N6-methyladenosine-modified circ_104797 sustains cisplatin resistance in bladder cancer through acting as RNA sponges.

BACKGROUND: Bladder cancer (BCa) ranks among the predominant malignancies affecting the urinary system. Cisplatin (CDDP) remains a cornerstone therapeutic agent for BCa management. Recent insights suggest pivotal roles of circular RNA (circRNA) and N6-methyladenosine (m6A) in modulating CDDP resistance in BCa, emphasizing the importance of elucidating these pathways to optimize cisplatin-based treatments. METHODS: Comprehensive bioinformatics assessments were undertaken to discern circ_104797 expression patterns, its specific interaction domains, and m6A motifs. These findings were subsequently corroborated through experimental validations. To ascertain the functional implications of circ_104797 in BCa metastasis, in vivo assays employing CRISPR/dCas13b-ALKBH5 were conducted. Techniques, such as RNA immunoprecipitation, biotin pull-down, RNA pull-down, luciferase reporter assays, and western blotting, were employed to delineate the underlying molecular intricacies. RESULTS: Our investigations revealed an elevated expression of circ_104797 in CDDP-resistant BCa cells, underscoring its pivotal role in sustaining cisplatin resistance. Remarkably, demethylation of circ_104797 markedly augmented the potency of cisplatin-mediated apoptosis. The amplification of circ_104797 in CDDP-resistant cells was attributed to enhanced RNA stability, stemming from an augmented m6A level at a distinct adenosine within circ_104797. Delving deeper, we discerned that circ_104797 functioned as a microRNA reservoir, specifically sequestering miR-103a and miR-660-3p, thereby potentiating cisplatin resistance. CONCLUSIONS: Our findings unveil a previously uncharted mechanism underpinning cisplatin resistance and advocate the potential therapeutic targeting of circ_104797 in cisplatin-administered patients with BCa, offering a promising avenue for advanced BCa management.

Integrin α2 promotes immune escape in non-small-cell lung cancer by enhancing PD-L1 expression in exosomes to inhibit CD8 + T-cell activity.

This study intended to delineate the mechanism and functional role of integrin α2 (ITGA2) in non-small-cell lung cancer (NSCLC) cell immune escape. Bioinformatics analysis was utilized to analyze ITGA2 expression in NSCLC tissues, and correlations between ITGA2 expression and patient survival time, ITGA2 expression and programmed cell death ligand 1 (PD-L1; CD274) expression, and ITGA2 expression and CD8+ T-cell infiltration. Quantitative real-time polymerase chain reaction detected ITGA2 expression. Transmission electron microscopy was applied to examine the morphology of exosomes, and western blot measured CD9, CD63, and PD-L1 levels. CCK-8 measured cell viability. Cell toxicity experiment measured the killing effect of CD8+ T cells on cancer cells. Enzyme-linked immunosorbent assay assessed secretion levels of interleukin-2, interferon-gamma, tumor necrosis factor-alpha, and PD-L1 expression in exosomes. Immunohistochemistry detected ITGA2, CD8, and PD-L1 expression in patient tissue samples. ITGA2 was highly expressed in NSCLC, and Pearson correlation analysis showed a negative correlation of ITGA2 with CD8+ T-cell infiltration and a positive correlation of ITGA2 with PD-L1 expression. Cell experiments showed that silencing ITGA2 hindered NSCLC cell progression and increased levels of CD8+ T-cell secretory factors. Further mechanism studies found that ITGA2 reduced CD8+ T-cell-mediated antitumor immunity via the increase in PD-L1 expression. Clinical sample testing unveiled that ITGA2 was upregulated in NSCLC tissues. PD-L1 upregulation was seen in exosomes separated from patient blood, and correlation analysis showed a positive correlation of exosomal PD-L1 expression in blood with ITGA2 expression in tissues. This study displays a novel mechanism and role of ITGA2 in NSCLC immune escape, providing directions for the clinical therapy of NSCLC patients.

Role of iron in host-microbiota interaction and its effects on intestinal mucosal growth and immune plasticity in a piglet model.

Iron is an essential trace element for both the host and resident microbes in the gut. In this study, iron was administered orally and parenterally to anemic piglets to investigate the role of iron in host-microbiota interaction and its effects on intestinal mucosal growth and immune plasticity. We found that oral iron administration easily increased the abundance of Proteobacteria and Escherichia-Shigella, and decreased the abundance of Lactobacillus in the ileum. Furthermore, similar bacterial changes, namely an increase in Proteobacteria, Escherichia-Shigella, and Fusobacterium and a reduction in the Christensenellaceae_R-7_group, were observed in the colon of both iron-supplemented groups. Spearman's correlation analysis indicated that the changed Fusobacterium, Fusobacteria and Proteobacteria in the colon were positively correlated with hemoglobin, colon and spleen iron levels. Nevertheless, it was found that activated mTOR1 signaling, improved villous height and crypt depth in the ileum, enhanced immune communication, and increased protein expression of IL-22 and IL-10 in the colon of both iron-supplemented groups. In conclusion, the benefits of improved host iron outweigh the risks of altered gut microbiota for intestinal mucosal growth and immune regulation in treating iron deficiency anemia.

Micafungin: A promising inhibitor of UBE2M in cancer cell growth suppression.

Neddylation is a protein modification process similar to ubiquitination, carried out through a series of activating (E1), conjugating (E2), and ligating (E3) enzymes. This process has been found to be overactive in various cancers, leading to increased oncogenic activities. Ubiquitin-conjugating enzyme 2 M (UBE2M) is one of two neddylation enzymes that play a vital role in this pathway. Studies have shown that targeting UBE2M in cancer treatment is crucial, as it regulates many molecular mechanisms like DNA damage, apoptosis, and cell proliferation. However, developing small molecule inhibitors against UBE2M remains challenging due to the lack of suitable druggable pockets. We have discovered that Micafungin, an antifungal agent that inhibits the production of 1,3-ß-D-glucan in fungal cell walls, acts as a neddylation inhibitor that targets UBE2M. Biochemical studies reveal that Micafungin obstructs neddylation and stabilizes UBE2M. In cellular experiments, the drug was found to interact with UBE2M, prevent neddylation, accumulate cullin ring ligases (CRLs) substrates, reduce cell survival and migration, and induce DNA damage in gastric cancer cells. This research uncovers a new anti-cancer mechanism for Micafungin, paving the way for the development of a novel class of neddylation inhibitors that target UBE2M.

Dietary iron regulates intestinal goblet cell function and alleviates Salmonella typhimurium invasion in mice.

Iron is an important micronutrient that plays a vital role in host defenses and bacterial pathogenicity. As iron treatments increase the risk of infection by stimulating the growth and virulence of bacterial pathogens, their roles in anti-infection immunity have frequently been underestimated. To estimate whether adequate dietary iron intake would help defend against pathogenic bacterial infection, mice were fed iron-deficient (2 mg kg-1 feed), iron-sufficient (35 mg kg-1 feed), or iron-enriched diet (350 mg kg-1 feed) for 12 weeks, followed by oral infection with Salmonella typhimurium. Our results revealed that dietary iron intake improved mucus layer function and decelerated the invasion of the pathogenic bacteria, Salmonella typhimurium. Positive correlations between serum iron and the number of goblet cells and mucin2 were found in response to total iron intake in mice. Unabsorbed iron in the intestinal tract affected the gut microbiota composition, and the abundance of Bacteroidales, family Muribaculaceae, was positively correlated with their mucin2 expression. However, the results from antibiotic-treated mice showed that the dietary iron-regulated mucin layer function was not microbial-dependent. Furthermore, in vitro studies revealed that ferric citrate directly induced mucin2 expression and promoted the proliferation of goblet cells in both ileal and colonic organoids. Thus, dietary iron intake improves serum iron levels, regulates goblet cell regeneration and mucin layer function, and plays a positive role in the prevention of pathogenic bacteria.

Efficacy and safety evaluation of complete intrafascial prostatectomy in suspected prostate cancer patients with dysuria: a retrospective cohort study.

Background: Suspected localized prostate cancer (PCa) patients with dysuria Complete intrafascial prostatectomy (CIP) can remove the whole prostate gland with the maximal retain of adjacent normal tissues around the prostate, and can be applied in some suspected localized prostate cancer (PCa) patients with dysuria. However, precious few studies have assessed the efficacy and safety of CIP in these patients without preoperative needle biopsies. Methods: In this retrospective single-arm cohort study, all 22 suspected PCa patients with dysuria who underwent CIP at our hospital were enrolled. The clinical data including age, prostate-specific antigen (PSA), free-serum PSA, prostate volume, perioperative and postoperative complications were collected. The PSA level at 6 weeks after CIP and recoveries of urinary continence and erectile function were acquired in the follow-up procedures, and were used as the main measurements of efficacy and safety for CIP respectively. Results: The patients had an average age of 71.91±8.29 years and an average preoperative PSA level of 10.75±4.25 ng/mL. The operations for all 22 patients were successfully completed. The average operation time was 135.20±41.44 min (range, 40.0-215.0 min), and the average blood loss volume was 128.64±145.09 mL. In total, 17 patients (77.27%) had PCa confirmed by postoperative pathology, and 5 patients (22.73%) had benign prostatic hyperplasia. The PSA level dropped to 0.010±0.004 ng/mL at 6 weeks after surgery. According to the loose criteria to assess urinary incontinence, the patients achieved continence rates of 63.6% immediately after the operation, 95.5% at 1 month, and 100% at 3 months. According to the strict criteria, the continence rates immediately, and at 1, 3, 6, and 9 months after surgery were 27.3%, 63.6%, 90.9%, 95.5%, and 100%, respectively. None of the patients complained of urinary obstruction symptoms after surgery. Before CIP, all the patients had erectile dysfunction and an International Index of Erectile Function 5 (IIEF-5) score of 9.64±5.91. After surgery, the patients had IIEF-5 scores at 3, 6, and 12 months of 5.45±4.43, 6.95±5.30, and 7.57±5.69, respectively. Conclusions: Although the study had some limitations, CIP may be a prudent option for patients with suspected localized PCa who also present with dysuria.

Maternal iron supplementation during pregnancy affects placental function and iron status in offspring.

BACKGROUND: Iron deficiency and overload during pregnancy damage to maternal and fetal health. Placenta as an organ for the transport of nutrients between mother and fetus protects fetus from the harmful effects of iron deficiency and iron overload through regulation of placental iron homeostasis. METHODS: To determine the effect of dietary iron supplementation during pregnancy on reproduction and the mechanism of placental iron regulation, we designed dietary high iron (HI: 344 mg/kg), medium iron (MI: 40 mg/kg), low iron (LI: 2 mg/kg) groups of pregnant female mice fed ferrous citrate 2 weeks before mating to 18.5 days of gestation. RESULTS: We find dietary iron supplementation during pregnancy effect maternal liver iron, placental iron, hemoglobin and fetal iron. Dietary iron significantly improves reproductive performance as litter weight and fetal weight. Correlation analysis suggest placental iron increased with liver iron, higher and lower liver iron is not conducive to the accumulation of fetal iron, placental iron deficiency and excess reduce litter weight. Placental transcriptome analysis revealed DEGs with the same trend in HI and LI groups compared with MI group, dietary iron may change biology process of ion transport and gland development in placenta. Granzyme may affect the placental trophoblast structure prior to delivery with iron overload uniquely. CONCLUSION: This research highlights the importance of moderate iron supplements in pregnancy due to damage of reproduction by affecting placental function under different dose of maternal iron supplementation.

Construction of Decision Trees Based on Gene Expression Omnibus Data to Classify Bladder Cancer and Its Subtypes.

BACKGROUND Bladder cancer is a malignant tumor of the genitourinary system. Different subtypes of bladder cancer have different treatment methods and prognoses. Therefore, identifying hub genes affecting other genes is of great significance for the treatment of bladder cancer. MATERIAL AND METHODS We obtained expression profiles from the GSE13507 and GSE77952 datasets from the Gene Expression Omnibus database. First, principal component analysis was used to identify the difference in gene expression in different types of tissues. Differential expression analysis was used to find the differentially expressed genes between normal and tumor tissues, and between tumors with and without muscle infiltration. Further, based on differentially expressed genes, we constructed 2 decision trees for differentiating between tumor and normal tissues, and between muscle-infiltrating and non-muscle-infiltrating tumor tissues. A receiver operating characteristic curve was used to evaluate the prediction effect of the decision trees. RESULTS FAM107A and C8orf4 showed significantly lower expression in bladder cancer tissues than in normal tissues. Regarding muscle infiltration, CTHRC1 showed lower expression and HMGCS2 showed higher expression in non-muscle-infiltrating samples than in those with muscle infiltration. We constructed 2 decision trees for differentiating between tumor and normal tissue, and between tissues with and without muscle infiltration. Both decision trees showed good prediction results. CONCLUSIONS These newly discovered hub genes will be helpful in understanding the occurrence and development of different subtypes of bladder cancer, and will provide new therapeutic targets and biomarkers for bladder cancer.

lncRNA small nucleolar RNA host gene 12 promotes renal cell carcinoma progression by modulating the miR­200c­5p/collagen type XI α1 chain pathway.

Renal cell carcinoma (RCC) is a primary malignant kidney cancer subtype. It has been suggested that long non­coding RNAs (lncRNAs) serve important roles in the progression of kidney cancer. In fact, the lncRNA small nucleolar RNA host gene 12 (SNHG12) was discovered to be overexpressed in various types of cancer. However, to the best of our knowledge, the role of SNHG12 in RCC remains unclear. The present study aimed to investigate the function of SNHG12 and its underlying molecular mechanism of action in RCC. In patient samples and datasets from The Cancer Genome Atlas. Reverse transcription­quantitative PCR, demonstrated that SNHG12 expression levels were upregulated in RCC tumor tissues, but not in normal kidney tissues. SNHG12 upregulation was also observed in RCC cell lines. Kaplan­Meier survival analysis indicated a poor prognosis for those patients with RCC who had upregulated SNHG12 expression levels. Following lentivirus transduction, SNHG12 was successfully knocked down (validated by western blot analysis) and cell migration and invasion assays were performed. SNHG12 knockdown markedly inhibited cell viability and invasion, while increasing apoptosis in both A498 and 786O cell lines. The results of the luciferase reporter assay suggested that SNHG12 exerted its role by sponging microRNA (miR)­200c­5p, which led to the upregulation of its target gene, collagen type XI α1 chain (COL11A1). This was further validated, as miR­200c­5p inhibition reduced the effects of SNHG12 downregulation on cell viability and apoptosis, without affecting SNHG12 expression levels. Furthermore, the findings indicated that SNHG12 may partially exert its role through COL11A1, which was also upregulated in RCC. In conclusion, the results of the present study suggested that the SNHG12/miR­200c­5p/COL11A1 axis may be crucial for RCC progression, which provided an insight into potential therapeutic strategies for RCC treatment.

LSD1 deletion represses gastric cancer migration by upregulating a novel miR-142-5p target protein CD9.

LSD1 (histone lysine specific demethylase 1) takes part in the physiological process of cell differentiation, EMT (epithelial-mesenchymal transition) and immune response. In this study, we found LSD1 expression in metastatic gastric cancer tissues was significantly higher than that in normal tissues. Furthermore, LSD1 deletion was found to suppress gastric cancer migration by decreasing intracellular miR-142-5p, which further led to the upregulation of migration suppressor CD9, a newly identified target of miR-142-5p. While LSD1 was reported as a demethylase of H3K4me1/2, H3K9me1/2 and several non-histone proteins, this is a new evidence for LSD1 as a functional regulator of miRNA. On the other hand, our data suggested that promoting the secretion of miR-142-5p using small extracellular vesicles as vehicles is a new mechanism for LSD1 abrogation to down-regulate intracellular miR-142-5p. Taken together, this study uncovered a new mechanism for LSD1 that can contribute to gastric cancer migration by facilitating miR-142-5p to target CD9.

Removal of sulfamethoxazole in water by electro-enhanced Co2+/peroxydisulfate system with activated carbon fiber-cathode.

The ACF-cathode/Co2+/PDS system was validated to effectively remove sulfamethoxazole (SMX), a typical carcinogenic and refractory antibiotic from the aqueous environment. The experimental conditions such as initial pH, PDS, Co2+ concentrations, and current density were optimized. Moreover, the system exhibited excellent ability for SMX degradation in surface water and tap water. It was proved that ACF-cathode/Co2+/PDS consumes much less electrical energy per order (EEO) values than Pt-cathode/Co2+/PDS processes. More importantly, due to the cathodic protection, the removal rate of SMX within 30 min was satisfactory even after ACF used for 10 cycles continuously. In addition, the cobalt residue in the ACF-cathode/Co2+/PDS process was much lower than that of Pt-cathode/Co2+/PDS system due to the deposition of cobalt on ACF surface. The catalytic system not only had high catalytic performance, but also had less cobalt residue in the solution and lower power consumption. Therefore, the study provided a novel technology for the removal of refractory pollutants in water.

Sanggenon O induced apoptosis of A549 cells is counterbalanced by protective autophagy.

Sanggenon O (SO) is a Diels-Alder type adduct extracted fromMorus alba, which has been used for its anti-inflammatory action in the Oriental medicine. However, whether it has regulatory effect on human cancer cell proliferation and what the underlying mechanism remains unknown. Here, we found that SO could significantly inhibit the growth and proliferation of A549 cells and induce its pro-apoptotic action through a caspase-dependent pathway. It could also impair the mitochondria which can be reflected by mitochondrial membrane permeabilization. Besides, SQSTM1 up-regulation and autophagic flux measurement demonstrated that exposure to SO led to autophagosome accumulation, which plays a protective role in SO-treated cells. In addition, knocking down of LC3B increased SO triggered apoptotic cell rates. These results indicated that SO has great potential as a promising candidate combined with autophagy inhibitor for the treatment of NSCLC. In conclusion, our results identified a novel mechanism by which SO exerts potent anticancer activity.

Inhibition of malignant human bladder cancer phenotypes through the down-regulation of the long non-coding RNA SNHG7.

There is abundant evidence that long non-coding RNAs play important roles in the development of tumors. In the present study, our main aim was to explore the relationship between lncRNA SNHG7 and human bladder cancer cells, thus finding a novel target for bladder cancer therapy and diagnosis. Expression of lncRNA SNHG7 was evaluated using real-time quantitative polymerase chain reaction in bladder tumor tissues and paired adjacent normal tissues from 72 patients diagnosed with urothelial bladder carcinoma. We analyzed the differences in expression according to grading and staging. Human bladder cancer cell lines UMUC, 5637, T24 and SW780 were transiently transfected with lncRNA SNHG7-specific siRNA and negative control siRNA. The changes in malignant phenotypes in transfected bladder cancer cells were determined using CCK-8 assay, wound-healing assay and ELISA. We found that lncRNA SNHG7 was correlated with human bladder cancer. lncRNA SNHG7 was overexpressed in bladder cancer tissues compared to paired normal tissues and expression of SNHG7 was higher in high-grade than low-grade tumors. The malignant phenotypes were significantly inhibited when we inhibited expression of lncRNA SNHG7 in several bladder cell lines. SNHG7 plays an oncogenic role in human bladder cancer and may be a potential novel therapeutic target for treating bladder cancer.

Long non-coding RNA HOXA-AS2 promotes the migration, invasion and stemness of bladder cancer via regulating miR-125b/Smad2 axis.

Long non-coding RNA HOXA-AS2 (HOXA cluster antisense RNA 2) has been reported to function as an oncogene in different types of cancers including breast cancer, liver cancer, gastric cancer and colorectal cancer, etc. However, its role in the development and progression of bladder cancer remains unknown. This study aimed to examine the expression of HOXA-AS2 in bladder cancer, to explore its role in the migration, invasion and stemness of bladder cancer cells and to further identify the potential downstream target miRNAs of HOXA-AS2 in this type of cancer. Our results firstly demonstrated the upregulation of HOXA-AS2 in both bladder cancer cells and clinical bladder tumors. Such upregulation was also positively correlated with the advanced stage, invasion and lymph node metastasis of bladder cancer as well as the expression of cancer stem cell marker OCT4 in patients. After knockdown of HOXA-AS2 in bladder cancer 5637 and T24 cells, the migration, invasion and stemness of cancer cells were significantly inhibited, indicating the capability of HOXA-AS2 to promote the migration, invasion and stemness of bladder cancer cells. Knockdown of HOXA-AS2 also suppressed in vivo tumor growth in the nude mice. Furthermore, this study also identified miR-125b as a downstream target of HOXA-AS2 and revealed the downregulation of miR-125b by HOXA-AS2 as well as the involvement of HOXA-AS2/miR-125b/Smad2 interactions in the functional role of HOXA-AS2 in mediating the migration, invasion and stemness of bladder cancer cells. Together, our findings suggest that HOXA-AS2 might be a potential biomarker and target for the diagnosis, monitoring and treatment of bladder cancer.

Aniline trimer-including carboxymethylated ß-cyclodextrin as an efficient corrosion inhibitor for Q235 carbon steel in 1 M HCl solution.

In this work, a water-soluble host-guest complex containing carboxymethylated beta-cyclodextrin (CM-ß-CD) and an aniline trimer (AT) was synthesized. The application of AT-CM-ß-CD as an inhibitor for alleviating the corrosion of Q235 carbon steel in 1 M HCl solution was investigated by potentiodynamic polarization and electrochemical impedance spectroscopy (EIS). Results showed that the inhibition efficiency was significantly increased in the presence of AT-CM-ß-CD, and the inhibition efficiency was up to 99.2% when the concentration of AT-CM-ß-CD was 250 mg L-1. Field emission scanning electron microscopy (SEM) and laser scanning confocal microscopy (LSCM) confirmed that the corrosion inhibitor had excellent corrosion inhibition effects due to the formation of an adsorption film on the surface of Q235 carbon steel. According to the data extracted from the Langmuir adsorption model, AT-CM-ß-CD absorption involves both physisorption and chemisorption.

Tribological properties of attapulgite/La2O3 nanocomposite as lubricant additive for a steel/steel contact.

Attapulgite is a layered silicate with good friction-reduction and self-repairing properties. In order to further improve its tribological properties, the present work mainly focuses on the preparation of attapulgite/La2O3 nanocomposite and study on its tribological behaviors. The tribological properties of mineral lubricating oil (150SN) containing attapulgite/La2O3 nanocomposite were investigated through an Optimal SRV-IV oscillating friction and wear tester. The rubbing surfaces and generated tribofilms were characterized by SEM, EDS, XPS and nanoindentation. Results indicated that the friction-reducing ability and antiwear property of the oil were both remarkably improved by attapulgite/La2O3 nanocomposite. A tribofilm mainly composed of Fe, Fe3C, FeO, Fe2O3, FeOOH, SiO, SiO2 and organic compound was formed on the rubbing surface under the lubrication of oil with attapulgite/La2O3 nanocomposite. The tribofilm possess excellent self-lubricating ability and mechanical properties, which is responsible for the reduction of friction and wear.

Sirt1 regulates apoptosis and extracellular matrix degradation in resveratrol-treated osteoarthritis chondrocytes via the Wnt/ß-catenin signaling pathways.

Osteoarthritis (OA) has become a major public health problem with the increased aging population. Previous studies have demonstrated that resveratrol (RES) was able to increase the level of sirtuin 1 (Sirt1) in OA chondrocytes. However, further investigations are required to elucidate the precise molecular mechanism of RES and the potential link between Sirt1 and RES. Therefore, the present study used 30 clinical OA chondrocyte to examine chondrocyte viability, apoptosis rate and the mRNA and protein expression levels of Sirt1 and relevant genes implicated in apoptosis, extracellular matrix (ECM) degradation and Wnt/ß-catenin signaling pathway. RES and nicotinamide were used as the stimulus and inhibitor, respectively. The results demonstrated that the apoptotic rate reduced as the cell population decreased from 13.83 to 6.55% in response to 10 µM RES. Expression levels of B-cell lymphoma 2 (Bcl-2) associated X protein (Bax), procaspase-3 and -9, matrix metalloproteinase 1 (MMP1), MMP3, MMP13, Wnt3a, Wnt5a, Wnt7a and ß-catenin were significantly inhibited (P<0.01), whereas the level of Bcl-2 was significantly increased (P<0.01) in OA chondrocytes treated with 10 µM RES. These observations suggested that Sirt1 may regulate apoptosis and ECM degradation in RES-treated osteoarthritis chondrocytes via the Wnt/ß-catenin signaling pathway.

Hydroxysafflor yellow A ameliorates lipopolysaccharide-induced acute lung injury in mice via modulating toll-like receptor 4 signaling pathways.

Hydroxysafflor yellow A (HSYA) is a main bio-active compound important of a traditional Chinese medicine named Carthamus tinctorius L. and has been shown to possess various effects, especially anti-inflammatory benefits and potential protections against acute lung injury (ALI) in previous studies. Therefore, in this present study, we aimed to evaluating effects of HSYA on lipopolysaccharide (LPS)-induced ALI in mice. ALI was induced by intratracheal instillation of LPS into lung, and dexamethasone was used as a positive control. Results demonstrated that HSYA abated LPS-induced pathological change and attenuated lung vascular permeability and edema. HSYA down-regulated both the ability of myeloperoxidase (MPO) in lung tissues and levels of inflammatory mediators including tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6 and IFN(interferon)-ß in serum. Moreover, HSYA prevented toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and TIR-domain-containing adapter-inducing interferon-ß (TRIF) protein up-expressions. In addition, the activations of mitogen-activated protein kinases including p38, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) were blocked by HSYA. And also, the phosphorylations of interferon regulatory factor 3 (IRF3), translocation of nuclear factor kappa B (NF-κB)/p65 and inhibitory kappa B (IκB)-α were inhibited by HSYA. In conclusion, HSYA attenuated inflammatory response in ALI mice through inhibition of TLR 4-dependent signaling pathways.

Synthesis and antidiabetic activity of 5,7-dihydroxyflavonoids and analogs.

In a study to evaluate the structural elements essential for the antidiabetic activity of flavonoids, we synthesized two series of flavonoids, 5,7-dihydroxyflavanones and 5,7-dihydroxyflavones. In a screening for potential antidiabetic activity, most of the flavonoids showed a remarkable in vitro activity, and compounds 1f, 2d, and 3c were significantly more effective than the positive control, metformin. The biological activity was mainly affected by structural modification at the ring B moiety of the flavonoid skeleton. The results suggest that 5,7-dihydroxyflavonoids can be considered as promising candidates in the development of new antidiabetic lead compounds.

Pt(IV) complexes as prodrugs for cisplatin.

The antitumor effects of platinum(IV) complexes, considered prodrugs for cisplatin, are believed to be due to biological reduction of Pt(IV) to Pt(II), with the reduction products binding to DNA and other cellular targets. In this work we used pBR322 DNA to capture the products of reduction of oxoplatin, c,t,c-[PtCl(2)(OH)(2)(NH(3))(2)], 3, and a carboxylate-modified analog, c,t,c-[PtCl(2)(OH)(O(2)CCH(2)CH(2)CO(2)H)(NH(3))(2)], 4, by ascorbic acid (AsA) or glutathione (GSH). Since carbonate plays a significant role in the speciation of platinum complexes in solution, we also investigated the effects of carbonate on the reduction/DNA-binding process. In pH 7.4 buffer in the absence of carbonate, both 3 and 4 are reduced by AsA to cisplatin (confirmed using ((195))Pt NMR), which binds to and unwinds closed circular DNA in a manner consistent with the formation of the well-known 1, 2 intrastrand DNA crosslink. However, when GSH is used as the reducing agent for 3 and 4, ((195))Pt NMR shows that cisplatin is not produced in the reaction medium. Although the Pt(II) products bind to closed circular DNA, their effect on the mobility of Form I DNA is different from that produced by cisplatin. When physiological carbonate is present in the reduction medium, ((13))C NMR shows that Pt(II) carbonato complexes form which block or impede platinum binding to DNA. The results of the study vis-à-vis the ability of the Pt(IV) complexes to act as prodrugs for cisplatin are discussed.