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Clear cell renal cell carcinoma (ccRCC) is the most common histological and devastating subtype of renal cell carcinoma. Necroptosis is a form of programmed cell death that causes prominent inflammatory responses. miRNAs play a significant role in cancer progression through necroptosis. However, the prognostic value of necroptosis-related miRNAs remains ambiguous. In this study, 39 necroptosis-related miRNAs (NRMs) were extracted and 17 differentially expressed NRMs between normal and tumor samples were identified using data form The Cancer Genome Atlas (TCGA). After applying univariate Cox proportional hazard regression analysis and LASSO Cox regression model, six necroptosis-related miRNA signatures were identified in the training cohort and their expression levels were verified by qRT-PCR. Using the expression levels of these miRNAs, all patients were divided into the high- and low-risk groups. Patients in the high-risk group showed poor overall survival ( P < 0.0001 ). Time-dependent ROC curves confirmed the good performance of our signature. The results were verified in the testing cohort and the entire TCGA cohort. Univariate and multivariate Cox regression models demonstrated that the risk score was an independent prognostic factor. Additionally, a predictive nomogram with good performance was constructed to enhance the implementation of the constructed signature in a clinical setting. We then employed miRBD, miRTarBase, and TargetScan to predict the target genes of six necroptosis-related miRNAs. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that 392 potential target genes were enriched in cell proliferation-related biological processes. Six miRNAs and 59 differentially expressed target genes were used to construct an miRNA–mRNA interaction network, and 11 hub genes were selected for survival and tumor infiltration analysis. Drug sensitivity analysis revealed potential drugs that may contribute to cancer management. Hence, necroptosis-related genes play an important role in cancer biology. We developed, for the first time, a necroptosis-related miRNA signature to predict ccRCC prognosis.

Aims Patients with heart failure (HF) have a poor prognosis and are categorized by ejection fraction. We performed a meta‐analysis to compare baseline characteristics and long‐term outcomes of patients with heart failure with reduced (HFrEF), mid‐range (HFmrEF), and preserved ejection fraction (HFpEF). Methods and Results A total of 27 prospective studies were included. Patients with HFpEF were older and had a higher proportion of females, hypertension, diabetes, and insufficient neuroendocrine antagonist treatments, while patients with HFrEF and HFmrEF had a higher prevalence of coronary heart disease and chronic kidney disease. After more than 1‐year of follow‐up, all‐cause mortality was significantly lower in patients with HFmrEF 9388/25 042 (37.49%) than those with HFrEF 39 333/90 023 (43.69%) and HFpEF 24 828/52 492 (47.30%) (p

Long noncoding RNAs (lncRNAs) have been reported to exert important roles in tumors, including clear cell renal cell carcinoma (ccRCC). PVT1 is an important oncogenic lncRNA which has critical effects on onset and development of various cancers, however, the underlying mechanism of PVT1 functioning in ccRCC remains largely unknown. VHL deficiency-induced HIF2α accumulation is one of the major factors for ccRCC. Here, we identified the potential molecular mechanism of PVT1 in promoting ccRCC development by stabilizing HIF2α. PVT1 was significantly upregulated in ccRCC tissues and high PVT1 expression was associated with poor prognosis of ccRCC patients. Both gain-of-function and loss-of function experiments revealed that PVT1 enhanced ccRCC cells proliferation, migration, and invasion and induced tumor angiogenesis in vitro and in vivo. Mechanistically, PVT1 interacted with HIF2α protein and enhanced its stability by protecting it from ubiquitination-dependent degradation, thereby exerting its biological significance. Meanwhile, HIF2α bound to the enhancer of PVT1 to transactivate its expression. Furthermore, HIF2α specific inhibitor could repress PVT1 expression and its oncogenic functions. Therefore, our study demonstrates that the PVT1/ HIF2α positive feedback loop involves in tumorigenesis and progression of ccRCC, which may be exploited for anticancer therapy.

Objective: The aim of this study was to investigate and compare the diagnostic performance of dynamic contrast-enhanced (DCE)-MRI, multiparametric MRI (mpMRI), and multimodality imaging (MMI) combining mpMRI and mammography (MG) for discriminating breast non-mass-like enhancement (NME) lesions. Methods: This retrospective study enrolled 193 patients with 199 lesions who underwent 3.0 T MRI and MG from January 2017 to December 2019. The features of DCE-MRI, turbo inversion recovery magnitude (TIRM), and diffusion-weighted imaging (DWI) were assessed by two breast radiologists. Then, all lesions were divided into microcalcification and non-microcalcification groups to assess the features of MG. Comparisons were performed between groups using univariate analyses. Then, multivariate analyses were performed to construct diagnostic models for distinguishing NME lesions. Diagnostic performance was evaluated by using the area under the curve (AUC) and the differences between AUCs were evaluated by using the DeLong test. Results: Overall (n = 199), mpMRI outperformed DCE-MRI alone (AUCmpMRI = 0.924 vs. AUCDCE-MRI = 0.884; p = 0.007). Furthermore, MMI outperformed both mpMRI and MG (the microcalcification group [n = 140]: AUCMMI = 0.997 vs. AUCmpMRI = 0.978, p = 0.018 and AUCMMI = 0.997 vs. AUCMG = 0.912, p < 0.001; the non-microcalcification group [n = 59]: AUCMMI = 0.857 vs. AUCmpMRI = 0.768, p = 0.044 and AUCMMI = 0.857 vs. AUCMG = 0.759, p = 0.039). Conclusion & advances in knowledge: DCE-MRI combined with DWI and TIRM information could improve the diagnostic performance for discriminating NME lesions compared with DCE-MRI alone. Furthermore, MMI combining mpMRI and MG showed better discrimination than both mpMRI and MG.

To verify the superiority of motor imagery acupuncture in improving muscle tension for patients with upper limb hemiplegia in early stroke.A total of 64 patients of stroke hemiplegia with upper limb flaccid paralysis were randomly divided into an observation group (32 cases, 1 case dropped off ) and a control group (32 cases, 4 cases dropped off ). The observation group was treated with motor imagery acupuncture (both acupuncture and motor imagery therapy at affected upper limb were performed).The control group was treated with acupuncture plus motor imagery therapy at affected lower limb, 2 h later after acupuncture, motor imagery therapy was applied to upper limb. Baihui (GV 20) to Taiyang (EX-HN 5) of healthy side, Fengchi (GB 20) and Jianyu (LI 15), Jianjing (GB 21), Quchi (LI 11), Waiguan (TE 5) on the affected side, ect. were selected in both groups, once a day, 5 times a week for 4 weeks. Before and after treatment, 4, 8 weeks after treatment, the modified Ashworth scale (MAS) grade and Brunnstrom stage were compared in the two groups.Compared before treatment, the muscle tension of shoulder, elbow and wrist each time point after treatment was increased in the two groups (Motor imagery acupuncture could promote hemiplegia upper limb muscle tension recovery in patients of stroke hemiplegia with upper limb flaccid paralysis, make the patients gradually shift to the separate fine movement mode, inhibit and relieve the appearance and development of spasm.

Background: Wound infiltration analgesia provides effective postoperative pain control in patients undergoing laparoscopic cholecystectomy (LC). However, the efficacy and safety of wound infiltration with different doses of ropivacaine is not well defined. This study investigated the analgesic effects and pharmacokinetic profile of varying concentrations of ropivacaine at port sites under laparoscopy assistance. Methods: In this randomized, double-blinded study, 132 patients were assigned to 4 groups: Group H: in which patients were infiltrated with 0.75% ropivacaine; Group M: 0.5% ropivacaine; Group L: 0.2% ropivacaine; and Group C: 0.9% normal saline only. The primary outcome was pain intensity estimated using numeric rating scale (NRS) at discharging from PACU and at 4 hours, 6 hours, 8 hours, and 24 hours after infiltration. Secondary outcomes included plasma concentrations of ropivacaine at 30 minutes after wound infiltration, rescue analgesia requirements after surgery, perioperative vital signs changes, and side effects. Results: The NRS in Group C was significantly higher at rest, and when coughing upon leaving PACU and at 4 hours, 6 hours, 8 hours, and 24 hours after infiltration (P .05). Intra-operative consumption of sevoflurane and remifentanil, HR at skin incision and MAP at skin incision, as well as 5 minutes after skin incision were significantly higher in Group C than in the other 3 groups (P .05). The concentration of ropivacaine at 30 minutes after infiltration in Group H was significantly higher than that of Group L and Group M (P .05). Conclusions: Laparoscopy-assisted wound infiltration with ropivacaine successfully decreases pain intensity in patients undergoing LC regardless of the doses used. Infiltration with higher doses results in higher plasma concentrations, but below the systematic toxicity threshold.

SuHeXiang (SHX) has been used to treat a wide range of diseases, including those related to the central nervous system. However, the effects of SHX on mood disorders are still elusive. This study aimed to investigate the effects of SHX essential oil on stress-induced depression of mice. In an acute stress-induced depression model, mice inhaled vehicle (1% Tween 80) for 10 min or 10% SHX for 10 or 30 min once daily for 12 continuous days. In the chronic mild stress (CMS)-induced depression model, mice were exposed to a 28-d CMS treatment. Tail suspension test (TST), forced swimming test (FST), sucrose preference test (SPT), open field test (OFT), and novelty suppressed feeding (NSF) test were conducted. In addition, serum levels of angiogenin (ANG), thrombopoietin (TPO), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) were evaluated by enzyme-linked immunosorbent assay (ELISA) assays. The results showed that in mice exposed to acute stress, repeated SHX inhalation exerted significant antidepressant and anxiolytic activities, and also reduced the serum levels of ANG, TPO, IL-6, and TNF-α. It also significantly reversed the depressive and anxiety-like behaviors, and reduced the serum levels of ANG and TPO in mice exposed to CMS. This is the first report to show that SHX inhalation could produce significant antidepressant and anxiolytic-like effects. These effects might be mediated by SHX ability to modulate the inflammatory response, and reduce dysfunction of vascular genesis and thrombosis. These results support further exploration for developing SHX inhalation as a novel therapeutic strategy for depression and stress-related disorders.

Objective The aim of this study was to evaluate the additional effects of acupuncture treatment on motor function in patients with subacute hemorrhagic stroke. Design One hundred and thirty-four patients with subacute hemorrhagic stroke were randomized to receive acupuncture treatment plus conventional treatment (treatment group) or conventional treatment only (control group). Acupuncture treatments were given in 24 sessions over 4 weeks, with 3-month follow-up period. Blinded evaluation was based on Fugl-Meyer Assessment, Barthel Index with an intention-to-treat analysis. For those patients who were able to walk, a three-dimensional gait analysis system was employed to objectively record spatiotemporal and kinematic parameters. Results Compared with control group, the treatment group showed a significantly greater over-time improvement in total Fugl-Meyer, lower-limb Fugl-Meyer, but not in upper-limb Fugl-Meyer and Barthel Index. The spatiotemporal parameters of velocity, step length, cadence, step width all showed significant difference between the 2 groups. The velocity in treatment group decreased unexpectedly at day 14, then increased sharply and overcame control group at day 28. The treatment group also showed a significantly greater increase in peak circumduction, peak hip hiking, hip range of motion, knee range of motion and a tendency for the ankle range of motion. Conclusions Acupuncture may promote the motor function recovery of hemorrhagic stroke patients in subacute phase mainly by enhancing the lower limb ability. It probably diminishes the compensation strategies earlier to correct the abnormal gait pattern. Although this adjustment may result in a compromise in the improvement of gait velocity temporarily, patients would benefit from it in a long run.

Background and Purpose: Lower limb spasticity is often a significant problem in stoke rehabilitation. The purpose of this study was to investigate the effects of acupuncture treatment on lower limb spasticity in patients following hemorrhagic stroke. Methods: Fifty-nine patients following hemorrhagic stroke were randomized to receive acupuncture treatment combined with conventional treatment (treatment group [TG]) or conventional treatment only (control group [CG]). Acupuncture treatments were given in 24 sessions over 4 weeks. Blinded evaluation was based on Modified Ashworth Scale (MAS), short intracortical inhibition (SICI), and Hmax/Mmax ratio as the primary outcomes. In addition, Fugl-Meyer Assessment (FMA), Barthel Index (BI), motor evoked potential (MEP) and surface integrated electromyogram (IEMG) were employed as the secondary outcomes. All the evaluations were performed at 14 and 28 days after the start of the treatment. Results: Compared with the CG, the TG showed a significantly greater over-time decrease in MAS for knee (p = 0.022) and ankle (p = 0.017), SICI (p = 0.000) and Hmax/Mmax ratio (p = 0.000). In all patients of TG, we found a greater improvement in lower-limb FMA and MEP but not in BI. IEMG show that TG obtained a greater reduction in spastic agonist muscles and a greater enhancement in spastic antagonist muscles. A significant correlation between a greater decrease in ankle MAS and a greater increase in SICI for spastic muscles was found (r = 0.390, p = 0.002). Conclusions: Acupuncture could improve the lower limb spasticity and motor function, thus providing a safe and economical approach for treating stroke patients. The potential mechanism underpinning the greater improvement may be attributed to a reshape of corticospinal plasticity induced by acupuncture.

The present study aimed to investigate the effect of Buyang Huanwu decoction (BYHWD) on tumor growth, metastasis and angiogenesis in nude mice bearing human hepatocellular carcinoma (HCC) HCCLM3 xenografts. A total of 96 nude mice bearing HCCLM3 xenografts were randomly divided into four groups: BYHWD group (LB), Yi‑qi decoction group (LY), Huo‑xue decoction group (LH) and model group (LM). Each of these groups was divided into three subgroups (n=8), which were observed on days 21, 25, 38 following treatment, respectively. The tumor weights, volumes and pulmonary metastases were recorded. The expression of CD105 and the microvessel density (MVD) were assessed, and the expression levels of vascular endothelial growth factor (VEGF), hypoxia‑inducible factor 1α (HIF‑1α), and regulator of G protein signaling 5 (RGS‑5) were analyzed using immunohistochemical staining. Compared with the LM group, no significant decrease in tumor weight or volume were observed in the herbal medicine treatment groups, the number of the metastases in the lungs decreased, whereas the expression levels of RGS‑5 and HIF‑1α decreased in the LB group on day 35. However, the expression levels of VEGF increased in the LB group on days 28 and 35 post‑treatment. The results of the present study suggested that BYHWD may inhibit angiogenesis and metastasis by affecting the expression levels of VEGF, RGS‑5 and HIF‑1α, and suggested that BYHWD may contribute to the tumor microenvironment and vasculature normalization in HCC.

Background Liver tumor initiating cells (TICs) have self-renewal and differentiate capacities, and largely contribute to tumor initiation, metastasis and drug resistance. MAPK signaling is a critical pathway in many biological processes, while its role in liver TICs hasn’t been explored. Methods Online-available dataset was used for unbiased screening. Liver TICs were examined CD133 FACS or oncosphere formation. TIC self-renewal was detected by oncosphere formation and tumor initiation assay. LncRNA function was detected by loss of function or gain of function assays. The molecular mechanism of lncRNA was explored by RNA pulldown, RNA immunoprecipitation, ChIP, western blot and double FISH. Results Here, we examined the expression profiles of MAPK components (MAPKs, MAP2Ks, MAP3Ks, MAP4Ks), and found MAPK6 is most highly expressed in liver cancer samples. Moreover, a divergent lncRNA (long noncoding RNA) of MAPK6, termed lncMAPK6 here, is also overexpressed along with liver tumorigenesis. LncMAPK6 promotes liver tumor propagation and TIC self-renewal through MAPK6. LncMAPK6 interacts with and recruits RNA polymerase II to MAPK6 promoter, and finally activates the transcription of MAPK6. Through MAPK6 transcriptional regulation, lncMAPK6 drives MARK signaling activation. LncMAPK6-MAPK6 pathway can be used for liver TIC targeting. Altogether, lncMAPK6 promotes MARK signaling and the self-renewal of liver TICs through MAPK6 expression. Conclusion MAPK6 was the most highly expressed MAPK component in liver cancer and liver TICs and lncMAPK6 participated in the transcriptional regulation of MAPK6in cis. This work revealed the importance role of MAPK signaling in liver TIC self-renewal and added a new layer for liver TIC and MAPK6 expression regulation.

Background: The prophylactic efficacy of statin pretreatment for the prevention of contrast-induced nephropathy (CIN) in patients undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI) remains controversial. The aim of the study was to perform a meta-analysis of randomized controlled trials (RCTs) to assess the effectiveness of short-term moderate or high-dose rosuvastatin pretreatment in preventing CIN. Methods: We included RCTs comparing short-term moderate or high-dose rosuvastatin treatment versus low-dose rosuvastatin treatment or placebo for preventing CIN. The primary endpoint was the incidence of CIN within 2 to 5 days after contrast administration, and related-parameters including serum creatinine (SCr), cystatin C (CysC), hypersensitive C-reactive protein (hs-CRP), urine microalbumin (mALB) were also extracted. Results: Fifteen RCTs with a total of 2673 patients were identified and analyzed. Patients who received moderate or high-dose rosuvastatin pretreatment had a 55% lower risk of CIN compared with low-dose rosuvastatin pretreatment or placebo group based on a fixed effect model (RR = 0.45, 95% CI 0.35–0.58, P

Nuclear receptors (NRs) are closely associated with various major diseases such as cancer, diabetes, inflammatory disease, and osteoporosis. Therefore, NRs have become a frequent target for drug development. During the process of developing drugs against these diseases by targeting NRs, we are often facing a problem: Given a NR and chemical compound, can we identify whether they are really in interaction with each other in a cell? To address this problem, a predictor called “iNR-Drug” was developed. In the predictor, the drug compound concerned was formulated by a 256-D (dimensional) vector derived from its molecular fingerprint, and the NR by a 500-D vector formed by incorporating its sequential evolution information and physicochemical features into the general form of pseudo amino acid composition, and the prediction engine was operated by the SVM (support vector machine) algorithm. Compared with the existing prediction methods in this area, iNR-Drug not only can yield a higher success rate, but is also featured by a user-friendly web-server established at http://www.jci-bioinfo.cn/iNR-Drug/, which is particularly useful for most experimental scientists to obtain their desired data in a timely manner. It is anticipated that the iNR-Drug server may become a useful high throughput tool for both basic research and drug development, and that the current approach may be easily extended to study the interactions of drug with other targets as well.

Many crucial functions in life, such as heartbeat, sensory transduction and central nervous system response, are controlled by cell signalings via various ion channels. Therefore, ion channels have become an excellent drug target, and study of ion channel-drug interaction networks is an important topic for drug development. However, it is both time-consuming and costly to determine whether a drug and a protein ion channel are interacting with each other in a cellular network by means of experimental techniques. Although some computational methods were developed in this regard based on the knowledge of the 3D (three-dimensional) structure of protein, unfortunately their usage is quite limited because the 3D structures for most protein ion channels are still unknown. With the avalanche of protein sequences generated in the post-genomic age, it is highly desirable to develop the sequence-based computational method to address this problem. To take up the challenge, we developed a new predictor called iCDI-PseFpt, in which the protein ion-channel sample is formulated by the PseAAC (pseudo amino acid composition) generated with the gray model theory, the drug compound by the 2D molecular fingerprint, and the operation engine is the fuzzy K-nearest neighbor algorithm. The overall success rate achieved by iCDI-PseFpt via the jackknife cross-validation was 87.27%, which is remarkably higher than that by any of the existing predictors in this area. As a user-friendly web-server, iCDI-PseFpt is freely accessible to the public at the website http://www.jci-bioinfo.cn/iCDI-PseFpt/. Furthermore, for the convenience of most experimental scientists, a step-by-step guide is provided on how to use the web-server to get the desired results without the need to follow the complicated math equations presented in the paper just for its integrity. It has not escaped our notice that the current approach can also be used to study other drug-target interaction networks.

Background/Purpose Effective stone disintegration by extracorporeal shockwave lithotripsy (ESWL) may depend on patient- and stone-related factors. We investigated predictors of disintegration failure in ESWL for a solitary ureteral calculus. Methods From July 2008 to May 2010, 203 patients who underwent ESWL for a solitary ureteral calculus were enrolled. Clinical and radiologic data were collected, and factors related to ESWL failure were analyzed. Results Fifty-two patients (25.6%) showed ESWL failure, with a mean follow-up of 41 days. Forty patients (19.7%) required retreatment, including 12 who underwent repeat ESWL and 28 who underwent curative ureteroscopy. Patients with ESWL failure had significantly higher body weight, body mass index (BMI), and buttock circumference (BC) than patients for whom ESWL was successful. Univariate analysis showed that stone burden (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.03–1.06) and BC (OR, 1.06; 95% CI, 1.01–1.11) were predictors of ESWL failure, while BMI was a potential predictor with borderline significance (OR, 1.09; 95% CI, 0.99–1.20). Multivariate analysis showed that stone burden (OR, 1.04; 95% CI, 1.03–1.06) was a significant predictor for all patients. On stratifying patients according to the level of ureteral calculi, BC was found to be an independent predictor (OR, 1.35; 95% CI, 1.02–1.80) for ESWL failure for middle/lower ureteral calculi and BMI (OR, 1.47; 95% CI, 1.13–1.91) for upper ureteral calculi. Conclusion Stone burden is the main predictor of ESWL failure for all patients with ureteral calculi. BC and BMI are independent predictors for ESWL failure for middle/lower and upper ureteral calculi, respectively.

Statins are being widely used for the therapy and prevention of several types of tumors, including human chronic myelogenous leukemia, but the underlying molecular mechanisms still remain unknown. Therefore, inhibition of cell proliferation, apoptosis and involved molecules were investigated in K562 cells after incubation with simvastatin.The results showed that simvastatin diminished K562 cell proliferation and induced apoptosis. At the same time, the level of reactive oxygen species (ROS) and intracellular calcium concentration increased. Furthermore, nitric oxide (NO) content and inducible NO synthase (iNOS) mRNA expression were significantly higher in the simvastatin-treated group than in the corresponding control group. The elevated ROS level and intracellular calcium concentration, enhanced mRNA expression of iNOS and total NO content might be responsible for the apoptotic and anti-proliferative effects of simvastatin in K562 cells.

The current study investigated the efficacy of losartan and amlodipine in protecting spontaneously hypertensive stroke-prone (SHRSP) rats against the risk of stroke. SHRSP rats were administered losartan, amlodipine or the vehicle for 6 weeks. There were no significant differences in systolic blood pressure (SBP) in rats treated with losartan or amlodipine, however, following drug withdrawal, rats treated with losartan maintained reduced SBP for a longer time compared with rats treated with amlodipine. In addition, rats treated with losartan exhibited thinner vascular walls and improved systolic and diastolic function. Clinical stroke scores in the losartan group were significantly reduced compared with those in the amlodipine and vehicle groups. However, rats treated with losartan exhibited higher levels of angiotensin II and lower levels of aldosterone in the serum and brain cortex compared with the vehicle and amlodipine-treated rats. Furthermore, losartan significantly reduced the abnormal expression of angiotensin II receptors type 1 and 2 in SHRSP rats, whilst amlodipine did not. These results suggest that losartan may be more efficacious than amlodipine in ameliorating blood pressure deterioration and reducing stroke risk in SHRSP rats via regulation of the renin angiotensin system.

Information about the interactions of drug compounds with proteins in cellular networking is very important for drug development. Unfortunately, all the existing predictors for identifying drug-protein interactions were trained by a skewed benchmark data-set where the number of non-interactive drug-protein pairs is overwhelmingly larger than that of the interactive ones. Using this kind of highly unbalanced benchmark data-set to train predictors would lead to the outcome that many interactive drug-protein pairs might be mispredicted as non-interactive. Since the minority interactive pairs often contain the most important information for drug design, it is necessary to minimize this kind of misprediction. In this study, we adopted the neighborhood cleaning rule and synthetic minority over-sampling technique to treat the skewed benchmark datasets and balance the positive and negative subsets. The new benchmark datasets thus obtained are called the optimized benchmark datasets, based on which a new predictor called iDrug-Target was developed that contains four sub-predictors: iDrug-GPCR, iDrug-Chl, iDrug-Ezy, and iDrug-NR, specialized for identifying the interactions of drug compounds with GPCRs (G-protein-coupled receptors), ion channels, enzymes, and NR (nuclear receptors), respectively. Rigorous cross-validations on a set of experiment-confirmed datasets have indicated that these new predictors remarkably outperformed the existing ones for the same purpose. To maximize users' convenience, a public accessible Web server for iDrug-Target has been established at http://www.jci-bioinfo.cn/iDrug-Target/ , by which users can easily get their desired results. It has not escaped our notice that the aforementioned strategy can be widely used in many other areas as well.

Involved with many diseases such as cancer, diabetes, neurodegenerative, inflammatory and respiratory disorders, GPCRs (G-protein-coupled receptors) are the most frequent targets for drug development: over 50% of all prescription drugs currently on the market are actually acting by targeting GPCRs directly or indirectly. Found in every living thing and nearly all cells, ion channels play crucial roles for many vital functions in life, such as heartbeat, sensory transduction, and central nervous system response. Their dysfunction may have significant impact to human health, and hence ion channels are deemed as "the next GPCRs". To develop GPCR-targeting or ion-channel-targeting drugs, the first important step is to identify the interactions between potential drug compounds with the two kinds of protein receptors in the cellular networking. In this minireview, we are to introduce two predictors. One is called iGPCR-Drug accessible at http://www.jci-bioinfo.cn/iGPCR-Drug/; the other called iCDI-PseFpt at http://www.jci-bioinfo.cn/iCDI-PseFpt. The former is for identifying the interactions of drug compounds with GPCRs; while the latter for that with ion channels. In both predictors, the drug compound was formulated by the two-dimensional molecular fingerprint, and the protein receptor by the pseudo amino acid composition generated with the grey model theory, while the operation engine was the fuzzy K-nearest neighbor algorithm. For the convenience of most experimental pharmaceutical and medical scientists, a step-bystep guide is provided on how to use each of the two web-servers to get the desired results without the need to follow the complicated mathematics involved originally for their establishment.

Fibroblasts, far frombeing merely bystander cells, are known to play a specific role in inflammation resolution after an acute injury. As the endogenous “braking signal,” resolvins possess potent anti-inflammatory and proresolution actions. We demonstrated that the expression of COX-2 protein was significantly peaked initially at 6 hours but then also at 48 hours after LPS stimulation in lung fibroblasts. PGE2levels also peaked at 6 hours, and PGD2levels were increased and peaked at 48 hours. However, no significant change in the protein expression of COX-1 was observed after treatment with LPS in lung fibroblasts. Exogenous resolvin D1 inhibited the first peak of COX-2 expression as well as the production of PGE2induced by LPS. In contrast, exogenous resolvin D1 increased the second peak of COX-2 expression as well as the production of PGD2induced by LPS. In addition, resolvin D1 inhibited COX-2 expression at 6 hours, which was partly through PI3K/AKT and ERK2 signalling pathways.

Involved in many diseases such as cancer, diabetes, neurodegenerative, inflammatory and respiratory disorders, G-protein-coupled receptors (GPCRs) are among the most frequent targets of therapeutic drugs. It is time-consuming and expensive to determine whether a drug and a GPCR are to interact with each other in a cellular network purely by means of experimental techniques. Although some computational methods were developed in this regard based on the knowledge of the 3D (dimensional) structure of protein, unfortunately their usage is quite limited because the 3D structures for most GPCRs are still unknown. To overcome the situation, a sequence-based classifier, called "iGPCR-drug", was developed to predict the interactions between GPCRs and drugs in cellular networking. In the predictor, the drug compound is formulated by a 2D (dimensional) fingerprint via a 256D vector, GPCR by the PseAAC (pseudo amino acid composition) generated with the grey model theory, and the prediction engine is operated by the fuzzy K-nearest neighbour algorithm. Moreover, a user-friendly web-server for iGPCR-drug was established at http://www.jci-bioinfo.cn/iGPCR-Drug/. For the convenience of most experimental scientists, a step-by-step guide is provided on how to use the web-server to get the desired results without the need to follow the complicated math equations presented in this paper just for its integrity. The overall success rate achieved by iGPCR-drug via the jackknife test was 85.5%, which is remarkably higher than the rate by the existing peer method developed in 2010 although no web server was ever established for it. It is anticipated that iGPCR-Drug may become a useful high throughput tool for both basic research and drug development, and that the approach presented here can also be extended to study other drug - target interaction networks.

Current approaches for treatment of late-stage breast cancer rarely result in a long-term cure. In part this is due to tumor stroma that prevents access of systemically or intratumorally applied therapeutics. We propose a stem cell gene therapy approach for controlled tumor stroma degradation that uses the pathophysiologic process of recruitment of inflammatory cells into the tumor. This approach involves genetic modification of hematopoietic stem cells (HSCs) and their subsequent transplantation into tumor-bearing mice. We show that inducible, intratumoral expression of relaxin (Rlx) either by transplanting tumor cells that contained the Rlx gene or by transplantation of mouse HSCs transduced with an Rlx-expressing lentivirus vector delays tumor growth in a mouse model of breast cancer. The antitumor effect of Rlx was mediated through degradation of tumor stroma, which provided increased access of infiltrating antitumor immune cells to their target tumor cells. Furthermore, we have shown in a human/mouse chimeric model that genetically modified HSCs expressing a transgene can access the tumor site. Our findings are relevant for cancer gene therapy and immunotherapy.

Background: Statins, a family of 3-hydroxy-3-methylglutaryl CoA (HMG CoA) reductase inhibitors, are being investigated for the therapy and prevention of cancers. Here we aimed to investigate the effects of simvastatin on chronic myelogenous leukemia (CML) cells in vitro and in vivo, and to elucidate the mechanisms. Methods: Cell proliferation and cell cycle were measured after K562 cells were incubated with simvastatin, and differentially expressed genes were determined by oligonucleotide microarray. Changes of 2 genes obtained by oligonucleotide microarray were validated by real-time RT-PCR, and immunohistochemistry was performed to determine expression of proliferating cell nuclear antigen (PCNA). Finally, a xenograft tumor model was constructed to evaluate the effects of simvastatin in vivo. Results: Simvastatin could inhibit K562 cell proliferation, and the inhibition rate was approximately 30% after treatment with 20 µmol/l simvastatin for 48 h. Cell cycle was arrested in G1 phase, as shown by flow cytometry results. Fifteen downregulated, 9 upregulated cell cycle-related genes and decreased PCNA protein were observed in the presence of simvastatin. Furthermore, simvastatin exhibited impairment of xenograft tumor growth in nude mice and also blocked cell cycle in G1 phase. Conclusion: Simvastatin can inhibit CML cell proliferation in vitro and in vivo, and its mechanisms might be involved in cell cycle regulation.

A patient sustained high-voltage electrical burns with third-degree burns over 35.5% of his body surface, which included a large direct wound on the left chest wall, exposing the heart. The heart and lungs were severely injured. Subsequently, hydrothorax, hydropericardium, and respiratory failure developed. He was successfully treated with fluid resuscitation, antibiotics, drainage of the pericardium and pleural cavities, early removal of necrotic tissue, skin grafting, and reconstruction of the chest wall with a 13 x 27-cm delay-flap, as well as a number of supportive measures. The patient gradually recovered and was discharged in 6 months.

The Caf1 secretion pathway of Yersinia pestis is one of the most well-characterized export machineries. To facilitate the secretion of human epidermal growth factor (hEGF) in Escherichia coli, a DNA fragment containing the synthetic gene for hEGF was joined to a sequence encoding the signal peptide of Yersinia pestis Caf1 protein.The gene for hEGF was synthesized by overlapping polymerase chain reaction technique and was placed under the control of the caf1 gene promoter in the recombinant plasmid pHL401 which was used to transfect E. coli BL-21 for production of hEGF. The biological function of recombinant hEGF was measured by estimating its ability to stimulate the proliferation of human embryonic kidney-293 cells.The results indicated that the expressed hybrid protein was processed during the secretion process. The majority of the mature hEGF was recovered from the periplasm and medium fractions, with a small amount of the expressed hEGF deposited in the cytoplasm. Furthermore, it was found that the cell proliferation was enhanced by the recombinant hEGF.These results suggested that the recombinant hEGF was successfully secreted through the inner membrane of cells into the periplasm and then through the outer membrane into the medium via the action of the signal peptide of Y. pestis Caf1 in E. coli. The mitogenic activity of hEGF in cells was demonstrated.

Background: Thrombomodulin (TM) is an endothelial cell surface thrombin‐binding protein with anticoagulation ability by thrombin‐mediated activation of protein C. An increase of plasma soluble TM level is reported to be associated with severity and worse outcome of coronary artery disease. Hypothesis: This prospective study investigated the relation of the elevated levels of plasma soluble TM and inflammatory and myonecrotic markers in patients undergoing percutaneous coronary intervention (PCI). Methods: Plasma levels of soluble TM, C‐reactive protein (CRP), and creatine kinase and its MB isoenzyme were measured before and after PCI in 100 patients undergoing PCIs. Results: Peak TM levels after PCIs were significantly higher thanbaseline (3.39 ± 1.63 vs. 2.90 ± 1.57 ng/ml, p< 0.001). The peak TM levels after PCIs correlated significantly with the peak CRP and MB levels, and the maximal inflation duration (r = 0.423, p

In order to investigate the clinical efficacy of non-myeloablative allogeneic stem cell transplantation (allo-NST) and related technology in patients with hematologic malignancies, twenty-six cases of hematological malignancies (10 AL, 14 CML, 2 MM patients) received NST following conditioning regimens with fludara + cyclophosphamide + ATG (14 cases) and busulfan or melphalan + cyclophosphamide + ATG (12 cases), G-CSF (600 micro g/d) or G-CSF (300 micro g/d) + GM-CSF (300 micro g/d) were used for mobilizing peripheral blood stem cell. A combination of cyclosporine A (CsA) and methotrexate (MTX) was administered for GVHD prophylaxis. Patients will be eligible for donor lymphocyte infusion (DLI) or donor stem cell infusion (DSI) given in graded increments according to the chimeric formation and clinical reaction. Generally the dose of the first infusion was 1 x 10(7)/kg at 4th week post-transplantation. The engraftment analysis included the detection of microsatellite short tandem repeats (STRs), Bcr/Abl fusion gene, Philadelphia chromosome, HLA-locus analysis, sex chromosome and ABO blood type or blood subtype. The results showed that 22 patients (84.62%) were engrafted, among which 18 patients were full donor chimerism (FDC) up to now. Acute GVHD occurred in 3/26 cases (11.54%). Chronic GVHD was diagnosed in 6 of 26 (23.07%) evaluable patients. The incidence of infection and hemorrhage was low and slight. It is concluded that allo-NST is a safe and effective therapeutic method for hematologic malignancies, but the related technology such as selection of indication, conditioning regimen and transplantation immunotherapy should be studied further.

Hemostasis (HS) in 134 healthy subjects of over 20 years old was investigated. The cases with HS symptom were 45.5%, which increased with age. TXB2, 6-keto-PGF1 alpha and T/K ratio were measured by radioimmuno assay (RIA).elevation of TXB2 was more significant in the middle age and old age than in the young group (P0.01). But the level of 6-keto-PGF1 alpha in various age group didn't changed significantly; while the ratio between TXB2 and 6-keto-PGF1 alpha was more significant in the aged than in the young person (P0.01). The results revealed that there was hypercoagulable tendency with the increase of age, and it was correlated with TXB2 and 6-keto-PGF1 alpha. It is significant in theory and practice to prevent and cure the cardiovascular and cerebrovascular disease as well as HS with the traditional Chinese medicine.