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1.
J Org Chem ; 89(6): 4113-4119, 2024 Mar 15.
Article in English | MEDLINE | ID: mdl-38448366

ABSTRACT

The first example of an electrochemical multicomponent synthesis of selenium-containing compounds with inexpensive and abundant elemental selenium as the selenating reagent was developed. A variety of selenazol-2-amines were constructed in high yields with good functional group tolerance under metal-free and chemical oxidant-free conditions.

2.
Cell Mol Life Sci ; 81(1): 3, 2023 Dec 06.
Article in English | MEDLINE | ID: mdl-38055060

ABSTRACT

MFSD7b belongs to the Major Facilitator Superfamily of transporters that transport small molecules. Two isoforms of MFSD7b have been identified and they are reported to be heme exporters that play a crucial role in maintaining the cytosolic and mitochondrial heme levels, respectively. Mutations of MFSD7b (also known as FLVCR1) have been linked to retinitis pigmentosa, posterior column ataxia, and hereditary sensory and autonomic neuropathy. Although MFSD7b functions have been linked to heme detoxification by exporting excess heme from erythroid cells, it is ubiquitously expressed with a high level in the kidney, gastrointestinal tract, lungs, liver, and brain. Here, we showed that MFSD7b functions as a facilitative choline transporter. Expression of MFSD7b slightly but significantly increased choline import, while its knockdown reduced choline influx in mammalian cells. The influx of choline transported by MFSD7b is dependent on the expression of choline metabolizing enzymes such as choline kinase (CHKA) and intracellular choline levels, but it is independent of gradient of cations. Additionally, we showed that choline transport function of Mfsd7b is conserved from fly to man. Employing our transport assays, we showed that missense mutations of MFSD7b caused reduced choline transport functions. Our results show that MFSD7b functions as a facilitative choline transporter in mammalian cells.


Subject(s)
Choline , Membrane Transport Proteins , Mutation, Missense , Animals , Humans , Choline/metabolism , Heme , Mammals , Membrane Transport Proteins/genetics
3.
J Biol Chem ; 298(11): 102570, 2022 11.
Article in English | MEDLINE | ID: mdl-36209827

ABSTRACT

Dengue virus (DENV) is a flavivirus causing an estimated 390 million infections per year around the world. Despite the immense global health and economic impact of this virus, its true receptor(s) for internalization into live cells has not yet been identified, and no successful antivirals or treatments have been isolated to this date. This study aims to improve our understanding of virus entry routes by exploring the sialic acid-based cell surface molecule GM1a and its role in DENV infection. We studied the interaction of the virus with GM1a using fluorescence correlation spectroscopy, fluorescence crosscorrelation spectroscopy, imaging fluorescence correlation spectroscopy, amide hydrogen/deuterium exchange mass spectrometry, and isothermal titration calorimetry. Additionally, we explored the effect of this interaction on infectivity and movement of the virus during infection was explored using plaque assay and fluorescence-based imaging and single particle tracking. GM1a was deemed to interact with DENV at domain I (DI) and domain II (DII) of the E protein of the protein coat at quaternary contacts of a fully assembled virus, leading to a 10-fold and 7-fold increase in infectivity for DENV1 and DENV2 in mammalian cell systems, respectively. We determined that the interaction of the virus with GM1a triggers a speeding up of virus movement on live cell surfaces, possibly resulting from a reduction in rigidity of cellular rafts during infection. Collectively, our results suggest that GM1a functions as a coreceptor/attachment factor for DENV during infection in mammalian systems.


Subject(s)
Dengue Virus , Dengue , Flavivirus , Animals , Humans , Dengue Virus/metabolism , Viral Envelope Proteins/metabolism , Gangliosides/metabolism , Flavivirus/metabolism , Mammals/metabolism
4.
Molecules ; 28(3)2023 Feb 01.
Article in English | MEDLINE | ID: mdl-36771059

ABSTRACT

The first example of paired electrolysis-enabled cyanation of diaryl diselenides, with KSCN as the green cyanating agent, has been developed. A broad range of aryl selenocyanates can be efficiently synthesized under chemical-oxidant- and additive-free, energy-saving and mild conditions.

5.
Arch Microbiol ; 204(9): 564, 2022 Aug 18.
Article in English | MEDLINE | ID: mdl-35982255

ABSTRACT

Sanghuangporus sp., a medicinal and edible homologous macrofungus known as 'forest gold', which has good effects on antitumor, hypolipidemia and the treatment of gynecological diseases. However, the natural resources of fruiting body are on the verge of depletion due to its long growth cycle and over exploitation. The growth and metabolism of macrofungi are known to depend on the diverse bacterial community. Here, we characterized the diversity and potential function of bacteria inhabiting in the fruiting body of the most widely applied S. vaninii using a combination method of high-throughput sequencing with pure culturing for the first time, and tested the biological activities of bacterial isolates, of which Illumina NovaSeq provided a more comprehensive results on the bacterial community structure. Total 33 phyla, 82 classes, 195 orders, 355 families, 601 genera and 679 species were identified in the fruiting body, and our results revealed that the community was predominated by the common Proteobacteria, Gammaproteobacteria, Burkholderiales, Methylophilaceae (partly consistent with pure-culturing findings), and was dominated by the genera of distinctive Methylotenera and Methylomonas (yet-uncultured taxa). Simultaneously, the functional analysis showed that companion bacteria were involved in the pathways of carbohydrate transport and metabolism, metabolism of terpenoids and polyketides, cell wall/membrane/envelope biogenesis, etc. Hence, it was inferred that bacteria associated with fruiting body may have the potential to adjust the growth, development and active metabolite production of host S. vaninii combined with the tested results of indole-3-acetic acid and total antioxidant capacity. Altogether, this report first provided new findings which can be inspiring for further in-depth studies to exploit bioactive microbial resources for increased production of Sanghuangporus, as well as to explore the relationship between medicinal macrofungi and their associated endophytes.


Subject(s)
Ascomycota , Basidiomycota , Ascomycota/metabolism , Bacteria , Fruiting Bodies, Fungal/metabolism , Humans
6.
Eur J Neurol ; 29(2): 422-431, 2022 02.
Article in English | MEDLINE | ID: mdl-34710256

ABSTRACT

BACKGROUND AND PURPOSE: The present study aimed to explore whether and how omega-3 (ω-3) supplementation could interact with genetic factors to modulate cognitive functions, amyloid pathologies, and Alzheimer's disease (AD) risk. METHODS: A total of 1,670 non-demented participants (mean age 73 years, 47% females, 41% APOE ε4 carriers) were followed up for 10 years. Hierarchical regressions, linear mixed-effects models, and Cox proportional hazards models were used to examine the interaction effects of ω-3 supplementation with APOE ε4 and polygenic hazard scores, after adjusting for age, gender, education, cognitive diagnosis, insomnia, depression, anxiety, and cardiovascular risk score. RESULTS: Individuals who progress to AD during the follow-up tend to take a shorter duration of ω-3 at baseline than those stable, for whom the difference remained significant only amongst APOE ε4 carriers (p < 0.01). The interaction term (APOE ε4 × ω-3) accounted for a significant amount of variance in cognition and cerebral amyloid burden. Long-term ω-3 use protected cognition (especially memory function) and lowered amyloid burden and AD risk only amongst APOE ε4 carriers. Mediation analysis suggested that amyloid pathologies, brain reserve capacities, and brain metabolism mediated the relationships of ω-3 use with memory and global cognition for APOE ε4 (+) carriers. Similar interaction and mediation effects were also indicated amongst high-risk subjects defined by polygenic hazard scores. CONCLUSIONS: Long-term ω-3 intake may have a role in AD prevention in genetically at-risk populations.


Subject(s)
Alzheimer Disease , Apolipoprotein E4 , Aged , Alzheimer Disease/genetics , Alzheimer Disease/prevention & control , Apolipoprotein E4/genetics , Cognition , Dietary Supplements , Female , Genotype , Humans , Male , Risk Factors
7.
Bioorg Med Chem ; 56: 116599, 2022 02 15.
Article in English | MEDLINE | ID: mdl-35041998

ABSTRACT

The aminobenzamide is selective to class I histone deacetylases (HDACs) and displays unique tight-binding/slow-off HDAC-binding mechanism. Herein, we report a series of 9-substituted purine aminobenzamides that selectively inhibit class I HDACs. The activities in vitro showed compound 9d exhibited 12 folds more potent than MS-275 against HDAC1 isoform and showed excellent inhibitory activity on cancer cells, including HCT-116, MDA-MB-231, K562 cell lines. The metabolic stability of 9d was much better than that of the well-known HDAC inhibitor SAHA. Pulse exposure test of western blot assay demonstrated that 9a, 9d induced histone acetylation in a similar manner to MS-275. Further biological validation demonstrated that 9d prevented cell transition from G1 phase to S phase by reducing Cyclin D1, CDK2 and lifting p21, induced early apoptosis by upregulating BAX and downregulating Bcl-2 in HCT-116 cells.


Subject(s)
Antineoplastic Agents/pharmacology , Benzamides/pharmacology , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Purines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzamides/chemical synthesis , Benzamides/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Humans , Molecular Docking Simulation , Molecular Structure , Purines/chemistry , Structure-Activity Relationship
8.
Pharm Biol ; 60(1): 1055-1062, 2022 Dec.
Article in English | MEDLINE | ID: mdl-35634726

ABSTRACT

CONTEXT: Mulisan decoction (MLS) is a classic formula of traditional Chinese medicine for treating hyperhidrosis. The mechanism remains unclear. OBJECTIVE: To investigate the antiperspirant effect and underlying mechanisms of MLS. MATERIALS AND METHODS: Fifty rats were divided into control, model, and three doses of MLS intervention groups (n = 10). Rats except for control group were induced diseases features of the applicable scope of MLS via i.p. reserpine (0.5 mg/kg/d) for 10 days. From day 11, MLS groups were administrated orally MLS at 0.6, 3, and 15 g/kg once a day for 14 days, respectively. After the last administration, sweating was induced in all rats via s.c. pilocarpine (25 mg/kg), the right hind foot of rats was stained, and sweat point numbers were observed. Rat serum was collected to detect IL-2, IL-6, IFN-γ, and TNF-α. Rat plasma was collected for endogenous metabolite analysis via UPLC-QE-Focus-MS. RESULTS: Rats treated with MLS presented a significant decrease in sweat point numbers (13.5%), increase in body weight (13.2%), and promotion in the balance of Th1/Th2 cytokine ratio via increasing IL-2 (38.3%), IFN-γ (20.1%), and TNF-α (22.0%) and decreasing IL-6 (24.7%) compared with the model group (p < 0.05). Plasma metabolomics disclosed 15 potential biomarkers related to model rats, of which two could be significantly reversed by MLS (p < 0.05). The involved pathways were pantothenate and CoA biosynthesis, and porphyrin metabolism. CONCLUSIONS: MLS demonstrated a good antiperspirant effect and metabolism improvement. These findings inspire more clinical study validation on immune improvement and antiperspirant effect.


Subject(s)
Antiperspirants , Hyperhidrosis , Medicine, Chinese Traditional , Animals , Antiperspirants/pharmacology , Hyperhidrosis/drug therapy , Interleukin-2 , Interleukin-6 , Metabolomics , Rats , Tumor Necrosis Factor-alpha
9.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 52(3): 534-538, 2021 May.
Article in Zh | MEDLINE | ID: mdl-34018378

ABSTRACT

The 12-year-old patient was admitted to the hospital on September 19, 2019 for "vaginal bleeding for 2 + months and pelvic mass to be diagnosed". The patient and her family explicitly denied any previous history of diethylstilbestrol exposure. After admission, relevant examinations were conducted and hysteroscopic exploration was performed under general anesthesia. During the procedure, cervical neoplasms were extracted and pathology results indicated cervical cancer. Then, extensive transabdominal hysterectomy+bilateral salpingectomy+bilateral ovarian transposition+pelvic lymph node dissection+para-aortic lymph node sampling were performed. Postoperative pathology analysis of the removed tissue showed that clear cell carcinoma of cervix (CCAC) had infiltrated into 1/3 of the cervical stroma and there was downward involvement of the vaginal wall; the cancer metastasized to the left obturator lymph node and the left internal and external iliac lymph nodes. Immunohistochemical staining of the removed tissue showed the following results: cytokeratin 7 (+), cytokeratin 20 (-), Napsin-A (+), cell adhesion molecule CD15 (+), heatocyte nuclear factor-1 ß (+), Sal-like protein 4 (-), tumor suppressor gene P16 protein (+), estrogen receptor (+), progesterone receptor (-), tumor suppressor gene P53 protein (focal positive), tumor suppressor gene WT-1 protein (-) and Ki67 antigen (about 40% positive). The patient was diagnosed with CCAC stage ⅢC1p. Four cycles of postoperative systemic chemotherapy (fluorouracil+cisplatin) and 25 times of three-dimensional afterloading radiotherapy were performed. The patient did follow-up visits and did not show obvious signs of recurrence. The clinical manifestations of this disease are basically the same as those of cervical squamous cell carcinoma, and if the patient is younger, it can be easily misdiagnosed as dysfunctional uterine bleeding, indicating the need for differential diagnosis.


Subject(s)
Neoplasm Recurrence, Local , Uterine Cervical Neoplasms , Child , Female , Humans , Hysterectomy , Lymph Node Excision , Uterine Cervical Neoplasms/surgery
10.
J Exp Bot ; 71(3): 1078-1091, 2020 01 23.
Article in English | MEDLINE | ID: mdl-31626291

ABSTRACT

Phospholipids constitute the main component of biomembranes. During low-temperature storage and transportation of harvested bell peppers (Capsicum annuum), chilling injury participates in their decay. A primary cause of this chilling injury is phospholipid degradation. In this study, three genes encoding phospholipase D (PLD) were identified from bell peppers and their activities were examined under cold stress. Low temperature (4 °C) induced strong accumulation of the CaPLDα4 transcript, suggesting that it is associated with the phenomenon of phospholipid degradation and destruction of cell membranes. Low temperature also significantly induced increased amounts of NAM-ATAF1/2-CUC2 (NAC) domain transcription factors. CaNAC1 was found to interact with the promoter of CaPLD4 in a yeast one-hybrid screen. Electrophoretic mobility shift and ß-glucuronidase reporter assays demonstrated that CaNAC1 binds to the CTGCAG motif in the CaPLDα4 promoter, thereby activating its transcription and controlling phospholipid degradation. The ubiquitination sites of the CaNAC1 protein were characterized by liquid chromatography-tandem mass spectrometry. We conclude that CaNAC1 is a transcriptional activator of CaPLDα4 and suggested that it participates in the degradation of membrane lipids in bell peppers when they are stored at low temperature.


Subject(s)
Capsicum/metabolism , Gene Expression Regulation, Plant , Phospholipase D/metabolism , Phospholipids/metabolism , Transcription Factors/metabolism , Amino Acid Sequence , Capsicum/ultrastructure , Cold-Shock Response , Fruit/ultrastructure , Ubiquitination
11.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 51(3): 320-324, 2020 May.
Article in Zh | MEDLINE | ID: mdl-32543136

ABSTRACT

OBJECTIVE: To study the relationship between down-regulated expression of X linked inhibitor of apoptosis protein (XIAP) gene and the reversal effect of taxol-resistance by using siRNA interference technology in the taxol-resistant ovarian cancer. METHODS: Randomly assigned the nude mice into six groups (6 in each group) . Group A: normal saline; Group B: taxol; Group C: siRNA-NC+normal saline; Group D: siRNA-NC+taxol; Group E: siRNA XIAP+normal saline; Group F: siRNA XIAP+taxol. Each group was dealt with the corresponding processing depending on the agreed protocol and the transplanted tumors had a multi-point injection with reagents related siRNA, one time every 3 days, 9 times (27 d) in total. Taxol (2 mg/kg) was used in the intraperitoneal injection, 0.2 mL every time, once a week, for four weeks. After 27 d of siRNA treatment, xenograft volumes and qualities were measured and the inhibitory rate was calculated; RNA expression levels and protein levels of XIAP gene in xenografts were detected respectively by real-time fluorescent quantitative PCR and Western blot. Apoptosis of the transplanted tumor cells was examined by TUNEL method. RESULTS: Among the six groups, the proliferation of transplanted tumor in Group F was the slowest, and the tumor inhibition rate was the highest compared with control Group A, followed by Group E, and the tumor inhibition rate was the lowest in Group C. Group F and E expressed the lowest XIAP mRNA and protein expressions ( P<0.05, vs. the other 4 groups) .The apoptosis rate was highest in Group F, followed by Group E, and lowest in Group A and C ( P<0.05). CONCLUSION: XIAP siRNA has synergy with taxol in taxol-resistant ovarian cancer cells.


Subject(s)
Ovarian Neoplasms , X-Linked Inhibitor of Apoptosis Protein , Animals , Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis , Cell Line, Tumor , Cell Proliferation , Drug Resistance, Neoplasm/genetics , Female , Humans , Mice , Mice, Nude , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Paclitaxel/pharmacology , RNA, Small Interfering/genetics , X-Linked Inhibitor of Apoptosis Protein/genetics
12.
Zhongguo Zhong Yao Za Zhi ; 44(20): 4360-4365, 2019 Oct.
Article in Zh | MEDLINE | ID: mdl-31872620

ABSTRACT

Many clinical studies on Cheezheng Xiaotong Tiegao have been accumulated since it was launched in 1993,but they have not been comprehensively analyzed and evaluated. This study systematically retrieved relevant studies in six databases at home and abroad as of December 2017. This study analyzed the statistics of the included studies in several aspects,including publication time,region,fund,disease category and type of study. In this study,various tools were used to evaluate the methodological quality of included studies,such as the Cochrane collaboration's tool for assessing the risk of bias in randomized trials,MINORS,IHE,AMSTAR2.The results showed that the literatures were mainly published from 2010 to 2011,and a total of 28 projects were financially supported.The most involved disease was arthropathy. The randomized controlled trials were the majority in the included studies,but the quality was low,and most of the literatures didn't report the allocation concealment and blinding. This study comprehensively reflected the current situations and shortcomings of the clinical studies of Cheezheng Xiaotong Tiegao,and put forward several suggestions,in the expectation of providing a reference for the future clinical research direction of Cheezheng Xiaotong Tiegao.


Subject(s)
Bibliometrics , Drugs, Chinese Herbal
13.
Zhongguo Zhong Yao Za Zhi ; 44(24): 5277-5281, 2019 Dec.
Article in Zh | MEDLINE | ID: mdl-32237368

ABSTRACT

Pudilan Xiaoyan Oral Liquid has effects in clearing away heat and detoxifying,and is used to treat pharynx and throat swelling caused by the syndrome of excessive heat and toxin accumulation. Its efficacy is to relieve swelling and pain( redness,swelling and hot pain). It is included in the Chinese Pharmacopoeia of 2015 Edition,and has been listed in provincial health insurance directories of Shaanxi,Jiangsu,Liaoning,Hunan,Tianjin,Xinjiang and Hebei. It has been recommended by health departments of Beijing,Chongqing and other provinces as a preferred drug for the prevention and treatment of H1 N1 and HFMD,and listed in the diagnosis and Treatment Guide of HFMD by the Ministry of Health,the Clinical Application Guide of Chinese Patent Medicine edited by the Lung Department Disease Branch of China Association of Chinese Medicine,and the Clinical Practice Guide of Single Administration/Combined Administration of Antibiotics in Treatment of Common Infectious Diseases by China Association of Chinese Medicine. To further improve the clinician's understanding of drugs and better guide the rational clinical application,we invited front-line clinical experts from respiratory department,infectious department and dermatology of traditional Chinese and Western medicine to develop and compile the expert consensus. The consensus fully considered the clinical evidence and the expert clinical experience to give recommendations for clinical problems with evidence support and consensus suggestions for clinical problems without evidence support by the nominal group method.This consensus is based on clinical research evidence and expert experience in a simple and clear format,which provides a preliminary reference for the clinical use of the drug.


Subject(s)
Drugs, Chinese Herbal/therapeutic use , Medicine, Chinese Traditional , China , Consensus , Humans , Nonprescription Drugs
14.
Org Biomol Chem ; 16(46): 9064-9068, 2018 11 28.
Article in English | MEDLINE | ID: mdl-30456395

ABSTRACT

A simple and practical method for the synthesis of alkenyl dithiocyanates and alkenyl diselenocyanates has been developed via stereoselective difunctionalization of alkynes with NaSCN or KSeCN at room temperature. Through this methodology, a series of alkenyl dithiocyanates and alkenyl diselenocyanates could be efficiently and conveniently obtained in moderate to good yields under mild and metal-free conditions by the simple use of oxone and PhI(OAc)2 as the oxidants.

15.
J BUON ; 23(4): 1082-1091, 2018.
Article in English | MEDLINE | ID: mdl-30358215

ABSTRACT

PURPOSE: Mutations in the gene encoding the AT-rich interacting domain containing protein 1A (ARID1A) are frequently observed in endometrial cancer, although the molecular mechanisms linking the genetic changes remain poorly understood. This study aimed to elucidate the influence of ARID1A mutations on endometrial cancer cells and tissues. METHODS: Reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blot and immunohistochemistry (IHC) were used to investigate the expression of ARID1A in endometrial cancer cells and tissues. Lentiviral vector (LV)-shARID1A was constructed and transfected into HEC-1-A cells. The efficiency of mutated ARID1A knockdown was determined by RT-qPCR and western blotting. The proliferation and apoptosis capacity was examined by colony formation, MTT proliferation, Annexin V-APC cell apoptosis and cell cycle analysis. RESULTS: ARID1A was lower in endometrial cancer cells and endometrial carcinoma tissue than in normal endometrial cells and benign endometrium (p<0.05). Small interfering RNA (siRNA)-ARID1A were transfected into HEC-1-A cells and we observed reduced cell growth and proliferation, increased apoptosis, and a significantly increased proportion of cells in the G2/M phase. CONCLUSION: Our results suggest that ARID1A mutation in endometrial cancer helped cell proliferation and inhibited cell apoptosis and also caused cell cycle arrest at the G2/M phase.


Subject(s)
Endometrial Neoplasms/genetics , Nuclear Proteins/genetics , Transcription Factors/genetics , Apoptosis/genetics , Base Sequence , Cell Division/genetics , Cell Line, Tumor , Cell Proliferation/genetics , DNA-Binding Proteins , Endometrial Neoplasms/metabolism , Endometrial Neoplasms/pathology , Female , G2 Phase/genetics , Gene Knockdown Techniques , Humans , Nuclear Proteins/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Transcription Factors/metabolism , Transfection
16.
Xenobiotica ; 47(6): 526-537, 2017 Jun.
Article in English | MEDLINE | ID: mdl-27412909

ABSTRACT

1. The objective of this study was to investigate the pharmacokinetics, excretion, and metabolic fate of cycloastragenol (CA) in rats. 2. An LC-MS method was developed and used to quantify CA in biological samples. Rats were orally administrated with CA at 10, 20, and 40 mg/kg or intravenously administrated at 10 mg/kg to determine pharmacokinetic parameters of CA. For excretion experiment, urine, feces, and bile were collected at 24 h after oral administration (40 mg/kg), also at 12 h after intravenous administration (10 mg/kg). An LC-MS/MS method was developed to identify the metabolites of CA. 3. The results showed that the oral bioavailability of CA was about 25.70% at 10 mg/kg. CA was excreted through bile and feces and eliminated predominantly by the kidney in rats. It also might exist an enterohepatic circulation of CA in rats. CA could be metabolized widely in vivo in rat, seven, six, and one phase I metabolites were found in feces, urine, and bile samples respectively, but no phase II metabolite was found. 4. In summary, this study defined pharmacokinetics characteristics of CA, described its excretion, and established its in vivo metabolism in rats.


Subject(s)
Enzyme Activators/metabolism , Sapogenins/metabolism , Administration, Oral , Animals , Bile/metabolism , Body Fluids , Chromatography, High Pressure Liquid , Feces , Rats , Tandem Mass Spectrometry , Telomerase/metabolism , Tissue Distribution
17.
J Comput Aided Mol Des ; 30(10): 889-898, 2016 10.
Article in English | MEDLINE | ID: mdl-27640149

ABSTRACT

Drug-induced liver injury (DILI) is one of the major safety concerns in drug development. Although various toxicological studies assessing DILI risk have been developed, these methods were not sufficient in predicting DILI in humans. Thus, developing new tools and approaches to better predict DILI risk in humans has become an important and urgent task. In this study, we aimed to develop a computational model for assessment of the DILI risk with using a larger scale human dataset and Naïve Bayes classifier. The established Naïve Bayes prediction model was evaluated by 5-fold cross validation and an external test set. For the training set, the overall prediction accuracy of the 5-fold cross validation was 94.0 %. The sensitivity, specificity, positive predictive value and negative predictive value were 97.1, 89.2, 93.5 and 95.1 %, respectively. The test set with the concordance of 72.6 %, sensitivity of 72.5 %, specificity of 72.7 %, positive predictive value of 80.4 %, negative predictive value of 63.2 %. Furthermore, some important molecular descriptors related to DILI risk and some toxic/non-toxic fragments were identified. Thus, we hope the prediction model established here would be employed for the assessment of human DILI risk, and the obtained molecular descriptors and substructures should be taken into consideration in the design of new candidate compounds to help medicinal chemists rationally select the chemicals with the best prospects to be effective and safe.


Subject(s)
Chemical and Drug Induced Liver Injury/etiology , Drug-Related Side Effects and Adverse Reactions/complications , Models, Biological , Pharmaceutical Preparations/chemistry , Bayes Theorem , Drug Discovery , Humans , Molecular Structure , Structure-Activity Relationship
18.
Zhongguo Zhong Yao Za Zhi ; 40(7): 1370-5, 2015 Apr.
Article in Zh | MEDLINE | ID: mdl-26281563

ABSTRACT

Rats were continuously given different doses of water extract of Polygonum multiflorum (1, 10 g x kg(-1)) for 7 days to prepare liver microsomes. Cocktail in vitro incubation approach and Real-time quantitative PCR technology were used to observe the effect of water extract of P. multiflorum on CYP450 enzymatic activities and mRNA expressions in rat liver. Compared with the blank control group, both 1, 10 g x kg(-1) water extract of P. multiflorum treated groups showed significant inhibitions in CYP2E1 enzymatic activities and mRNA expressions (enzymatic activities of CYP2E1, P < 0.01; mRNA expression of CYP2E1, P < 0.05 in 1 g x kg(-1) group, P < 0.01 in 10 g x kg(-1) group). They revealed a significant increase in the enzymatic activity of CYP3A1 (P < 0.01), but without significant change in mRNA expressions. The 10 g x kg(-1) group showed a significant inhibition in CYP1A2 enzymatic activities and mRNA expressions in rat livers (P < 0.01).


Subject(s)
Cytochrome P-450 CYP1A2/genetics , Cytochrome P-450 CYP2E1/genetics , Cytochrome P-450 Enzyme Inhibitors/administration & dosage , Drugs, Chinese Herbal/administration & dosage , Liver/drug effects , Liver/enzymology , Polygonum/chemistry , Animals , Cytochrome P-450 CYP1A2/metabolism , Cytochrome P-450 CYP2E1/metabolism , Cytochrome P-450 Enzyme Inhibitors/isolation & purification , Drugs, Chinese Herbal/isolation & purification , Male , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley
19.
Am J Transl Res ; 16(8): 3654-3666, 2024.
Article in English | MEDLINE | ID: mdl-39262737

ABSTRACT

OBJECTIVE: To construct a diagnostic model for follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC), both subtypes of differentiated thyroid carcinoma (DTC), using color Doppler ultrasound signs in conjunction with serum laboratory markers. METHODS: We conducted a retrospective analysis of patients with thyroid nodules who underwent ultrasonography at Yulin Hospital from February 2021 to March 2023. The cohort included 269 subjects: 105 with benign nodules and 164 with DTC (59 with FTC and 105 with PTC). We compared baseline demographics and laboratory indices between the groups. Diagnostic values of ultrasound features and laboratory markers were assessed using receiver operating characteristic (ROC) curves, and logistic regression was employed to pinpoint independent diagnostic factors for FTC. A predictive nomogram was subsequently developed based on these factors. RESULTS: There were significant differences between the benign and malignant groups regarding ultrasound signs (including border, morphology, echogenicity, calcification, blood flow, lymph node zoning) and laboratory indices (free triiodothyronine (FT3), free thyroxine (FT4), thyroglobulin (Tg), thyroid-stimulating hormone (TSH), vascular endothelial growth factor (VEGF), tumor-specific growth factor (TSGF)), with all P-values <0.05. The areas under the curve (AUCs) for FT3, FT4, Tg, TSH, VEGF, and TSGF were all above 0.75, with Tg achieving the highest at 0.91. Logistic regression identified borders, morphology, echogenicity, VEGF, and TSGF as independent diagnostic factors for distinguishing between FTC and PTC, with significant P-values. The constructed nomogram demonstrated an AUC of 0.853, indicating high diagnostic accuracy. Both calibration and decision curve analysis (DCA) validated the model's stability and clinical utility. CONCLUSION: We successfully developed a nomogram combining ultrasound features and serum markers that enhances the diagnostic precision for FTC. This model offers a valuable tool for clinical diagnostics in differentiated thyroid cancer.

20.
BMC Psychol ; 12(1): 443, 2024 Aug 16.
Article in English | MEDLINE | ID: mdl-39152489

ABSTRACT

Neuroticism appears to be a factor that triggers social aggression, but the relationship between neuroticism and social aggression and its underlying mechanisms is unclear. Questionnaire data from 942 college students ranging in age from 17 to 24 (Mage = 20.33, SD = 1.03) were analysed to assess whether depression symptoms mediated the relationship between neuroticism and social aggression, and to test a moderating effect of perceived social support. Results showed that neuroticism positively predicted social aggression and this association was mediated by depression symptoms. Moderation was found for the association between neuroticism and depression symptoms, as well as between neuroticism and social aggression, and that neuroticism had a stronger predictive effect on depression symptoms and social aggression under low compared to high perceived social support. These findings may inform prevention and intervention efforts to reduce social aggression.


Subject(s)
Aggression , Depression , Neuroticism , Humans , Aggression/psychology , Male , Female , Young Adult , Depression/psychology , Adolescent , Social Support , Surveys and Questionnaires , Students/psychology , Students/statistics & numerical data , Adult , Mediation Analysis , Social Behavior
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