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1.
Virol J ; 17(1): 34, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32164742

RESUMO

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs about 22 nucleotides in length, which play an important role in gene regulation of both eukaryotes and viruses. They can promote RNA cleavage and repress translation via base-pairing with complementary sequences within mRNA molecules. MAIN BODY: Human cytomegalovirus (HCMV) encodes a large number of miRNAs that regulate transcriptions of both host cells and themselves to favor viral infection and inhibit the host's immune response. To date, ~ 26 mature HCMV miRNAs have been identified. Nevertheless, their roles in viral infection are ambiguous, and the mechanisms have not been fully revealed. Therefore, we discuss the methods used in HCMV miRNA research and summarize the important roles of HCMV miRNAs and their potential mechanisms in infection. CONCLUSIONS: To study the miRNAs encoded by viruses and their roles in viral replication, expression, and infection will not only contribute to the planning of effective antiviral therapies, but also provide new molecular targets for the development of antiviral drugs.

2.
Langmuir ; 36(7): 1709-1717, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32004005

RESUMO

During the evolution of life on earth, the emergence of lipid membrane-bounded compartments is one of the most enigmatic events. Endosymbiosis has been hypothesized as one of the solutions. In this work, using a coacervate droplet formed by single-stranded oligonucleotides (ss-oligo) and poly(l-lysine) (PLL) as the protocell model, we monitored the uptake of liposomes of different types and studied the dynamic behavior of the resulting composite droplet under the electric field. The coacervate droplet exhibits affinity for the liposomes of varying charges. However, the permeation of liposome is also controlled by electrostatic interactions. Dominated by electrostatic attraction, the positively charged liposome is retained inside the droplet as growing fibrous structures, while the negatively charged liposome is mainly coated on the droplet surface. Permeation and even distribution occur when the liposome and the droplet carry the same charges, or at least one of them is neutral. As an electric field is applied to trigger repetitive cycles of vacuolization in the ss-oligo/PLL droplet, the fibrous structure formed by the positively charged liposome is basically intact, while a new phase is generated together with uneven mass transport as the negatively charged liposome is internalized. Interestingly, the release of daughter droplets with similar components occurs on the droplet containing neutral liposomes. Our work not only provides a step toward creating protocells with hierarchical structures and biofunctions using a biogenetic material via simple mixing but also sheds light on the possible origin of the lipid structure inside a living organism.

3.
iScience ; 23(2): 100857, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-32058968

RESUMO

Hsp90 is a target for anti-cancer drug development. Both the conformational events tuned by ATP/ADP and co-chaperones and the chaperoning cycle timing are required for Hsp90's fully functional display. Interfering with either one of the conformational events or the cycle timing will down-regulate Hsp90's function. In this manuscript, non-covalent allosteric modulators (SOMCL-16-171 and SOMCL-16-175) targeting Hsp90α's middle domain (Hsp90M) were developed for the first time. Multiple techniques were then applied to characterize the interactions between two active compounds and Hsp90α. Two loops and one α-helix (F349-N360, K443-E451, and D372-G387) in Hsp90M were identified responsible for the recognition of SOMCL-16-171 and SOMCL-16-175. Meanwhile, the binding of SOMCL-16-171 and SOMCL-16-175 to Hsp90M was demonstrated to allosterically modulate the structure and function of Hsp90α's N-terminal domain. Finally, cellular assays were conducted to evaluate the cellular activity of SOMCL-16-175, and the results indicate that SOMCL-16-175 destabilizes Hsp90's client proteins and reduces cell viability.

5.
BMC Gastroenterol ; 20(1): 21, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996143

RESUMO

BACKGROUND: Enteral nutrition should be implemented as early as possible in patients with moderate or severe acute pancreatitis. This study was designed to evaluate the feasibility and Deffectiveness of ultrasound-guided Freka-Trelumina tube placement for enteral nutrition in acute pancreatitis. METHODS: Patients with severe acute pancreatitis admitted to Shengjing Hospital of China Medical University who needed Freka-Trelumina tube placement for enteral nutrition and gastrointestinal decompression were included in the current study. The relevant evaluation indicators of tube placement included the success rate of tube placement, tube placement time, tube shift rate, and blocking rate. In addition, the evaluation indicators of ultrasound-guided tube placement (from 1 January 2018 to 31 July 2019) were compared with those of previous endoscope-guided placement (from 1 January 2015 to 31 December 2017) by analysing the data from the electronic medical record system. RESULTS: The success rate of ultrasound-guided tube placement was 90.7% (49/54). All 49 patients tolerated the Freka-Trelumina feeding tube. The average ultrasound-guided tube placement time for the 49 patients was 18.4 ± 12.8 min (range, 5-36 min). The Freka-Trelumina feeding tube had a shift rate of 10.2% (5/49). The blocking rate of the Freka-Trelumina feeding tube was 12.2% (6/49). The success rate of tube placement, tube shift rate and blocking rate for endoscope-guided tube placement were 100% (62/62), 11.3% (7/62), and 12.9% (8/62), respectively. The average endoscope-guided tube placement time for the 62 patients was 16.5 ± 5.7 min (range, 12-31 min). The comparison between the ultrasound-guided group and the endoscope-guided group showed that the success rate of tube placement, tube placement time, tube shift rate and blocking rate were similar. CONCLUSION: The ultrasound-guided method can be done non-invasively at the bedside, which is safe and convenient, and the Freka-Trelumina feeding tube can be placed in time to achieve the goal of early enteral nutrition and gastrointestinal decompression.

6.
Cancer Res ; 80(4): 675-688, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31948940

RESUMO

Suppression of gluconeogenesis elevates glycolysis and is commonly observed in tumors derived from gluconeogenic tissues including liver and kidney, yet the definitive regulatory mechanism remains elusive. Here, we screened an array of transcription regulators and identified the enhancer of zeste homolog 2 (EZH2) as a key factor that inhibits gluconeogenesis in cancer cells. Specifically, EZH2 repressed the expression of a rate-limiting gluconeogenic enzyme fructose-1, 6-bisphosphatase 1 (FBP1) and promoted tumor growth primarily through FBP1 suppression. Furthermore, EZH2 was upregulated by genotoxins that commonly induce hepatic and renal tumorigenesis. Genotoxin treatments augmented EZH2 acetylation, leading to reduced association between EZH2 and its E3 ubiquitin ligase SMURF2. Consequently, EZH2 became less ubiquitinated and more stabilized, promoting FBP1 attenuation and tumor formation. Intriguingly, FBP1 physically interacted with EZH2, competed for EZH2 binding, and dissembled the polycomb complex. Therefore, FBP1 suppresses polycomb-initiated transcriptional responses and constitutes a double-negative feedback loop indispensable for EZH2-promoted tumorigenesis. Finally, EZH2 and FBP1 levels were inversely correlated in tumor tissues and accurately predicted patient survival. This work reveals an unexpected cross-talk between epigenetic and metabolic events, and identifies a new feedback circuitry that highlights EZH2 inhibitors as liver and kidney cancer therapeutics. SIGNIFICANCE: A novel feedback loop involving EZH2 and suppression of the gluconeogenesis enzyme FBP1 promotes hepatocellular cancer growth.See related commentary by Leithner, p. 657.

7.
Mol Cancer Ther ; 19(2): 564-574, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31645443

RESUMO

Ceramide (Cer) is an active cellular sphingolipid that can induce apoptosis or proliferation-arrest of cancer cells. Nanoparticle-based delivery offers an effective approach for overcoming bioavailability and biopharmaceutics issues attributable to the pronounced hydrophobicity of Cer. Missense mutations of the protein p53, which have been detected in approximately 42% of cancer cases, not only lose the tumor suppression activity of wild-type p53, but also gain oncogenic functions promoting tumor progression and drug resistance. Our previous works showed that cellular Cer can eradicate cancer cells that carry a p53 deletion-mutation by modulating alternative pre-mRNA splicing, restoring wild-type p53 protein expression. Here, we report that new ceramide-rubusoside (Cer-RUB) nanomicelles considerably enhance Cer in vivo bioavailability and restore p53-dependent tumor suppression in cancer cells carrying a p53 missense mutation. Natural RUB encapsulated short-chain C6-Cer so as to form Cer-RUB nanomicelles (∼32 nm in diameter) that substantially enhanced Cer solubility and its levels in tissues and tumors of mice dosed intraperitoneally. Intriguingly, Cer-RUB nanomicelle treatments restored p53-dependent tumor suppression and sensitivity to cisplatin in OVCAR-3 ovarian cancer cells and xenograft tumors carrying p53 R248Q mutation. Moreover, Cer-RUB nanomicelles showed no signs of significant nonspecific toxicity to noncancerous cells or normal tissues, including bone marrow. Furthermore, Cer-RUB nanomicelles restored p53 phosphorylated protein and downstream function to wild-type levels in p53 R172H/+ transgenic mice. Altogether, this study, for the first time, indicates that natural Cer-RUB nanomicelles offer a feasible approach for efficaciously and safely targeting cancers carrying p53 missense mutations.

8.
Obes Surg ; 30(1): 279-289, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31605365

RESUMO

BACKGROUND: Duodenal-jejunal bypass (DJB) can dramatically improve type 2 diabetes independent of weight loss and food restriction. Increasing evidence has demonstrated that brain insulin signaling plays an important role in the pathophysiology of type 2 diabetes. This study explores whether the antidiabetic effect of DJB is involved in brain insulin signaling activation and brain glucose utilization. METHODS: A diabetic rat model was established by high-fat and high-glucose diet. DJB or sham surgery was performed in diabetic rats. 18F-FDG PET scanning was used to detect glucose uptake in different organs, particularly in the brain. The levels of glucose transporters, glucose utilization-related proteins (HK1 and PFK2), insulin, and insulin signaling pathway-related proteins (InsR, IRS1/2, PI3K, and p-Akt) in the brain tissues were evaluated and analyzed. RESULTS: The results showed that DJB significantly improved basal glycemic parameters and reversed the decreasing glucose uptake in the brains of type 2 diabetic rats. DJB significantly increased not only the expression levels of brain insulin, IRS1/2, PI3K, and p-Akt but also the levels of the glucose utilization enzymes HK1 and PFK2 in the brain. CONCLUSION: These results indicate that enhanced brain insulin signaling transduction and brain glucose utilization play important roles in the antidiabetic effect of DJB.

9.
Oncogene ; 39(3): 720-721, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31511646

RESUMO

A correction to this paper has been published and can be accessed via a link at the top of the paper.

10.
J Phys Chem A ; 124(1): 82-89, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31815471

RESUMO

A new terbium (III) luminescent compound {[Tb2(PDC)2(ox)(H2O)4](H2O)2}n was synthesized by the self-assembly of Tb3+ ions with 3,5-pyridinedicarboxylate (PDC) and oxalate (ox) ligands and characterized by fluorescence spectroscopy and single-crystal X-ray diffraction. The density functional theory (DFT) and high-level correlated ab initio wave function methods with Spin-Orbit Coupling correction (CASSCF/SO and CAS-NEVPT2/SOC) were successfully applied to predict the absorption and emission spectra of this strongly correlated lanthanide system in excellent agreement with the experimental results.

11.
Prostaglandins Other Lipid Mediat ; 146: 106402, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31841664

RESUMO

Although C6-Ceramide has attracted much attention as a possible tumor suppressor, the delivery of C6-Ceramide is still challenging due to its inherent hydrophobicity and insolubility. In this study we explored the use of a natural compound rubusoside (RUB) as a solubilizer to enhance the solubility of a fluorescence-labeled C6-Ceramide (NBD C6-Ceramide) and to characterize its pharmacokinetics and tissue distribution in an animal model. RUB significantly enhanced the solubility of NBD C6-Ceramide by forming nanomicelles, and efficiently delivered NBD C6-Ceramide in rats by oral and intravenous administration. RUB loaded 1.96 % of NBD C6-Ceramide in the nanomicelles and solubilized it to a concentration of 3.6 mg/mL in water. NBD C6-Ceramide in nanomicelles remained stable in aqueous solutions, allowing intravenous administration without the use of any organic solvents or surfactants. After oral administration, NBD C6-Ceramide rapidly rose to peak plasma concentrations within the first 90 min, distributed to tissues, and remained in vivo for more than 24 h. Tissular levels of NBD C6-Ceramide from high to low were associated with heart, lung, cerebellum, testicle, spleen, liver, kidney, and brain. Altogether, our study demonstrated that RUB-assisted nanomicelles can serve as an efficient and convenient delivery system for short-chain C6-Ceramide and enable in vivo evaluation of potential new cancer treatments.

12.
Aging Dis ; 10(6): 1199-1206, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31788332

RESUMO

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease characterized by selective impairment of upper and lower motor neurons. We aimed to investigate the genetic spectrum and variability in Chinese patients with ALS. A total of 24 familial ALS (FALS) and 21 early-onset sporadic ALS (SALS) of Chinese ancestry were enrolled. Targeted next-generation sequencing (NGS) was performed in the probands, followed by verification by Sanger sequencing and co-segregation analysis. Clinical features of patients with pathogenic or likely pathogenic variants were present. The mutation frequency of ALS-related genes was then analyzed in Chinese population. In this cohort, 17 known mutations (9 SOD1, 5 FUS, 2 TARDBP and one SETX) were identified in 14 FALS and 6 early-onset SALS. Moreover, 7 novel variants (SOD1 c.112G>C, OPTN c.811C>T, ERBB4 c.965T>A, DCTN1 c.1915C>T, NEFH c.2602G>A, NEK1 c.3622G>A, and TAF15 c.1535G>A) were identified. In southeastern Chinese FALS, the mutation frequency of SOD1, FUS, and TARDBP was 52.9%, 8.8%, 8.8% respectively. In early-onset SALS, FUS mutations were the most common (22.6%). In Chinese ALS cases, p.H47R is most frequent SOD1 mutations, while p.R521 is most common FUS mutation and p.M337V is most common TARDBP mutation. Our results revealed that mutations in SOD1, FUS and TARDBP are the most common cause of Chinese FALS, while FUS mutations are the most common cause of early-onset SALS. The genetic spectrum is different between Chinese ALS and Caucasian ALS.

13.
Aging Dis ; 10(5): 1003-1011, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31595198

RESUMO

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder caused by CAG triplet repeats expansion in exon 1 of the Huntingtin gene (HTT). In China, HD is considered to have a low prevalence. The goal of this study was to describe the clinical characteristic and genetic profiles of HD in a Chinese cohort. A total of 322 individuals with expanded CAG repeats were consecutively recruited from the neurologic clinics of three medical centers in Southeastern China between 2008 and 2018. Among them, 80 were pre-symptomatic mutation carriers and 242 were symptomatic patients. The mean age at onset (AAO), defined here as the age at motor symptom onset, of the 242 manifest HD individuals was 40.3 ± 11.9 years and the mean CAG repeat length was 46.1 ± 7.5 in the group of symptomatic patients. Initial symptoms were abnormal movements in 88.8% of the patients with psychiatric symptoms in 6.2%, cognitive impairment in 3.3% and others in 1.7%. The AAO of motor was negatively correlated with the CAG repeat length in an exponential regression analysis (R 2 = 0.74, P<0.001). Analysis of 46 parent-child pairs showed that the CAG repeat length was longer in the offspring group (45.8 ±7.6) than in the parent group (43.8 ±3.0) (p=0.005). Overall, this study provides clinical and genetic profiles in a cohort of Chinese patients with HD, which should contribute to a better understanding of this disorder.

14.
Proc Natl Acad Sci U S A ; 116(41): 20398-20403, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31548408

RESUMO

Detoxification of the highly toxic cadmium element is essential for the survival of living organisms. Pseudomonas putida CadR, a MerR family transcriptional regulator, has been reported to exhibit an ultraspecific response to the cadmium ion. Our crystallographic and spectroscopic studies reveal that the extra cadmium selectivity of CadR is mediated by the unexpected cooperation of thiolate-rich site I and histidine-rich site II. Cadmium binding in site I mediates the reorientation of protein domains and facilitates the assembly of site II. Subsequently, site II bridge-links 2 DNA binding domains through ligands His140/His145 in the C-terminal histidine-rich tail. With dynamic transit between 2 conformational states, this bridge could stabilize the regulator into an optimal conformation that is critical for enhancing the transcriptional activity of the cadmium detoxification system. Our results provide dynamic insight into how nature utilizes the unique cooperative binding mechanism in multisite proteins to recognize cadmium ions specifically.

15.
Front Neurol ; 10: 938, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31551907

RESUMO

Exophiala dermatitidis, a dematiaceous fungus typically found in decaying organic matter worldwide, is a rare cause of fungal infections. Cerebral phaeohyphomycosis is a sporadic but often fatal infection of the brain caused by E. dermatitidis. However, due to limited reports, little is known about its specific predisposing factors, clinical manifestation, and optimal treatment modality. Here, we report a clinical presentation and management of cerebral phaeohyphomycosis in a Chinese patient. An otherwise healthy, young male who was diagnosed with neck fungal lymphadenitis caused by E. dermatitidis 7 months prior and was treated with itraconazole, presented later with progressive intracranial hypertension and persistent coma. Culture of the neck lymphoid tissue produced growth of a black yeast-like fungus, which was identified as E. dermatitidis by sequencing of the ribosomal DNA internal transcribed spacer (ITS) domains. Accordingly, a cerebral biopsy was performed, and the pathological report showed mycelia and fungal granulomas. We also sequenced CARD9 in the patient and found him to be homozygous for loss-of-function mutation; his parents were heterozygous for the same mutation. This is a first case report of cerebral phaeohyphomycosis caused by E. dermatitidis in a CARD9-deficient Chinese patient. He eventually succumbed to brain herniation and severe lung infection with a poor response to therapy. Thus, previously healthy patients with unexplained invasive E. dermatitidis infection, at any age, should be tested for inherited CARD9 deficiency.

16.
Biol Pharm Bull ; 42(9): 1482-1490, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474709

RESUMO

Zhengganxifeng decoction (ZGXFD) is a traditional Chinese medicinal formula, from "Medical Zhong parameter West recorded" by Xichun Zhang, which has been applied to the treatment of clinical essential hypertension. Besides its effect in blood pressure reduction, ZGXFD is also known to be a radical therapy with little or no side effects. Compared with western medicines, Chinese medicinal formulas have the advantage of simultaneously attacking multiple targets. However, such a property brings trouble to the pharmacological studies of Chinese medicines. This study investigated the composition of gut microbiota in spontaneously hypertensive rats (SHR) treated with ZGXFD. ZGXFD was shown to cause similar effects in the treatment group as benazepril: both were able to reduce in SHR the microbial diversity, Firmicutes to Bacteroidetes (F/B) ratio and coccus to bacillus (C/B) ratio. Meanwhile, ZGXFD can maintain the integrity of intestinal mechanistic barrier and elevate the percentage of bacteria producing short chain fatty acids (SCFA). By investigating renin-angiotensin system (RAS) system, we found that ZGXFD can decrease the expression of angiotensin-converting-enzyme (ACE) in lungs, which in turn causes a increase in AngI produces angiotensin1-7 (Ang1-7) and decrease in AngII. ZGXFD regulate blood pressure in SHR via RAS.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Medicamentos de Ervas Chinesas/uso terapêutico , Microbioma Gastrointestinal/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Ácidos Graxos Voláteis/metabolismo , Microbioma Gastrointestinal/fisiologia , Hipertensão/microbiologia , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
18.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 33(7): 883-888, 2019 Jul 15.
Artigo em Chinês | MEDLINE | ID: mdl-31298008

RESUMO

Objective: To investigate the effect of transforming growth factor ß 1 (TGF-ß 1) induced proliferation of ligamentum flavum cells and ligamentum flavum hypertrophy and its effect on connective tissue growth factor (CTGF) expression. Methods: The ligamentum flavum tissue in lumbar intervertebral disc herniation was extracted and the ligamentum flavum cells were isolated and cultured by collagenase pre-digestion method. Morphological observation, immunofluorescence staining observation, and MTT assay were used for cell identification. The 3rd generation ligamentum flavum cells were divided into 5 groups. The cells of groups A, B, C, and D were respectively sealed with 3 ng/mL TGF-ß 1, 50 ng/mL CTGF, 3 ng/mL TGF-ß 1+CTGF neutralizing antibody, and 50 ng/mL CTGF+CTGF neutralizing antibody. Serum free DMEM was added to group E as the control. MTT assay was used to detect the effects of TGF-ß 1 and CTGF on the proliferation of ligamentum flavum cells. Western blot was used to detect the expression of CTGF protein. Real-time fluorescence quantitative PCR (qRT-PCR) was used to detect the expression of collagen type Ⅰ, collagen type Ⅲ, and CTGF genes. Results: The morphological diversity of cultured ligamentum flavum cells showed typical phenotype of ligamentum flavum fibroblasts; all cells expressed collagen type Ⅰ and vimentin, and some cells expressed collagen type Ⅲ; MTT identification showed that with the prolongation of culture time, the absorbance ( A) value of each generation of cells increased gradually, and the A value of the same generation of cells at each time point was significantly different ( P<0.05), there was no significant difference in A value between the cells of each generation at the same time point ( P>0.05). After cultured for 24 hours, MTT assay showed that the A value of cells in groups A and B was significantly higher than that of group E ( P<0.05). After adding CTGF neutralizing antibody, the A value of cells in groups C and D decreased, but it was still higher than that of group E ( P<0.05). There were also significant differences among groups A, C and groups B, D ( P<0.05). Western blot analysis showed that the relative expression of CTGF protein in groups A and B was significantly higher than that in group E ( P<0.05), while the relative expression of CTGF protein in groups C and D was significantly lower than that in group E ( P<0.05), and the difference between groups A, C and groups B, D was also significant ( P<0.05). qRT-PCR detection showed that the mRNA relative expression of CTGF, collagen type Ⅰ, and collagen type Ⅲ in group A was significantly higher than that in group E ( P<0.05). After adding neutralizing antibody, the mRNA relative expression of genes in group C was inhibited and were significantly lower than that in group A, but still significantly higher than that in group E ( P<0.05). The mRNA relative expressions of collagen type Ⅰ and collagen type Ⅲ in group B was significantly higher than that in group E ( P<0.05), but the mRNA relative expression of CTGF was not significantly different from that in group E ( P>0.05); after neutralizing antibody was added, the mRNA relative expression of collagen type Ⅰ and collagen type Ⅲ in group D was inhibited and was significantly lower than that in group B, but still significantly higher than that in group E ( P<0.05); there was no significant difference in the mRNA relative expression of CTGF between group D and groups B, E ( P>0.05). Conclusion: TGF-ß 1 can promote CTGF, collagen typeⅠ, collagen type Ⅲ gene level and protein expression in ligamentum flavum cells, and TGF-ß 1 can synergistically promote proliferation of ligamentum flavum cells through CTGF.


Assuntos
Proliferação de Células , Fator de Crescimento do Tecido Conjuntivo , Ligamento Amarelo , Fator de Crescimento Transformador beta1 , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Fator de Crescimento do Tecido Conjuntivo/fisiologia , Humanos , Ligamento Amarelo/fisiologia , Fator de Crescimento Transformador beta1/fisiologia
19.
Transl Neurodegener ; 8: 19, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31289639

RESUMO

Background: Although many causative genes of hereditary spastic paraplegia (HSP) have been uncovered in recent years, there are still approximately 50% of HSP patients without genetically diagnosis, especially in autosomal recessive (AR) HSP patients. Rare studies have been performed to determine the genetic spectrum and clinical profiles of recessive HSP patients in the Chinese population. Methods: In this study, we investigated 24 Chinese index AR/sporadic patients by targeted next-generation sequencing (NGS), Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Further functional studies were performed to identify pathogenicity of those uncertain significance variants. Results: We identified 11 mutations in HSP related genes including 7 novel mutations, including two (p.V1979_L1980delinsX, p.F2343 fs) in SPG11, two (p.T55 M, p.S308 T) in AP5Z1, one (p.S242 N) in ALDH18A1, one (p.D597fs) in GBA2, and one (p.Q486X) in ATP13A2 in 8 index patients and their family members. Mutations in ALDH18A1, AP5Z1, CAPN1 and ATP13A2 genes were firstly reported in the Chinese population. Furthermore, the clinical phenotypes of the patients carrying mutations were described in detail. The mutation (p.S242 N) in ALDH18A1 decreased enzyme activity of P5CS and mutations (p.T55 M, p.S308 T) in AP5Z1 induced lysosomal dysfunction. Conclusion: Our results expanded the genetic spectrum and clinical profiles of AR-HSP patients and further demonstrated the efficiency and reliability of targeted NGS diagnosing suspected HSP patients.

20.
Medicine (Baltimore) ; 98(29): e16561, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31335741

RESUMO

BACKGROUND: Peptic ulcer disease (PUD) is a major burden worldwide. Several challenges remain with standard Western treatment of PUD, such as persistent weakness, fatigue, and relapse. A dietary traditional Chinese medicine (TCM) formula, Hou Gu Mi Xi (HGMX), has been developed as a complementary treatment for PUD. AIMS: This multicenter, double-blind, randomized controlled trial will assess efficacy and safety of HGMX in patients with PUD. METHODS: Three hundred sixty eligible patients will be assigned to receive HGMX, placebo, HGMX + rabeprazole or placebo + rabeprazole for 4 weeks after 2 weeks of standard Western treatment. This first step, with a 2 × 2 factorial design, will focus on assessing the main and interaction effects of HGMX and rabeprazole on ulcer healing. Then, rabeprazole will be stopped, and HGMX will be continued for up to 1 year. The second step, with a placebo-controlled design, will compare the long-term effects of HGMX and placebo. Extended follow-up with no treatment will continue for up to 2 years. Independent and paired t tests, Pearson χ test and the rank-sum test will be used to compare between-group differences. The P value will be adjusted using the O'Brien & Fleming method for multiple comparisons. EXPECTED OUTCOMES: The primary outcomes are total efficacy rate of PUD treatment, quality of ulcer healing, and changes in spleen qi deficiency symptoms. The secondary outcomes include ulcer area, PUD recurrence, Helicobacter pylori eradication rate, gastric function, body weight, and body mass index. Adverse events (AEs), severe AEs, treatment-related AEs, and withdrawal owing to AEs will be recorded to assess treatment safety. DISCUSSION: The trial results will provide high-quality evidence for HGMX, as a complementary therapy, for the long-term management of PUD and will be valuable for the development of related guidelines and regulations. TRIAL REGISTRATION: The protocol of this trial was approved in all research hospitals and was registered in ClinicalTrials.gov at October 25, 2017(No. NCT03320538).


Assuntos
Antiulcerosos/efeitos adversos , Antiulcerosos/uso terapêutico , Medicamentos de Ervas Chinesas/efeitos adversos , Medicamentos de Ervas Chinesas/uso terapêutico , Úlcera Péptica/tratamento farmacológico , Método Duplo-Cego , Quimioterapia Combinada , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori , Humanos , Úlcera Péptica/microbiologia , Prevenção Secundária
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