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Ocular hypertension (OHT), the common situation in adult patients in the outpatients, occurs ∼5% worldwide. However, there are still some practical problems in differentiation of OHT with early primary open-angle glaucoma (POAG) using current standard methods. Application of high resolution diffusion tensor imaging (DTI) enables us to the differentiate axonal architecture of visual pathway between POAG and OHT subjects. Among 32 POAG patients recruited (15 OHT and 14 control subjects), 62.5% of glaucoma were in early stage for the current study. All subjects underwent ophthalmological assessments with standard automated perimetry and optical coherence tomography (OCT). DTI was applied to measure fraction anisotropy (FA) and mean diffusivity (MD) of optic tract (OT), lateral geniculate body (LGN) and optic radiation (OR) using voxel-based analysis. Our data demonstrated that FA values of bilateral OR in POAG were significantly lower in the right or left than that of OHT patients (left OR: 0.51 ± 0.04 vs. 0.54 ± 0.03, p < 0.05; right OR: 0.51 ± 0.05 vs. 0.54 ± 0.03, p < 0.05). In right LGN, MD values were higher in POAG patients compared with OHT subjects (9.81 ± 1.45 vs. 8.23 ± 0.62, p < 0.05). However, no significant difference of all of the DTI parameters was observed between OHT and control subjects. DTI parameters in POAG patients were positively correlated with morphological and functional measurements ( p < 0.05). Vertical cup to disc ratio (VCDR) was correlated with ipsilateral FA of OT ( p < 0.05), ipsilateral MD of OT ( p < 0.05), ipsilateral MD of LGN ( p < 0.05), and contralateral MD of OT ( p < 0.05). Mean deviation of visual field (MDVF) was correlated with ipsilateral FA of OT ( p < 0.05), ipsilateral MD of OT ( p < 0.05), and ipsilateral FA of LGN ( p < 0.05). Our study demonstrated that DTI can differentiate POAG from OHT subjects in optic pathway, particularly in early POAG, and DTI parameters can quantify the progression of POAG.

Insulin degrading enzyme (IDE), a metalloprotease that degrades amyloid-β (Aβ) peptides and insulin, is associated with Alzheimer's disease and diabetes. The mechanism of IDE catalyzed degrading of Aβ peptides, which is of fundamental importance in the design of therapeutic methods for Alzheimer's disease, has not been fully understood. In this work, combined quantum mechanics and molecular mechanics (QM/MM) style Møller-Plesset second order perturbation theory (MP2) geometry optimization calculations are performed to investigate the catalytic mechanism of the Aβ40 Phe19-Phe20 peptide bond cleavage by human IDE. The analyses using QM/MM MP2 optimization suggest that a neutral water molecule is at the active site of the enzyme-substrate (ES) complex. The water molecule is in hydrogen bonding with the nearby anionic Glu111 of IDE but not directly bound to the catalytic Zn ion. This is confirmed by QM/MM DFTB3 molecular dynamics simulation. Our studies also reveal that the hydrolysis of the Aβ40 Phe19-Phe20 peptide bond by IDE consists of four key steps. The neutral water is first activated by moving toward and binding to the Zn ion. A gem-diol intermediate is then formed by the activated neutral water molecule attacking the C atom of the Phe19-Phe20 peptide bond. The next is the protonation of the N atom of Phe19-Phe20 peptide bond to form an intermediate with an elongated C-N bond. The final step is the breaking of the Phe19-Phe20 C-N bond. The final step is the rate-determining step with a calculated Gibbs free energy of activation of 17.34 kcal/mol, in good agreement with the experimental value 16.7 kcal/mol. This mechanism provides the basis for the design of biochemical methods to modulate the activity of IDE in humans.

In this study, twenty curcumin analogue hybrids as potential anticancer agents through regulation protein of TrxR were designed and synthesized. Results of anticancer activity showed that 5,7-dimethoxy-3-(3-(2-((1E, 4E)-3-oxo-5-(pyridin-2-yl)penta-1,4-dien-1- yl)phenoxy)propoxy)-2-(3,4,5-trimethoxyphenyl)-4H-chromen-4-one (compound 7d) could induce gastric cancer cells apoptosis by arresting cell cycle, break mitochondria function and inhibit TrxR activity. Meanwhile, western blot revealed that this compound could dramatically up expression of Bax/Bcl-2 ratio and high expression of TrxR oxidation. These results preliminarily show that the important role of ROS mediated activation of ASK1/MAPK signaling pathways by this title compound., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Research on brain function after brachial plexus injury focuses on local cortical functional reorganization, and few studies have focused on brain networks after brachial plexus injury. Changes in brain networks may help understanding of brain plasticity at the global level. We hypothesized that topology of the global cerebral resting-state functional network changes after unilateral brachial plexus injury. Thus, in this cross-sectional study, we recruited eight male patients with unilateral brachial plexus injury (right handedness, mean age of 27.9 ± 5.4 years old) and eight male healthy controls (right handedness, mean age of 28.6 ± 3.2). After acquiring and preprocessing resting-state magnetic resonance imaging data, the cerebrum was divided into 90 regions and Pearson's correlation coefficient calculated between regions. These correlation matrices were then converted into a binary matrix with affixed sparsity values of 0.1-0.46. Under sparsity conditions, both groups satisfied this small-world property. The clustering coefficient was markedly lower, while average shortest path remarkably higher in patients compared with healthy controls. These findings confirm that cerebral functional networks in patients still show small-world characteristics, which are highly effective in information transmission in the brain, as well as normal controls. Alternatively, varied small-worldness suggests that capacity of information transmission and integration in different brain regions in brachial plexus injury patients is damaged., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest

Objective: To compare the effects of electroacupuncture (EA) and mild-warm moxibustion (Mox) therapies for constipation-predominant irritable bowel syndrome (C-IBS) patients., Methods: Sixty C-IBS patients were assigned to 2 groups by simple randomized method, i.e. EA group (30 cases) and Mox group (30 cases). Both EA and Mox treatments were performed on bilateral Tianshu (ST 25) and Shangjuxu (ST 37) for 30 min each time, 6 times per week, for 4 consecutive weeks. The gastrointestinal symptoms and psychological symptoms of the two groups were scored before and after treatment. The effects on the corresponding functional brain areas, namely the anterior cingulate cortex (ACC), insular cortex (IC) and prefrontal cortex (PFC) were observed by functional magnetic resonance imaging (fMRI) before and after treatment., Results: Compared with the Mox group, greater improvements in abdominal distension, defecation frequency, diffificulty in defecation and stool features were observed in the EA group (all P<0.01), both Hamilton Anxiety Rating Scale and Hamilton Depression Rating Scale scores were signifificantly decreased in the EA group (all P<0.01). Finally, decreased activated voxel values were observed in the ACC, right IC and PFC brain regions of EA group with 150 mL colorectal distension stimulation (P<0.05 or P<0.01)., Conclusions: Both EA and Mox could signifificantly improve some of the most intrusive symptoms of C-IBS patients, and EA was more effective than Mox. The therapeutic effect of these two therapies might through modulating of the brain-gut axis function. (Registration No. ChiCTRTRC-11001349).

Riverine environments have been threatened by anthropogenic perturbations worldwide, whereby their fish assemblages have been modified by habitat changes and nonendemic species invasions. We assessed changes in fish assemblages by comparing the species presence in historical and contemporary fish data in the Yellow River from 1965 to 2015. The temporal change in species assemblages was found with increased nonendemic species and fewer natives. Fish species richness of the river declined 35.4% over the past fifty years. Moreover, the decreased mean Bray-Curtis dissimilarity among reaches suggested that the fish assemblages of different reaches in the Yellow River were becoming more similar over time. However, temporal patterns of fish assemblages varied among reaches. In the upper Yellow River, higher species richness and more invasive species were found than those in the historical record, while the lower reaches experienced significant species loss. Dam constructions, exotic fish invasions, and flow reductions played the vital role in structuring the temporal fish assemblages in the Yellow River. It is suggested that river basins which experienced different types and levels of stressors by anthropogenic perturbations can produce varied effects on their temporal trends of species assemblages.

Insulin degrading enzyme (IDE) plays key roles in degrading peptides vital in type two diabetes, Alzheimer's, inflammation, and other human diseases. However, the process through which IDE recognizes peptides that tend to form amyloid fibrils remained unsolved. We used cryoEM to understand both the apo- and insulin-bound dimeric IDE states, revealing that IDE displays a large opening between the homologous ~55 kDa N- and C-terminal halves to allow selective substrate capture based on size and charge complementarity. We also used cryoEM, X-ray crystallography, SAXS, and HDX-MS to elucidate the molecular basis of how amyloidogenic peptides stabilize the disordered IDE catalytic cleft, thereby inducing selective degradation by substrate-assisted catalysis. Furthermore, our insulin-bound IDE structures explain how IDE processively degrades insulin by stochastically cutting either chain without breaking disulfide bonds. Together, our studies provide a mechanism for how IDE selectively degrades amyloidogenic peptides and offers structural insights for developing IDE-based therapies., Competing Interests: ZZ, WL, LB, YT, HW, AW, MF, VW, LM, DL, WS, RD, BD, DL, AK, SK, AK, SL, BC, CP, WT No competing interests declared, (© 2018, Zhang et al.)

BuChE inhibitors play important roles in treatment of patients with advanced Alzheimer's disease (AD). A series of tricyclic pyrazolo[1,5-d][1,4]benzoxazepin-5(6H)-one derivatives were synthesized and evaluated as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. Some derivatives showed selective BuChE inhibitory activity, which was influenced by the volumes of the substituted groups at the C6 position and halogen substituents at the benzene ring of tricyclic scaffold. Among them, compounds 3f and 3o with dihalogen and 6-ethyl substituent showed the most potent activity (IC 50  = 2.95, 2.04 μM, and mixed-type, non-competitive inhibition against BuChE, respectively). Eutomer (6R)-3o exhibited better BuChE inhibitory activity than (6S)-3o. Compound 3o exhibited nontoxic, good ADMET properties, and remarkable neuroprotective activity. Docking studies revealed the same binding orientation within the active site of target enzyme. Compound 3o was nicely bound to BuChE via three hydrogen bonds, one Alkyl interaction and three Pi-Alkyl interactions. The selective BuChE inhibitors had a potential use in progressive neurodegenerative disorder., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Introduction: Arteriovenous fistula is a lifeline for end-stage kidney disease patients on dialysis. The quality of the vein and artery to be used plays a crucial role in attaining a functioning, reliable and long-lasting arteriovenous fistula. The aim of the study is to present an alternative for haemodialysis access to preserve the upper arm vasculature for future use - the forearm loop arteriovenous fistula., Methods: From October 2015 to September 2016, 202 patients with chronic kidney disease (CKD), stages 4 and 5, underwent arteriovenous fistula creation at the Universiti Sains Malaysia Hospital, Malaysia. Nine patients, with severe atherosclerosis of the distal artery, but with satisfactory veins, underwent forearm loop arteriovenous fistula creation. Maturation of the fistula was based on the classification by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI)., Results: All nine patients who underwent forearm loop arteriovenous fistula have had diabetes mellitus for more than 10 years. Only one fistula failed to mature within 6 weeks. Two arteriovenous fistulas thrombosed at 3 and 5 months, respectively, after the commencement of haemodialysis. However, the other six matured fistulas are still functioning well after a year of regular usage., Conclusions: Distal forearm arteries in diabetics may be severely atherosclerotic. Forearm loop arteriovenous fistula can be considered as the primary access for cases decided as inconvenient for fistula creation due to severe occlusive atherosclerotic disease of the forearm arteries; in order to preserve upper arm veins for future access procedures.

Antibody Fab fragments have been exploited with significant success to facilitate the structure determination of challenging macromolecules as crystallization chaperones and as molecular fiducial marks for single particle cryo-electron microscopy approaches. However, the inherent flexibility of the "elbow" regions, which link the constant and variable domains of the Fab, can introduce disorder and thus diminish their effectiveness. We have developed a phage display engineering strategy to generate synthetic Fab variants that significantly reduces elbow flexibility, while maintaining their high affinity and stability. This strategy was validated using previously recalcitrant Fab-antigen complexes where introduction of an engineered elbow region enhanced crystallization and diffraction resolution. Furthermore, incorporation of the mutations appears to be generally portable to other synthetic antibodies and may serve as a universal strategy to enhance the success rates of Fabs as structure determination chaperones., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the utility of the whole-lesion histogram apparent diffusion coefficient (ADC) for characterizing the heterogeneity of mucinous breast carcinoma (MBC) and to determine which ADC metrics may help to best differentiate subtypes of MBC., Materials and Methods: This retrospective study involved 52 MBC patients, including 37 pure MBC (PMBC) and 15 mixed MBC (MMBC). The PMBC patients were subtyped into PMBC-A (20 cases) and PMBC-B (17 cases) groups. All patients underwent preoperative diffusion-weighted imaging (DWI) at 1.5T and the whole-lesion ADC assessments were generated. Histogram-derived ADC parameters were compared between PMBC vs. MMBC and PMBC-A vs. PMBC-B, and receiver operating characteristic (ROC) curve analysis was used to determine optimal histogram parameters for differentiating these groups., Results: The PMBC group exhibited significantly higher ADC values for the mean (P = 0.004), 25 th (P = 0.004), 50 th (P = 0.004), 75 th (P = 0.006), and 90 th percentiles (P = 0.013) and skewness (P = 0.021) than did the MMBC group. The 25 th percentile of ADC values achieved the highest area under the curve (AUC) (0.792), with a cutoff value of 1.345 × 10 -3 mm 2 /s, in distinguishing PMBC and MMBC. The PMBC-A group showed significantly higher ADC values for the mean (P = 0.049), 25 th (P = 0.015), and 50 th (P = 0.026) percentiles and skewness (P = 0.004) than did the PMBC-B group. The 25 th percentile of the ADC cutoff value (1.476 × 10 -3 mm 2 /s) demonstrated the best AUC (0.837) among the ADC values for distinguishing PMBC-A and PMBC-B., Conclusion: Whole-lesion ADC histogram analysis enables comprehensive evaluation of an MBC in its entirety and differentiating subtypes of MBC. Thus, it may be a helpful and supportive tool for conventional MRI., Level of Evidence: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:391-400., (© 2017 International Society for Magnetic Resonance in Medicine.)

Rationale: Ozone autohemotherapy as an alternative treatment method has been applied to the treatment of several diseases. Here, we report a patient used ozone autohemotherapy to treat her hypertension and diabetes. Nevertheless, the patient occurred sudden dizziness and black haze due to hyperkalemia., Patient Concerns: A 54-year-old woman who was admitted to our emergency department complaining of sudden dizziness and black haze for 5 hours., Diagnoses: The blood potassium test showed hyperkalemia. Upon further inquiry of her medical history, the patient received ozone autohemotherapy to treat hypertension and diabetes for 9 days prior to admission., Interventions: The ozone therapy had been asked to stop. Insulin, sodium bicarbonate, and sodium polystyrene sulfonate were administered to the patient., Outcomes: After treatment, blood potassium remained in the normal range. After 3 days of treatment, the 24-hour dynamic electrocardiogram revealed sinus rhythm with an average heart rate of 82 beats/min, occasional ventricular premature beats, occasional ventricular premature beats, and no ST segment depression., Lessons: Although ozone therapy is widely used in the treatment of several diseases, adverse reactions should be given attention in clinical practice, especially in patients with chronic kidney disease., (Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.)

To develop novel anti-inflammatory agents, a series of unsaturated glycyrrhetic acids were designed, synthesized and evaluated for anti-inflammatory activity using RAW264.7 cells. The structure-activity relationship (SAR) of NO inhibitory activity was analyzed. α,β-Unsaturated glycyrrhetic acids showed better activity, among them, compounds 6k and 6l with piperazine unit exhibited the most potent nitric oxide (NO) and interleukin-6 (IL-6) inhibitory activity (IC 50  = 13.3 and 15.5 μM respectively). Furthermore, compound 6k could also significantly suppress LPS-induced iNOS and COX-2 expression and IL-6 production through MAPKs and NF-kB signaling pathway., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: This case series demonstrated the feasibility of the image-guided video-assisted thoracoscopic surgery (iVATS) for localization and removal of ground glass opacities (GGOs). The procedure was performed in a hybrid operating room (OR) using C-arm cone-beam computed tomography (CBCT) equipped with a laser-guided navigation system., Methods: Between October 1 st 2016 to July 31 st 2017, 14 consecutive patients presenting with GGOs underwent iVATS procedure. The efficacy and safety of the procedure were assessed through a retrospective chart review., Results: The median GGOs size was 7 mm [interquartile range (IQR): 4-10 mm] with a median depth-to-size (D-S) ratio of 1.16 (IQR: 0-2.3). All of the lesions were visible on intraoperative CBCT images and localizations were successful in all patients with a median localization time of 22 min (IQR: 16-44 min). No patient required a conversion to thoracotomy. There was no operative mortality and the median length of postoperative stay was 4 days (IQR: 3-6 days). The final pathological diagnoses were as follows: primary lung cancer (n=6), lung metastases (n=2), and benign lung lesions (n=6)., Conclusions: Our study suggests the iVATS could be a helpful tool for single-stage detection and removal of GGOs., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

To develop new anti-inflammatory agents with improved pharmaceutical profiles, a series of new phenyl-pyrazoline-coumarin derivatives (4a∼4m) were designed and synthesized. Compounds 4a and 4b were determined by X-ray crystallography. All of the compounds have been screened for their anti-inflammatory activity characterized by evaluating their inhibition against LPS-induced IL-6 release. Among them, compound 4m showed the highest anti-inflammatory activity with inhibiting IL-6, TNF-α and nitric oxide (NO) production lipopolysaccharide (LPS)-stimulated. The further study showed that title compound 4m could significantly suppress expressions of nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and the productions of IL-6, TNF-α, NO through NF-κB/MAPK signaling pathway. The anti-inflammatory activity of compound 4m was determined by carrageenan induced paw edema. Furthermore in vivo evaluation results indicated that compound 4m could inhibit AA-induced rat ankle joints., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Introduction: The benzopyran derivatives present a wide variety of biological activity and behaviour. At the same time the benzopyran derivatives support their use as therapeutic agents for multiple diseases. Their structural characteristics correlated to physicochemical properties seem to define the extent of the biological activity. Areas covered: This review summarizes new patents published on new benzopyran derivatives from 2009 to 2016. Expert opinion: Many benzopyran derivatives have vivo/vitro biological responses. Their clinical evaluation will be critical to assess therapeutic utility. The compounds containing benzopyran moiety is well defined as lead compounds for design of new more promising molecules.

Objective: To observe the expression levels of interleukin-1α (IL-1α) and matrix metalloproteinase-9 (MMP-9) in degenerated lumbar disc tissues and to investigate their clinical significance., Patients and Methods: Fifty patients with lumbar disc degeneration received the operative treatment were divided into three groups according to the magnetic resonance imaging (MRI) results: protrusion group, extrusion group, and free group. The degenerated intervertebral disc tissues were taken, and the normal intervertebral disc tissues of 20 patients received the operative treatment due to lumbar bursting fracture, and were selected as the control group. The bone mineral densities of all patients were measured. The mRNA and protein expression levels of MMP-9 and IL-1α were detected via Real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA), respectively., Results: The bone mass of patients with lumbar disc degeneration was significantly decreased compared with that of the control group, and the bone mass was decreased more significantly in a free group than that in protrusion group. The mRNA and protein levels in IL-1α and MMP-9 of patients with lumbar disc degeneration were significantly increased compared with those in control group; the mRNA and protein levels in IL-1α and MMP-9 of extrusion group and free group were significantly higher than those in protrusion group, and the mRNA and protein levels in IL-1α and MMP-9 of free group were significantly higher than those in extrusion group., Conclusions: The levels of IL-1α and MMP-9 in degenerated lumbar disc tissues are higher than normal levels, and the increasing levels are positively correlated with the disease condition.

Dominant-negative mutants of telomerase hTERT were demonstrated to have selective effects in tumor cells. However, no any effective and highly selective hTERT inhibitor has been developed so far. We focused on developing new hTERT modulators and synthesized a small molecular compound, named (4-bromophenyl)(3-hydroxy-4-methoxyphenyl)methanone. Our in vitro studies found that title compound showed high inhibitory activity against telomerase, had high antiproliferative capacity on SMMC-7721 cells with IC 50 value 88 nm, and had no obvious toxic effect on human normal hepatocyte cells with IC 50 value 10 μM. Our in vivo studies showed that this compound significantly inhibited tumor growth in xenograft tumor models. The further molecular mechanisms of title compound inhibition SMMC-7721 cell proliferation by modulating hTERT were explored; the results showed that endoplasmic reticulum stress (ERS) through ER over response (EOR) activates the expression of hTERT, and then induces ERS, which is believed to be intricately associated with oxidative stress and mitochondrial dysfunction, resulting in apoptotic cell death, thereby modulating the expression of downstream signaling molecules including CHOP (CAAT/enhancer-binding protein homologous protein)) and mitochondrion pathway of apoptosis, leading to inhibition of cell proliferation.

This corrects the article DOI: 10.1038/ncomms15375.

Altered cytokine production can lead to immune dysfunction in patients with cancer. The present study investigated the expression of T helper (Th)17 cytokines in patients with laryngeal squamous cell carcinoma (LSCC) and their clinical significance in providing new therapeutic insights. The prevalence of Th17 cells and their receptors in patients with LSCC was studied using immunohistochemical analysis via tissue microarray technology. Flow cytometry was used to investigate the percentage of Th17 and Th1 cells in peripheral blood mononuclear cells. Furthermore, the proliferation of Th17 cells and Th17-associated cytokines, including interleukin (IL)17, IL23 and RAR-related orphan receptor γt, was analyzed by reverse transcription-quantitative polymerase chain reaction. The results revealed that the prevalence of Th17 cells in patients with LSCC was elevated in their primary tumors, as well as in peripheral blood, compared with that in healthy controls. It was further demonstrated that Th17 cells could be induced and expanded in the tumor microenvironment through cytokines produced by the tumor cells. In conclusion, Th17 cells have a substantial impact on the carcinogenesis of LSCCs, and could serve as a potential therapeutic target to modulate the anti-tumor response in these carcinomas.

Eyelid reconstruction is complex and challenging since it is not only for structural and functional restoration, but also for an acceptable aesthetic result. In full thickness eyelid injuries, it will involve both anterior and posterior lamella. Therefore, when reconstructing the defect, it requires at least two layers; one will be a flap with blood supply, and the other can be a free graft. In this case, a rotational advancement cheek flap and composite graft were used to reconstruct the lower eyelid.

In the intestinal epithelium, the aberrant regulation of cell/cell junctions leads to intestinal barrier defects, which may promote the onset and enhance the severity of inflammatory bowel disease (IBD). However, it remains unclear how the coordinated behaviour of cytoskeletal network may contribute to cell junctional dynamics. In this report, we identified ACF7, a crosslinker of microtubules and F-actin, as an essential player in this process. Loss of ACF7 leads to aberrant microtubule organization, tight junction stabilization and impaired wound closure in vitro. With the mouse genetics approach, we show that ablation of ACF7 inhibits intestinal wound healing and greatly increases susceptibility to experimental colitis in mice. ACF7 level is also correlated with development and progression of ulcerative colitis (UC) in human patients. Together, our results reveal an important molecular mechanism whereby coordinated cytoskeletal dynamics contributes to cell adhesion regulation during intestinal wound repair and the development of IBD.

Background: Cognitive deficits have been identified as one of core clinical symptoms of major depressive disorder (MDD). Accumulating evidence indicated that triglycerides (TG) might be associated with MDD and cognitive decline., Objective: This study examined whether patients with MDD had poorer cognitive functions than healthy controls, and further investigate whether TG levels were involved in MDD, and its cognitive impairments in a Han Chinese population., Method: 115 patients with MDD and 119 healthy controls were enrolled. Cognitive functions were assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and serum TG levels were examined using enzymatic colorimetry., Results: TG levels were higher in patients with MDD than healthy controls after controlling for the variables. Cognitive test scores were lower in patients with MDD than healthy controls except for visuospatial/constructional index after controlling for the variables. TG levels were negatively correlated with visuospatial/constructional score, delayed memory score and RBANS total score of MDD. Further multivariate regression analysis showed that TG levels were negatively associated with visuospatial/constructional score, attention score, delayed memory score and RBANS total score of MDD., Conclusions: Our findings supported that serum TG levels might be involved in MDD, and play an important role in cognitive impairments of MDD, especially in delayed memory. Moreover, patients with MDD experienced greater cognitive impairments than healthy controls except for visuospatial/constructional index., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Accumulating evidence suggests that ribosomal proteins may have extraribosomal functions in various physiological and pathological processes, including cancer. We analyzed the expression of the CIRH1A ribosomal protein in colorectal carcinoma and para-carcinoma samples by bioinformatics analyses of data extracted from The Cancer Genome Atlas and in colorectal cancer cell lines in vitro by qPCR. CIRH1A was highly expressed in carcinoma samples and colorectal cancer cells. We also transduced the RKO colorectal cancer (CRC) cell line with lentivirus-mediated small interfering RNAs (siRNAs) and studied the impact that this knockdown of CIRH1A expression had on cell growth. RNA interference (RNAi)-mediated inhibition of CIRH1A expression significantly suppressed proliferation and increased apoptosis of transduced cells, and tended to arrest them in G1 phase. Our data suggest that CIRH1A plays a critical role in the proliferation, cell cycle distribution, and apoptosis of human malignant colorectal cells, and might therefore be a potential target for therapeutic strategies.

Background: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor type 1 blockers (ARBs) are often prescribed for renal transplant recipients (RTRs), but the outcomes of these medications in RTRs remain controversial., Methods: The PubMed, Embase, and Cochrane Library databases were systematically searched. Randomized controlled trials investigating the outcomes of ACEI/ARBs in RTRs were included for meta-analysis., Results: Twenty-two trials with 2242 patients were identified. After treatment for at least 12 months, ACEI/ARBs were associated with a decline in glomerular filtration rate (GFR) (weighed mean differences [WMD] -5.76 mL/min; 95% confidence intervals [CI]: -9.31 to -2.20) and a decrease in hemoglobin (WMD -9.81 g/L; 95% CI: -14.98 to -4.64). There were no significant differences in mortality between ACEI/ARB and non-ACEI/ARB groups (risk ratio [RR] 0.98, 95% CI: 0.58 to 1.76), nor in graft failure (RR 0.68, 95% CI: 0.38 to 1.32). After short-term treatment (less than 1 year), significant differences were found in changes of 24-hour proteinuria (WMD-0.57 g/d; 95% CI: -0.72 to -0.42) and serum potassium (WMD 0.25 mEq/L; 95% CI: 0.14 to 0.37) in ACEI/ARB groups compared to control arm, while these differences were not confirmed in the long run., Conclusion: This meta-analysis indicates ACEI/ARBs may be prescribed to RTRs with GFR and hemoglobin being carefully monitored., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To investigate the effect of Hugan Qingzhi tablets on lipid metabolism and inflammation in rats fed on high-fat diet and explore the underlying mechanisms., Methods: Sixty male Sprague-Dawley rats were randomly divided into 6 groups, namely HFD group (with high-fat diet and distilled water), control group (with normal diet and distilled water), fenofibrate group (with high-fat diet and treatment with 0.1 g

Objective: To explore the clinical and immunological features, gene mutations, treatment and prognosis in patients with activated phosphoinositide 3-kinase δ syndrome (APDS) caused by PIK3CD gene heterozygous germline mutation. Method: The data of clinical, immunological phenotype, treatment, and prognosis of 15 patients with APDS, who visited Children's Hospital of Chongqing Medical University, Peking Union Medical College Hospital, and Shenzhen Children's Hospital from June 2014 to November 2016, were collected and analyzed. Result: Of the 15 patients, 11 were males, remaining 4 patients were females. The median age of disease onset was 1 year, and median age at diagnosis was 4 years and 4 months. All patients had the de novo heterozygous germline mutation in PIK3CD (c. 3061G>A, p. E1021K). The common initial symptoms were respiratory infections, including pneumonia (12 cases) , bronchiectasis (5 cases). Other common clinical manifestations were recurrent and chronic diarrhea (11 cases), Epstein-Barr virus (EBV) and/or cytomegalovirus (CMV) viremia (10 cases), hepatosplenomegaly (13 cases), and lymphadenopathy (10 cases). The main immunological features were increased IgM (11 cases), decreased IgG (6 cases), decreased numbers of CD4 + T cell (7 cases) especially naïve CD4 + T cell (9 cases), reduced numbers of B cells (11 cases) particularly naïve B cells (9 cases), increased numbers of transitional B cells (5 cases) and CD8 + terminally differentiated effector memory T cells (5 cases). After 1-29 months follow up, 13 of the 15 cases remain survived, of whom 5 cases received regular intravenous immunoglobulin (IVIG) therapy, with reduced frequency of infections and improved severity of infections; of whom 3 cases received oral rapamycin therapy at the dosage of 1 mg/ (m 2 ·d) and with a decrease in nonneoplastic lymphoproliferation. Conclusion: E1021K is a hotspot for mutation in the PIK3CD gene in patients with APDS. Regular IVIG can improve their quality of life. Targetel treatment with rapamycin could mitigate hepatosplenomegaly.

Theranostic nanoparticles with both imaging and therapeutic abilities are highly promising in successful diagnosis and treatment of the most devastating cancers. In this study, the dual-modal imaging and photothermal effect of hyaluronan (HA)-modified superparamagnetic iron oxide nanoparticles (HA-SPIONs), which was developed in a previous study, were investigated for CD44 HA receptor-overexpressing breast cancer in both in vitro and in vivo experiments. Heat is found to be rapidly generated by near-infrared laser range irradiation of HA-SPIONs. When incubated with CD44 HA receptor-overexpressing MDA-MB-231 cells in vitro, HA-SPIONs exhibited significant specific cellular uptake and specific accumulation confirmed by Prussian blue staining. The in vitro and in vivo results of magnetic resonance imaging and photothermal ablation demonstrated that HA-SPIONs exhibited significant negative contrast enhancement on T 2 -weighted magnetic resonance imaging and photothermal effect targeted CD44 HA receptor-overexpressing breast cancer. All these results indicated that HA-SPIONs have great potential for effective diagnosis and treatment of cancer., Competing Interests: The authors report no conflicts of interest in this work.

Based on telomerase, thirteen novel phenstatin moiety linked stavudine derivatives (8a∼8e and 11a∼11f) were synthesized. The structures were determined by NMR and TOF-HRMS. The screening results showed that some compounds had better anti-cancer activity in vivo and in vitro. Among them, Compound 8d showed high inhibitory activity against telomerase and showed good antiproliferative activity against SGC-7901 cell with IC 50 value 0.77 μM by inducing cell cycle arrest at G2 phase. It also could improve SGC-7901 cell apoptosis, mitochondrial membrane potential assay indicated that the dissipation of MMP might participate in apoptosis induced by title compound. In vivo studies showed that compound 8d displayed potent anticancer activity with inhibition tumor growth., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Schizopygopsis pylzovi Kessler (Cypriniformes: Cyprinidae), an endemic species to China, is a major commercial fish in the upper reaches of the Yellow River. The complete mitochondrial DNA genome of S. pylzovi was sequenced. The mitogenome is 16,704 bp in length and includes 13 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes and two non-coding regions. The basic composition of S. pylzov is 28.5% for A, 27.0% for T, 26.1% for C, and 18.4% for G, with a slight AT bias of 55.5%. Gene order is similar to that of the typical vertebrate, as is nucleotide composition and codon usage. The complete mitogenome sequence of S. pylzovi would be useful to further phylogenetic analysis and genetic conservation for this endemic species.

Recent studies conducted on some "meta effect" photochemical reactions focused on aromatic carbonyls having a substitution on one meta position of the benzophenone (BP) and anthraquinone parent compound. In this paper, two different substitutions were introduced with one at each meta position of the BP parent compound to investigate possible competition between different types of meta effect photochemistry observed in acidic solutions containing water. The photochemical pathways of 3-hydroxymethyl-3'-fluorobenzophenone (1) and 3-fluoro-3'-methylbenzophenone (2) were explored in several solvents, including acidic water-containing solutions, using time-resolved spectroscopic experiments and density functional theory computations. It is observed that 1 can undergo a photoredox reaction and 2 can undergo a meta-methyl deprotonation reaction in acidic water-containing solutions. Comparison of these results to those previously reported for the analogous BP derivatives that contain only one substituent at a meta position indicates the introduction of electron-donating (such as hydroxyl) and electron-withdrawing groups (such as F) on the meta positions of BP can influence the meta effect photochemical reactions. It was found that involvement of an electron-donating moiety facilitates the meta effect photochemical reactions by stabilizing the crucial reactive biradical intermediate associated with the meta effect photochemical reactions.

Ibrutinib (ibr), a first-in-class Bruton tyrosine kinase (BTK) inhibitor, has demonstrated high response rates in both relapsed/refractory and treatment naïve chronic lymphocytic leukemia (CLL). However, about 25% of patients discontinue ibrutinib therapy at a median follow-up of 20 months and many patients discontinue the treatment due to leukemia progression or Richter transformation. Mutations affecting the C481 residue of BTK disrupt ibrutinib binding and have been characterized by us and others as the most common mechanism of ibrutinib resistance. Thus far, all described BTK mutations are located in its kinase domain and mutations outside this domain have never been described. Herein, we report a patient whose CLL progressed, was salvaged with ibrutinib and then relapsed. Serial analysis of samples throughout patient's clinical course identified a structurally novel mutation (BTKT316A) in the SH2 domain, but not kinase domain, of Bruton tyrosine kinase which was associated with disease relapse. Functionally, cells carrying BTKT316A show resistance to ibrutinib at both cellular and molecular levels to a similar extent as BTKC481S. Our study lends further insight into the diverse mechanisms of ibrutinib resistance that has important implications for the development of next-generation BTK inhibitors as well as mutation detection in relapsed patients.

Elevated serum levels of Interleukin-3 (IL-3), a major component of the cytokines, have been observed in chronic and medicated patients with schizophrenia, but this elevation may reflect either or both medication and illness chronicity effects. Thus, we compared serum IL-3 levels in first-episode drug-naive (FEDN) to chronic medicated patients with schizophrenia and examined the association of IL-3 with their psychopathological symptoms. Serum IL-3 levels were assessed in 55 FEDN patients, 52 chronic medicated patients and 43 healthy controls. Schizophrenia symptomatology was assessed with the Positive and Negative Syndrome Scale (PANSS). Serum IL-3 levels were measured by sandwich enzyme-linked immunosorbent assay (ELISA). We found significantly lower IL-3 levels in FEDN patients than both chronic patients and healthy controls (both p<0.001), while IL-3 levels in chronic patients were markedly higher than in healthy controls. No significant association was observed between IL-3 and any clinical psychopathology in FEDN patients; however, we found a significant correlation between serum IL-3 levels and the PANSS general psychopathology subscore in chronic medicated patients (p<0.05). Decreased IL-3 levels in FEDN patients suggest that suppressed immune function may be associated with developing schizophrenia, but as the disease progresses IL-3 levels increase perhaps related to medication treatment or other factors that occur during chronic illness., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Highly effective targeted tumor recognition via vectors is crucial for cancer detection. In contrast to antibodies and proteins, peptides are direct targeting ligands with a low molecular weight. In the present study, a peptide magnetic nanovector platform containing a lipid bilayer was designed using a peptide amphiphile (PA) as a skeleton material in a controlled manner without surface modification. Fluorescein isothiocyanate-labeled epidermal growth factor receptor (EGFR) peptide nanoparticles (NPs) could specifically bind to EGFR-positive liver tumor cells. EGFR peptide magnetic vesicles (EPMVs) could efficiently recognize and separate hepatoma carcinoma cells from cell solutions and treated blood samples (ratio of magnetic EPMVs versus anti-EpCAM NPs: 3.5 ± 0.29). Analysis of the circulating tumor cell (CTC) count in blood samples from 32 patients with liver cancer showed that EPMVs could be effectively applied for CTC capture. Thus, this nanoscale, targeted cargo-packaging technology may be useful for designing cancer diagnostic systems.

Genetic differences that specify unique aspects of human evolution have typically been identified by comparative analyses between the genomes of humans and closely related primates, including more recently the genomes of archaic hominins. Not all regions of the genome, however, are equally amenable to such study. Recurrent copy number variation (CNV) at chromosome 16p11.2 accounts for approximately 1% of cases of autism and is mediated by a complex set of segmental duplications, many of which arose recently during human evolution. Here we reconstruct the evolutionary history of the locus and identify bolA family member 2 (BOLA2) as a gene duplicated exclusively in Homo sapiens. We estimate that a 95-kilobase-pair segment containing BOLA2 duplicated across the critical region approximately 282 thousand years ago (ka), one of the latest among a series of genomic changes that dramatically restructured the locus during hominid evolution. All humans examined carried one or more copies of the duplication, which nearly fixed early in the human lineage--a pattern unlikely to have arisen so rapidly in the absence of selection (P < 0.0097). We show that the duplication of BOLA2 led to a novel, human-specific in-frame fusion transcript and that BOLA2 copy number correlates with both RNA expression (r = 0.36) and protein level (r = 0.65), with the greatest expression difference between human and chimpanzee in experimentally derived stem cells. Analyses of 152 patients carrying a chromosome 16p11. rearrangement show that more than 96% of breakpoints occur within the H. sapiens-specific duplication. In summary, the duplicative transposition of BOLA2 at the root of the H. sapiens lineage about 282 ka simultaneously increased copy number of a gene associated with iron homeostasis and predisposed our species to recurrent rearrangements associated with disease.

Conclusion: Long (GT)n repeat polymorphisms in the heme oxygenase-1 (HO-1) gene promoter and decreased serum HO-1 levels are associated with a higher susceptibility to laryngeal squamous cell carcinoma (LSCC)., Objective: In this case-control study, the association of HO-1 microsatellite (GT)n repeat polymorphisms and serum levels with the risk of LSCC was investigated., Methods: A total of 142 LSCC patients, 54 vocal leukoplakia patients and 98 healthy controls, were examined for (GT)n polymorphisms by sequencing, and the serum HO-1 levels were detected in a sub-set from participants above by ELISA., Results: Compared with the controls, the LSCC group had significantly higher frequencies of L-allele (> 29 repeats) and L-allele carriers (p < 0.001, OR = 2.037 and p = 0.005, OR = 2.152, respectively). The frequencies of lymph node metastasis and of moderate or poor differentiation were significantly higher in L-allele carriers compared to non-L-allele carriers (p < 0.05). Significantly lower serum HO-1 levels were detected in LSCC patients (p < 0.001), and patients with lower serum HO-1 levels had more advanced cancer stage and a higher lymph node metastasis rate (p < 0.05). Furthermore, the L-allele carriers had lower serum HO-1 concentrations compared with the non-L-allele carriers (p = 0.019).

Conclusion: Improved prognosis associated with HPV-positive status may depend on lower CD4/CD8 ratio. Th1 CD4(+ )T cells were found to be the major sub-set of T lymphocytes in the HPV positive laryngeal squamous cell carcinoma microenvironment., Background: To examine the prognostic significance of human papillomavirus (HPV) status in relation to the ratio of CD4/CD8 in LSCC., Methods: In this study, 46 LSCC biopsy samples were retrospectively assessed using immunohistochemistry for CD4(+ )and CD8(+ )tumor infiltrating lymphocytes (TILs). HPV status was determined by HPV in situ hybridization (ISH) and p16(INK4A) immunohistochemistry. Of the 46 samples, 21 were evaluated for the expression of IFN-γ and IL-4 by quantitative real-time PCR (qRT-PCR). The influence of HPV status on locoregional tumor control and T-cell sub-sets infiltrating tumor microenvironment were investigated., Results: Nineteen patients (41.3%) were classified as HPV positive, who had improved disease-free survival (28% in reduction, hazard ratio =0.10; 95% CI =0.011-0.938). A direct correlation between the HPV status and the ratio of CD4/CD8 or mean levels of CD8(+ )T cells was observed. Compared with the HPV-negative samples, HPV-positive samples had a higher ratio of IFN-γ/IL-4 (24.43 ± 29.89 vs 3.90 ± 4.03; p = 0.0375).

Aims: To isolate a novel strain that could degrade many kinds PAEs efficiently and investigate the DBP-degrading pathway in this strain., Methods and Results: Based on its 16S rRNA gene sequence, the strain was identified as Rhizobium sp. This strain, named LMB-1, can also utilize phthalates, such as DEHP, DMP, DBP and DEP. During the degradation of DBP, six possible metabolites, diethyl phthalate, mono-ethyl phthalate, di-methyl phthalate, mono-methyl phthalate, phthalic acid and tartaric acid, were identified by gas chromatography-mass spectrometry (GC-MS) analysis, and the degradation pathway of DBP was also identified in this study., Conclusions: In summary, strain LMB-1, identified as Rhizobium sp., was found to be capable of efficiently degrading PAEs, and it was determined that the strain degraded DMP completely within 45 h. DEP, DMP, MEP, MMP, PA and tartaric acid were detected during the course of DBP degradation by LMB-1. We propose that this strain could completely degrade DBP or other PAEs. Our results offer a novel and potential candidate, Rhizobium sp. LMB-1, for use in the bioremediation of cultivated soil contaminated by PAEs., Significance and Impact of the Study: This is the first report concerning the complete degradation of phthalate esters by Rhizobium sp., (© 2016 The Society for Applied Microbiology.)

SHARP1 is a basic helix‑loop‑helix transcription factor involved in various cellular processes, including proliferation and differentiation. The present study assessed the role of SHARP1 in the progression and invasion of thyroid cancer. PCR and western blot analysis demonstrated that in thyroid cancer tissues, SHARP1 was significantly downregulated at the mRNA and protein level compared with that in normal tissues. Furthermore, SHARP1 was downregulated in the TT and TPC‑1 thyroid cancer cell lines compared with a normal thyroid cell line, while it was upregulated in other thyroid cancer cell lines. Overexpression of SHARP1 in TT and TPC‑1 cells significantly inhibited the cell viability, migration and invasion in vitro. Furthermore, the protein and mRNA levels of HIF‑1α were found to be decreased in TT and TPC‑1 cells following forced overexpression of SHARP1. In addition, silencing of HIF‑1α reduced the viability, migration and invasion of TT and TPC-1 cells. In conclusion, the present study indicated that SHARP1 acts as a tumor suppressor in thyroid cancer and that its downregulation may contribute to the proliferation, migration and invasion of thyroid cancer cells through mechanisms possibly involving HIF‑1α, suggesting that SHARP1 may be an important therapeutic target for the treatment of thyroid cancer.

Turnover of focal adhesions allows cell retraction, which is essential for cell migration. The mammalian spectraplakin protein, ACF7 (Actin-Crosslinking Factor 7), promotes focal adhesion dynamics by targeting of microtubule plus ends towards focal adhesions. However, it remains unclear how the activity of ACF7 is regulated spatiotemporally to achieve focal adhesion-specific guidance of microtubule. To explore the potential mechanisms, we resolve the crystal structure of ACF7's NT (amino-terminal) domain, which mediates F-actin interactions. Structural analysis leads to identification of a key tyrosine residue at the calponin homology (CH) domain of ACF7, whose phosphorylation by Src/FAK (focal adhesion kinase) complex is essential for F-actin binding of ACF7. Using skin epidermis as a model system, we further demonstrate that the phosphorylation of ACF7 plays an indispensable role in focal adhesion dynamics and epidermal migration in vitro and in vivo. Together, our findings provide critical insights into the molecular mechanisms underlying coordinated cytoskeletal dynamics during cell movement.

CC chemokine ligand 5 (CCL5) and CCL3 are critical for immune surveillance and inflammation. Consequently, they are linked to the pathogenesis of many inflammatory conditions and are therapeutic targets. Oligomerization and glycosaminoglycan (GAG) binding of CCL5 and CCL3 are vital for the functions of these chemokines. Our structural and biophysical analyses of human CCL5 reveal that CCL5 oligomerization is a polymerization process in which CCL5 forms rod-shaped, double-helical oligomers. This CCL5 structure explains mutational data and offers a unified mechanism for CCL3, CCL4, and CCL5 assembly into high-molecular-weight, polydisperse oligomers. A conserved, positively charged BBXB motif is key for the binding of CC chemokines to GAG. However, this motif is partially buried when CCL3, CCL4, and CCL5 are oligomerized; thus, the mechanism by which GAG binds these chemokine oligomers has been elusive. Our structures of GAG-bound CCL5 and CCL3 oligomers reveal that these chemokine oligomers have distinct GAG-binding mechanisms. The CCL5 oligomer uses another positively charged and fully exposed motif, KKWVR, in GAG binding. However, residues from two partially buried BBXB motifs along with other residues combine to form a GAG-binding groove in the CCL3 oligomer. The N termini of CC chemokines are shown to be involved in receptor binding and oligomerization. We also report an alternative CCL3 oligomer structure that reveals how conformational changes in CCL3 N termini profoundly alter its surface properties and dimer-dimer interactions to affect GAG binding and oligomerization. Such complexity in oligomerization and GAG binding enables intricate, physiologically relevant regulation of CC chemokine functions.

Based on our recently reported selective hMAO-A inhibitors, on which, the intramolecular cyclization led to a very interesting change of isoform selectivity. A series of selective hMAO-B inhibitors (3a-3u) with novel scaffold of tricyclic pyrazolo[1,5-d][1,4]benzoxazepin-5(6H)-one were designed and synthesized. Compound 3u (IC50=221 nM) exhibited the best inhibitory activity and isoform selectivity against hMAO-B, superior to selegiline (IC50=321 nM), which is a commercial selective hMAO-B inhibitor used to Parkinson's disease. Modeling study indicated that the selectivity of our compounds to hMAO-B is determined by at least two residues, i.e., Ile 199 and Cys 172 (or corresponded Phe 208 and Asn 181 of hMAO-A). These data support further studies to assess rational design of more efficiently selective hMAO-B inhibitors., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

It is of our interest to generate and identify novel compounds with regulation telomerase for cancer therapy. In order to carry out more rational design, based on structure-based drug design, several series of N-substituted-dihydropyrazole derivatives, totally 78 compounds as potential human telomerase inhibitors were designed and synthesized. The results demonstrated that some compounds had potent anticancer activity against four tumor cell lines, and showed good selectivity on tumor cells over somatic cells. By the modified TRAP assay, compound 13i exhibited the most potent inhibitory activity against telomerase with an IC50 value of 0.98 μM. In vivo evaluation results indicated that compound 13i could inhibit growth of S180 and HepG2 tumor-bearing mice, and it also significantly enhanced the survival rate of EAC tumor-bearing mice. The further results in vivo confirmed that it could significantly improve pathological changes of N,N-diethylnitrosamine (DEN)-induced rat hepatic tumor. These data support further studies to assess rational design of more efficient telomerase inhibitors in the future., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Dominant-negative mutant of telomerase hTERT was demonstrated to show selective anticancer effects in tumor cells. But, an effective hTERT inhibitor with high selectivity has not been developed so far. Focused on hTERT, a novel dihydropyrazole-chromen (13k) controlling hTERT was designed. Title compound 13k occupied high antiproliferative activity against MGC-803 cells with IC50 value 1.41 μM, but it manifested obvious un-toxic effect on human normal gastric mucosa cells with the IC50 2.3 mM. Treated with compound 13k, the further inhibition mechanisms by modulating hTERT was explored, the results showed that expression of hTERT was clearly modulated, and then β-catenin activation was decreased, thereby the expression of downstream signaling molecules including c-myc and cyclin D1 was modulated, leading to inhibition MGC-803 cells proliferation., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Sixteen novel hesperetin derivatives containing Mannich base moiety were designed and synthesized and their anti-inflammatory activities were evaluated by inhibiting tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in mouse RAW264.7 macrophages. Compounds 3a-3k showed better hydrophilic, while compounds 3l-3p with aromatic groups was hydrophobic. The anti-inflammatory activity of title compounds was correlated with logP values, among them, compounds 3c, 3e and 3i with minus logP values exhibited best anti-inflammatory activity through decreasing both IL-6 and TNF-α. Furthermore, the expression of LPS-induced notch1 and inos was reduced by compounds 3c, 3e, and 3i, and compound 3e attenuated LPS-induced inos protein levels in a dose-dependent manner., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Stimulating fibroblast-like synoviocyte (FLS) apoptosis in rheumatoid arthritis (RA) is a promising strategy for clinical treatment. Previous studies have confirmed that geniposide shows a certain anti-arthritic effect in vivo. However, whether geniposide can induce RA FLS apoptosis and the underlying mechanisms has not been elucidated. Herein, adjuvant-induced arthritis (AIA) in rat was induced and FLS was isolated from synovial tissues by tissue explant cultivation method. MTT assay, Hoechst staining, and flow cytometric apoptosis assay were applied to evaluate apoptotic effect of geniposide on AIA FLS. Bcl-2, Bax, and caspase 3 messenger RNA (mRNA) levels, and extracellular-signal-regulated kinases (ERKs) and phosphorylated ERK protein levels were examined by real-time PCR and western blot, respectively. We found that geniposide dose-dependently inhibited AIA FLS proliferation in vitro. AIA FLS treated with geniposide displayed typical apoptotic morphological characteristics including nuclear shrinkage and chromatin condensation. Flow cytometric apoptosis assay indicated that geniposide significantly increased the apoptosis rate of AIA FLS. Additionally, geniposide treatment on AIA FLS decreased Bcl-2 mRNA level and increased Bax and caspase 3 mRNA levels, accompanied by reduced protein levels of phosphorylated-ERK1/2, without affecting total ERK1/2. In conclusion, geniposide effectively induces AIA FLS apoptosis through regulating the apoptosis-related gene expressions and inhibiting ERK signal pathway.

Purpose. This study was to investigate the effects of cornel iridoid glycoside (CIG) on spinal cord injury (SCI) in rats. Methods. The thoracic cord (at T9) of rats was injured by clip compression for 30 sec. Locomotor function was assessed using the Basso, Beattie, and Bresnahan (BBB) rating scale. Neuroanatomic stereological parameters as well as Nogo-A, p75 neurotrophin receptor (p75NTR), and ROCKII expression were measured by histological processing, immunohistochemistry, and stereological analyses. The axons passing through the lesion site were detected by BDA tracing. Results. Intragastric administration of CIG (60 and 180 mg/kg) improved the locomotor impairment at 10, 17, 24, and 31 days post-injury (dpi) compared with untreated SCI model rats. CIG treatment decreased the volume of the lesion epicenter (LEp) and increased the volume of spared tissue and the number of surviving neurons in the injured spinal cord at 31 dpi. CIG promoted the growth of BDA-positive axons and their passage through the lesion site and decreased the expression of Nogo-A, p75NTR, and ROCKII both in and around the LEp. Conclusion. CIG improved the locomotor impairment, decreased tissue damage, and downregulated the myelin-associated inhibition signaling pathway in SCI rats. The results suggest that CIG may be beneficial for SCI therapy., Competing Interests: The authors have declared that no conflict of interest exists.

Insulin-degrading enzyme (IDE) selectively degrades peptides, such as insulin, amylin, and amyloid β (Aβ) that form toxic aggregates, to maintain proteostasis. IDE defects are linked to the development of type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD). Structural and biochemical analyses revealed the molecular basis for IDE-mediated destruction of amyloidogenic peptides and this information has been exploited to develop promising inhibitors of IDE to improve glucose homeostasis. However, the inhibition of IDE can also lead to glucose intolerance. In this review, I focus on recent advances regarding our understanding of the structure and function of IDE and the discovery of IDE inhibitors, as well as challenges in developing IDE-based therapy for human diseases, particularly T2DM., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: To compare the effects of electroacupuncture (EA) and moxibustion therapies on patients with diarrhea-predominant irritable bowel syndrome (D-IBS)., Methods: A total of 60 D-IBS patients were randomly allocated to the EA group (30 cases) and moxibustion group (30 cases). Before and after treatment, the gastrointestinal symptoms and psychological symptoms were scored by Visual Analogue Scale, Bristol Stool Form Scale, Hamilton Anxiety Rating Scale (HAMA), and Hamilton Depression Rating Scale (HAMD); the expressions of 5-hydroxytryptamine (5-HT), 5-HT3 receptor (5-HT3R), and 5-HT4 receptor (5-HT4R) in the sigmoid mucosal tissue were measured by immunohistochemical staining. Additionally, the effects on the functional brain areas of the anterior cingulate cortex (ACC), insular cortex (IC) and prefrontal cortex (PFC) were observed by functional magnetic resonance imaging., Results: Compared with before treatment, both EA and moxibustion groups reported significant improvements in abdominal pain and abdominal bloating after treatment (P<0.01 or P<0.05). The moxibustion group reported greater improvements in defecation emergency, defecation frequency, and stool feature than the EA group (P<0.01). Both HAMA and HAMD scores were significantly decreased in the moxibustion group than in the EA group (P<0.01). Both groups demonstrated significantly reduced expressions of 5-HT, 5-HT3R and 5-HT4R in the colonic mucosa after treatment (P<0.01), with a greater reduction of 5-HT in the moxibustion group (P<0.05). Finally, decreased activated voxel values were observed in the left IC, right IC and PFC brain regions of patients in the moxibustion group under stimulation with 150 mL colorectal distension after treatment (P<0.05 or P<0.01), while in the EA group only PFC area demonstrated a reduction (P<0.05)., Conclusion: Moxibustion can significantly improve the symptoms of D-IBS, suggesting that moxibustion may be a more effective therapy than EA for D-IBS patients.