Inhibition of α-glucosidase by 2-thiobarbituric acid: Molecular dynamics simulation integrating parabolic noncompetitive inhibition kinetics

Qin, Xiu-Yuan,Lee, Jinhyuk,Zheng, Li,Yang, Jun-Mo,Gong, Yan,Park, Yong-Doo Elsevier 2018 Process biochemistry Vol.65 No.-

<P><B>Abstract</B></P> <P>The phenomenon of α-glucosidase inhibition has attracted the attention of researchers due to its association with type 2 diabetes treatment in humans. In this study, we found that 2-thiobarbituric acid (TBA) induces complex inhibition of α-glucosidase using kinetics tests and molecular dynamics (MD) simulations. Computational MD and docking simulations demonstrate that TBA interacts with three residues on active sites of α-glucosidase such as Met69, Arg212, and His348. These biochemical tests indicate that TBA reversibly inhibits α-glucosidase in a parabolic noncompetitive manner (<I>IC</I> <SUB>50</SUB> =17.13±1.14mM; <I>K</I> <SUB>i</SUB> =13.25±0.56mM) and that this inhibition is accompanied by a biphasic kinetic process. The tertiary conformational changes were not synchronized with TBA inhibition but we observed hydrophobic disruption after inactivation at higher concentrations of TBA. Our results provide insight into the functional roles of residues located at the active sites of α-glucosidase, and we suggest that compounds similar to TBA (heterocyclic compounds) targeting the key residues of active sites are potential α-glucosidase inhibitors.</P> <P><B>Highlights</B></P> <P> <UL> <LI> 2-Thiobarbituric acid (TBA) induces complex inhibition of α-glucosidase. </LI> <LI> Computational MD simulations demonstrate that TBA interacts with Met69, Arg212, and His348. </LI> <LI> TBA reversibly inhibits α-glucosidase in a parabolic noncompetitive manner (<I>IC</I> <SUB>50</SUB> =17.13±1.14mM; <I>K</I> <SUB>i</SUB> =13.25±0.56mM). </LI> <LI> The high dose of TBA induces hydrophobic disruption after inactivation. </LI> <LI> Heterocyclic compounds targeting the key residues of active sites are potential α-glucosidase inhibitors. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Cell surface vimentin-targeted monoclonal antibody 86C increases sensitivity to temozolomide in glioma stem cells

Noh, Hyangsoon,Zhao, Qingnan,Yan, Jun,Kong, Ling-Yuan,Gabrusiewicz, Konrad,Hong, Sungguan,Xia, Xueqing,Heimberger, Amy B.,Li, Shulin Elsevier 2018 Cancer letters Vol.433 No.-

<P><B>Abstract</B></P> <P>Glioblastoma multiforme (GBM) is the most prevalent and aggressive brain tumor. The current standard therapy, which includes radiation and chemotherapy, is frequently ineffective partially because of drug resistance and poor penetration of the blood-brain barrier. Reducing resistance and increasing sensitivity to chemotherapy may improve outcomes. Glioma stem cells (GSCs) are a source of relapse and chemoresistance in GBM; sensitization of GSCs to temozoliomide (TMZ), the primary chemotherapeutic agent used to treat GBM, is therefore integral for therapeutic efficacy. We previously discovered a unique tumor-specific target, cell surface vimentin (CSV), on patient-derived GSCs. In this study, we found that the anti-CSV monoclonal antibody 86C efficiently increased GSC sensitivity to TMZ. The combination TMZ+86C induced significantly greater antitumor effects than TMZ alone in eight of 12 GSC lines. TMZ+86C–sensitive GSCs had higher CSV expression overall and faster CSV resurfacing among CSV<SUP>−</SUP> GSCs compared with TMZ+86C–resistant GSCs. Finally, TMZ+86C increased apoptosis of tumor cells and prolonged survival compared with either drug alone in GBM mouse models. The combination of TMZ+86C represents a promising strategy to reverse GSC chemoresistance.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Anti-CSV monoclonal antibody 86C sensitize GSCs to TMZ treatment. </LI> <LI> GSCs with higher CSV expression are more sensitive to TMZ+86C. </LI> <LI> GSCs with higher CSV resurfacing rate among CSV<SUP>−</SUP> cells are more sensitive to TMZ+86C. </LI> <LI> TMZ+86C increased apoptosis and prolonged survival in GBM models. </LI> <LI> Tumor-specific CSV antibody 86C can efficiently target human GSCs to increase their sensitivity to TMZ. </LI> </UL> </P>

Functional Evaluation of Transplanted Kidneys with Reduced Field-of-View Diffusion-Weighted Imaging at 3T

Yuan Xie,Yanjun Li,Jiqiu Wen,Xue Li,Zhe Zhang,Jianrui Li,Yan’e Zhao,Peng Wang,Jun Zhang,Ying Tian,Long Jiang Zhang,Guang Ming Lu 대한영상의학회 2018 Korean Journal of Radiology Vol.19 No.2

Objective: To determine the feasibility of reduced field-of-view diffusion-weighted imaging (rFOV DWI) with multi-b values to detect functional variability in transplanted kidneys. Materials and Methods: Using a 3T MRI scanner, multi-b rFOV DWI of transplanted kidney or native kidney was performed in 40 renal transplantation recipients and 18 healthy volunteers. The patients were stratified, according to an estimated glomerular filtration rate (eGFR): Group 1, eGFR ≥ 60 mL/min/1.73 m2; Group 2, eGFR ≥ 30 mL/min/1.73 m2 and < 60 mL/min/1.73 m2; Group 3, eGFR < 30 mL/min/1.73 m2. Total apparent diffusion coefficient (ADCT), perfusion-free ADC (ADCD) and perfusion fraction (FP) of kidneys were calculated and compared among the four groups. Correlations between the imaging results and eGFR were assessed. Results: All volunteers had eGFR ≥ 60 mL/min/1.73 m2, while 16, 16, and 8 patients were included in Groups 1, 2, and 3, respectively. In the renal cortex, ADCT was higher in Group 1 ([1.65 ± 0.13] x 10-3 mm2/s) than Group 3 ([1.44 ± 0.11] x 10-3 mm2/s) (p < 0.05), and the inter-group differences of FP values were significant (all p < 0.05) (0.330 ± 0.024, 0.309 ± 0.019, 0.278 ± 0.033, and 0.250 ± 0.028 for control group, Groups 1, 2, and 3, respectively). Renal cortical ADCT, ADCD, FP, and renal medullary ADCT and FP correlated positively with eGFR (r = 0.596, 0.403, 0.711, 0.341, and 0.323, respectively; all p < 0.05). When using 0.278 as the cutoff value, renal cortical FP had a sensitivity of 97.1% and a specificity of 66.7% for predicting decreased renal function. Conclusion: Multi-b rFOV DWI presents transplanted kidneys with high resolution, which is a promising functional tool for non-invasively monitoring function of transplanted kidneys.

Analysis of the Baroreceptor and Vestibular Receptor Inputs in the Rostral Ventrolateral Medulla following Hypotension in Conscious Rats

Yan Lan,Huan-Jun Lu,Xian Jiang,Li-Wei Li,Yan-Zhao Yang,Guang-Shi Jin,박주영,김민선,박병림,Yuan-Zhe Jin 대한약리학회 2015 The Korean Journal of Physiology & Pharmacology Vol.19 No.2

Input signals originating from baroreceptors and vestibular receptors are integrated in the rostralventrolateral medulla (RVLM) to maintain blood pressure during postural movement. The contributionof baroreceptors and vestibular receptors in the maintenance of blood pressure following hypotensionwere quantitatively analyzed by measuring phosphorylated extracellular regulated protein kinase(pERK) expression and glutamate release in the RVLM. The expression of pERK and glutamate releasein the RVLM were measured in conscious rats that had undergone bilateral labyrinthectomy (BL)and/or sinoaortic denervation (SAD) following hypotension induced by a sodium nitroprusside (SNP)infusion. The expression of pERK was significantly increased in the RVLM in the control groupfollowing SNP infusion, and expression peaked 10 min after SNP infusion. The number of pERKpositive neurons increased following SNP infusion in BL, SAD, and BL+SAD groups, although theincrease was smaller than seen in the control group. The SAD group showed a relatively higherreduction in pERK expression when compared with the BL group. The level of glutamate release wassignificantly increased in the RVLM in control, BL, SAD groups following SNP infusion, and thispeaked 10 min after SNP infusion. The SAD group showed a relatively higher reduction in glutamaterelease when compared with the BL group. These results suggest that the baroreceptors are morepowerful in pERK expression and glutamate release in the RVLM following hypotension than thevestibular receptors, but the vestibular receptors still have an important role in the RVLM.

Efficacy and Safety of Neurokinin-1 Receptor Antagonists for Prevention of Chemotherapy-Induced Nausea and Vomiting: Systematic Review and Meta-analysis of Randomized Controlled Trials

Yuan, Dong-Mei,Li, Qian,Zhang, Qin,Xiao, Xin-Wu,Yao, Yan-Wen,Zhang, Yan,Lv, Yan-Ling,Liu, Hong-Bin,Lv, Tang-Feng,Song, Yong Asian Pacific Journal of Cancer Prevention 2016 Asian Pacific journal of cancer prevention Vol.17 No.4

Objectives: Can addition of neurokinin-1 receptor antagonists (NK1-RAs) be considered as an ideal strategy for the prevention of chemotherapy-induced nausea and vomiting (CINV)? Researchers differ on this question. Materials and Methods: Electronic databases were searched for randomized control trials (RCTs) that evaluated the effectiveness and safety of NK1-RAs in preventing CINV. The primary end point was complete response (CR) in the acute, delayed, and overall phases after chemotherapy. Subgroup analyses evaluated the types of NK1-RAs, routines of administration, types of malignancies, regimens used in combination with NK1-RAs, and age of patients included in the studies. The incidences of different types of adverse events were also extracted to estimate the safety of NK1-RAs. Results: A total of 38 RCTs involving 13,923 patients were identified. The CR rate of patients receiving NK-RAs was significantly higher than patients in the control groups during overall phase (70.8% vs 56.0%, P<0.001), acute phase (85.1% vs 79.6%, P<0.001), and delayed phase (71.4% vs 58.2%, P<0.001). There were three studies including patients of children or adolescents, the CR rate was also significantly higher in the treatment group (overall phase: OR=2.807, P<0.001; acute phase: OR=2.863, P =0.012; delayed phase: OR=2.417, P<0.001). For all the other outcomes, patients in the NK1-RAs groups showed improvements compared to the control groups (incidence of nausea: 45.2% vs 45.9%, P<0.001; occurrence of vomiting: 22.6% vs 38.9%, P<0.001; usage of rescue drugs: 23.5% vs 34.1%, P<0.001). The pooled side effects from NK1-RAs did not significantly differ from previous reports and the toxicity rates in patients less than eighteen years old also did not diff between the two groups (P=0.497). However, we found that constipation and insomnia were more common in the patients of control groups, whereas diarrhea and hiccups were more frequently detected in patients receiving NK1-RAs. Conclusions: NK1-RAs improved the CR rate of CINV. They are effective for both adults and children. The use of NK1-RAs might be associated with the appearance of diarrhea and hiccups, while decreasing the possibility of constipation and insomnia.

Effect of Glutamate on the Vestibulo-Solitary Projection after Sodium Nitroprusside-Induced Hypotension in Conscious Rats

Li-Wei Li,Guang-Shi Jin,Yan-Zhao Yang,Abdul Nasir Ameer,김민선,박병림,Yuan-Zhe Jin 대한약리학회 2015 The Korean Journal of Physiology & Pharmacology Vol.19 No.3

Orthostatic hypotension is most common in elderly people, and its prevalence increases with age. Attenuation of the vestibulo-sympathetic reflex (VSR) is commonly associated with orthostatic hypotension. In this study, we investigated the role of glutamate on the vestibulo-solitary projection of the VSR pathway to clarify the pathophysiology of orthostatic hypotension. Blood pressure and expression of both pERK and c-Fos protein were evaluated in the nucleus tractus solitarius (NTS) after microinjection of glutamate into the medial vestibular nucleus (MVN) in conscious rats with sodium nitroprusside (SNP)-induced hypotension that received baroreceptor unloading via sinoaortic denervation (SAD). SNP-induced hypotension increased the expression of both pERK and c-Fos protein in the NTS, which was abolished by pretreatment with glutamate receptor antagonists (MK801 or CNQX) in the MVN. Microinjection of glutamate receptor agonists (NMDA or AMPA) into the MVN increased the expression of both pERK and c-Fos protein in the NTS without causing changes in blood pressure. These results indicate that both NMDA and AMPA receptors play a significant role in the vestibulo-solitary projection of the VSR pathway for maintaining blood pressure, and that glutamatergic transmission in this projection might play a key role in the pathophysiology of orthostatic hypotension.

Urinary Biomarkers for the Noninvasive Detection of Gastric Cancer

Li, Dehong,Yan, Li,Lin, Fugui,Yuan, Xiumei,Yang, Xingwen,Yang, Xiaoyan,Wei, Lianhua,Yang, Yang,Lu, Yan The Korean Gastric Cancer Association 2022 Journal of gastric cancer Vol.22 No.-

Gastric cancer (GC) is associated with high morbidity and mortality rates. Thus, early diagnosis is important to improve disease prognosis. Endoscopic assessment represents the most reliable imaging method for GC diagnosis; however, it is semi-invasive and costly and heavily depends on the skills of the endoscopist, which limit its clinical applicability. Therefore, the search for new sensitive biomarkers for the early detection of GC using noninvasive sampling collection methods has attracted much attention among scientists. Urine is considered an ideal biofluid, as it is readily accessible, less complex, and relatively stable than plasma and serum. Over the years, substantial progress has been made in screening for potential urinary biomarkers for GC. This review explores the possible applications and limitations of urinary biomarkers in GC detection and diagnosis.

Additive Role of the Vestibular End Organ and Baroreceptors on the Regulation of Blood Pressure in Rats

Yan Lan,Yan-Zhao Yang,Xian Jiang,Guang-Shi Jin,김민선,박병림,Yuan-Zhe Jin,Li-Wei Li 대한약리학회 2013 The Korean Journal of Physiology & Pharmacology Vol.17 No.4

Contribution of the vestibular end organ to regulation of arterial pressure was quantitatively compared with the role of baroreceptors in terms of baroreflex sensitivity and c-Fos protein expression in the rostral ventrolateral medulla (RVLM). Baroreflex sensitivity and c-Fos protein expression in the RVLM were measured in conscious rats that had undergone bilateral labyrinthectomy (BL) and/or baroreceptor unloading. BL attenuated baroreflex sensitivity during intravenous infusion of sodium nitroprusside (SNP), but did not significantly affect the sensitivity following infusion of phenylephrine (PE). Baroreflex sensitivity became positive following sinoaortic denervation (SAD) during infusion of PE and attenuated sensitivity during infusion of SNP. Baroreflex sensitivity also became positive following double ablation (BL+SAD) during infusion of PE, and attenuated sensitivity during infusion of SNP. c-Fos protein expression increased significantly in the RVLM in the sham group after SNP administration. However, the BL, SAD, and SAD+BL groups showed significant decreases in c-Fos protein expression compared with that in the sham group. The SAD group showed more reduced c-Fos protein expression than that in the BL group, and the SAD+BL group showed less expression than that in the SAD group. These results suggest that the vestibular system cooperates with baroreceptors to maintain arterial pressure during hypotension but that baroreceptors regulate arterial pressure during both hypotension and hypertension. Additionally, afferent signals for maintaining blood pressure from the vestibular end organs and the baroreceptors may be integrated in the RVLM.

Antiviral activity of Herba Patrinea (a Chinese medicinal herb) against respiratory syncytial virus in vitro

Li, Hong-Yuan,Li, Shan-Shan,Liu, Dian-Li,Dong, Yan-Mei,Tian, Wen-Jing Kyung Hee Oriental Medicine Research Center 2003 Oriental pharmacy and experimental medicine Vol.3 No.2

Respiratory syncytial virus (RSV) has long been considered an important cause of severe lower respiratory tract infection in infants and young children throughout the world. Unfortunately, no effective treatment of RSV exists. Therefore, New agents are needed to reduce the impact of RSV. We have studied the anti-viral effect of traditional Chinese midicinal herbs for over ten years and find Herba Patrinea (a Chinese medicinal herb) has the anti-RSV effect in vitro. In this study, the Herba Patrinea was extracted with hot water, condensed and sterilized. The cytotoxicity of the aqueous extract was tested by adding the diluted extract directly to HeLa cells and its effect on anti-RSV was estimated by the CPEI assay. As a result, the median cytotoxic concentration $(CC_{50})$ of Herba Patrinea was 32 mg/ ml by morphological observation, the median effective concentration (50% effective concentration, $EC_{50}$) of the Herba Patrinea against replication of the Long strain of RSV in HeLa cells were 1.25 mg/ml. The selectivity index $(SI=CC_{50}/EC{50})$ is 25.6. Moreover, Herba Patrinea gave a dose-dependent response in inhibiting RSV. In time of addition experiment, Herba Patrinea inhibited replication of RSV in HeLa cells when it was added at 0h, 2h, and 4h after virus infection. In summary, the results of this study suggest Herba Patrinea may be a novel anti-RSV drug and it is worthy of further studying.

JCAD deficiency attenuates activation of hepatic stellate cells and cholestatic fibrosis

Li Xie,Hui Chen,Li Zhang,Yue Ma,Yuan Zhou,Yong-Yu Yang,Chang Liu,Yu-Li Wang,Ya-Jun Yan,Jia Ding,Xiao Teng,Qiang Yang,Xiu-Ping Liu,Jian Wu 대한간학회 2024 Clinical and Molecular Hepatology(대한간학회지) Vol.30 No.2

Background/Aims: Cholestatic liver diseases including primary biliary cholangitis (PBC) are associated with active hepatic fibrogenesis, which ultimately progresses to cirrhosis. Activated hepatic stellate cells (HSCs) are the main fibrogenic effectors in response to cholangiocyte damage. JCAD regulates cell proliferation and malignant transformation in nonalcoholic steatoheaptitis-associated hepatocellular carcinoma (NASH-HCC). However, its participation in cholestatic fibrosis has not been explored yet. Methods: Serial sections of liver tissue of PBC patients were stained with immunofluorescence. Hepatic fibrosis was induced by bile duct ligation (BDL) in wild-type (WT), global JCAD knockout mice (JCAD-KO) and HSC-specific JCAD knockout mice (HSC-JCAD-KO), and evaluated by histopathology and biochemical tests. In situ-activated HSCs isolated from BDL mice were used to determine effects of JCAD on HSC activation. Results: In consistence with staining of liver sections from PBC patients, immunofluorescent staining revealed that JCAD expression was identified in smooth muscle α-actin (α-SMA)-positive fibroblast-like cells and was significantly up-regulated in WT mice with BDL. JCAD deficiency remarkably ameliorated BDL-induced hepatic injury and fibrosis, as documented by liver hydroxyproline content, when compared to WT mice with BDL. Histopathologically, collagen deposition was dramatically reduced in both JCAD-KO and HSC-JCAD-KO mice compared to WT mice, as visualized by Trichrome staining and semi-quantitative scores. Moreover, JCAD deprivation significantly attenuated in situ HSC activation and reduced expression of fibrotic genes after BDL. Conclusions: JCAD deficiency effectively suppressed hepatic fibrosis induced by BDL in mice, and the underlying mechanisms are largely through suppressed Hippo-YAP signaling activity in HSCs.