Types of parental psychological control and rural and urban Chinese adolescents' psychological well-being and academic functioning.

The present study took a differentiated perspective on parental psychological control to examine its impact on adolescent adjustment among urban (n = 349, females: 53%) and rural (n = 293, females: 54%) Chinese adolescents (Mage  = 12.14 years). Four times over the first 2 years of Junior High school (from October, 2016 to April, 2018), adolescents reported on parental psychological control, their psychological well-being (life satisfaction and depressive symptoms), and academic relative autonomy. Adolescents' grades also were obtained. The findings show generally negative effects of social comparison shame, love withdrawal and harsh psychological control (but not shared shame or parental relationship-oriented guilt induction) on adolescents' psychological well-being, and negative effects of social comparison shame on adolescents' academic functioning.

An opioid receptor-independent mechanism underlies motility dysfunction and visceral hyperalgesia in opioid-induced bowel dysfunction.

Constipation and abdominal pain are commonly encountered in opioid-induced bowel dysfunction (OBD). The underlying mechanisms are incompletely understood, and treatments are not satisfactory. As patients with OBD often have fecal retention, we aimed to determine whether fecal retention plays a pathogenic role in the development of constipation and abdominal pain in OBD, and if so to investigate the mechanisms. A rodent model of OBD was established by daily morphine treatment at 10 mg/kg for 7 days. Bowel movements, colonic muscle contractility, visceromotor response to colorectal distention, and cell excitability of colon-projecting dorsal root ganglion neurons were determined in rats fed with normal pellet food, or with clear liquid diet. Morphine treatment (Mor) reduced fecal outputs starting on day 1, and caused fecal retention afterward. Compared with controls, Mor rats demonstrated suppressed muscle contractility, increased neuronal excitability, and visceral hypersensitivity. Expression of cyclooxygenase-2 (COX-2) and nerve growth factor (NGF) was upregulated in the smooth muscle of the distended colon in Mor rats. However, prevention of fecal retention by feeding rats with clear liquid diet blocked upregulation of COX-2 and NGF, restored muscle contractility, and attenuated visceral hypersensitivity in Mor rats. Moreover, inhibition of COX-2 improved smooth muscle function and fecal outputs, whereas anti-NGF antibody administration attenuated visceral hypersensitivity in Mor rats. Morphine-induced fecal retention is an independent pathogenic factor for motility dysfunction and visceral hypersensitivity in rats with OBD. Liquid diet may have therapeutic potential for OBD by preventing fecal retention-induced mechanotranscription of COX-2 and NGF.NEW & NOTEWORTHY Our preclinical study shows that fecal retention is a pathogenic factor in opioid-induced bowel dysfunction, as prevention of fecal retention with liquid diet improved motility and attenuated visceral hyperalgesia in morphine-treated animals by blocking expression of cyclooxygenase-2 and nerve growth factor in the colon.

Discovery of novel CDK inhibitors via scaffold hopping from CAN508.

Cyclin-dependent kinases (CDKs) are promising drug targets for various human diseases, especially for cancers. Scaffold hopping strategy was applied on CAN508, a known selective CDK9 inhibitor, and a series of pyrazolo[3,4-b]pyridine compounds were synthesized and evaluated in vitro as CDK2 and CDK9 inhibitors. Most compounds exhibited moderate to potent inhibitory activities against both CDK2/cyclin A and CDK9/cyclin T1 systems. Among them, compound 2e showed IC50 values of 0.36 µM for CDK2 and 1.8 µM for CDK9, respectively. Notably, the scaffold alteration seems to cause a shift in the selectivity profile of the inhibitors. In contrast to CAN508, compound 2k demonstrated remarkable selectivity toward CDK2 (265-fold over CDK9). Docking studies on compound 2k provided hints for further design of more potent and selective CDK2/CDK9 inhibitors.

[SAR of benzoyl sulfathiazole derivatives as PTP1B inhibitors].

Protein tyrosine phosphatase (PTP) 1B is a potential target for the treatment of diabetes and obesity. We have previously identified the benzoyl sulfathiazole derivative II as a non-competitive PTP1B inhibitor with in vivo insulin sensitizing effects. Preliminary SAR study on this compound series has been carried out herein, and thirteen new compounds have been designed and synthesized. Among them, compound 10 exhibited potent inhibition against human recombinant PTP1B with the IC50 value of 3.97 micromol x L(-1), and is comparable to that of compound II.

Design, synthesis and insulin-sensitising effects of novel PTP1B inhibitors.

Fifteen novel sulfathiazole-related compounds were designed as PTP1B inhibitors based on a previously reported allosteric inhibitor (1) of PTP1B. These compounds were synthesized and evaluated against human recombinant PTP1B. Six compounds (3, 4, 8 and 14-16) exhibited significant inhibitory activity against PTP1B. The most active compound (16) showed IC50 value of 3.2 µM and kinetic analysis indicated that it is a non-competitive inhibitor of PTP1B. Furthermore, compound 16 demonstrated excellent selectivity to PTP1B over other PTPs. It also displayed in vivo insulin sensitizing effect in the insulin resistant mice.

Discovery of novel PTP1B inhibitors via pharmacophore-oriented scaffold hopping from Ertiprotafib.

An integrated molecular design strategy combining pharmacophore recognition and scaffold hopping was exploited to discover novel PTP1B inhibitors based on the known PTP1B inhibitor Ertiprotafib. A composite pharmacophore model was proposed from the interaction mode of Ertiprotafib, and 21 diverse molecules from five distinct structural classes were designed and synthesized accordingly. New compounds with considerable inhibition against PTP1B were identified from each series, and the most active compound 3a showed IC50 value of 1.3 µmol L(-1) against human recombinant PTP1B. Docking study indicated that the new inhibitors assumed binding modes similar to that of Ertiprotafib.

Discovery of novel andrographolide derivatives as cytotoxic agents.

The natural diterpenoid andrographolide (1) exhibits various biological activities. Seventeen derivatives of 1 were prepared via esterification and etherification of 14-dehydroxy-11,12-didehydroandrographolide (2). Most derivatives demonstrated significant inhibition against tumor cell growth. The most active compounds, 3b and 3c, had GI50 values of 1.46-9.19 µM against A549, DU145, KB and KB-Vin tumor cells. In an immunocytochemical study, treatment with compound 3c disrupted microtubule dynamics in PC-3 cells, but caused no accumulation of metaphase cells, which is a phenotype dissimilar from that of 1. This difference suggests that structural modification of 1 resulted in a shift in the underlying molecular mechanism.

Rapid Degradation of Rhodamine B through Visible-Photocatalytic Advanced Oxidation Using Self-Degradable Natural Perylene Quinone Derivatives-Hypocrellins.

Hypocrellins (HYPs) are natural perylene quinone derivatives from Ascomycota fungi. Based on the excellent photosensitization properties of HYPs, this work proposed a photocatalytic advanced oxidation process (PAOP) that uses HYPs to degrade rhodamine B (RhB) as a model organic pollutant. A synergistic activity of HYPs and H2O2 (0.18 mM of HYPs, 0.33% w/v of H2O2) was suggested, resulting in a yield of 82.4% for RhB degradation after 60 min under visible light irradiation at 470−475 nm. The principle of pseudo-first-order kinetics was used to describe the decomposition reaction with a calculated constant (k) of 0.02899 min−1 (R2 = 0.983). Light-induced self-degradation of HYPs could be activated under alkaline (pH > 7) conditions, promising HYPs as an advanced property to alleviate the current dilemma of secondary pollution by synthetic photocatalysts in the remediation of emerging organic pollutants.

Glucokinase-activating sesquinlignans from the rhizomes of Acorus tatarinowii Schott.

Three novel sesquinlignans, tatanans A (1), B (2), and C (3), have been isolated from the rhizomes of Acorus tatarinowii Schott. Their structures were established by spectroscopic techniques and single-crystal X-ray analysis. Tatanans A-C potently increase GK enzymatic activity with EC(1.5) values in the range of 0.16-1.85 µM. The potent GK activity and unique structural features of tatanans make them promising leads for therapeutic development of antihyperglycemic drugs.

Nanobodies targeting immune checkpoint molecules for tumor immunotherapy and immunoimaging (Review).

The immune checkpoint blockade is an effective strategy to enhance the anti­tumor T cell effector activity, thus becoming one of the most promising immunotherapeutic strategies in the history of cancer treatment. Several immune checkpoint inhibitor have been approved by the FDA, such as anti­CTLA­4, anti­PD­1, anti­PD­L1 monoclonal antibodies. Most tumor patients benefitted from these antibodies, but some of the patients did not respond to them. To increase the effectiveness of immunotherapy, including immune checkpoint blockade therapies, miniaturization of antibodies has been introduced. A single­domain antibody, also known as nanobody, is an attractive reagent for immunotherapy and immunoimaging thanks to its unique structural characteristic consisting of a variable region of a single heavy chain antibody. This structure confers to the nanobody a light molecular weight, making it smaller than conventional antibodies, although remaining able to bind to a specific antigen. Therefore, this review summarizes the production of nanobodies targeting immune checkpoint molecules and the application of nanobodies targeting immune checkpoint molecules in immunotherapy and immunoimaging.

Chronic colitis upregulates microRNAs suppressing brain-derived neurotrophic factor in the adult heart.

Ulcerative colitis and Crohn's disease are classified as chronic inflammatory bowel diseases (IBD) with known extraintestinal manifestations. The interplay between heart and gut in IBD has previously been noted, but the mechanisms remain elusive. Our objective was to identify microRNAs mediating molecular remodeling and resulting cardiac impairment in a rat model of colitis. To induce chronic colitis, dextran sodium sulfate (DSS) was given to adult rats for 5 days followed by 9 days with normal drinking water for 4 cycles over 8 weeks. Echocardiography was performed to evaluate heart function. DSS-induced colitis led to a significant decrease in ejection fraction, increased left ventricular mass and size, and elevated B-type natriuretic protein. MicroRNA profiling showed a total of 56 miRNAs significantly increased in the heart by colitis, 8 of which are predicted to target brain-derived neurotrophic factor (BDNF). RT-qPCR validated the increases of miR-1b, Let-7d, and miR-155. Transient transfection revealed that miR-155 significantly suppresses BDNF in H9c2 cells. Importantly, DSS colitis markedly decreased BDNF in both myocardium and serum. Levels of various proteins critical to cardiac homeostasis were also altered. Functional studies showed that BDNF increases cell viability and mitigates H2O2-induced oxidative damage in H9c2 cells, demonstrating its protective role in the adult heart. Mechanistically, cellular experiments identified IL-1ß as the inflammatory mediator upregulating cardiac miR-155; this effect was confirmed in adult rats. Furthermore, IL-1ß neutralizing antibody ameliorated the DSS-induced increase in miR-155 and concurrent decrease in BDNF in the adult heart, showing therapeutic potential. Our findings indicate that chronic colitis impairs heart function through an IL-1ß→miR-155→BDNF signaling axis.

Clinical factors associated with initial Helicobacter pylori eradication therapy: a retrospective study in China.

The eradication rate of Helicobacter pylori (H. pylori) has been decreasing every year, mainly due to the increase in antibiotic resistance. In fact, many other factors may affect H. pylori eradication. To analyze the clinical factors affecting the initial eradication therapy in Chinese patients with H. pylori infection. We conducted a retrospective study on 264 outpatients who were diagnosed with H. pylori-associated chronic gastritis and peptic ulcer disease between January and December 2015 at a large tertiary hospital in China. The patients were divided into three groups: ECA, RCA, and RCM (R: 20 mg rabeprazole, E: 40 mg esomeprazole, C: 0.5 g clarithromycin, A: 1.0 g amoxicillin and M: 0.4 g metronidazole). The patients were treated for 14 days and followed up for 1 year. The 14C-urea breath test (14C-UBT) was performed 4 weeks after the completion of the eradication therapy. The eradication rate was higher in ≥ 40-year-old patients than in < 40-year-old-patients (85.7% vs. 54.7%, p = 0.002). Multivariate analyses revealed only age ≥ 40 years to be significantly associated with a high H. pylori eradication rate [odds ratio (OR) 4.58, p = 0.003]. The H. pylori eradication rate in patients with duodenal ulcers was significantly higher than that in patients with gastric ulcers (79% vs. 60%, p = 0.012). Age could be a predictor of successful H. pylori eradication. Patients with duodenal ulcers had a higher H. pylori eradication rate than those with other lesions.

The synthesis of analogs of shuangkangsu, a novel natural cycloperoxide glucoside from Lonicera japonica Thunb.

Four novel optically pure cycloperoxide glucosides 9a, 9b, 10a, and 10b, analogs of shuangkangsu--a natural product with unusual skeleton and antivirus activity from the buds of Lonicera japonica Thunb, were firstly synthesized by employing peroxidation and glucosidation reactions from phthalaldehyde or 4,5-dichloro phthalaldehyde and glucose.

Synthesis of the anti-virus compound shuangkangsu's analogs.

Four novel cyclic peroxide glucosides 15a, 15b, 16a, and 16b, optically pure analogs of shuangkangsu (1), which is an anti-virus natural product with an unusual skeleton isolated from the buds of Lonicera japonica Thunb, were first synthesized totally in six steps including cycloaddition of furan with diethyl acetylenedicarboxylate and glycosylation.

SAR study on N2,N4-disubstituted pyrimidine-2,4-diamines as effective CDK2/CDK9 inhibitors and antiproliferative agents.

Cyclin-dependent kinases (CDKs) are pivotal kinases in cell cycle transition and gene transcription. A series of N2,N4-diphenylpyrimidine-2,4-diamines were previously identified as potent CDK2/CDK9 inhibitors. To explore the SAR of this structural prototype, twenty-four novel N2,N4-disubstituted pyrimidine-2,4-diamines were designed and synthesized. Among them, twenty-one compounds exhibited potent inhibitory activities against both CDK2/cyclin A and CDK9/cyclin T1 systems, and the most potent CDK2 and CDK9 inhibitors, 3g and 3c, showed IC50 values of 83 nM and 65 nM respectively. Most of these compounds displayed significant inhibition against the tested tumor cell lines in the SRB assay, and in particular, remained active against the triple-negative breast cancer (TNBC) cell line MDA-MB-231. Flow cytometer analysis of compounds 2a, 2d and 3b in MDA-MB-231 cells indicated that these compounds induced cell cycle arrest in G2/M phase. Docking studies on compound 3g were performed, which provided conducive clues for further molecular optimization.

Novel benzamido derivatives as PTP1B inhibitors with anti-hyperglycemic and lipid-lowering efficacy.

Based on a non-competitive and selective PTP1B inhibitor reported by us previously, thirty-nine benzamido derivatives were designed and synthesized as novel PTP1B inhibitors. Among them, twelve compounds exhibited IC50 values at micromolar level against human recombinant PTP1B, and most of them exhibited significant selectivity to PTP1B over TC-PTP and CD45. Further evaluation of the most potent compound 27 on high-fat diet (HFD)-induced insulin-resistant (IR) obese mice indicated that 27 could modulate glucose metabolism and ameliorate dyslipidemia simultaneously.

Microsomal Prostaglandin E Synthase-1 Plays a Critical Role in Long-term Motility Dysfunction after Bowel Obstruction.

Motility dysfunction is present not only during bowel obstruction (BO), but after obstruction is resolved. Previous studies found that lumen distension associated mechano-transcription of COX-2 and production of PGE2 in gut smooth muscle cells (SMC) account for motility dysfunction during obstruction. We hypothesized that PGE2 may exert autocrine effect in SMC to induce microsomal prostaglandin E synthase-1 (mPGES-1), which contributes to motility dysfunction after obstruction is resolved. Partial colon obstruction was induced in rats with an obstruction band, which was released 7 days later. Rats were further studied in the post-BO state. Circular muscle contractility of the mid colon (previously distended during obstruction) remained suppressed, and colon transit was impaired in the post-BO state. The COX-2, mPGES-1, and PGE2 levels were all increased in the distended bowel during obstruction. However, after obstruction was resolved, COX-2 expression returned to normal, whereas mPGES-1 and PGE2 levels remained increased. Expression of mPGES-1 in colon SMC was inducible by stretch or PGE2. Administration of mPGES-1 inhibitor Cay 10526 either before or after the release of obstruction normalized PGE2 levels and improved motility in the post-BO rats. In conclusion, mPGES-1 plays a critical role in the continuous suppression of motor function in the post-BO state.

Three new cytotoxic Diels-Alder-type adducts from Morus australis.

Three new natural products, australisines A-C (1-3, resp.), were isolated from the stem bark of Morus australis, together with eight related compounds, including mulberrofurans E-G, J, and Q, mongolicin C, chalcomoracin, and kuwanon G. Their structures were fully characterized by spectroscopic methods. Compounds 1-3, mulberrofuran G, mongolicin C, and chalcomoracin showed moderate cytotoxic activities against five human cancer cell lines, with IC50 values ranging from 4.6-9.2 microg/ml, as determined by MTT assay.

Isolation, modification, and aldose reductase inhibitory activity of rosmarinic acid derivatives from the roots of Salvia grandifolia.

To find aldose reductase inhibitors, two previously unreported compounds, grandifolias H and I, and five known compounds, including rosmarinic acid and rosmarinic acid derivatives, were isolated from the roots of Salvia grandifolia. A series of rosmarinic acid derivatives was obtained from rosmarinic acid using simple synthetic methods. The aldose reductase inhibitory activity of the isolated and synthesized compounds was assessed. Seven of the tested compounds showed moderate aldose reductase inhibition (IC50=0.06-0.30µM). The structure-activity relationship of aldose reductase inhibitory activity of rosmarinic acid derivatives was discussed for the first time. This study provided useful information that will facilitate the development of aldose reductase inhibitors.

Risk factors for postoperative intra-abdominal septic complications after surgery in Crohn's disease: A meta-analysis of observational studies.

BACKGROUND AND AIMS: Postoperative intra-abdominal septic complications [IASCs] are the most feared risks of surgery for Crohn's disease[CD]. The risk factors for IASCs still remain controversial. The aim of this study was to assess the risk factors for IASCs in CD patients undergoing abdominal surgery. METHODS: MEDLINE, Cochrane Library, and EMBASE were searched to identify observational studies reporting the risk factors for IASCs in CD patients. A meta-analysis was conducted to investigate the impact of various risk factors on IASCs in CD. The GRADE [Grading of Recommendations Assessment, Development and Evaluation] approach was used for quality assessment of evidence on outcome levels. RESULTS: This review included 15 studies evaluating 3807 patients undergoing 4189 operations. The meta-analyses found that low albumin levels (odds ratio [OR]: 1.93; 95% confidence interval [CI]: 1.362.75), preoperative steroids use [OR: 1.99; 95% CI: 1.54-2.57], a preoperative abscess [OR: 1.94; 95% CI: 1.263.0], previous surgery history [OR: 1.50; 95% CI: 1.151.97] may be risk factors for IASCs. There were no associations between anastomosis methods [OR: 0.94; 95% CI: 0.58-1.53], biologics therapy [OR: 1.29; 95% CI: 0.792.11], and immunomodulator use [OR: 1.07; 95% CI: 0.661.73] with the risk of IASCs. Due to observational design, the quality of evidence was regarded low or moderate for these risk factors by the GRADE approach. CONCLUSIONS: This meta-analysis provides some evidence that steroids use, previous surgical history, a preoperative abscess, and low albumin levels may be associated with higher rates of IASCs in CD. Knowledge about those risk factors may influence treatment and procedure-related decisions, and possibly reduce the ss rate.