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Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of anticancer treatment, which may influence its successful completion. The Huang-Qi-Gui-Zhi-Wu-Wu decoction (HQGZWWD) has been widely used to treat CIPN in China although the pharmacological mechanisms involved have not been clarified. Using the network pharmacology approach, this study investigated the potential pathogenesis of CIPN and the therapeutic mechanisms exerted by the HQGZWWD herbal formula in CIPN. The targets of HQGZWWD were identified using traditional Chinese medicine (TCM) databases (TCMSP and ETCM) and prediction platforms (PharmMapper and TargetNet), and the genes of CIPN were collected by DisGeNET, GeneCards, and literature search. The common target interaction network between herbal formula and diseases was constructed by using Cytoscape. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to reveal the mechanism and efficacy of HQGZWWD in the treatment of CIPN. A total of 153 CIPN-related genes were screened, and a protein-protein interaction (PPI) network with 96 nodes and 424 edges was constructed. Sixty-three active components were retrieved from HQGZWWD, with a herb-composite compound-target network including 748 nodes and 5448 edges. Forty-one targets belong to the above two networks. The analysis of network results and literature review shows that the main pathological processes of CIPN may be the inflammatory response and nerve injury, and HQGZWWD plays a therapeutic role in CIPN by regulating inflammatory response and repairing nerve injury, thus verifying the reliable efficacy of this herbal formula. In addition, we found two new potential therapeutic targets (CDK7 and GSTM2) warranting further investigation. This study fully illustrates that TCM has the characteristics of a multicompound, multitarget, and multipathway treatment, which is of great significance to study the curative effect of herbal formulations. [ABSTRACT FROM AUTHOR]

Significant progress in osteochondral tissue engineering has been made for biomaterials designed to deliver growth factors that promote tissue regeneration. However, due to diffusion characteristics of hydrogels, the accurate delivery of signaling molecules remains a challenge. In comparison to the direct delivery of growth factors, gene therapy can overcome these challenges by allowing the simultaneous delivery of growth factors and transcription factors, thereby enhancing the multifactorial processes of tissue formation. Scaffold-based gene therapy provides a promising approach for tissue engineering through transfecting cells to enhance the sustained expression of the protein of interest or through silencing target genes associated with bone and joint disease. Reports of the efficacy of gene therapy to regenerate bone/cartilage tissue regeneration are widespread, but reviews on osteochondral tissue engineering using scaffold-based gene therapy are sparse. Herein, we review the recent advances in gene therapy with a focus on tissue engineering scaffolds for osteochondral regeneration. [ABSTRACT FROM AUTHOR]

Background. Therapy of nourishing kidney has been used for treating memory deficits of Alzheimer’s disease (AD) for thousands of years based on traditional Chinese medicine. However, we found the therapy of dredging the bowels could alleviate both memory deficits and mental symptoms of AD in clinic. Objective. To determine whether the therapy of dredging the bowels could enhance the neuroprotective effect of nourishing kidney herbs for treating AD rats, and to explore the underlying mechanism of the combination of nourishing kidney and dredging the bowels (NKDB) herbs. Methods. 60 rats were randomly divided into sham-operated group (SOG), model group (MG), nourishing kidney group (NKG), dredging the bowels group (DBG), nourishing kidney and dredging the bowels group (NKDBG), and donepezil hydrochloride group (DHG). The model establishment was performed by injecting Aβ 1-42 into the hippocampal CA1 region. Animals received aqueous solution of Chinese herbal medicine or western medicine while SOG received only distilled water. Ability of learning and memory were assessed by Morris water maze. Acetylcholinesterase(AChE) and choline acetyltransferase (ChAT) activity and positive cells in the hippocampus were detected by the biochemical and immunofluorescent assay. Results. All rats were in the same baseline. While after model establishment, ability of learning and memory of MG, NKG, DBG, NKDBG, and DHG were significantly impaired compared with SOG. Whereas after treatment, ability of learning and memory of NKG, DBG, NKDBG, and DHG were significantly improved compared with MG. Additionally, AChE activity of NKG, DBG, and NKDBG was significantly decreased, meanwhile ChAT activity showed an increased tendency. The number of AChE-positive cells and ChAT-positive cells of both NKDBG and DHG were significantly decreased and increased respectively, superior to those when compared with NKG and DBG. What’s more, there was no significant difference between NKDBG and DHG. Conclusion. Therapy of dredging the bowels could enhance the neuroprotective effect of nourishing kidney herbs by reversing morphological damage of hippocampal cholinergic system. Furthermore, treatment with NKDB herbs could be effectively against AD, providing a practical therapeutic strategy in clinic. [ABSTRACT FROM AUTHOR]

The testis‐specific Y‐encoded‐like protein (TSPYL) gene family includes TSPYL1 to TSPYL6. We previously reported that TSPYL5 regulates cytochrome P450 (CYP) 19A1 expression. Here we show that TSPYLs, especially TSPYL 1, 2, and 4, can regulate the expression of many CYP genes, including CYP17A1, a key enzyme in androgen biosynthesis, and CYP3A4, an enzyme that catalyzes the metabolism of abiraterone, a CYP17 inhibitor. Furthermore, a common TSPYL1 single nucleotide polymorphism (SNP), rs3828743 (G/A) (Pro62Ser), abolishes TSPYL1's ability to suppress CYP3A4 expression, resulting in reduced abiraterone concentrations and increased cell proliferation. Data from a prospective clinical trial of 87 metastatic castration‐resistant prostate cancer patients treated with abiraterone acetate/prednisone showed that the variant SNP genotype (A) was significantly associated with worse response and progression‐free survival. In summary, TSPYL genes are novel CYP gene transcription regulators, and genetic alteration within these genes significantly influences response to drug therapy through transcriptional regulation of CYP450 genes. [ABSTRACT FROM AUTHOR]

This study aimed to provide more data support for early diagnosis and treatment of neonatal purulent meningitis through retrospective analysis of its clinical diagnosis and treatment, pathogen distribution, and drug resistance in 5 third-class A hospitals in Southwest and Northwest China from January 2011 to December 2015. It was found that both the positive rates of blood and cerebrospinal fluid culture were low, and Escherichia coli should be the main pathogenic bacteria. Drug-resistant strains with varying degrees to the third generation of cephalosporin antibiotics have appeared currently. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common malignancy in women and the second leading cause of cancer death in women. Triple negative breast cancer (TNBC) subtype is a breast cancer subset without ER (estrogen receptor), PR (progesterone receptor) and HER2 (human epidermal growth factor receptor 2) expression, limiting treatment options and presenting a poorer survival rate. Thus, we investigated whether histone deacetylation inhibitor (HDACi) could be used as potential anti-cancer therapy on breast cancer cells. In this study, we found TNBC and HER2-enriched breast cancers are extremely sensitive to Panobinostat, Belinostat of HDACi via experiments of cell viability assay, apoptotic marker identification and flow cytometry measurement. On the other hand, we developed a bioluminescence-based live cell non-invasive apoptosis detection sensor (NIADS) detection system to evaluate the quantitative and kinetic analyses of apoptotic cell death by HDAC treatment on breast cancer cells. In addition, the use of HDACi may also contribute a synergic anti-cancer effect with co-treatment of chemotherapeutic agent such as doxorubicin on TNBC cells (MDA-MB-231), but not in breast normal epithelia cells (MCF-10A), providing therapeutic benefits against breast tumor in the clinic. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the effects of radial extracorporeal shock wave therapy (rESWT) on scar characteristics and transforming growth factor (TGF)-β1/Smad signaling in order to explore a potential modality for the treatment of hypertrophic scars (HS). The HS model was generated in rabbit ears, then rabbits were randomly divided into 3 groups: Lower (L)-ESWT [treated with rESWT with lower energy flux density (EFD) of 0.1 mJ/mm2], higher (H)-ESWT (treated with a higher EFD of 0.18 mJ/mm2) and the sham ESWT group (S-ESWT; no ESWT treatment). Scar characteristics (wrinkles, texture, diameter, area, volume of elevation, hemoglobin and melanin) were assessed using the Antera 3D® system. The protein and mRNA expression of TGF-β1, Smad2, Smad3 and Smad7 was assessed by enzyme-linked immunosorbent assay and reverse transcription-quantitative polymerase chain reaction, respectively. The Antera 3D® results indicated that wrinkles and hemoglobin of the HS were significantly improved in both of the rESWT groups when compared with the S-ESWT group. However, these changes appeared much earlier in the L-ESWT group than the H-ESWT. Scar texture was also improved in the L-ESWT group. However, rESWT did not influence HS diameter, area, volume of elevation or melanin levels. rESWT had no effect on TGF-β1 or Smad7 expression in either of rESWT groups. Although no difference was observed in Smad2 mRNA expression in the L-ESWT group, the Smad3 mRNA and protein expression significantly decreased when compared with the H-ESWT and S-ESWT groups. By contrast, Smad2 and Smad3 mRNA expression were upregulated in the H-ESWT group. These results demonstrated that rESWT with 0.1 mJ/mm2 EFD improved some characteristics of the HS tissue. Downregulation of Smad3 expression may underlie this inhibitory effect. Inhibition of the TGF-β1/Smad signal transduction pathway may be a potential therapeutic target for the management of HS. [ABSTRACT FROM AUTHOR]

Background: To investigate the clinical characteristics and treatment outcomes in necrotizing fasciitis (NF) patients in a reconstructive unit in northeastern China.Methods: Medical records of patients diagnosed with and treated for NF in the extremities from November 2013 to December 2016 were retrospectively reviewed. Demographic data, clinical presentation, duration of signs and symptoms, location of infection, predisposing factors, causative microbiological organisms, laboratory risk indicator for necrotizing fasciitis (LRINEC) score, number of surgical debridements, length of hospital stay, treatments, and outcomes were recorded.Results: A total of 39 consecutive patients were treated for severe NF (32 male and 7 female). Diabetes mellitus and blunt trauma were the most common risk factors (13 and 9 cases, respectively). The positive predictive value of the LRINEC score in NF diagnosis was 46.2%. Mean duration of signs and symptoms was 4.6 days. Staphylococcus aureus was the most commonly isolated bacteria (20 cases). All patients underwent their first debridement within 12 h of presentation (mean, 4.6 h). Mean number of surgical treatments was 2.8 (range, 2-5) per patient, including debridements. All patients survived, and mean length of hospital stay was 30.81 (range, 21-43) days. Three patients underwent limb amputation.Conclusions: In our clinical experience, early detection and aggressive debridement are the cornerstones of NF treatment. Antibiotic therapy and intensive care support is essential in severe cases of NF. Anaerobic tissue culture and frozen section biopsy could be adopted as routine tests for diagnosis and decision-making in NF. These findings should inform clinical decisions about the treatment of individual patients with NF. [ABSTRACT FROM AUTHOR]

Purpose This study aims to achieve customized prosthesis for total joint arthroplasty and total hip arthroplasty. Selective laser sintering (SLS) as additive manufacturing could enable small-scale fabrication of customized Ultra High Molecular Weight Polyethylene (UHMWPE) components; however, the processes for SLS of UHMWPE need to be improved.Design/methodology/approach This paper begins by improving the preheating system of the SLS fabricating equipment and then fabricating cuboids with the same size and cuboids with same volume and different size to study the warpage, demonstrating the effect of the value and uniformity of the preheating temperature on component fabrication. Warpage, density and tensile properties are investigated from the perspective of energy input density. Finally, complicated industrial parts are produced effectively by using optimized technological parameters.Findings The results show that components can be fabricated effectively after the optimization of the SLS technological parameters i.e. the preheating temperature the laser power the scanning interval and the scanning speed. The resulting warpage was found to be less than 0.1 mm along with the density as 83.25 and the tensile strength up to 14.1 Mpa. UHMWPE sample parts with good appearance and strength are obtained after ascertaining the effect of each factor on the fabrication of the sample parts.Originality/value It is very challenging to fabricate UHMWPE sample parts by SLS. This is a new step in the fabrication of customized UHMWPE sample parts. [ABSTRACT FROM AUTHOR]

Purpose: To determine the minimum required guiding catheter length for embolization of various intracranial aneurysms in anterior circulation and to analyze the effect of various patient factors on the required catheter length and potential interaction with its stability. Materials and Methods: From December 2016 to March 2017, 90 patients with 93 anterior circulation aneurysms were enrolled. Three types of guiding catheters (Envoy, Envoy DA, and Envoy DA XB; Codman Neurovascular, Raynham, MA, USA) were used. We measured the in-the-body length of the catheter and checked the catheter tip location in the carotid artery. We analyzed factors affecting the in-the-body length and stability of the guiding catheter system. Results: The average (±standard deviation) in-the-body length of the catheter was 84.2±5.9 cm. The length was significantly longer in men (89.1±5.6 vs. 82.1±4.6 cm, P<0.001), patients older than 65 years (87.7±7.8 vs. 82.7±4.2 cm, P<0.001), patients with a more tortuous arch (arch type 2 and 3) (87.5±7.4 vs. 82.7±4.4 cm, P<0.001), and patients with a distal aneurysm location (distal group) (86.2±5.0 vs. 82.7±6.1 cm, P=0.004). A shift in the tip location was noted in 19 patients (20.4%); there was no significant different among the 3 catheters (P=0.942). Conclusion: The minimum required length of a guiding catheter was 84 cm on average for elective anterior- circulation aneurysm embolization. The length increased in men older than 65 years with a more tortuous arch. We could reach a higher position with distal access catheters with little difference in the stability once we reached the target location. [ABSTRACT FROM AUTHOR]

Background: We previously performed a case-control genome-wide association study in women treated with selective estrogen receptor modulators (SERMs) for breast cancer prevention and identified single nucleotide polymorphisms (SNPs) in ZNF423 as potential biomarkers for response to SERM therapy. The ZNF423rs9940645 SNP, which is approximately 200 bp away from the estrogen response elements, resulted in the SNP, estrogen, and SERM-dependent regulation of ZNF423 expression and, "downstream", that of BRCA1.Methods: Electrophoretic mobility shift assay-mass spectrometry was performed to identify proteins binding to the ZNF423 SNP and coordinating with estrogen receptor alpha (ERα). Clustered, regularly interspaced short palindromic repeats (CRISPR)/Cas9 genome editing was applied to generate ZR75-1 breast cancer cells with different ZNF423 SNP genotypes. Both cultured cells and mouse xenograft models with different ZNF423 SNP genotypes were used to study the cellular responses to SERMs and poly(ADP-ribose) polymerase (PARP) inhibitors.Results: We identified calmodulin-like protein 3 (CALML3) as a key sensor of this SNP and a coregulator of ERα, which contributes to differential gene transcription regulation in an estrogen and SERM-dependent fashion. Furthermore, using CRISPR/Cas9-engineered ZR75-1 breast cancer cells with different ZNF423 SNP genotypes, striking differences in cellular responses to SERMs and PARP inhibitors, alone or in combination, were observed not only in cells but also in a mouse xenograft model.Conclusions: Our results have demonstrated the mechanism by which the ZNF423 rs9940645 SNP might regulate gene expression and drug response as well as its potential role in achieving more highly individualized breast cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Studies have demonstrated that catheter ablation of atrial fibrillation is associated with better rhythm control than drug therapy. The present study aimed to assess the clinical outcomes and health-related quality of life of ablation therapy in a real world setting.Methods: A prospective, non-randomized, single center study in a real-world clinical setting in China was conducted. Patients were followed up at 3, 6, and 9 months after baseline encounter. Propensity score matched patients receiving ablation or anti-arrhythmic drug therapy were compared. Incidence rate of atrial fibrillation recurrence and quality of life outcomes were measured and analyzed using log-rank test, multivariate logistic regression and mixed-effects linear regression respectively.Results: In this study, 151 atrial fibrillation patients treated by ablation therapy and 318 patients treated by anti-arrhythmic drugs were enrolled. During follow up, 82.0% in the ablation arm and 22.4% in the drug arm had no documented atrial fibrillation recurrence [HR for atrial fibrillation recurrence 0.07 (95%CI: 0.02-0.21, p < 0.0001)] among paroxysmal atrial fibrillation patients. The corresponding no recurrent rate were 66.7% and 18.5% [0.21 (0.05-0.95, p = 0.04)] respectively among persistent atrial fibrillation patients. Improvement in Short Form-36 physical component scores, Short Form-36 mental component scores and total Atrial Fibrillation Effect on Quality-of-life scores were 16.33 (14.05-18.61, p < 0.001), 8.10 (6.11-10.09, p < 0.001) and 18.28 (16.11-20.45, p < 0.001) respectively among paroxysmal AF patients and 6.32 (3.15-9.49, p < 0.001), 3.99 (1.82-6.16, p < 0.001) and 13.97 (10.89-17.05, p < 0.001) respectively among persistent AF patients. Improvements in total Atrial Fibrillation Effect on Quality-of-life score were also significant in ablation arm while no significant improvement of total Atrial Fibrillation Effect on Quality-of-life score in the drug arm.Conclusion: Compared with drug therapy, catheter ablation is associated with significant lower AF recurrence and improved overall quality of life.Trial Registration: The present study has been registered on clinicaltrials.gov. The ClinicalTrials.gov ID is NCT01878981 . The registration date is May 29, 2013. [ABSTRACT FROM AUTHOR]

Background: Acquired drug resistance to the chemotherapeutic drug irinotecan (the active metabolite of which is SN-38) is one of the significant obstacles in the treatment of advanced colorectal cancer (CRC). The molecular mechanism or targets mediating irinotecan resistance are still unclear. It is urgent to find the irinotecan response biomarkers to improve CRC patients’ therapy. Methods: Genetic Omnibus Database GSE42387 which contained the gene expression profiles of parental and irinotecan-resistant HCT-116 cell lines was used. Differentially expressed genes (DEGs) between parental and irinotecan-resistant cells, protein-protein interactions (PPIs), gene ontologies (GOs) and pathway analysis were performed to identify the overall biological changes. The most common DEGs in the PPIs, GOs and pathways were identified and were validated clinically by their ability to predict overall survival and disease free survival. The gene-gene expression correlation and gene-resistance correlation was also evaluated in CRC patients using The Cancer Genomic Atlas data (TCGA). Results: The 135 DEGs were identified of which 36 were upregulated and 99 were down regulated. After mapping the PPI networks, the GOs and the pathways, nine genes (GNAS, PRKACB, MECOM, PLA2G4C, BMP6, BDNF, DLG4, FGF2 and FGF9) were found to be commonly enriched. Signal transduction was the most significant GO and MAPK pathway was the most significant pathway. The five genes (FGF2, FGF9, PRKACB, MECOM and PLA2G4C) in the MAPK pathway were all contained in the signal transduction and the levels of those genes were upregulated. The FGF2, FGF9 and MECOM expression were highly associated with CRC patients’ survival rate but not PRKACB and PLA2G4C. In addition, FGF9 was also associated with irinotecan resistance and poor disease free survival. FGF2, FGF9 and PRKACB were positively correlated with each other while MECOM correlated positively with FGF9 and PLA2G4C, and correlated negatively with FGF2 and PRKACB after doing gene-gene expression correlation. Conclusion: Targeting the MAPK signal transduction pathway through the targeting of the FGF2, FGF9, MECOM, PLA2G4C and PRKACB might increase tumor responsiveness to irinotecan treatment. [ABSTRACT FROM AUTHOR]

Background Spinal epidural arteriovenous fistulas (SEDAVFs) are peculiar and poorly understood lesions with a poorly understood natural history. They usually are subclassified into 2 types according to their drainage components. This study aimed to describe a new type of SEDAVFs that is featured with a unique drainage pattern and present our natural history hypothesis of SEDAVFs. Methods Five SEDAVF cases of the new type were reviewed retrospectively from a high case-volume spinal vascular malformation database. The clinical manifestations, neuroradiologic findings, angioarchitecture, treatment strategies, and clinical outcomes were assessed. Results All patients presented with spontaneous spinal epidural hematoma, and 2 of them exhibited rebleeding. The median age at the initial episode was 20 years. Spinal digital subtraction angiography revealed slow-flow epidural fistulas drained by spinal epidural venous plexus without intradural drainage or engorged venous pouches in all 5 patients. Three patients underwent microsurgical treatment. The outcomes of all of the patients were favorable. Conclusions Our study reported a special type of hemorrhagic SEDAVF without an intradural drainage component or epidural mass effect. The key diagnostic clue was early opacification of spinal epidural venous plexus on spinal angiogram. We believe SEDAVFs may form at an early age and gradually develop with time. Different types of SEDAVFs may represent different developing stages of one disease, and our type may represent the early stage of SEDAVFs. [ABSTRACT FROM AUTHOR]

Pancreatic cancer remains the fourth leading cause of cancer-related death in the USA with a 5-year survival rate of 5 %. The effects of epidermal growth factor receptor and vascular endothelial growth factor A blockade with chemotherapy on pancreatic tumor growth were examined. Mice bearing human PANC-1 cell xenografts were divided into three groups: T-CR (gemcitabine, cisplatin, and 5-fluorouracil), T-TR (cetuximab, bevacizumab, gemcitabine, cisplatin, and 5-fluorouracil), and vehicle control (T). The therapies were administered via intraperitoneal injections every 4 days for seven cycles from 7 weeks after cancer cell implantation. Mice treated with T-TR had significant reductions in tumor weight as compared to the control group ( p < 0.05). Although mice in the T-CR group experienced a significant reduction in body weight gain, serum albumin, and gastrocnemius muscle mass ( p < 0.05), no such reductions were observed in the T-TR group. Mice treated with T-TR had slightly increased CD11c DC and CD49b NK cell levels in the spleen ( p < 0.05) and significantly lower tumor VEGF expression ( p < 0.05). Tumor carcinoembryonic antigen expression was significantly reduced in both treatment groups ( p < 0.05). Thus, addition of bevacizumab and cetuximab to gemcitabine, cisplatin, and fluorouracil may represent an effective treatment option for pancreatic cancer that warrants further study. [ABSTRACT FROM AUTHOR]

Background Spontaneous spinal epidural hematoma (SSEH) is a rare neurologic emergency of the spinal cord. Its cause and treatment strategy remain controversial. This study aimed to evaluate a significant cause of SSEH and to discuss the treatment strategy according to the clinical outcomes of patients in 2 institutions. Methods Fifty-five cases of SSEH treated at our institutions between February 2002 and February 2016 were retrospectively analyzed. Results The mean age of the first SSEH onset was 31.8 years. The follow-up rate was 72.7%, with 28 patients (70%) showing satisfactory clinical outcomes. Forty patients received preoperative spinal digital subtraction angiography. Spinal epidural (extradural) arteriovenous fistula was detected in 6 patients (15%), 5 of whom showed 1 type of special slow-flow shunt. Nineteen patients (34.5%) suffered from multiple episodes until they underwent invasive treatments or last follow-up. Rebleeding was confirmed in 8 patients. None of the patients had a subsequent episode or rebleeding after invasive treatment. The risk factors for poor clinical outcome included advanced age at initial onset ( P = 0.020), a short progression interval ( P = 0.030), no symptom relief after admission ( P = 0.011), hypesthesia ( P = 0.017), complete spinal cord injury ( P = 0.001), and hematoma below the T4 level ( P = 0.014). Conclusions Spinal epidural (extradural) arteriovenous fistula is a significant cause of SSEH. Standard spinal digital subtraction angiography is necessary for patients with SSEH. Conservative treatment could not prevent occurrence of multiple episodes or rebleeding in patients. Microsurgery should be recommended as the preferred treatment strategy for SSEH. Endovascular embolization is also recommended if applicable. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) stress is a particular process with an imbalance of homeostasis, which plays an important role in pancreatitis, but little is known about how ER stress is implicated in severe acute pancreatitis (SAP) induced pancreatic beta-cell injury. To investigate the effect of 4-phenylbutyric acid (4-PBA) on the beta-cell injury following SAP and the underlying mechanism, twenty-four Sprague-Dawley rats were randomly divided into sham-operation (SO) group, SAP model group, and 4-PBA treatment group. SAP model was induced by infusion of 5% sodium taurocholate into the biliopancreatic duct. 4-PBA or normal saline was injected intraperitoneally for 3 days in respective group before successful modeling. Results showed that 4-PBA attenuated the following: (1) pancreas and islet pathological injuries, (2) serum TNF-α and IL-1β, (3) serum insulin and glucose, (4) beta-cell ultrastructural changes, (5) ER stress markers (BiP, ORP150, and CHOP), Caspase-3, and insulin expression in islet. These results suggested that 4-PBA mitigates pancreatic beta-cell injury and endocrine disorder in SAP, presumably because of its role in inhibiting excessive endoplasmic reticulum stress. This may serve as a new therapeutic target for reducing pancreatic beta-cell injury and endocrine disorder in SAP upon 4-PBA treatment. [ABSTRACT FROM AUTHOR]

An understanding of the molecular mechanisms involved in the regulation of estrogen receptor alpha (ERα)-mediated neuroprotective effects is valuable for the development of therapeutic strategy against neuronal ischemic injury. Here, we report the upregulated expression of metastasis-associated protein 1 (MTA1), a master chromatin modifier and transcriptional regulator, in the murine middle cerebral artery occlusion (MCAO) model. Inhibition of MTA1 expression by in vivo short interfering RNA treatment potentiated neuronal apoptosis in a caspase-3-dependent manner and thereafter aggravated MCAO-induced neuronal damage. Mechanistically, the pro-survival effects of MTA1 required the participation of ERα signaling. We also provide in vitro evidence that MTA1 enhances the binding of ERα with the BCL2 promoter upon ischemic insults via recruitment of HDAC2 together with other unidentified coregulators, thus promoting the ERα-mediated transactivation of the BCL2 gene. Collectively, our results suggest that the augmentation of endogenous MTA1 expression during neuronal ischemic injury acts additionally to an endocrinous cascade orchestrating intimate interactions between ERα and BCL2 pathways and operates as an indispensable defensive mechanism in response to neuronal ischemia/reperfusion stress. Future studies in this field will shed light on the modulation of the complicated neuroprotective effects by estrogen signaling. [ABSTRACT FROM AUTHOR]

Objective: For multi-level spondylolysis patients, surgeons commonly choose to fix all the segments with pars interarticularis defect even those without slippage and not responsible for clinical symptoms. In this study, we tried to study the necessity of the preventative long-segment surgery for the defected segment without slippage in treatment of multi-level spondylolysis patients from a biomechanical perspective. Method: We established a bi-level spondylolysis model with pars defects at L4 and L5 segments, and simulated posterior lumbar interbody fusion (PLIF) and pedicle screw fixation at L5-S1 level. Then we compared the biomechanical changes at L4 segment before and after surgery in neutral, flexion, extension, lateral bending and axial rotation position. Results: The stress on L4 pars interarticularis was very similar before and after surgery, and reached the highest in axial rotation. The L3-L4 intradiscal pressure was almost the same, while L4-L5 intradiscal pressure changed a little in lateral bending (increase from 1.993 to 2.160 MPa) and axial rotation (decrease from 1.639 to 1.307 MPa) after surgery. The PLIF surgery caused a little increase of range of motion at adjacent L4-L5 and L3-L4 levels, but the change is very tiny (1 degree). Conclusion: The PLIF surgery will not cause significant biomechanical change at adjacent segment with pars defect in multi-level spondylolysis. On the contrary, excessive long-segment surgery will damage surrounding soft tissues which are important for maintaining the stability of spine. So a preventative long-segment surgery is not necessary for multi-level spondylolysis as long as there are no soft tissue degeneration signs at adjacent level. [ABSTRACT FROM AUTHOR]

Purpose: To describe Type 1 retinopathy of prematurity (ROP) and its laser treatment outcomes in premature infants with birth weight > 1250 g in Eastern China. Methods: A retrospective review of 3175 ROP records was conducted at Shanghai Eye & ENT Hospital of Fudan University. The records were collected at the ROP clinic from 2006 to 2014, including their demographic and medical information such as gestational age, birth weight, supplemental oxygen therapy, systemic complications, ROP stage, location, presence of plus disease. All infants were examined by RetCam fundus camera. Those with Type 1 ROP were also examined by indirect ophthalmoscope before undergoing transpupillary laser treatment. Results: A total of 12 infants (24 eyes) with Type 1 ROP and birth weight > 1250 g were enrolled. All infants enrolled had plus disease and ROP in zone II retina. Specifically, 16 eyes (67%) had stage 2 ROP. 8 eyes (33%) had stage 3 ROP. ROP regressed in 23 eyes (96%) following laser treatment. Partial retinal detachment developed in one eye (4%). No severe involution sequelaes or laser-related complications were recorded. Mean follow-up was 30±6 weeks. Conclusion: Type 1 ROP may occur in large premature infants who have undergone supplemental oxygen therapy. This Type 1 ROP is mainly located in zone II retina. Laser treatment is a safe and effective intervention for these infants. [ABSTRACT FROM AUTHOR]

Hydrogen (H2), a new antioxidant, was reported to reduce •OH and ONOO− selectively and inhibit certain proinflammatory mediators to product, without disturbing metabolic redox reactions or ROS involved in cell signaling. We herein aim to explore its protective effects on acute renal injury in sodium taurocholate-induced acute pancreatitis and its possible mechanisms. Rats were injected with hydrogen-rich saline (HRS group) or normal saline (SO and SAP group) through tail intravenously (6 mL/kg) and compensated subcutaneously (20 mL/kg) after successful modeling. Results showed that hydrogen-rich saline attenuated the following: (1) serum Cr and BUN, (2) pancreatic and renal pathological injuries, (3) renal MDA, (4) renal MPO, (5) serum IL-1β, IL-6, and renal TNF- α , HMGB1, and (6) tyrosine nitration, IκB degradation, and NF-κB activation in renal tissues. In addition, it increased the level of IL-10 and SOD activity in renal tissues. These results proved that hydrogen-rich saline attenuates acute renal injury in sodium taurocholate-induced acute pancreatitis, presumably because of its detoxification activity against excessive ROS, and inhibits the activation of NF-κB by affecting IκB nitration and degradation. Our findings highlight the potential value of hydrogen-rich saline as a new therapeutic method on acute renal injury in severe acute pancreatitis clinically. [ABSTRACT FROM AUTHOR]

Fermented wheat germ extract (FWGE) is a nutrient supplement and a potential antitumor ingredient for developing an integrated chemotherapy with standard chemotherapeutic drugs for treating ovarian cancer patients. In this study, we evaluated the tumor suppression efficiency of FWGE in human ovarian carcinoma cells, SKOV-3 and ES-2, and found the half-maximal inhibitory concentrations (IC50s) to be 643.76 μg/mL and 246.11 μg/mL after 48 h of FWGE treatment. FWGE treatment also induced programmed cell death by activating the caspase-7 cleavage in both SKOV-3 and ES-2 cells, but only caspase-3 and poly(adenosine diphosphate-ribose) polymerase cleavages were activated in SKOV-3 cells. Moreover, FWGE exhibited combination drug effects with cisplatin and docetaxel in SKOV-3 and ES-2 cells by enhancing the cytotoxicity of both drugs. In conclusion, we found that FWGE not only suppressed cell growth but also induced caspase-3-related and caspase-7-related cell death in human ovarian carcinoma cells. FWGE treatment further enhanced the cytotoxicity of cisplatin and docetaxel, suggesting that FWGE is a potential ingredient in the development of adjuvant chemotherapy with cisplatin or docetaxel for treating ovarian cancer patients. [ABSTRACT FROM AUTHOR]

Fermented wheat germ extract (FWGE) is a nutrient supplement and a potential antitumor ingredient for developing an integrated chemotherapy with standard chemotherapeutic drugs for treating ovarian cancer patients. In this study, we evaluated the tumor suppression efficiency of FWGE in human ovarian carcinoma cells, SKOV-3 and ES-2, and found the half-maximal inhibitory concentrations (IC50s) to be 643.76 µg/mL and 246.11 µg/mL after 48h of FWGE treatment. FWGE treatment also induced programmed cell death by activating the caspase-7 cleavage in both SKOV-3 and ES-2 cells, but only caspase-3 and poly(adenosine diphosphate-ribose) polymerase cleavages were activated in SKOV-3 cells. Moreover, FWGE exhibited combination drug effects with cisplatin and docetaxel in SKOV-3 and ES-2 cells by enhancing the cytotoxicity of both drugs. In conclusion, we found that FWGE not only suppressed cell growth but also induced caspase-3-related and caspase-7-related cell death in human ovarian carcinoma cells. FWGE treatment further enhanced the cytotoxicity of cisplatin and docetaxel, suggesting that FWGE is a potential ingredient in the development of adjuvant chemotherapy with cisplatin or docetaxel for treating ovarian cancer patients. [ABSTRACT FROM AUTHOR]

Background: Community health service center (CHSC) in China is always regarded as a good facility of primary care, which plays an important role in chronic non-communicable disease management. This study aimed to investigate the blood pressure (BP) control rate in a real life CHSC-based management program and its determinants. Methods: The study enrolled 3191 patients (mean age of 70 ± 10 years, 43% males) in a hypertension management program provided by the Yulin CHSC (Chengdu, China), which had been running for 9 years. Uncontrolled BP was defined as the systolic BP of ≥140 mmHg and/or the diastolic BP of ≥90 mmHg, and its associated factors were analyzed by using logistic regression. Results: The duration of stay in the program was 33 ± 25 months. When compared with the BP at entry, the recent BP was significantly lowered (147 ± 17 vs. 133 ± 8 mmHg; 83 ± 11 vs. 75 ± 6 mmHg) and the BP control rate was dramatically increased (32 vs. 85%) (all p < 0.001). The age of >70 years [1.40 (odds ratio), 1.15-1.71 (95% confidence interval)], female gender (0.76, 0.63-0.93), longer stay of >33 months (0.77, 0.63-0.94), doctor in charge (0.97, 0.95-0.99), and the use of calcium channel blocker (1.35, 1.09-1.67) were significantly related to uncontrolled BP at the recent follow up (all p < 0.05). Conclusions: This CHSC-run hypertension program provides an ideal platform of multi-intervention management, which is effective in achieving higher BP control rate in community patient population. However, the BP control status could be affected by age, gender and adherence of the patients, as well as practice behavior of the doctors. [ABSTRACT FROM AUTHOR]

Colorectal cancer is a common cancer worldwide, and chemotherapy is a mainstream approach for advanced and recurrent cases. Development of effective complementary drugs could help improve tumor suppression efficiency and control adverse effects from chemotherapy. The aqueous extract of Solanum nigrum leaves (AE-SN) is an essential component in many traditional Chinese medicine formulas for treating cancer, but there is a lack of evidence verifying its tumor suppression efficacy in colorectal cancer. The purpose of this study is to evaluate the tumor suppression efficacy of AE-SN using DLD-1 and HT-29 human colorectal carcinoma cells and examine the combined drug effect when combined with the chemotherapeutic drugs cisplatin, doxorubicin, docetaxel, and 5-fluorouracil. The results indicated that AE-SN induced autophagy via microtubule-associated protein 1 light chain 3 A/B II accumulation but not caspase-3-dependent apoptosis in both cell lines. The IC50s after 48 hours of treatment were 0.541 and 0.948 mg/ml AE-SN in DLD-1 and HT-29, respectively. AE-SN also demonstrated a combined drug effect with all tested drugs by enhancing cytotoxicity in tumor cells. Our results suggest that AE-SN has potential in the development of complementary chemotherapy for colorectal cancer. [ABSTRACT FROM AUTHOR]

Abstract: This study investigates the use of a modified coaxial electrospinning process in the production of drug-loaded cellulose acetate (CA) nanofibers. With CA employed as a filament-forming matrix and ketoprofen (KET) as an active pharmaceutical ingredient, modified coaxial processes using sheath fluids comprising only mixed solvents were undertaken. With a sheath-to-core flow rate ratio of 0.2:1, the nanofibers prepared from the coaxial process had a smaller average diameter, narrower size distribution, more uniform structures, and smoother surface morphologies than those generated from single fluid electrospinning. In addition, the coaxial fibers provided a better zero-order drug release profile. The use of a sheath solvent means that the core jet is subjected to electrical drawing for a longer period, facilitating homogeneous core jet solidification and retarding the formation of wrinkles on the surface of the nanofibers. This modified coaxial electrospinning protocol allows the systematic fabrication of functional polymer nanofibers with improved quality. [Copyright &y& Elsevier]

Due to the emergence of drug-resistance, first-line therapy with fluconazole (FLC) increasingly resulted in clinical failure for the treatment of candidemia. Our previous studies found that in vitro RTA2 was involved in the calcineurin-mediated resistance to FLC in C. albicans. In this study, we found that calcium-activated-calcineurin significantly reduced the in vitro sensitivity of C. albicans to FLC by blocking the impairment of FLC to the plasma membrane via Rta2p. Furthermore, we found that RTA2 itself was not involved in C. albicans virulence, but the disruption of RTA2 dramatically increased the therapeutic efficacy of FLC in a murine model of systemic candidiasis. Conversely, both re-introduction of one RTA2 allele and ectopic expression of RTA2 significantly reduced FLC efficacy in a mammalian host. Finally, we found that calcium- activated-calcineurin, through its target Rta2p, dramatically reduced the efficacy of FLC against candidemia. Given the critical roles of Rta2p in controlling the efficacy of FLC, Rta2p can be a potential drug target for antifungal therapies. [ABSTRACT FROM AUTHOR]

This paper investigated the potential effects of zerumbone pretreatment on an acute necrotizing pancreatitis rat model induced by sodium taurocholate. The pancreatitis injury was evaluated by serum AMY, sPLA2, and pancreatic pathological score. Pancreatitisinduced hepatic injury was measured by ALT, AST, and hepatic histopathology. The expression of I-κBα and NF-κB protein was evaluated by western blot and immunohistochemistry assay while ICAM-1 and IL-1β mRNA were examined by RT-PCR. The results showed that AMY, sPLA2, ALT, and AST levels and histopathological assay of pancreatic and hepatic tissues were significantly reduced following administration of zerumbone. Applying zerumbone also has been shown to inhibit NF-κB protein and downregulation of ICAM-1 and IL-1β mRNA. The present paper suggests that treatment of zerumbone on rat attenuates the severity of acute necrotizing pancreatitis and pancreatitis-induced hepatic injury, via inhibiting NF-κB activation and downregulating the expression of ICAM-1 and IL-1β. [ABSTRACT FROM AUTHOR]

Successful reconstruction of extensive anterior chest wall defect following major electrical burn represents a very challenging surgery. Herein we report the first case using pedicled full-thickness abdominal flap combined with skin grafting to treat this injury with severe infection and exposure of pericardium and ribs in a Chinese patient. Following the performance of chest debridement to remove necrotic and infected tissues and the injection of broad-spectrum antibiotics to reduce infection, a pedicled full-thickness abdominal flap was used to cover the exposed pericardium and ribs, and skin grafting from the right leg of the patient was done to cover the exposed vital tissues. The patient was followed up for a total of 3·5 years, and satisfactory cosmetic and functional outcomes were obtained without complications. This report provides an effective method for the surgeons who encounter similar cases where reconstruction of extensive anterior chest wall is required. [ABSTRACT FROM AUTHOR]

Background: Platelet-rich plasma (PRP) is becoming a promising strategy to treat early intervertebral disc degeneration (IDD) in clinics. Pure PRP without leukocytes (P-PRP) may decrease the catabolic and inflammatory changes in the early degenerated intervertebral discs. The aim of this study was to investigate the effects of P-PRP on nucleus pulposus-derived stem cells (NPSCs) isolated from early degenerated intervertebral discs in vitro. Methods: NPSCs isolated from early degenerated discs of rabbits were treated with P-PRP or leukocyte-platelet-rich PRP (L-PRP) in vitro, followed by measuring cell proliferation, stem cell marker expression, inflammatory gene expression, and anabolic and catabolic protein expression by immunostaining, quantitative real-time polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay. Results: Cell proliferation was induced by P-PRP in a dose-dependent manner with maximum proliferation at 10% P-PRP dose. P-PRP induced differentiation of NPSCs into active nucleus pulposus cells. P-PRP mainly increased the expression of anabolic genes and relative proteins, aggrecan (AGC), collagen types II (Col II), while L-PRP predominantly increased the expression of catabolic and inflammatory genes, matrix metalloproteinase-1 (MMP-1), MMP-13, interleukin-1 beta (IL-1β), IL-6, tumor necrosis factor alpha (TNF-α), and protein production of IL-1β and TNF-α. Conclusions: Leukocytes in PRP activate inflammatory and catabolic effects on NPSCs from early degenerated intervertebral discs. Hence, P-PRP may be a more suitable therapeutic strategy for early IDD. [ABSTRACT FROM AUTHOR]

To analyze the clinical effect of extracorporeal membrane oxygenation (ECMO) in children with acute fulminant myocarditis, we retrospectively analyzed the data of five children with acute fulminant myocarditis in the intensive care unit (ICU) at the Affiliated Children’s Hospital, Zhejiang University from February 2009 to November 2012. The study group included two boys and three girls ranging in age from 9 to 13 years (median 10 years). Body weight ranged from 25 to 33 kg (mean 29.6 kg). They underwent extracorporeal membrane oxygenation (ECMO) through a venous-arterial ECMO model with an average ECMO supporting time of 89.8 h (40–142 h). Extracorporeal circulation was established in all five children. After treatment with ECMO, the heart rate, blood pressure, and oxygen saturation were greatly improved in the four children who survived. These four children were successfully weaned from ECMO and discharged from hospital machine-free, for a survival rate of 80% (4/5). One child died still dependent on the machine. Cause of death was irrecoverable cardiac function and multiple organ failure. Complications during ECMO included three cases of suture bleeding, one case of acute hemolytic renal failure and suture bleeding, and one case of hyperglycemia. During the follow-up period of 4–50 months, the four surviving children recovered with normal cardiac function and no abnormal functions of other organs. The application of ECMO in acute fulminant myocarditis, even in local centers that experience low incidence of this disease, remains an effective approach. Larger studies to determine optimal timing of placement on ECMO to guide local centers are warranted. [ABSTRACT FROM AUTHOR]

Abstract: Previous studies showed that hyperbaric oxygen (HBO) promoted cell proliferation in hypoxic–ischemic (HI) neonate rats. Neural stem cells (NSC) existed in the brain lifelong and can be activated. This study was undertaken to assess whether HBO treatment promoted the proliferation of NSC and repaired the brain damage regardless of when it is started, thus to explore the therapeutic window of HBO treatment. Seven-day-old Sprague–Dawley rats underwent left carotid ligation followed by 2 h of hypoxic stress (8% O2 at 37 °C). Hyperbaric oxygen therapy was administered 3, 6, 12, 24, and 72 h after HI. 5-bromo-2′-deoxyurindine and 5-bromo-2′-deoxyuridine/nestin were detected by immunofluorescence and nestin was examined by western blot analysis 10 days after HI. T-maze forced alternation, the foot-fault test, and the radial arm maze were conducted at P 22 days (14 days after HI), P 30 days, and P 34 days. Thereafter, cerebral morphology was examined by Nissl-staining 28 days after HI. There were remarkable increases in the proliferation of neural stem cells in the HBO-treated group, 3, 6, 12, and 24 h after HI, as compared with the HIBD group. The HBO-treated group, 3, 6, and 12 h after HI, performed better in the behavioral test and had less neural loss in the hippocampal CA1 region as compared with the HIBD group. The therapeutic window for effective HBO treatment could be delayed up to 12 h after HIBD, while the effect decreased 24 h after HI. [Copyright &y& Elsevier]

Abstract Numerous experimental studies and clinical observations suggest that cerebral ischemia may contribute to the pathogenesis of Alzheimer’s disease (AD). Two-vessel occlusion caused cerebral ischemia model is often used in the study of vascular dementia (VaD). But how cerebral ischemia works on AD rat model which induced by intracerebroventricular injection of Aβ 1-42 remains unclear. In the following study, we investigated the characteristics of rat model caused by intracerebroventricular injection of Aβ 1-42 or two-vessel occlusion (2-VO) only and by both of the two operations. The animal cognitive functions were accessed by the Morris water maze. Regional cerebral blood flow was detected by Laser Doppler Blood Flowmeter. HE&Nissl staining, Congo red staining and immunohistochemistry were used to observe the status of neuronal loss, Aβ deposition and the phosphorylated tau expression in hippocampus, respectively. We also measured the contents of AchE and ChAT in serum and hippocampus by Enzyme Linked Immunosorbent Assay. The MWM results showed that rats of Aβ 1–42 +2-VO group had a disorder in cognitive functions, at an early stage of one week after modeling, comparing with rats of sham group. The regional cerebral blood flow (rCBF) was significantly reduced in Aβ 1-42 +2-VO and 2-VO group one week after modeling, and still maintained low perfusion levels four weeks after modeling. HE and Nissl staining showed that Aβ 1-42 +2-VO rats’ hippocampal CA1 neurons were in disorder, degeneration and necrosis, severe neuronal loss from the first week to the fourth week, while this phenomenon only appeared in the fourth week after modeling in rats of Aβ 1-42 group and 2-VO group. Congo red staining showed that Aβ 1-42 + 2-VO group rats’ hippocampus CA1 had amyloid deposits from the first week to the fourth week, Aβ 1-42 group were not find amyloid deposition significantly until four weeks after modeling, however, 2-VO group had no significant amyloid deposition all the time. Notably, IHC showed that, two weeks after modeling, the p-tau positive total area and integrated optical density of hippocampal CA1 region were significantly increased in Aβ 1-42 + 2-VO group rats, while 2-VO group and Aβ 1-42 group rats had no significantly changes all the time. We also found that the content of AchE was increased both in serum and hippocampus of Aβ 1-42 + 2-VO group rats, and ChAT was decreased. However, there was no significantly change in cortex of content of AchE: acetylcholinesterase (AchE) and choline acetylase (ChAT) all three groups. Together, our study suggest that intracerebroventricular injection of Aβ 1-42 combined with two-vessel occlusion may accelerate Alzheimer’s disease development in rats. Also, this may serve as a less-time consuming new model to study the Alzheimer’s disease and especially AD accompanied by cerebral ischemia. [ABSTRACT FROM AUTHOR]

Objectives Recombinant tissue plasminogen activator (rtPA) is widely used for patients with thromboembolic disease, and increasing evidence indicates that it can directly induce neurotoxicity independent of its thrombolysis property. Here, we aimed to confirm the long-term effect of rtPA on animal's behavior, and investigate the underlying pathogenesis. Methods and results Male Sprague-Dawley rats randomly received a dose of rtPA (10 mg/kg) or sterile saline. Three months later, the animals receiving rtPA displayed anxiety-like behaviors in the open field and novelty-suppressed feeding tests. To investigate the possible pathogenesis, gas chromatography-mass spectrometry-based metabolomics analysis was performed, with 18 differential metabolites identified in the hippocampus 24 h after the treatments. Based upon these differential metabolites, a metabolite-protein integrated network was generated, which indicated that ERK1/2-glutamic acid decarboxylase (GAD) 1-γ aminobutyric acid (GABA) cascade may be related to long-term anxiety-like behaviors. The GABA levels in hippocampus were decreased 24 h post-treatment and three months later, confirmed by a high performance liquid chromatography method. We also examined the expression of GAD1 and GAD2 using western blotting or immunohistochemical staining. Levels of GAD1 were persistently decreased after treatment, while GAD2 levels, GAD1-immunoreactive, and GAD2-immunoreactive neurons showed no significant differences. The underlying pathogenesis also involved activation of ERK1/2, confirmed by increased phospho-ERK1/2 24 h post-treatment. Conclusions RtPA can induce long-term anxiety-like behaviors after a clinical injected dose. The underlying pathogenesis involves the ERK1/2-GAD1-GABA cascade in the hippocampus. This pharmacological side effect of rtPA may further exacerbate post-stroke anxiety disorder for stroke patients. [ABSTRACT FROM AUTHOR]

Incorporation of bioactive drugs and biofunctionalization of polyester fibrous scaffolds are essential means to improve their bio-functions and histocompatibility for regenerative medicine. However, it is still a challenge to biofunctionalize such drug carriers via traditional biochemical methods while maintaining their properties without changes in drug activity and loading ratio. Here, we demonstrated a facile approach for biofunctionalization of PLGA fibrous scaffolds with various molecules (i.e., PEG polymer, RGD peptide and bFGF growth factor for cell repellent, adhesion and proliferation, respectively) via mussel-Inspired poly(dopamine) (PDA) coating in aqueous solution. By virtue of the mild and efficient nature of this approach, the drug-loaded PLGA fibers could be easily biofunctionalized and showed negligible effects on the scaffold properties, especially drug activity and loading ratio. Further, in vivo study showed that, a ginsenoside-Rg3-loaded fibrous scaffold functionalized with bFGF growth factor could not only promote the early-stage wound healing in rabbit ear wounds (bio-signal from bFGF), but also inhibit later-stage hypertrophic scars formation (release of Rg3 drug). Therefore, the mussel-inspired method for bio-modification provides a facile and effective strategy to combine drug and bio-function in one system, thus facilitating a synergistic effect of drug-therapy and bio-signal when such biomaterial is used for regenerative medicine. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate whether fisetin is a potential radiosensitizer for human colorectal cancer cells, which are relatively resistant to radiotherapy. Methods and Materials: Cell survival was examined by clonogenic survival assay, and DNA fragmentation was assessed by terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling assay. The effects of treatments on cell cycle distribution and apoptosis were examined by flow cytometry. Western blot analysis was performed to ascertain the protein levels of γ-H2AX, phospho-Chk2, active caspase-3, PARP cleavage, phospho-p38, phospho-AKT, and phospho-ERK1/2. Results: Fisetin pretreatment enhanced the radiosensitivity of p53-mutant HT-29 human colorectal cancer cells but not human keratocyte HaCaT cells; it also prolonged radiation-induced G2/M arrest, enhanced radiation-induced cell growth arrest in HT-29 cells, and suppressed radiation-induced phospho-H2AX (Ser-139) and phospho-Chk2 (Thr-68) in p53-mutant HT-29 cells. Pretreatment with fisetin enhanced radiation-induced caspase-dependent apoptosis in HT-29 cells. Fisetin pretreatment augmented radiation-induced phosphorylation of p38 mitogen-activated protein kinase, which is involved in caspase-mediated apoptosis, and SB202190 significantly reduced apoptosis and radiosensitivity in fisetin-pretreated HT-29 cells. By contrast, both phospho-AKT and phospho-ERK1/2, which are involved in cell proliferation and antiapoptotic pathways, were suppressed after irradiation combined with fisetin pretreatment. Conclusions: To our knowledge, this study is the first to provide evidence that fisetin exerts a radiosensitizing effect in p53-mutant HT-29 cells. Fisetin could potentially be developed as a novel radiosensitizer against radioresistant human cancer cells. [Copyright &y& Elsevier]