Berberine ameliorates contrast-induced acute kidney injury by regulating HDAC4-FoxO3a axis-induced autophagy: In vivo and in vitro.

In hospitals, contrast-induced acute kidney injury (CI-AKI) is a major cause of renal failure. This study evaluates berberine's (BBR) renal protection and its potential HDAC4 mechanism. CI-AKI in rats was induced with 10 mL kg-1 ioversol. Rats were divided into five groups: Ctrl, BBR, CI-AKI, CI-AKI + BBR, and CI-AKI + Tasq. The renal function of CI-AKI rats was determined by measuring serum creatinine and blood urea nitrogen. Histopathological changes and apoptosis of renal tubular epithelial cells were observed by HE and terminal deoxynucleotidyl transferase (TdTase)-mediated dUTP-biotin nick end labeling (TUNEL) staining. Transmission electron microscopy was used to observe autophagic structures. In vitro, a CI-AKI cell model was created with ioversol-treated HK-2 cells. Treatments included BBR, Rapa, HCQ, and Tasq. Analyses focused on proteins and genes associated with kidney injury, apoptosis, autophagy, and the HDAC4-FoxO3a axis. BBR showed significant protective effects against CI-AKI both in vivo and in vitro. It inhibited apoptosis by increasing Bcl-2 protein levels and decreasing Bax levels. BBR also activated autophagy, as indicated by changes in autophagy-related proteins and autophagic flux. The study further revealed that the contrast agent ioversol increased the expression of HDAC4, which led to elevated levels of phosphorylated FoxO3a (p-FoxO3a) and acetylated FoxO3a (Ac-FoxO3a). However, BBR inhibited HDAC4 expression, resulting in decreased levels of p-FoxO3a and Ac-FoxO3a. This activation of autophagy-related genes, regulated by the transcription factor FoxO3a, played a role in BBR's protective effects. BBR, a traditional Chinese medicine, shows promise against CI-AKI. It may counteract CI-AKI by modulating HDAC4 and FoxO3a, enhancing autophagy, and limiting apoptosis.

Investigation of the mechanism of tanshinone IIA to improve cognitive function via synaptic plasticity in epileptic rats.

CONTEXT: Tanshinone IIA is an extract of Salvia miltiorrhiza Bunge (Labiatae) used to treat cardiovascular disorders. It shows potential anticonvulsant and cognition-protective properties. OBJECTIVE: We investigated the mechanism of tanshinone IIA on antiepileptic and cognition-protective effects in the model of epileptic rats. MATERIALS AND METHODS: Lithium chloride (LiCl)-pilocarpine-induced epileptic Wistar rats were randomly assigned to the following groups (n = 12): control (blank), model, sodium valproate (VPA, 189 mg/kg/d, positive control), tanshinone IIA low dose (TS IIA-L, 10 mg/kg/d), medium dose (TS IIA-M, 20 mg/kg/d) and high dose (TS IIA-H, 30 mg/kg/d). Then, epileptic behavioural observations, Morris water maze test, Timm staining, transmission electron microscopy, immunofluorescence staining, western blotting and RT-qPCR were measured. RESULTS: Compared with the model group, tanshinone IIA reduced the frequency and severity of seizures, improved cognitive impairment, and inhibited hippocampal mossy fibre sprouting score (TS IIA-M 1.50 ± 0.22, TS IIA-H 1.17 ± 0.31 vs. model 2.83 ± 0.31), as well as improved the ultrastructural disorder. Tanshinone IIA increased levels of synapse-associated proteins synaptophysin (SYN) and postsynaptic dense substance 95 (PSD-95) (SYN: TS IIA 28.82 ± 2.51, 33.18 ± 2.89, 37.29 ± 1.69 vs. model 20.23 ± 3.96; PSD-95: TS IIA 23.10 ± 0.91, 26.82 ± 1.41, 27.00 ± 0.80 vs. model 18.28 ± 1.01). DISCUSSION AND CONCLUSIONS: Tanshinone IIA shows antiepileptic and cognitive function-improving effects, primarily via regulating synaptic plasticity. This research generates a theoretical foundation for future research on potential clinical applications for tanshinone IIA.

Antiovarian cancer mechanism of esculetin: inducing G0/G1 arrest and apoptosis via JAK2/STAT3 signalling pathway.

OBJECTIVES: Esculetin is a coumarin derivative, which is extracted from the dried barks of fraxinus chinensis Roxb. Although it is reported esculetin possesses multiple pharmacological activities, its associated regulatory mechanism on ovarian cancer isn't well investigated. METHODS: Cytotoxicity is evaluated by MTT, clonogenic and living/dead cells staining assays. Migration and invasion effects are investigated by wound healing, and transwell assays. The effect of cell cycle and apoptosis are analyzed by flow cytometry and western blotting. Mitochondrial membrane potential and intracellular reactive oxygen species (ROS) is assessed by fluorescence microscope. Analysis of animal experiments are carried out by various pathological section assays. KEY FINDINGS: Esculetin exerts an anti- ovarian cancer effect. It is found that apoptosis induction is promoted by the accumulation of excessive ROS and inhibition of JAK2/STAT3 signalling pathway. In addition, exposure to esculetin leads to the cell viability reduction, migration and invasion capability decrease and G0/G1 phase cell cycle arrest induced by down-regulating downstream targets of STAT3. In vivo experimental results also indicate esculetin can inhibit tumour growth of mice. CONCLUSIONS: Our study provides some strong evidences to support esculetin as a potential anti-cancer agent in ovarian cancer.

Down-regulated C4orf19 confers poor prognosis in colon adenocarcinoma identified by gene co-expression network.

Colon adenocarcinoma (COAD) is the most common histologic subtype of colorectal cancer (CRC), and its prognosis is poor. Unlike traditional research in molecular biology, which is limited to analyzing the function of a single gene or protein in malignant tumors. The Weighted gene correlation network analysis (WGCNA) technique is used to describe the gene association model among different samples in order to identify highly collaborative genes. In this study, a computational strategy was used to conduct a systematic study of prognosis-related genes (PRGs) of COAD from the TCGA database. PRGs were subsequently used for WGCNA, which included 379 COAD patient expression profiles and 39 controls. As a consequence, nine gene modules were built. Among these, the brown module had not only a negative relationship with COAD, but also simultaneously in inverse relationship with the clinical stage, stage T, stage M and stage N. C4orf19, which was identified as one of the DEG and hub genes in the brown module by calculating modular connectivity, has a negative correlation with the clinical stage and TMN stage. In addition, the downward-regulated C4orf19 protein was detected in COAD clinical specimens. Finally, in vitro experiments have confirmed that regulated C4orf19 can promote COAD cell proliferation, invasion and migration, and the biological mechanism of C4orf19 perhaps by influencing the nitrogen metabolic pathway.

Expression and clinical significance of B cell translocation gene 2 in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is widely known as a highly fatal cancer, and thus it is important to identify tumor-specific and radiosensitivity-specific markers in ESCC. B cell translocation gene 2 (BTG2) has been considered a novel tumor suppressor gene or radiotherapy sensitivity-associated gene. However, the relationship between BTG2 and ESCC development and radiotherapy sensitivity is uncertain. The present study aims to explore the expression and clinical significance of B cell translocation gene 2 (BTG2) in ESCC by analyzing the RNAseq data from the TCGA and immunohistochemical staining of ESCC samples. We found that the level of BTG2 mRNA was significantly decreased in ESCC patients, and further decreased significantly in radiotherapy resistant patients compared to sensitive patients. The positive expression rate of BTG2 protein was 56.0% (103/184) in 184 ESCC tissue samples and 84.0% (42/50) in normal esophageal mucosal samples, respectively. The positive ratios of BTG2 expression in radiotherapy-sensitive group and radiotherapy resistant group were 57.9% (22/38) and 23.5% (4/17), respectively. Furthermore, the analysis indicates that the expression level of BTG2 significantly correlated with lymph node metastasis and clinical staging in ESCC patients. A multivariate analysis with Cox regression model showed that BTG2 level was an independent risk factor affecting the prognosis of ESCC patients. Above all, the downregulation of BTG2 may be used as a molecular marker to identify and predict ESCC progression and radiosensitivity.

Integrated transcriptomics explored the cancer-promoting genes CDKN3 in esophageal squamous cell cancer.

BACKGROUND AND OBJECTIVES: Each individual studies is limited to multi-factors and potentially lead to a significant difference of results among them. The present study aim to explore the critical genes related to the development of Esophageal squamous cell carcinoma (ESCC) by integrated transcriptomics and to investigate the clinical significance by experimental validation. METHODS: Datasets of protein-coding genes expression which involved in ESCC were downloaded from Gene Expression Omnibus (GEO) database. The "Robustrankaggreg" package in language was used for data integration, and the different expression genes (DEGs) were identified based the cut-off criteria as follows: adjust p-value < 0.05, |fold change (FC)| ≥ 1.5; The protein expression of seed gene in 184 cases of primary ESCC tissues and 50 tumor adjacent normal tissues (at least 5 cm away from the tumor, and defind as the controls) were detected by immunohistochemistry; The relationship between the expression level of seed genes and clinical parameter were analyze. Enumeration data were represented by frequency or percentage (%) and were tested by x2 test. The P value of less than 0.05 was considered statistically significant. RESULTS: A total of 244 DEGs were identified by comparing gene expression patterns between ESCC patients and the controls based on integrating dataset of GSE77861, GSE77861, GSE100942, GSE26886, GSE17351, GSE38129, GSE33426, GSE20347 and GSE23400; The Cyclin-dependent kinase inhibitor 3 (CDKN3) were identified the top 1 seed gene of top cluster by use of protein-protein Interaction network and plug-in Molecular Complex Detection; The level of CDKN3 mRNA was significantly increased in ESCC patients compared to controls; The positive expression rate of CDKN3 protein in ESCC tissue samples was 32 and 61.4% in control, respectively. The correlations between the expression level of CDKN3 and lymph node metastasis or clinical staging of ESCC patients are statistically significant. CONCLUSION: Integrated transcriptomics is an efficient approach to system biology. By this procedure, our study improved the understanding of the transcriptome status of ESCC.

Anti-infective treatment of purulent meningitis caused by carbapenem-resistant Klebsiella pneumoniae in a newborn: a case report.

The widespread use of carbapenems has caused a notable spread of carbapenem-resistant Klebsiella pneumoniae (CRKP). The incidence of CRKP-associated infections is rising significantly in neonatal intensive care units (NICUs), which poses a grave challenge to clinical treatment. This paper is to highlight the drug treatment of CRKP with purulent meningitis in children and explore the safety of levofloxacin in children. We retrospectively analyzed the clinical data of combination therapy with levofloxacin and aztreonam in a newborn with purulent meningitis caused by CRKP. As clinical pharmacists, we evaluated the risks and benefits of quinolones for anti-infective treatment in newborns, helped clinicians adjust the anti-infective protocol of levofloxacin combined with aztreonam and provided pharmaceutical care throughout the course of treatment. In the end, the child had no fever, no dyspnea, and no obvious abnormalities in brain color Doppler ultrasound. The intracranial infection was finally controlled, and the child improved and was discharged, with no apparent neurological, skeletal, joint, tendon, or cardiac adverse events. For newborns with CRKP-associated purulent meningitis, fluoroquinolones combined with other drugs such as polymyxin, tigecycline, aminoglycosides, minocycline, that Klebsiella pneumoniae is susceptible to (when no safe and effective anti-infective alternatives are available) can reduce the mortality rate of newborns with purulent meningitis caused by carbapenem-resistant gram-negative bacteria. We analyzed the drug resistance mechanisms of CRKP, the selection of antibiotic agents, the safety of quinolones in children, the permeability of the blood-brain barrier to quinolones, and the selection of the quinolone dose. Personalized combination therapy improves treatment outcomes and reduces adverse reactions, especially in patients with resistant bacteria infection.

Theoretical Study of Effects of Anchoring Groups on Photovoltaic Properties of a Triarylamine-Based p-Type Sensitizer.

The effects of anchoring groups on triarylamine-based p-type dyes were studied by substituting the strong electron-withdrawing carboxyl group with the weak electron-withdrawing pyridyl and the electron-rich catechol groups. Judged by the index t, the charge separation would be improved greatly when the carboxyl group of P4 is replaced by the pyridyl or catechol groups. Although carboxyl as an anchoring group lowers the HOMO energy and facilitates the hole injection in comparison with pyridyl and catechol groups, the weak electron-withdrawing pyridyl and the electron-rich catechol groups facilitate the charge separation. E g becomes narrow as the electron-withdrawing abilities of the anchoring groups decrease or as the conjugation extends. Both the extended π-spacers and the substitution of carboxyl with pyridyl and catechol groups promote the redshifts of adsorption wavelengths. The oscillator strengths for all dyes are over 2.00, indicating that all the dyes are able to harvest the sunlight strongly. The ΔG CR values of P4, DF4, and DZ4 are smaller than those of the other dyes. Also, these dyes have larger adsorption over infrared visible light, indicating that these dyes may be good candidates for p-type DSSCs.

Endothelin-1 rs9296344 associates with the susceptibility of childhood primary nephrotic syndrome.

BACKGROUND: Recently, the rs5370 single nucleotide polymorphisms (SNPs) of Endothelin-1 (EDN1) showed association with the susceptibility of childhood primary nephrotic syndrome (CPNS). This study aims to investigate potential relationships between other EDN1 SNPs and CPNS. METHODS: Seven SNPs (rs5370, rs10478723, rs1476046, rs1800541, rs2070698, rs2071942, and rs9296344) of the EDN1 gene were genotyped in 579 CPNS patients and 586 age-matched healthy children. Then, we analyzed potential associations of the six SNPs with susceptibility of CPNS by using rs5370 as a conditional variant in a logistic regression model. SNP-SNP interaction analysis was performed to investigate the joint effects of the seven SNPs in the pathogenesis of CPNS. RESULTS: Independent with rs5370, only rs9296344 significantly associated (T vs C, odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.57-0.88, P = .001) with the susceptibility of CPNS. Meanwhile, no joint effect among the analyzed seven SNPs was discovered in this study. CONCLUSIONS: This study discovered that C allele of rs9296344 on EDN1 is a novel independent risk factor for CPNS.

Theoretical study of aromatic hydroxylation of the [Cu2(H-XYL)O2]2+ complex mediated by a side-on peroxo dicopper core and Cu-ligand effects.

In this work, the aromatic hydroxylation mechanism of the [Cu2(H-XYL)O2]2+ complex mediated by a peroxo dicopper core and Cu-ligand effects are investigated by using hybrid density functional theory (DFT) and the broken symmetry B3LYP method. Based on the calculated free-energy profiles, we proposed two available mechanisms. The first reaction steps of both mechanisms involve concerted O-O bond cleavage and C-O bond formation and the second step involves the Wagner-Meerwein rearrangement of the substrate by a [1,2] H shift (HA shift from CA to CC) or (HA shift from CA to OA) across the phenyl ring to form stable dienone intermediates, and this is followed by the protonation of bridging oxygen atoms to produce the final hydroxylated dicopper(ii) product. The HA shift from CA to CC mechanism is the energetically most favorable, in which the first reaction step is the rate-limiting reaction, with a calculated free-energy barrier of 19.0 kcal mol-1 and a deuterium kinetic isotope effect of 1.0, in agreement with experimental observations. The calculation also shows that the reaction started from the P-type species of [Cu2(H-XYL)O2]2+ which is capable of mediating the direct hydroxylation of aromatic substrates without the intermediacy of an O-type species. Finally, we designed some new complexes with different Cu-ligands and found the complex that computationally possesses a higher activity in mediating the hydroxylation of the ligand based aromatic substrate; here, Cu loses a pyridyl ligand donor by dissociation, compared to the [Cu2(H-XYL)O2]2+ complex.

Smoking and drinking influence the advancing of ischemic stroke disease by targeting PTGS2 and TNFAIP3.

In the present study, we explored the influence of cigarette smoking and alcohol drinking on gene expression level and related functions and pathways on the development of ischemic stroke (IS) disease. The gene expression profile of E-GEOD-22255 was obtained from 20 IS samples (7 patients without smoking or drinking history and 13 patients with smoking or drinking history) and 20 controls (9 normal controls without smoking or drinking history and 11 controls with smoking or drinking history). The correlation degree between gene expression and grouping were measured by significance analysis of microarray (SAM). Smoking or drinking-related DEGs were screened. GO functional and KEGG pathway enrichment analyses were processed. Based on the KEGG database, a pathway relationship network was constructed. DEGs in significant functions and pathways were inserted and regarded as key DEGs. Gene co-expression network was constructed based on the expression value of key genes. In total, 319 IS-related DEGs, which were induced by smoking and drinking, were screened and enriched in various functions and pathways, including inflammatory response, nuclear factor-κB (NF-κB) signaling pathway and influenza A. Pathway relationship network was constructed with 44 nodes and the hub node was the MAPK signaling pathway. After merging, 87 key DEGs were obtained. The gene co-expression network with 43 node edges was constructed and the hub node was prostaglandin-endoperoxide synthase 2. In IS patients, smoking and drinking may induce different expression of many genes, including PTGS2, TNFAIP3, ZFP36 and NFKBIZ. In addition, these genes participated in various pathways, such as inflammatory response.

IR Spectra of Different O2-Content Hemoglobin from Computational Study: Promising Detector of Hemoglobin Variant in Medical Diagnosis.

IR spectra of heme and different O2-content hemoglobin were studied by the quantum computation method at the molecule level. IR spectra of heme and different O2-content hemoglobin were quantificationally characterized from 0 to 100 THz. The IR spectra of oxy-heme and de-oxy-heme are obviously different at the frequency regions of 9.08-9.48, 38.38-39.78, 50.46-50.82, and 89.04-91.00 THz. At 24.72 THz, there exists the absorption peak for oxy-heme, whereas there is not the absorption peak for de-oxy-heme. Whether the heme contains Fe-O-O bond or not has the great influence on its IR spectra and vibration intensities of functional groups in the mid-infrared area. The IR adsorption peak shape changes hardly for different O2-content hemoglobin. However, there exist three frequency regions corresponding to the large change of IR adsorption intensities for containing-O2 hemoglobin in comparison with de-oxy-hemoglobin, which are 11.08-15.93, 44.70-50.22, and 88.00-96.68 THz regions, respectively. The most differential values with IR intensity of different O2-content hemoglobin all exceed 1.0 × 104 L mol-1 cm-1. With the increase of oxygen content, the absorption peak appears in the high-frequency region for the containing-O2 hemoglobin in comparison with de-oxy-hemoglobin. The more the O2-content is, the greater the absorption peak is at the high-frequency region. The IR spectra of different O2-content hemoglobin are so obviously different in the mid-infrared region that it is very easy to distinguish the hemoglobin variant by means of IR spectra detector. IR spectra of hemoglobin from quantum computation can provide scientific basis and specific identification of hemoglobin variant resulting from different O2 contents in medical diagnosis.

Preparation and drug release properties of chitosan/organomodified palygorskite microspheres.

The novel composite microspheres, based on the hybridization of chitosan (CS) and organomodified palygorskite (OPAL), were prepared by emulsion cross-linking technique and applied as a drug carrier. Palygorskite, a kind of natural one-dimensional clay, was modified with hexadecyl betaine (BS-16) to improve the compatibility and affinity with chitosan matrix, and worked as a perfect micron-filler to enhance drug encapsulation and retard drug migration. The structure of the microspheres was characterized by fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM) and X-ray diffraction (XRD) techniques. The swelling behavior of the microspheres and the effect of the amount of OPAL and BS-16 on the properties of the drug loading and releasing have been investigated. Compared to the pure chitosan microspheres (CM), the composite one with 20wt% OPAL modified by 20mmol/100g BS-16 possessed the higher encapsulation efficiency and the slower and continuous cumulative release for diclofenac sodium (DS) in phosphate buffer solution (pH 6.8). The study of drug release kinetics in vitro found that the drug release mechanism of the microspheres changed from the simple diffusion-control to diffusion and dissolution-control as the OPAL content in matrix increased from 0 to 20wt%.

Density functional theory study on (LiNH2)n (n=1-5) clusters.

Geometrical structures and relative stabilities of (LiNH(2))(n) (n = 1-5) clusters were studied using density functional theory (DFT) at the B3LYP/6-31G* and B3LYP/6-31++G* levels. The electronic structures, vibrational properties, N-H bond dissociation energies (BDE), thermodynamic properties, bond properties and ionization potentials were analyzed for the most stable isomers. The calculated results show that the Li-N and Li-Li bonds can be formed more easily than those of the Li-H or N-H bonds in the clusters, in which NH(2) is bound to the framework of Li atomic clusters with fused rings. The average binding energies for each LiNH(2) unit increase gradually from 142 kJ mol(-1) up to about 180 kJ mol(-1) with increasing n. Natural bond orbital (NBO) analysis suggests that the bonds between Li and NH(2) are of strong ionicity. Three-center-two-electron Li-N-Li bonding exists in the (LiNH(2))(2) dimer. The N-H BDE values indicate that the change in N-H BDE values from the monomer a1 to the singlet-state clusters is small. The N-H bonds in singlet state clusters are stable, while the N-H bonds in triplet clusters dissociate easily. A study of their thermodynamic properties suggests that monomer a1 forms clusters (b1, c1, d2 and e1) easily at low temperature, and clusters with fewer numbers of rings tend to transfer to ones with more rings at low temperature. E(g), E(HOMO) and E(av) decrease gradually, and become constant. Ring-like (LiNH(2))(3,4) clusters possess higher ionization energy (VIE) and E(g), but lower values of E(HOMO). Ring-like (LiNH(2))(3,4) clusters are more stable than other types. A comparison of structures and spectra between clusters and crystal showed that the NH(2) moiety in clusters has a structure and spectral features similar to those of the crystal.