The antiviral mechanisms, effects, safety and adverse effects of chloroquine.

Chloroquine, a 4-aminoquinoline derivative, was initially used to treat malaria. It was later found to have immunomodulating, anti-infective, anti-thrombotic, anti-tumor, and metabolic effects. Recently, many studies have focused on the application of chloroquine in viral infections. Most in vitro studies suggested that chloroquine exerted some benefit in infections from viruses. However, animal experiment and clinical trials that attempted to use chloroquine in prevention or treatment of viral infections have reported disappointing results. It might be attributable to inadequate steady-state whole blood chloroquine concentration necessary for exerting its antiviral effects. A 16 µM/L steady-state whole blood concentration of chloroquine should suffice in antiviral treatment with minimal toxicity. Furthermore, chloroquine has both acute and cumulative toxicity. Hence, not only the appropriate treatment dose is crucial, the occurrence of adverse reactions should also be closely monitored and treated in time. Herein, we report the antiviral mechanisms, effects, safety and adverse effects of chloroquine.

MiR-503-5p regulates cell epithelial-to-mesenchymal transition, metastasis and prognosis of hepatocellular carcinoma through inhibiting WEE1.

OBJECTIVE: To explore the role and underlying mechanism of MicroRNA-503-5p (miR-503-5p) in the metastasis and prognosis of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Sixty-three pairs of surgical HCC specimens and adjacent tissue samples were obtained, and Huh7, Hep3B, HCCLM3, MHCC-97H, MHCC-97L, LO2, and HEK293T cell lines were used for this study. The transwell assay was used to detect cell migration and invasion. Additionally, Western blot and quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) were used to detect relative protein and mRNA expression levels, respectively. RESULTS: High miR-503-5p expression inhibited cell mobility in HCCLM3 cells, while low miR-503-5p expression promoted cell migration and invasion in HCCLM3 cells. The same effect of miR-503-5p on EMT was also observed in HCC through Western blot. We then performed a dual-luciferase assay to show that WEE1 is a direct target of miR-503-5p in HCC. Furthermore, WEE1 knockdown inhibited EMT and cell metastasis in HCC cells. WEE1 overexpression impaired the inhibitory effect of miR-503-5p in HCC CONCLUSIONS: MiR-503-5p inhibited cell EMT and metastasis through inhibiting WEE1, which predicted prognosis of HCC. MiR-503-5p and WEE1 may be used as potential biomarkers for the prognosis of HCC.

Metal-polydopamine frameworks and their transformation to hollow metal/N-doped carbon particles.

We present a new strategy for in situ transformation of metal-organic framework (MOF) crystals to hollow metal-organic structures through polycondensation of dopamine. The hollow metal-polydopamine (PDA) particles are formed by a coordination assembly of metal ions (Co and Zn) and PDA, inheriting the morphology of MOF (ZIF-67 and ZIF-8) crystals. The hollow porous metal/N-carbon particles morphosynthetically transformed from hollow metal-PDA particles exhibit excellent oxygen reduction electrocatalytic activity. The strategy presented here is promising for synthesizing hollow metal-organic polymer (metal-carbon) particles with diverse morphologies for energy and environmental applications.

Methylprednisolone combined with low-dose indomethacin treating acute fibrinous and organizing pneumonia after a surgical resection of rectal adenocarcinoma: a case report and literature review.

OBJECTIVE: Acute Fibrinous and Organizing Pneumonia (AFOP) is a new pathologic pattern of acute lung injury characterized by the presence of intra-alveolar fibrin in the form of fibrin "balls" in a patchy distribution. CASE REPORT: A 65-years-old female after a surgical resection of rectal adenocarcinoma presented with typical manifestations of hospital-acquired pneumonia, but she didn't respond to the anti infective therapy. After an explicit diagnosis of AFOP via percutaneous needle lung biopsy, she got an impressive improvement with a long-term therapy of methylprednisolone and low-dose indomethacin. To date, a total of non-overlapped 45 individual AFOP cases and 4 single-center studies involving AFOP have been reported. The most common coexisting diseases are infections, connective tissue diseases and hematological diseases. Corticosteroids and immunosuppressants are the most common agents prescribed in AFOP. The prognosis of AFOP is unfavorable, associated with the pathologic characteristics and the clinical parameters. CONCLUSIONS: The immune system activated by infection may play an important role in the pathogenesis of AFOP. Low-dose indomethacin combined with methylprednisolone may be a new choice for AFOP treatment.

Hypereosinophilic obliterative bronchiolitis with an elevated level of serum CEA: a case report and a review of the literature.

A 44-year-old man presented with chronic, persistent cough and occasional wheezing. Airflow obstruction, blood eosinophilia and a remarkable elevated level of serum carcinoembryonic antigen (CEA) were found. Radiographic and pathological studies confirmed eosinophilic bronchiolitis. There was no evidence of neoplasms by extensive examinations. After a protracted oral steroid therapy, the blood eosinophil count, the serum CEA level and the lung lesions were all improved in parallel, whereas fixed airflow obstruction remained. This case was diagnosed as a new distinct syndrome, hypereosinophilic obliterative bronchiolits. Serum CEA and blood eosinophil cell count served as good markers of the disease condition for this syndrome.

Beneficial effects of statins on outcomes in pneumonia: a systematic review and meta-analysis.

OBJECTIVES: There exist reports that statin treatment has beneficial effects for patients with pneumonia. The objective of this study was to evaluate whether the available published data support that statins as adjunctive therapy could reduce mortality associated with pneumonia and, thus, help to assess whether a randomized controlled study is warranted. MATERIALS AND METHODS: A meta-analysis of observational studies such as cohort studies and case-control studies identified in Pubmed, Scopus, EMBASE, the Cochrane Central Register of Controlled Trials and Clinicaltrials.gov. Eligible patients were adults with pneumonia. Studies that reported mortality of pneumonia grouped by statins usage were included. Data was analyzed and pooled using Revman 5.1. RESULTS: Fourteen studies with 269,739 participants were included in this study. Pooled analysis showed that statin treatment was associated with lower 30-day mortality, with an OR of 0.44 (95% CI, 0.29-0.67), and an adjusted OR of 0.59 (95% CI 0.48-0.73, NNT30d = 19). Statin therapy was also associated with lower long-term (> 30 days) mortality, with an OR of 0.49 (95% CI, 0.29-0.84) and an adjusted OR of 0.65 (95% CI, 0.51-0.82, NNTlong-term = 15). For pneumonia inpatients, the raw data demonstrated no significant benefit from statin therapy (OR = 0.86, 95% CI, 0.56-1.34). Adjusted data showed a marginal benefit (adjusted OR = 0.89, 95% CI, 0.81-0.97, NNTinpatient = 230). Subgroup analysis revealed that current statin users might have better outcomes than recent or past statins users. CONCLUSIONS: This meta-analysis supports that patients who happen to be receiving statin therapy have less mortality from pneumonia. However, it remains unclear whether initiation of statins at time of diagnosis is beneficial. There is only modest evidence to support the value of a well-designed randomized controlled clinical trial.

Retrovirus-mediated siRNA targeting TRPM7 gene induces apoptosis in RBL-2H3 cells.

BACKGROUND AND OBJECTIVE: Calcium signaling is important for both normal physiologic processes and pathology of various diseases. Transient receptor potential melastatin 7 (TRPM7) gene has been reported to be a potential candidate for calcium influx. The present study aimed to investigate the possible role of TRPM7 channels in apoptosis in rat basophilic leukemia mast cell line (RBL-2H3), which is widely used in mast cell-associated studies. MATERIALS AND METHODS: A recombinant retrovirus vector siRNA targeting rat TRPM7 gene was constructed and identified. Cellular survival was assessed by MTT. Cell apoptosis was evaluated by flow cytometry and TUNEL-FITC/Hoechst 33258 staining. RESULTS: The transfection efficiency by retrovirus vector was about 60%-70%. Transfection with TRPM7 siRNA significantly reduced TRPM7 expression both at mRNA and protein levels. Suppression of TRPM7 expression by siRNA led to significantly decreased cellular survival rates and increased apoptosis rates in RBL-2H3 cells. CONCLUSIONS: This study indicates that TRPM7 is involved in the apoptosis process in RBL-2H3 cells.

The effect of formoterol on airway goblet cell hyperplasia and protein Muc5ac expression in asthmatic mice.

OBJECTIVES: Aim for this study was to investigate the effect of long-acting beta2-adrenoceptor agonist formoterol on airway goblet cell hyperplasia and protein Muc5ac expression in asthmatic mice. MATERIALS AND METHODS: Forty female BABL/c mice were randomly divided into four groups with 10 mice in each. Mice in group A were treated with saline as control, and mice in group B, group C and group D were sensitized by intraperitoneal injection of 10 microg alum precipitated chicken egg ovalbumin (OVA) to establish asthmatic model, but group C were pretreated with formoterol and group D were pretreated with dexamethasone. All mice were killed 24 hours after the final OVA challenging. The left lung tissue sections were stained with periodic acid Schiff (PAS) for identification of goblet cell hyperplasia. Immunohistochemistry was used to identify the protein of Muc5ac. The right lung was isolated for detecting Muc5ac mRNA by the method of real-time fluorescence quantitative reverse transcription Polymerase Chain Reaction (real-time qRT-PCR). RESULTS: The number of the goblet cells, the percentage of goblet cell to total cell, the transcription and the expression of Muc5ac were significantly higher in group B than those in group A [(163.63 +/- 16.68) vs. (0.46 +/- 0.16), (77.36 +/- 5.05) % vs. (0.03 +/- 0.01) % (10.31 +/- 0.73) vs. (1.00 +/- 0.13), (0.64 +/- 0.03) vs. (0.19 +/- 0.03) respectively, all P < 0.05]. The number of the goblet cells, the percentage of goblet cell to total cell, the transcription and the expression of Muc5ac were significantly lower in group C than those in group B [(52.04 +/- 4.60) vs (163.63 +/- 16.68), (30.05 +/-3.72) % vs. (77.36 +/- 5.05) %, (1.64 +/- 0.14) vs. (10.31 +/- 0.73), (0.26 +/- 0.01) vs (0.64 +/- 0.03) respectively, all P < 0.05] The number of the goblet cells, the percentage of goblet cell to total cell, the transcription and the expression of Muc5ac were significantly lower in group D than those in group B [(63.41 +/- 6.39) vs. (163.63 +/- 16.68), (38.52 +/- 3.83)% vs. (77.36 +/- 5.05) %, (1.72 +/- 0.10) vs. (10.31 +/- 0.73), (0.31 +/- 0.01) vs. (0.64 +/- 0.03) respectively, all P < 0.05]. For mentioned above, no significant differences were found between group C and group D [(52.04 +/- 4.60) vs. (63.41 +/- 6.39), (30.05 +/- 3.72) % vs. (38.52 +/- 3.83) %, (1.64 +/- 0.14) vs. (1.72 +/- 0.10), (0.26 +/- 0.01) vs. (0.31 +/- 0.01) respectively, all P < 0.05]. CONCLUSIONS: This study demonstrates that the long-acting beta2-receptor agonist formoterol may inhibit airway goblet cell hyperplasia and protein Muc5ac expression in asthmatic mice.

Decreased renal mRNA expression of TRPM6 is associated with hypomagnesemia in C57BL/6 asthmatic mice.

BACKGROUND AND OBJECTIVES: Hypomagnesemia has been reported up to 40% in asthma patients, and a relationship between hypomagnesemia and asthma severity has been previously characterized. However, the mechanism for hypomagnesemia in asthma patients is not clear. Transient receptor potential melastatin 6 (TRPM6) is a newly identified channel that is involved in active epithelial magnesium transport, and downregulation of TRPM6 in the kidney was related to reduced Mg2+ reabsorption in mouse model. The aim of the study was to investigate whether plasma and erythrocyte magnesium levels were correlated with renal expression of TRPM6 mRNA in C57BL/6 asthmatic mice. MATERIALS AND METHODS: 48 healthy C57BL/6 mice were randomly divided into asthmatic group and control group with 24 mice in each group. Each group were randomly taken out 8 mice at 1d, 21d, 34d to detect plasma Mg2+, intracellular Mg2+ and renal TRPM6 mRNA expressions. RESULTS: There were no significant difference in plasma Mg2+, intracellular Mg2+ and TRPM6 mRNA expression of renal tissues between asthmatic group and control group at 1d. However, plasma Mg2+ and intracellular Mg2+ as well as TRPM6 mRNA of renal tissues in asthmatic group were significantly lower than that of control group at 21d and at 34d. Both plasma Mg2+ and intracellular Mg2+ were positively correlated with TRPM6 mRNA expression in the renal tissues. CONCLUSION: This study indicates that the consistently reduced expression of TRPM6 mRNA may play a role in the pathogenesis of hypomagnesemia in C57BL/6 asthmatic mice.

Radiobiological investigations of soft X-rays near carbon, nitrogen, oxygen K-shell edges on Aspergillus oryzae spores.

Soft X-rays at carbon, nitrogen, oxygen K-shell edges have special radiobiological effects. Using Aspergillus oryzae spores as sample, the radiation effects of soft X-rays near the K-shell edges of C, N and O elements from synchrotron radiation were investigated. Also the dose depositions of different X-ray energies in spore were discussed. At the same time, the spores were irradiated by gamma rays from 60Co and relative biological effects were compared with those produced by soft X-rays. The results showed that soft X-rays near K-shell edges of O element had higher ability of radiation damage than that of X-rays near K-shell edges of C and N elements as compared with one another. But they all had higher killing abilities per unit dose than that of gamma rays from 60Co. The relative biological effects (RBEs), the comparison of dose to gamma rays at 10% survival level, of the three soft X-rays were 1.65, 1.73 and 1.91, respectively.

Role of gastroesophageal reflux disease in asthmatic patients.

The association between gastroesophageal reflux disease (GERD) and asthma is well accepted. The prevalence of GERD increases in asthmatics compared with normal controls, whereas GERD may induce or exacerbate asthma. They interact with each other in a cause and effect relationship. But the mechanism by which GERD might induce or aggravate asthmatic symptoms remains unclear. Two mechanisms have been proposed, including (1) acid in the inflamed esophagus acting on exposed receptor causes an increase in bronchial hyper-responsiveness via the vagal reflex; (2) microaspiration of gastric contents damage the bronchial mucosa, which result in inflammation of the mucosa and bronchial hyper-responsiveness. Among the GERD diagnostic methods, ambulatory esophageal pH monitoring bears the highest sensitivity. Ambulatory esophageal pH monitoring is recommended in patients without classic reflux symptoms or those with difficult to control asthma. Both medical and surgical antireflux therapy could improve asthma symptoms, asthma medication requirements, and even pulmonary function in a proportion of asthmatics.

The fetus and the maternal immune system: pregnancy as a model to study peripheral T-cell tolerance.

In this article, we discuss recent findings that describe how maternal T cells respond upon encountering fetal antigens. Many earlier studies have characterized changes in the maternal T-cell repertoire of both humans and mice, yet it has been difficult to understand the significance of these findings since there has been no way to decipher if the alterations were the result of encounters with fetal antigens or were nonspecific changes related to pregnancy itself. Now, in the mouse, the availability of TCR transgenic mice and other technological advances allow direct visualization of the fate of maternal T cells that are reactive to the fetus and provide a means to probe the mechanisms by which tolerance to the fetus is maintained. This article focuses on how the fetus more closely resembles "developmental self' than a true allograft and how the study of maternal T-cell interactions with fetally derived antigens can be useful as a model for the study of peripheral T-cell tolerance.

Multiple mechanisms of peripheral T cell tolerance to the fetal "allograft".

The fetus represents a foreign entity to the maternal immune system, yet this "natural" allograft is not normally rejected. This unique situation provides a physiologic system to evaluate peripheral tolerance in which the maternal immune system is challenged with relatively rare Ags not previously encountered in the thymus. Using H-Y-specific TCR transgenic mice, we demonstrate that T cells specific for fetal Ags decrease in an Ag-specific manner during pregnancy and remain low postpartum, the result of an encounter with fetal cells expressing the appropriate MHC/peptide complexes. The finding that placental trophoblasts can induce Fas-mediated death of T cells is consistent with peripheral clonal deletion as one mechanism of tolerance. The remaining clonotypic T cells are unresponsive to antigenic stimulation, although neither TCR nor coreceptor is down-regulated. Our study demonstrates that specific recognition of fetal allogeneic Ags by maternal T cells results in tolerance induction of reactive T cells via multiple mechanisms.

[A prospective epidemiological investigation on the effect of China-mode attenuated live vaccine against hepatitis A in the population of Liu Zhou].

An 24-month prospective epidemiological investigation on the results of China-mode Hepatitis A attenuated live vaccine against hepatitis A by random group sampling was carried out. The incidence of case group was 15.91/10(5) (5/31421), the incidence of control group was 95.92/10(5) (30/ 31277) which showed a significant difference. In case group 2081 persons who missed vaccination, there was one person developed hepatitis A, making the incidence 48.05/10(5). In control group 760 persons were vaccinated by mistake and there was no case developed in this sub-population. There were 644 cases of hepatitis A in the external control group, the incidence was 90.14/10(5). Data showed that there was no significant difference among external control group, control group and persons from case group who missed vaccination. Comparing the data from case group and from the above 3 groups, the protective rates were 82.35%, 83.41% and 66.89%. respectively. When conparing the data from persons who had been mistakenly vaccinated in control group, there was no significant difference being noticed.

Geometries, charges, dipole moments and interaction energies of normal, tautomeric and novel bases.

Ab initio molecular orbital calculations with the STO-3G and 4-31G basis sets are performed to study the geometries and interactions of natural and "novel" Watson-Crick base pairs, as well as some non-Watson-Crick base pairs. First the optimized geometries of bases are determined using the STO-3G basis set, and then for the base pairs with the STO-3G and 4-31G basis sets. Interaction energies of these base pairs are evaluated, and their relative stabilities are discussed. Hydrogen bond features, partial charges and dipole moments of the base pairs are described. The calculated stabilities are in reasonable agreement with the limited available experimental data from thermal melting studies. Hydrogen bond geometries at the 4-31G level are in good agreement with the crystal structure data. The order of relative stabilities is found to be: iG:iC > G:C > G:T* > rG:rC > A*:C > Am:U > tau:kappa > chi:kappa > G*:T > A:C* > A:U = A:T where, A*, T*, G* and C* are tautomers, iG and iC are iso-G and iso-C, Am is 2-amino adenine, chi is xanthosine, kappa is 2,4-diaminopyrimidine, tau is 7-methyl oxoformycin B, rG is modified guanine with substitutions at positions 5 and 7, and rC is modified cytosine with a substitution at position 6. Pairing strengths with modified bases may affect the efficiency of protein production.

Stability and cooperativity of nucleic acid base triplets.

Geometries and stabilities of various base triplets have been studied using ab initio quantum chemical methods. Their optimized geometries are determined using the STO-3G basis set, and those of Hoogsteen and reverse Hoogsteen base pairs are evaluated with the 4-31G basis set. Moreover, the preferred hydrogen bond patterns of the bases in triple helices are discussed. A cooperative effect for base pairing in triplets is presented, and it can be either positive or negative. Almost all base triplets that contain Watson-Crick G:C base pairs show a positive cooperativity. Conversely, the base triplets with Watson-Crick A:T base pairs mostly display a negative cooperativity. The interaction energies of base triplets are reported and the relative stabilities of base triplets are found as follows: A+.GC > C+.GC(H) > C+.GC(rH) > G.GC(H) > G.GC(rH) > A.GC > T.AT(rH) > U.AU(H) > U.AT(H) > A.AT > G.AT > T.AT(m) > G.TA(2) > G.TA(1) H and rH denote the Hoogsteen and reverse Hoogsteen positions of the third base that would lead to parallel and antiparallel orientations respectively of the third chain with respect to the Watson-Crick paired purine chain. 'm' denotes the middle pairing scheme, in which the third base hydrogen bonds to both bases of Watson-Crick pair.

Conformational analysis of receptor selective tachykinin analogs: senktide and septide.

The conformational behavior in solution of two receptor selective tachykinin agonists, senktide (succinyl-D-F-MeF-G-L-M-NH2) and septide (pQ-F-F-P-L-M-NH2) is described. Two dimensional cross relaxation NMR spectroscopy is used together with coupling constant data to obtain interproton distance constraints. These results are used in conjunction with semi-empirical energy computations to indicate favorable conformations. Senktide is found to have a high degree of conformational order which is attributed to rotational restriction associated with the N-methylation of phenylalanine. The lowest energy conformation in accord with the experimental interproton distances contains a beta-turn. Interproton distances indicate that septide exists as a random coil or in an extended chain conformation. Energy computations suggest that septide is primarily an extended chain with internal reorientation restricted by the proline residue. These results may be related to the selectivity of these peptides for different receptors, in that the analogs, with conformations more stable than tachykinins, are more receptor selective.

Laser-induced multiphoton fluorescence of hemoglobin.

Hemoglobin (Hb) and other samples were irradiated by the 1064 nm nanosecond pulses of an Nd:YAG laser. At room temperature, we observed two red fluorescence bands, which resulted from the absorption of two 1064 nm photons in Hb, and measured the fluorescence emission spectra in the red spectral region for Hb and hematoporphyrin derivative. A red shift of the wavelength and a mirror image in the intensity of fluorescence emissions by two-photon excitation were observed. It is shown that the fluorescence of Hb originates from the heme group. In addition, we also observed fluorescence emission at 392 nm for Hb, which may be from its tryptophan groups.