The association between disruption of the circadian rhythm and aggravation of colitis in mice.

Delayed recovery from ulcerative colitis is mainly due to impaired healing of the intestinal epithelium after inflammation. The circadian rhythm controls cell proliferation and energy metabolism. However, the role of circadian genes in inflammatory bowel disease is largely unknown. The purpose of this study was to investigate whether disrupting the circadian rhythm in mice can worsen colitis by altering mitochondrial energy metabolism. Mice in the experimental groups were under physiologic stress with an 8-h light shift jet-lag schedule every 3 days, whereas those in the control group were not. Subsequently, half of the mice in the control and jet-lagged groups were given dextran sodium sulfate (DSS) to induce colitis. Mice in each group were euthanized at zeitgeber time (ZT)0, ZT4, ZT8, ZT12, ZT16, and ZT20. To investigate the effects of jet lag on the mice, colon specimens were subjected to hematoxylin and eosin staining to analyse mRNA and protein expression of core circadian clock genes (Bmal1, Clock, Per1, Per2, Cry1, Cry2, and Nr1d1). We analysed the mitochondrial morphology, adenosine triphosphate (ATP) levels, and the expression of dynamin-related protein 1 (Drp1) and ser637-phosphorylated (p)-Drp1, which are closely related to ATP production. We further investigated the effect of PER2 knock-down in the colon epithelial cells (CCD 841 CoN) by measuring ATP and cell proliferation levels. Disrupting the circadian rhythm changed the oscillation of clock genes in the colon of mice, altered the mitochondrial morphology of the colon specimens, decreased the expression of p-Drp1, reduced ATP production, and exacerbated inflammatory responses in mice with DSS-induced colitis. Additionally, silencing of PER2 in the colon epithelial cells reduced ATP production and cell proliferation. Disrupting the circadian rhythm in mice decreases mitochondrial energy metabolism in the colon and exacerbates symptoms of colitis.

Association Between White Matter Hyperintensities and Chronic Kidney Disease: A Systematic Review and Meta-Analysis.

Objectives: Previous studies of the associations between white matter hyperintensities (WMH) and chronic kidney disease (CKD) were still conflicting; therefore, our study aimed to conduct a systematic review of all of the available research on this topic and a meta-analysis of the association between WMH and CKD among observational studies. Setting and Design: Systematic review and meta-analysis. Outcome Measures: Severity of WMH. Methods and Participants: All relevant studies in public databases were examined until 15 November 2020. Two independent reviewers assessed all the included studies using the Cross-Sectional/Prevalence Study Quality (CSSQ) scale, and then literature review and meta-analyses were undertaken. Results: We pooled the odds ratio (OR) for the presence of WMH, periventricular hyperintensities (PVH), and deep subcortical white matter hyperintensities (DWMH) of patients with CKD vs. non-CKD patients by subgroup analysis, and the results obtained were WMH OR 2.07, 95% CI [1.58, 2.70], PVH OR 2.41, 95% CI [1.90, 3.05], and DWMH OR 2.11, 95% CI [1.60, 2.80], respectively. The main outcome showed that patients with CKD were more likely to have WMH in the brain compared to the normal controls. Another meta-analysis showed a statistically significant decline in renal function in patients with moderate to severe WMH compared with those with no to mild WMH. Conclusions: The findings indicated that patients with CKD were more likely to experience WMH than demographically matched controls. On the other hand, patients with moderate to severe WMH in the brain had poor renal function more frequently than those with no to mild WMH.

Comparison of Safety of Different Vaccine Boosters Following Two-Dose Inactivated Vaccines: A Parallel Controlled Prospective Study.

A vaccine booster to maintain high antibody levels and provide effective protection against COVID-19 has been recommended. However, little is known about the safety of a booster for different vaccines. We conducted a parallel controlled prospective study to compare the safety of a booster usingfour common vaccines in China. In total, 320 eligible participants who had received two doses of an inactivated vaccine were equally allocated to receive a booster of the same vaccine (Group A), a different inactivated vaccine (Group B), an adenovirus type-5 vectored vaccine (Group C), or a protein subunit vaccine (Group D). A higher risk of adverse reactions, observed up to 28 days after injection, was found in Groups C and D, compared to Group A, with odds ratios (OR) of 11.63 (95% confidence interval (CI): 4.22-32.05) and 4.38 (1.53-12.56), respectively. Recipients in Group C were more likely to report ≥two reactions (OR = 29.18, 95% CI: 3.70-229.82), and had a higher risk of injection site pain, dizziness, and fatigue. A gender and age disparity in the risk of adverse reactions was identified. Despite the majority of reactions being mild, heterologous booster strategies do increase the risk of adverse reactions, relative to homologous boosters, in subjects who have had two doses of inactive vaccine.

Copper-Based Hybrid Polyion Complexes for Fenton-Like Reactions.

An innovative strategy allowing the development of a new generation of easy-to-prepare and easy-to-use nano-sized catalysts with high tenability is presented. This strategy is based on the formation of hybrid polyion complexes (HPICs) from the complexation of copper with a block copolymer consisting of an ionizable complexing block and a neutral stabilizer block. These complexes have a well-defined structure and size with a hydrodynamic diameter around 29 nm. They are stable in aqueous solution over a pH range from 4 to 8 and are not sensitive to NaCl salt addition or dilution effects. As a proof-of-concept the degradation of naphthol blue black in water through the use of the Fenton or photo-Fenton reaction is studied. Their performances are comparable to a classical homogeneous reaction, whereas HPICs are easily recyclable by simple dialysis.

Role of non-inflammatory factors in intestinal fibrosis.

Intestinal fibrosis is a common complication of inflammatory bowel disease (IBD), resulting in strictures and ultimately obstruction, which is a significant clinical problem. Fibrosis is mainly triggered by local chronic inflammation and occurs when excessive extracellular matrix deposition is caused by activated mesenchymal cells. Despite the advance of anti-inflammatory therapies in IBD, the incidence and preventive strategies of intestinal fibrosis and strictures in IBD have not significantly changed over time. This shows that inflammation is necessary for fibrosis, but it does not necessarily affect the fibrotic progression. This review summarizes current knowledge about the non-inflammatory mechanisms implicated in the gut fibrotic process of IBD, which may pave the way for new mechanisms and anti-fibrotic therapies.

Medicinal chemistry strategies in seeking coronavirus inhibitors / 药学学报

The epidemic caused by coronavirus poses a serious threat to human health, but there is no specific drug or vaccine for the treatment of this kind of virus infection. Herein, this article selects typical case studies in recent years and reviews the medicinal chemistry strategies of anti-SARS-CoV, MERS-CoV and other coronavirus drugs from the perspective of medicinal chemistry, and tries to provide some clues to current drug research againstSARS-CoV-2.

Anti-HIV lignans from Justicia procumbens / 中国天然药物

Twenty-one lignans including three new ones (1, 2 and 13) were isolated from Justicia procumbens. The chemical structures of the new lignans were determined by spectroscopic means including 1D and 2D NMR analysis. These compounds were evaluated for their cytotoxic and anti-HIV activities. The new secoisolariciresinol dimethyl ether acetate (13) exhibited anti-HIV-1 activity with an IC value of 5.27 μmol·L and a selective index (SI) value of 2.2. The known arylnaphthalene lignan procumbenoside A (3) and diphyllin (8) demonstrated inhibitory activity against HIV-1 with IC values of 4.95 (SI > 6.2) and 0.38 μmol·L (SI = 5.3), respectively.

MiR-200a and miR-200b target PTEN to regulate the endometrial cancer cell growth in vitro

OBJECTIVE@#To study whether miR-200a and miR-200b target PTEN gene expression to regulate the endometrial cancer cell growth in vitro.@*METHODS@#Endometrial cancer cells ECC-1 were cultured and transfected with the miR-200a and miR-200b mimics and inhibitors as well as the negative control mimics and inhibitors, and then the cell proliferation activity as well as the expression of PTEN and downstream genes in cells was determined; after transfection of miR-200a and miR-200b mimics as well as PTEN-3'UTR luciferase report gene plasmids, the fluorescence activity of luciferase reporter gene was determined.@*RESULTS@#12 h, 24 h and 48 h after transfection, the cell proliferation activity of miR-200a mimics group and miR-200b mimics group were significantly higher than those of NC mimics group while the cell proliferation activity of miR-200a inhibitor group and miR-200b inhibitor group were significantly lower than those of NC inhibitor group; 48 h after transfection, PTEN expression in cells and PTEN-3'UTR luciferase reporter gene fluorescence activity of miR-200a mimics group and miR-200b mimics group were significantly lower than those of NC mimics group while p-PI3K and p-Akt expression were significantly higher than those of NC mimics group; PTEN expression in cells and PTEN-3'UTR luciferase reporter gene fluorescence activity of miR-200a inhibitor group and miR-200b inhibitor group were significantly higher than those of NC inhibitor group while p-PI3K and p-Akt expression were significantly lower than those of NC inhibitor group.@*CONCLUSION@#miR-200a and miR-200b can promote the endometrial cancer cell growth in vitro by targeted inhibition of PTEN gene expression.

MiR-200a and miR-200b target PTEN to regulate the endometrial cancer cell growth in vitro

Objective To study whether miR-200a and miR-200b target PTEN gene expression to regulate the endometrial cancer cell growth in vitro. Methods Endometrial cancer cells ECC-1 were cultured and transfected with the miR-200a and miR-200b mimics and inhibitors as well as the negative control mimics and inhibitors, and then the cell proliferation activity as well as the expression of PTEN and downstream genes in cells was determined; after transfection of miR-200a and miR-200b mimics as well as PTEN-3′UTR luciferase report gene plasmids, the fluorescence activity of luciferase reporter gene was determined. Results 12 h, 24 h and 48 h after transfection, the cell proliferation activity of miR-200a mimics group and miR-200b mimics group were significantly higher than those of NC mimics group while the cell proliferation activity of miR-200a inhibitor group and miR-200b inhibitor group were significantly lower than those of NC inhibitor group; 48 h after transfection, PTEN expression in cells and PTEN-3′UTR luciferase reporter gene fluorescence activity of miR-200a mimics group and miR-200b mimics group were significantly lower than those of NC mimics group while p-PI3K and p-Akt expression were significantly higher than those of NC mimics group; PTEN expression in cells and PTEN-3′UTR luciferase reporter gene fluorescence activity of miR-200a inhibitor group and miR-200b inhibitor group were significantly higher than those of NC inhibitor group while p-PI3K and p-Akt expression were significantly lower than those of NC inhibitor group. Conclusion miR-200a and miR-200b can promote the endometrial cancer cell growth in vitro by targeted inhibition of PTEN gene expression.

Expression of matrix metalloproteinases and ovarian morphological changes in androgenized cyclic female guinea pigs.

This study was conducted to investigate expression of matrix metalloproteinases (MMPs) and ovarian morphological changes in androgenized cyclic female guinea pigs. Adult cyclic female guinea pigs were injected daily for 28 days with medium doses of testosterone propionate (TP; 1 mg/100g), high doses of TP (2 mg/100g), or saline (control). Serum concentrations of testosterone, estradiol (E2), and progesterone (P4) were measured. Histologic sections of ovaries were stained with hematoxylin-eosin and by immunohistochemistry. Expressions of steroidogenic acute regulatory protein, proliferating cell nuclear antigen, and MMP-2 and MMP-9 in the ovary were characterized by immunohistochemistry. After 28 days of TP injection, serum testosterone concentrations were increased dose-dependently. An appropriate dosage of TP could induce permanent anovulation in guinea pigs, making them a potential model for human polycystic ovary syndrome. MMP-2 and MMP-9 are jointly involved in the growth and atresia of ovarian follicles in cyclic guinea pigs. Increased numbers of atretic antral follicles in the ovary might be associated with the observed high expression of MMP-2 in androgenized cyclic guinea pigs.

Induction of follicular luteinization by equine chorionic gonadotropin in cyclic guinea pigs.

The effects of equine chorionic gonadotropin (eCG) on follicular development and ovulation in cyclic guinea pigs were investigated by histological and immunohistochemical analyses. Three groups of guinea pigs (n=12) were administrated subcutaneously with saline, 20 or 50 IU of eCG, respectively, on cyclic Day 12 (Day 1=vaginal openings). Ovaries were collected at 4 and 8 d after administration (6 animals per group each time). The eCG administration induced significant and distinct morphological changes in the ovaries, as it promoted the luteinization of granulosa cells, but not follicular development. In addition, proliferating cell nuclear antigen (PCNA) and steroidogenic acute regulatory protein (StAR) were immunolocalized specifically in luteinized follicles. Our experiments together indicate that eCG administration can induce follicular luteinization but not superovulation in guinea pigs. The eCG in cyclic guinea pigs functions similar to that of luteinizing hormone (LH), but not follicle-stimulating hormone (FSH).

Effects of Zn²âº and Cu²âº on loach ovaries and ova development.

This study compared the accumulation of Zn²âº and Cu²âº in the ovaries and ova of loaches under different concentrations of Zn²âº (1.00, 2.50 and 5.00 mg/L respectively) and Cu²âº (0.10, 0.25 and 0.50 mg/L respectively). The results showed that both Zn²âº and Cu²âº accumulated in the ovaries, and that the relationship between accumulation and time was linear over 20 days of exposure. The accumulation of the metals in ovaries was closely related to the concentration of exposure in the solutions (P<0.05), and was obviously affected by the time and doses. However, the Cu²âº concentration was significantly higher than Zn²âº (P<0.05). The development level of ova in the ovaries also correlated with the concentration and exposure period in the Zn²âº and Cu²âº solutions.This study compared the accumulation of Zn2+and Cu2+ in the ovaries and ova of loaches under different concentrations of Zn2+ (1.00, 2.50 and 5.00 mg/L respectively) and Cu2+ (0.10, 0.25 and 0.50 mg/L respectively). The results showed that both Zn2+ and Cu2+ accumulated in the ovaries, and that the relationship between accumulation and time was linear over 20 days of exposure. The accumulation of the metals in ovaries was closely related to the concentration of exposure in the solutions (P<0.05), and was obviously affected by the time and doses. However, the Cu2+ concentration was significantly higher than Zn2+(P<0.05). The development level of ova in the ovaries also correlated with the concentration and exposure period in the Zn2+ and Cu2+ solutions.

[Evaluation of efficacy and safety of ZD1839 as monotherapy in Chinese patients with advanced non-small cell lung cancer].

OBJECTIVE: To report the outcome of gefitinib for Chinese patients with advanced nonsmall cell lung cancer(NSCLC) at Peking Union Medical College Hospital. METHODS: From Oct. 2002 to Apr. 2006, 204 patients with advanced NSCLC received oral ZD1839 (250 mg/d) treatment. The were 110 (59.9%) men and 94 (40.1%) women aged between 25 and 85 years. Thirty-two patients had squamous cell carcinoma, 125 adenocarcinoma, 30 bronchoalveolar carcinoma or adenocarcinoma with partial bronchoalveolar carcinoma, 6 adenosquamous carcinoma, and 11 unspecified. Twenty-six patients had no history of chemotherapy, 62 had no disease progression after chemotherapy, and 111 failed to prior one or more regimens. Median survival was calculated using the Kaplan-Meier method and a Cox regression analysis was used to detect differences in median survival between strata. RESULTS: The median survival of all patients and of patients failed to prior chemotherapy were 16.3 months (95% confidential interval CI, 14.5 - 18.2) and 12.5 months (95% CI 9.3 - 15.7). The rate of 1-year survival was 57%. The objective tumor response rate and stable disease rate were 31.4% and 41.7% respectively. The median survival were significantly related with ECOG scores, pathology types, disease progression after chemotherapy, objective efficacy of gefitinib and changes of short-breathing. Among 26 patients with no prior chemotherapy, the median survival was not statistically significant compared with that of other patients. Among the enrolled patients, 111 had disease progression and 62 had stable disease after prior chemotherapy, and their median survivals was statistically different. At the time of this analysis, 142 patients had disease progression, 58 of whom withdrew from taking gefitinib, and 84 continued gefitinib therapy until death. The median survivals for these subgroups were not significantly different. Among 142 patients with disease progression, 40 received other systemic treatment, the median survival was statistically significant compared with that of other patients. Objective response was significantly related with age, smoking status, pathological type, change of short-breathing and rashes induced by gefitinib. Adverse events were generally mild (grade 1 and 2) and reversible. The most frequent adverse events were rash 72.6% (138/190) and diarrhea 33.7% (64/190). CONCLUSION: Our study suggests that treatment with gefitinib maybe well tolerate and beneficial for some Chinese patients after failure of prior chemotherapy.

[Efficacy and safety of gefitinib in maintenance therapy for patients with advanced non-small cell lung cancer].

OBJECTIVE: To evaluate the efficacy and safety of gefitinib as maintenance therapy for patient with advanced non-small lung cancer (NSCLC). METHODS: From Oct. 2002 to Apr. 2006, 173 patients with advanced NSCLC received oral gefitinib 250 mg per day after completion of induction chemotherapy (62 patients, maintenance therapy group) or recurrence after one or more regimens of chemotherapy (111 patients, recurrent group). Median survival (MS) and progress free survival (PFS) were calculated using the Kaplan-Meier method, and Cox regression analysis was used to analyze the difference between the sub-groups stratified by smoking, pathological type, liver metastasis and gefitinib treatment result. RESULTS: MS of maintenance therapy group and recurrent group were 25.0 months (95% CI: 19.3-30.7) and 12.5 months (95% CI: 9.3-15.7), respectively. There was a statistically significant difference between the above two groups (P = 0.0004). PFS of maintenance therapy group and recurrent group was 16.5 months (95% CI: 8.7-24.3) and 9.2 months (95% CI: 7.5-10.9), respectively. There was also a statistically significant difference between these two groups (P = 0. 0000). It was found that median MS in maintenance therapy group was significantly correlated with smoking status, pathology type, liver metastasis and objective response of gefitinib. CONCLUSION: Maintenance therapy with gefitinib after induction chemotherapy may improve overall survival in patient with non-small cell lung cancer.

Characterization of murine leukemia virus recombinants that express H5N1 subtype avian influenza virus hemagglutinin glycoproteins / 生物工程学报

One highly pathogenic strain of avian influenza virus (AIV) was isolated from goose in China recently, designated as F-3. In order to study the viral entry mechanisms, the hemagglutinin (HA) gene of H5N1 subtype AIV isolate was amplified by RT-PCR, and then cloned into pGEM-T vector and sequenced. The sequencing result has logging in GenBank, the accession number was AY639405. The HA gene of F-3 had a complete open reading frame (ORE) and composed of 1707 nucleotides, coding for 568 amino acids. The deduced amino acid sequence at the cleavage site of the HA protein was RKKR GLF, matched to the characteristic of virulent avian influenza strain. The HA gene were subcloned into pcDNA3, so the plasmid pcDNA-HA can express the HA glycoprotein. Co-transfected pcDNA-HA, pHIT60 (include Murine Leukemia Virus structural genes, namely gag and pol) and pHIT111 (retroviral vector genome,containing LacZ as a reporter) into 293T cells. The retroviral supernatant were harvested 48 hours post-transfection, filtered through 0.45 micromol/L filter. The supernatant were used to analysis the characteristic of the pseudotyping virions by Western blotting and infection test. Western blotting revealed the HA glycoproteins can be expressed on the virions, indicated the glycoproteins were incorporated onto the retroviral virions. Infection test were performed on 293T, NIH3T3 and COS-7, all the three kinds of cells infected were lacZ positive, indicating viral entry, and revealed the pseudotype virions of MuLV-HA were infectious. So the pseudotype system of MuLV particles with AIV Hemagglutinin proteins were setted up and it can be used to study the entry of avian influenza virus isolated from goose in China.

[Research and development of technique of regenerative environmental control and life support system].

Environmental control and life support system (ECLSS) is a critical subsystem of manned spacecraft that has the most typical characteristics of manned space flight. It is an indispensable safeguard for the life of astronaut in space. This article reviewed the main techniques and developments of oxygen and water closed loop recycling in regenerative environmental control and life support system. Through comparing and analyzing the current state of its space application as well as the strong and weak points of different technique routes, the directions of research and development of oxygen and water recycling technique for space station are proposed.