demonstrates the feasibility of using miRNAs as non-invasive biomarkers to discriminate esophageal cancer from healthy controls. However, further high-quality studies on more clearly defined esophageal cancer patient are needed to confirm our conclusion.

Unilateral perirenal fibrosis without aorta involvement.

Retroperitoneal fibrosis (RPF) located unilateral perirenal without aorta involvement is very rare. We report a case of unilateral perirenal fibrosis which was misdiagnosed as malignancy even after biopsy. RPF should be in mind in dealing with perirenal mass.

Platelet-activating factor receptor-mediated PI3K/AKT activation contributes to the malignant development of esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide and occurs at a relatively high frequency in China, yet the mechanisms underlying its devastating outcome remain unclear. Here we report that platelet-activating factor receptor (PAFR), a type of G-protein-coupled receptor, was upregulated in ESCC tumors and cell lines, compared with controls; PAFR levels were positively correlated with ESCC clinical stages and survival time. Overexpression of PAFR promoted the malignant development of ESCC in vitro and in vivo, whereas depletion of PAFR suppressed these effects. Interestingly, PAFR was observed to activate PI3K/AKT (phosphatidylinositol 3-kinase/AKT) through the upregulation of FAK kinase activity. AKT-triggered nuclear factor-κB transcriptionally activated PAFR expression. This mutual positive regulation between PAFR and AKT was required for the aggressiveness of ESCC cells both in vitro and in vivo. Furthermore, treating mice bearing ESCC tumors with cholesterol-conjugated PAFR small interfering RNA effectively inhibited tumor progression and the expression of AKT-mediated oncogenic proteins. Taken together, we made the first demonstration that dysregulation of PAFR and the positive regulatory loop between PAFR and pAKT contribute to malignant progression of ESCC.

Cutaneous basal cell carcinoma with endobronchial metastasis.

Although basal cell carcinoma is a very common malignancy, metastasis from this tumour is extremely rare. For this reason, many plastic surgeons, dermatologists and physicians dealing with skin malignancies consider this as a locally invasive malignancy. We present a rare case of metastatic basal cell carcinoma manifested as a bronchial tumour. This case highlights the fact that despite basal cell carcinoma's local invasive potential, the possibility of distant metastasis still exists and clinicians should therefore be cautious about interpreting extracutaneous symptoms. Chest physicians should always consider the possibility of this rare tumour in the lungs in patients with a history of large basal cell carcinomas in the head and neck region.

Diosmin protects against cerebral ischemia/reperfusion injury through activating JAK2/STAT3 signal pathway in mice.

BACKGROUND AND OBJECT: Apoptosis is a major form of cell death in cerebral ischemia/reperfusion (I/R) pathogenesis and may represent a target for treatment. Diosmin (DM), a micronized purified flavonoid drug, possesses an anti-apoptotic effect in the treatment of varicose veins and renal injury. However, the effect of DM in the acute phase of cerebral I/R is not clear. This study investigated DM's role in cerebral I/R and its potential mechanism. METHODS: Male CD-1 mice were subjected to transient middle cerebral artery occlusion (tMCAO). Experiment 1 was used to evaluate the time course expression of Janus tyrosine kinase-2 (JAK2), signal transducer and activator of transcription-3 (STAT3), phosphorylated JAK2 (pJAK2) and phosphorylated STAT3 (pSTAT3) after cerebral I/R, and six time points were included. In experiment 2, DM was given orally at doses of 50mg/kg or 100mg/kg for 6 consecutive days before receiving tMCAO. At 24h after reperfusion, neurological deficit, Nissl staining, brain water content and infarct volume were examined. Bcl-2, Bax, pJAK2, and pSTAT3 were detected by immunohistochemistry, qRT-PCR and Western blot. Confocal microscope was used to observe the location of pSTAT3 in the cerebral cortex. RESULTS: Compared with Vehicle group, the high dose of DM significantly alleviated neurological deficit, brain water content, infarct volume, increased the Nissl-positive cells, upregulated the expression of pJAK2, pSTAT3 and Bcl-2 and downregulated Bax (P<0.05). CONCLUSION: These results showed that DM protected against cerebral I/R injury through activating JAK2/STAT3 signal pathway.

Quercetagetin inhibits macrophage-derived chemokine in HaCaT human keratinocytes via the regulation of signal transducer and activator of transcription 1, suppressor of cytokine signalling 1 and transforming growth factor-ß1.

BACKGROUND: Inflammatory chemokines, such as macrophage-derived chemokine (MDC/CCL22), are elevated in the serum and lesioned skin of patients with atopic dermatitis (AD), and are ligands for C-C chemokine receptor 4, which is predominantly expressed on T helper 2 lymphocytes, basophils and natural killer cells. We have previously reported that quercetagetin has an inhibitory activity on inflammatory chemokines, which is induced by interferon (IFN)-γ and tumour necrosis factor (TNF)-α, occurring via inhibition of the signal transducer and activator of transcription 1 (STAT1) signal. OBJECTIVES: To investigate the specific mechanisms of quercetagetin on the STAT1 signal. METHODS: We confirmed the inhibitory activity of quercetagetin on MDC and STAT1 in HaCaT keratinocytes. The interaction between STAT1 and IFN-γR1 was investigated using immunoprecipitation. The small interfering RNA approach was used to investigate the role of suppressor of cytokine signalling 1 (SOCS1) and transforming growth factor (TGF)-ß1 induced by quercetagetin. RESULTS: Quercetagetin inhibited the expression of MDC at both the protein and mRNA levels in IFN-γ- and TNF-α-stimulated HaCaT human keratinocytes. Moreover, quercetagetin inhibited the phosphorylation of STAT1 through upregulation of SOCS1. Increased expression of SOCS1 disrupted the binding of STAT1 to IFN-γR1. Furthermore, quercetagetin augmented the expression of TGF-ß1, which is known to modulate the immune response and inflammation. CONCLUSIONS: These results suggest that quercetagetin may be a potent inhibitor of the STAT1 signal, which could be a new molecular target for anti-inflammatory treatment, and may thus have therapeutic applications as an immune modulator in inflammatory diseases such as AD.

Neuroprotection by valproic acid in an intrastriatal rotenone model of Parkinson's disease.

Rotenone, which is used as a pesticide and insecticide, has been shown to cause systemic inhibition of mitochondrial complex I activity, with consequent degeneration of dopaminergic neurons within the substantia nigra and striatum, as observed in Parkinson's disease. A novel intrastriatal rotenone model of Parkinson's disease was used to examine the neuroprotective effects of valproic acid (VPA), which is known to upregulate neurotrophic factors and other protective proteins in the brain. Sham or lesioned rats were treated with either vehicle or VPA at a dose of 4mg/mL in drinking water. The right striatum was lesioned by infusion of rotenone at three sites (2µg/site) along its rostro-caudal axis. A forelimb asymmetry (cylinder) test indicated a significant (p<0.01) decrease in use of the contralateral forelimb in rotenone-lesioned animals, in the third week post-lesioning, which was abolished by VPA treatment. Similarly, a significant (p<0.01) and persistent increase in use of the ipsilateral forelimb in lesioned animals over the 4weeks of testing, was not seen in animals treated with VPA. Results of the asymmetry test illustrate that intrastriatal infusion of rotenone causes contralateral motor dysfunction, which is blocked by VPA. The significant increase in ipsilateral forelimb use has not been documented previously, and presumably represents a compensatory response in lesioned animals. Six weeks post-surgery, animals were sacrificed by transcardial perfusion. Subsequent immunohistochemical examination revealed a decrease in tyrosine hydroxylase immunoreactivity within the striatum and substantia nigra of rotenone-lesioned animals. VPA treatment attenuated the decrease in tyrosine hydroxylase in the striatum and abolished it in the substantia nigra. Stereological cell counting indicated a significant (p<0.05) decrease in tyrosine hydroxylase-positive dopamine neurons in the substantia nigra of rotenone-lesioned animals, which was confirmed by Nissl staining. Importantly, this loss of dopamine neurons in rotenone-lesioned animals, was blocked by chronic VPA treatment. These findings strongly support the therapeutic potential of VPA in Parkinson's disease.