Risk of Pneumocystis jirovecii Pneumonia among Solid Organ Transplant Recipients: A Population-Based Study.

Few studies have comprehensively investigated the occurrence of Pneumocystis jirovecii pneumonia (PJP) among solid organ transplant (SOT) recipients. This study investigated the risk of PJP after organ transplantation. Each patient who underwent SOT was propensity-score-matched with four non-SOT individuals in terms of sex, age, insured salary, urbanization of residence, comorbidities, and year of enrollment. When considering the 3-year follow-up, the patients who had undergone SOT were at higher risk of PJP, with the adjusted odds ratio (aOR) being 17.18 (95% confidence interval (CI): 8.80-33.53). Furthermore, SOT recipients were also at higher PJP risk than the patients without SOT at 6 months, 1 year, and 2 years, with the aOR being 22.64 (95% CI: 7.53-68.11), 26.19 (95% CI: 9.89-69.37), and 23.06 (95% CI: 10.23-51.97), respectively. Patients comorbid with HIV infection, hematological malignancies, or vasculitis were at higher risk (aOR = 59.08, 95% CI = 20.30-171.92), (aOR = 11.94, 95% CI = 5.36-26.61), and (aOR = 21.72, 95% CI = 2.41-195.81), respectively. The recipients of SOT were at higher risk of PJP, and PJP can develop at any stage after transplantation. SOT recipients comorbid with HIV, hematologic malignancies, or vasculitis were at higher PJP risk.

High Concentration of Iopromide Induces Apoptosis and Autophagy in Human Embryonic Kidney Cells via Activating a ROS-dependent Cellular Stress Pathway.

BACKGROUND/AIM: The use of iodinated contrast media may impair renal function. However, no report has addressed the nephrotoxicity of high doses of iodinated contrast media in normal kidney cells and its associated molecular mechanisms. MATERIALS AND METHODS: Cell proliferation was assessed using the MTT assay. Cell death was evaluated through examining the morphological changes and TUNEL assay. Autophagy was detected through acridine orange staining and lysotracker staining. Reactive oxygen species production and AKT kinase activity were examined. RESULTS: Iopromide induced cell death and triggered apoptosis and autophagy in HEK 293 cells. Cell viability was significantly restored in the presence of a pan-caspase inhibitor or a ROS scavenger, N-acetyl-L-cysteine. AKT kinase activity was found to be reduced in iopromide-treated HEK 293 cells. CONCLUSION: High concentrations of iopromide induce cell damage, apoptosis, and autophagy through down-regulating AKT and ROS-activated cellular stress pathways in HEK 293 cells.

Establishment of a Novel Temozolomide Resistant Subline of Glioblastoma Multiforme Cells and Comparative Transcriptome Analysis With Parental Cells.

BACKGROUND/AIM: Glioblastoma multiforme (GBM) is a lethal disease with a high rate of chemoresistance to temozolomide (TMZ). The aim of the study was to establish a TMZ-resistant subline from the GBM-8401 cell line to determine the mechanisms of resistance and identify novel effective therapeutics for TMZ-resistant GBM. MATERIALS AND METHODS: Comparative transcriptome analysis of GBM-8401/TMZR cells and the parental line was performed using Ion Torrent sequencing. Differentially expressed genes (DEGs) between the GBM-8401/TMZR and GBM-8401 cell lines were analyzed. RESULTS: Transcriptomic profiling of GBM-8401/TMZR cells revealed DEGs involved in the retinoblastoma (RB) signaling, DNA damage response (DDR) pathway, and DNA repair mechanisms. CONCLUSION: In vitro and in vivo cell-based GBM models should be used in further biomedical studies to investigate the underlying mechanisms of TMZ-resistant GBM.

Androgen deprivation therapy and the risk of iron-deficiency anaemia among patients with prostate cancer: a population-based cohort study.

OBJECTIVES: The administration of androgen deprivation therapy (ADT) to patients with metastatic prostate cancer might be associated with some adverse effects such as anaemia; however, few studies have been performed in East Asian populations. This study aimed to investigate the association between ADT and iron-deficiency anaemia (IDA) among patients with prostate cancer in a population-based nationwide cohort. DESIGN: Cohort study. SETTING: Taiwan. PARTICIPANTS: Data for the cohort study were retrieved from the Taiwan National Health Insurance Research Database. Propensity score matching was used to select 7262 patients with prostate cancer who received ADT as the study group and 3631 patients who did not receive ADT as the control group. PRIMARY AND SECONDARY OUTCOME MEASURES: This study individually tracked patients over a 3-year study period and identified those who were subsequently diagnosed with IDA following the index date. RESULTS: The incidence rates of IDA in the study and control groups were 1.66 (95% CI CI 1.45 to 1.86) and 1.01 per 100 person-years (95% CI 0.78 to 1.25), respectively. Furthermore, proportional Cox regression revealed an HR of 1.62 (95% CI 1.24 to 2.12) for IDA in the study group after adjusting for patients' age, monthly income, geographic location, residential urbanisation level and incidence of hyperlipidaemia, diabetes, hypertension, coronary heart disease, inflammatory bowel disease, other cancers and gastrointestinal bleeding. CONCLUSION: Compared with its non-use among patients with prostate cancer, ADT use was associated with a higher risk of IDA.

Inverse Association of Fibrates and Liver Cancer: A Population-Based Case-Control Study in Taiwan.

This large-scale case-control study in Taiwan elucidated the potential connection between fibrate use and liver cancer by using the Longitudinal Health Insurance Database 2005 with a propensity-score-matching design. In total, 4173 patients diagnosed as having liver cancer were included as cases, and 4173 propensity-score-matched patients without liver cancer were identified as controls. The association between previous fibrate use and liver cancer occurrence was demonstrated using conditional logistic regression. Fibrate use was noted in 371 (8.89%) cases and 481 (11.53%) controls. After adjustments, the cases had significantly lower odds of previous fibrate use than did the controls (adjusted odds ratio 0.70, 95%CI 0.60-0.82); moreover, regardless of the patients' sex, age group, and comorbidities, the cases were less likely to have used fibrates than were the controls. Dose-dependent analysis revealed that 1-695 cumulative defined daily doses of fibrates may significantly induce a protective effect for liver cancer. Although other fibrate dose intervals did not reach statistical significance, the dose-response curve presented the trend of a protective effect for liver cancer among the fibrate users. In summary, fibrate use had a significant protective effect against liver cancer in this Asian population.

Casticin Induces DNA Damage and Impairs DNA Repair in Human Bladder Cancer TSGH-8301 Cells.

BACKGROUND/AIM: Casticin shows anti-cancer effects in many types of cancer. However, there is no information regarding its role in DNA damage in human bladder cancer. The aim of this study was to investigate the effects of casticin on TSGH-8301 cells in vitro. MATERIALS AND METHODS: Viability of cells was assayed by flow cytometry. DNA damage was assayed by DAPI staining, comet assay, and gel electrophoresis. Protein levels were examined by western blotting and confocal laser microscopy. RESULTS: Casticin decreased viability of cells and induced DNA damage. Furthermore, casticin decreased expression of p-ATM, p-ATR, MDC1 and MGMT levels after 48 h of treatment, however, it increased p-ATR and MGMT levels after 12 h. In contrast, casticin increased the levels of p-p53, p-H2A.X, and PARP after 48 h of treatment. As shown by confocal microscopy, casticin affected the translocation of DNA-PKcs and p-p53 to the nucleus of TSGH-8301 cells. CONCLUSION: Casticin decreased viability of human bladder cancer cells through DNA damage.

Steroid-Enriched Fraction of Achyranthes bidentata Protects Amyloid ß Peptide 1-40-Induced Cognitive Dysfunction and Neuroinflammation in Rats.

The roots of Achyranthes bidentata Blume (AB) is commonly used in the treatment of osteoporosis and dementia in traditional Chinese medicine. Pharmacological reports evidenced that AB possessed anti-osteoarthritis effects. However, there is little literature about the anti-dementia activities of AB. The present study was designed to prepare steroid-enriched fraction of AB (ABS) and investigate whether ABS can protect from cognitive dysfunction and neuroinflammation against Aß 1-40-induced Alzheimer's disease (AD) model in rats. ABS only contained 135.11 ± 4.28 mg of ecdysterone per gram. ABS (50 mg/kg) reversed the dysfunction of exploratory activity and memory function on plus-maze and Morris water maze caused by Aß 1-40 in rats. ABS (50 mg/kg) also decreased amyloid deposition, neurofibrillary tangle, neural damage, activated astrocyte, and microglial caused by Aß 1-40. Furthermore, ABS reversed the phenomenon of neural oxidative damage and neuroinflammation, including the higher levels of MDA and cytokines, and the lower activities of antioxidant enzymes and GSH levels caused by Aß 1-40 in rat cortex and hippocampus. Finally, ABS restored the activation of ERK pathway and decreased NF-κB phosphorylation and translocation altered by Aß 1-40. ABS alone (50 mg/kg) promoted cognitive function, activated brain antioxidant defense system, and decreased brain TNF-α levels in sham group. Therefore, ABS has the cognition-promoting and antidementia potential. Steroids especial ecdysterone are major active components of AB. The action mechanism is due to decreasing oxidative stress and neuroinflammation through modulating ERK pathway, NF-κB phosphorylation, and translocation in Aß 1-40-induced AD rat model.

Cuscuta chinensis and C. campestris Attenuate Scopolamine-Induced Memory Deficit and Oxidative Damage in Mice.

The seeds of Cuscuta chinensis Lam. and C. campestris Yuncker have been commonly used as Chinese medical material for preventing aging. Our previous studies have found that C. chinensis and C. campestris possess anti-inflammatory activities in rodents. However, their other biological activities, such as memory-improving properties, have not yet been explored. In the present study, we examined the memory-improving effects of the extracts of C. chinensis and C. campestris on scopolamine (SCOP)-induced memory deficit and explored their underlying mechanism in mice. Both Cuscuta species improved SCOP-induced memory deficits in the passive avoidance test, elevated plus-maze, and spatial performance test of the Morris water maze in mice. In addition, compared with mice injected with SCOP, mice pretreated with both Cuscuta species stayed for a longer time on the platform for the probe test of the Morris water maze. Moreover, both Cuscuta species reduced brain acetylcholinesterase activity and malondialdehyde levels that were increased by SCOP, and the species restored the activities of antioxidant enzymes (superoxide dismutase and catalase) and the levels of glutathione that were decreased by SCOP in the brains of mice. Both Cuscuta species further decreased brain interleukin-1ß and tumor necrosis factor-α levels that were elevated by SCOP. We demonstrated that both Cuscuta species exhibited a protective activity against SCOP-induced memory deficit, cholinergic dysfunction, oxidative damage, and neuroinflammation in mice, and C. campestris has better potential than C. chinensis. In addition, we provided evidence that the seeds of C. campestris can be used as Cuscutae Semen in Traditional Chinese Medicine.

Aqueous Extract of Davallia mariesii Attenuates 6-Hydroxydopamine-Induced Oxidative Damage and Apoptosis in B35 Cells Through Inhibition of Caspase Cascade and Activation of PI3K/AKT/GSK-3ß Pathway.

The medicinal ferns of Polydiaceae and Davalliaceae species are called "Gusuibu" by Chinese physicians and used as antiaging dietary medicines. Our previous report revealed that Drynaria fortunei (Polydiaceae) protected against 6-hydroxydopamine (6-OHDA)-induced oxidative damage via the PI3K/AKT pathway in B35 neuroblastoma cells. The present study compares the antioxidant phytoconstituent contents and radical scavenging capacities of five Davalliaceae species. The further aim was to clarify the protective mechanism of Davallia mariesii (DM) against 6-OHDA-induced oxidative damage and apoptosis in B35 cells. The results show that Araiostegia perdurans (AP) and DM extracts have better radical scavenging capacities against 1,1-diphenyl-2-picryhydrazyl (DPPH) and reactive oxygen species (ROS) than other Davalliaceae species. However, only DM extract inhibited 6-OHDA autoxidation under cell-free systems and increased cell viability, compared to B35 cells solely exposed to 6-OHDA. DM extract decreased apoptosis and restored mitochondrial expression in 6-OHDA-treated B35 cells. Additional data indicated that DM extract decreased intracellular ROS and nitric oxide levels generated by 6-OHDA exposure. DM extract also restored glutathione (GSH) levels and the activities of glutathione peroxidase and reductase, and then decreased the elevated malondialdehyde (MDA) levels. Finally, DM extract regulated the protein expression of the caspase cascade and PI3K/AKT/GSK-3ß pathways. These results suggest that the protective mechanism of DM extract against 6-OHDA-induced oxidative damage and apoptosis might be related to its radical scavenging capacity, maintaining the mitochondrial function to inhibit the Bcl-2/caspase cascade pathway and activating intracellular antioxidant defenses (GSH recycling, HO-1 and NQO-1) by modulating the activation of the PI3K/AKT/GSK-3ß pathway.

Bufalin inhibits gefitinib resistant NCI-H460 human lung cancer cell migration and invasion in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Bufalin, a component of Chan Su (frog), has been shown to have biological activities including anti-tumor effects. Gefitinib has been used as an anti-cancer drug in lung cancer patients; however, some patients eventually become gefitinib resistant. AIM OF THE STUDY: In this study, we investigated anti-metastasis effects of bufalin in gefitinib resistant NCI-H460 lung cancer cells. MATERIALS AND METHODS: The effects of the bufalin in gefitinib resistant NCI-H460 lung cancer cells were investigated on cell viability using flow cytometry. The adhesion capacity, wound healing assay, invasion and migration assay, and Western blot analysis were used to understand the molecular mechanisms in this study RESULTS: Under sub-lethal concentrations (from 2.5 up to 10nM), bufalin significantly inhibits cell adhension, migration and invasion nature of gefitinib resistant H460 cells. Western blotting assay revealed that bufalin depressed some of the key metastasis-related proteins, such as SOS-1, MMP-2 and Rho A underwent significant reduction. Phosphorylated Focal adhesion kinase (p-FAK), phosphorylated extracellular signal-regulated kinase (p-ERK1/2), Ras and E-cadherin were significantly reduced at 48h treatment. However, phosphorylated p38 (p-p38), phosphorylated c-Jun NH2-terminal kinase (p-JNK1/2) and NF-κBp65 were increased. CONCLUSIONS: Based on these observations, we suggest that bufalin can be used in anti-metastasis of gefitinib resistant NCI-H460 lung cancer cells in the future.

Anthranilic acid-based inhibitors of phosphodiesterase: design, synthesis, and bioactive evaluation.

Our previous studies identified two 2-benzoylaminobenzoate derivatives 1, which potently inhibited superoxide (O(2)˙(-)) generation induced by formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) in human neutrophils. In an attempt to improve their activities, a series of anthranilic acid derivatives were synthesized and their anti-inflammatory effects and underlying mechanisms were investigated in human neutrophils. Of these, compounds 17, 18, 46, 49, and 50 showed the most potent inhibitory effect on FMLP-induced release of O(2)˙(-) in human neutrophils with IC(50) values of 0.20, 0.16, 0.15, 0.06, and 0.29 µM, respectively. SAR analysis showed that the activities of most compounds were dependent on the ester chain length in the A ring. Conversely, a change in the linker between the A and B ring from amide to sulfonamide or N-methyl amide, as well as exchanges in the benzene rings (A or B rings) by isosteric replacements were unfavorable. Further studies indicated that inhibition of O(2)˙(-) production in human neutrophils by these anthranilic acids was associated with an elevation in cellular cAMP levels through the selective inhibition of phosphodiesterase 4. Compound 49 could be approved as a lead for the development of new drugs in the treatment of neutrophilic inflammatory diseases.

A molecular pharmacology study into the anti-inflammatory actions of Euphorbia hirta L. on the LPS-induced RAW 264.7 cells through selective iNOS protein inhibition.

Euphorbia hirta L. has been widely used in India and Chinese society. The molecular pharmacology basis of its anti-inflammatory effect is revealed in this work. The ethanol extract of Euphorbia hirta L. (Eh) and its active component were studied in lipopolysaccharide (LPS)-activated macrophage cells (RAW 264.7) as an established inflammation model. After activation, nitric oxide (NO) production and expression of iNOS protein and iNOS mRNA were measured by using a colorimetric assay (Griess reagent), western blotting, and reverse transcription polymerase chain reaction (RT-PCR), respectively. The alteration in the content of PGE(2), TNFalpha, and IL-6 was concurrently monitored by ELISA. In results, we found that in the concentration range without showing cytotoxicity, Eh produced a remarkable anti-inflammatory effect via its active component of beta-amyrin and showed a dose-related inhibition of LPS-induced NO production. This phenomenon is in accordance with a substantial inhibition of iNOS protein. However, the expression of iNOS gene was unaffected by Eh treatments. Compared with indomethacin, Eh has much more potency and a specific action of NO inhibition but Eh works less specifically on PGE(2), IL-6, and TNF-alpha inhibition. The extract of Euphorbia hirta L. and its component beta-amyrin are able to block most of the iNOS protein functions and NO induction, and could therefore be new selective NO inhibitors with great potential in treating arthritis inflammation.

Observation of biochemical imaging changes in human pancreatic cancer tissue using Fourier-transform infrared microspectroscopy.

Fourier-transform infrared (FT-IR) microspectroscopic mapping can be used to distinguish between different tissue structures, and to increase the image contrast between normal and cancerous regions of a given tissue sample. This study demonstrates the biochemical changes associated with a consistent link between cancerous tissue and various molecular changes in the IR spectra of human pancreatic cancer tissue using FT-IR mapping. Tissue samples were obtained immediately after resection in a patient who underwent a distal pancreatectomy including the pancreatic body and tail. The biochemical imaging changes of lipids, proteins, and nucleic acids in human pancreatic cancer tissue were analyzed via FT-IR microspectroscopy, using imaging, mapping, and line scan techniques. The intensities and frequencies of the absorption bands in the IR spectra of human pancreatic cancerous tissue were markedly reduced and shifted, particularly in the amide bands of protein and CH2 and CH3 stretching vibrations of lipids. The cancerous tissue contained significant protein content, and the distributions of DNA and lipid were very low, indicating low amounts of nucleic acids and lipids in human pancreatic cancer tissue. The analytical results indicate that these FT-IR microspectroscopic biochemical images reflect the distribution of cell components, which could be correlated with stained tissue in adenocarcinoma in pancreatic tissues. This study with samples of noncancerous and cancerous pancreatic tissues has clearly demonstrated that FT-IR microspectroscopy using the mapping method can be used for diagnosis.