Publications by authors named "Jing Pang"

183 Publications

Cardiac Aging: From Basic Research to Therapeutics.

Oxid Med Cell Longev 2021 9;2021:9570325. Epub 2021 Mar 9.

The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China.

With research progress on longevity, we have gradually recognized that cardiac aging causes changes in heart structure and function, including progressive myocardial remodeling, left ventricular hypertrophy, and decreases in systolic and diastolic function. Elucidating the regulatory mechanisms of cardiac aging is a great challenge for biologists and physicians worldwide. In this review, we discuss several key molecular mechanisms of cardiac aging and possible prevention and treatment methods developed in recent years. Insights into the process and mechanism of cardiac aging are necessary to protect against age-related diseases, extend lifespan, and reduce the increasing burden of cardiovascular disease in elderly individuals. We believe that research on cardiac aging is entering a new era of unique significance for the progress of clinical medicine and social welfare.
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http://dx.doi.org/10.1155/2021/9570325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969106PMC
March 2021

Higher postoperative plasma EV PD-L1 predicts poor survival in patients with gastric cancer.

J Immunother Cancer 2021 Mar;9(3)

Department of Biochemistry and Molecular Biology, School of Basic Medicine, Shanxi Key Laboratory of Birth Defects and Cell Regeneration, Key Laboratory of Cellular Physiology (Shanxi Medical University) of Ministry of Education, Shanxi Medical University, Taiyuan, China

Background: The satisfactory prognostic indicator of gastric cancer (GC) patients after surgery is still lacking. Perioperative plasma extracellular vesicular programmed cell death ligand-1 (ePD-L1) has been demonstrated as a potential prognosis biomarker in many types of cancers. The prognostic value of postoperative plasma ePD-L1 has not been characterized.

Methods: We evaluated the prognostic value of preoperative, postoperative and change in plasma ePD-L1, as well as plasma soluble PD-L1, in short-term survival of GC patients after surgery. The Kaplan-Meier survival model and Cox proportional hazards models for both univariate and multivariate analyzes were used. And the comparison between postoperative ePD-L1 and conventional serum biomarkers (carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9) and CA72-4) in prognostic of GC patients was made.

Results: The prognostic value of postoperative ePD-L1 is superior to that of preoperative ePD-L1 on GC patients after resection, and also superior to that of conventional serum biomarkers (CEA, CA19-9 and CA72-4). The levels of postoperative ePD-L1 and ePD-L1 change are independent prognostic factors for overall survival and recurrence free survival of GC patients. High plasma level of postoperative ePD-L1 correlates significantly with poor survival, while high change in ePD-L1 level brings the significant survival benefit.

Conclusions: The level of plasma postoperative ePD-L1 could be considered as a candidate prognostic biomarker of GC patients after resection.
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http://dx.doi.org/10.1136/jitc-2020-002218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986771PMC
March 2021

Differential microRNAs expression profiles in liver from three different lifestyle modification mice models.

BMC Genomics 2021 Mar 19;22(1):196. Epub 2021 Mar 19.

The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, People's Republic of China.

Background: MicroRNAs play an important role in many fundamental biological and pathological processes. Defining the microRNAs profile underlying the processes by beneficial and detrimental lifestyles, including caloric restriction (CR), exercise and high-fat diet (HF), is necessary for understanding both normal physiology and the pathogenesis of metabolic disease. We used the microarray to detect microRNAs expression in livers from CR, EX and HF mice models. After predicted potential target genes of differentially expressed microRNAs with four algorithms, we applied GO and KEGG to analyze the function of predicted microRNA targets.

Results: We describe the overall microRNAs expression pattern, and identified 84 differentially expressed microRNAs changed by one or two or even all the three lifestyle modifications. The common and different enriched categories of gene function and main biochemical and signal transduction pathways were presented.

Conclusions: We provided for the first time a comprehensive and thorough comparison of microRNAs expression profiles in liver among these lifestyle modifications. With this knowledge, our findings provide us with an overall vision of microRNAs in the molecular impact of lifestyle on health as well as useful clues for future and thorough research of the role of microRNAs.
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http://dx.doi.org/10.1186/s12864-021-07507-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977600PMC
March 2021

Age-Related Changes in Shear Wave Elastography Parameters of the Gastrocnemius Muscle in Association with Physical Performance in Healthy Adults.

Gerontology 2021 Mar 18:1-8. Epub 2021 Mar 18.

The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, China.

Background/aims: to investigate new indicators for early recognition of physical performance decline. Shear wave elastrography, a new ultrasound technique, was discussed in this study.

Methods: Gastrocnemius muscle thickness and muscle stiffness were detected by traditional ultrasound and shear wave elastrography in 108 Chinese aged 20-85 years, and then analyzed with physical performance together.

Results: After 70 years old, the decline rate of muscle stiffness under contractive state was significantly faster than that of muscle thickness, muscle relaxed stiffness, and physical performance indicators. The correlation analysis showed that gastrocnemius contractive stiffness was positively related with handgrip strength, step length, and fast gait speed after adjusted by age and gender. Among physical performance variants, step length had closer relationship with muscle strength than repeated chair stands.

Conclusions: The detection of gastrocnemius muscle by shear wave elastography reflected the change of lower-limb muscle stiffness with aging. Muscle contractive stiffness and step length measurement supplied novel ways for muscle performance and motor function assessment.
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http://dx.doi.org/10.1159/000512386DOI Listing
March 2021

Engineering endogenous l-proline biosynthetic pathway to boost trans-4-hydroxy-l-proline production in Escherichia coli.

J Biotechnol 2021 Mar 1;329:104-117. Epub 2021 Feb 1.

Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, 9 Section 4, Renmin Road South, Chengdu 610041, People's Republic of China; State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, People's Republic of China. Electronic address:

Non-proteinogenic trans-4-hydroxy-l-proline (t4HYP), a crucial naturally occurred amino acid, is present in most organisms. t4HYP is a regio- and stereo-selectively hydroxylated product of l-proline and a valuable building block for pharmaceutically important intermediates/ingredients synthesis. Microbial production of t4HYP has aroused extensive investigations because of its low-cost and environmentally benign features. Herein, we reported metabolic engineering of endogenous l-proline biosynthetic pathway to enhance t4HYP production in trace l-proline-producing Escherichia coli BL21(DE3) (21-S0). The genes responsible for by-product formation from l-proline, pyruvate, acetyl-CoA, and isocitrate in the biosynthetic network of 21-S0 were knocked out to channel the metabolic flux towards l-proline biosynthesis. PdhR was knocked out to remove its negative regulation and aceK was deleted to ensure isocitrate dehydrogenase's activity and to increase NADPH/NADP level. The other genes for l-proline biosynthesis were enhanced by integration of strong promoters and 5'-untranslated regions. The resulting engineered E. coli strains 21-S1 ∼ 21-S9 harboring a codon-optimized proline 4-hydroxylase-encoding gene (P4H) were grown and fermented. A titer of 4.82 g/L of t4HYP production in 21-S6 overexpressing P4H was obtained at conical flask level, comparing with the starting 21-S0 (26 mg/L). The present work paves an efficient metabolic engineering way for higher t4HYP production in E. coli.
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http://dx.doi.org/10.1016/j.jbiotec.2021.01.015DOI Listing
March 2021

HT-2 toxin affects cell viability of goat spermatogonial stem cells through AMPK-ULK1 autophagy pathways.

Theriogenology 2021 Apr 24;164:22-30. Epub 2021 Jan 24.

Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, NO. 1 Weigang, Nanjing, 210095, PR China. Electronic address:

HT-2 toxin is widely found in moldy crops and is the major metabolite of T-2 toxin, which has been shown to exert various toxic effects in farm animals. However, little is known about the effects of HT-2 toxin on male reproduction, particularly spermatogenesis. This study aims to investigate the toxic effects of HT-2 toxin on goat spermatogonial stem cells (SSCs) and related autophagy-regulated mechanisms. Our results showed that HT-2 toxin exposure resulted in decreased cell viability and proliferation, disrupted SSCs self-renewal, and reduced germ cell-related gene expression. HT-2 toxin exposure also induced oxidative stress and cell apoptosis, as shown by ROS accumulation, increased antioxidant enzyme activity levels, decreased the mitochondrial membrane potential, and increased caspase-9 mRNA and Bcl/bax protein levels. Additionally, HT-2 toxin exposure increased the expression of the autophagy-inducing genes Atg5, Atg7 and Beclin1 and the number of autophagosomes, which indicated that HT-2 toxin induced autophagy in the goat SSCs. Moreover, we also examined a possible mechanism by which HT-2 toxin exposure induced higher expression of AMPK, mTOR and ULK at both the mRNA and protein levels. our results indicated that HT-2 toxin caused apoptosis and autophagy by activating AMPK-mTOR-ULK1 pathway, which further affected SSCs viability.
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http://dx.doi.org/10.1016/j.theriogenology.2021.01.015DOI Listing
April 2021

Integrated Guidance for Enhancing the Care of Familial Hypercholesterolaemia in Australia.

Heart Lung Circ 2021 Mar 9;30(3):324-349. Epub 2020 Dec 9.

School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia.

Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected and inadequately treated, consistent with FH being a leading challenge for public health genomics. To further address the unmet need, we provide an updated guidance, presented as a series of systematically collated recommendations, on the care of patients and families with FH. These recommendations have been informed by an exponential growth in published works and new evidence over the last 5 years and are compatible with a contemporary global call to action on FH. Recommendations are given on the detection, diagnosis, assessment and management of FH in adults and children. Recommendations are also made on genetic testing and risk notification of biological relatives who should undergo cascade testing for FH. Guidance on management is based on the concepts of risk re-stratification, adherence to heart healthy lifestyles, treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-cholesterol lowering therapies, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein apheresis. Broad recommendations are also provided for the organisation and development of health care services. Recommendations on best practice need to be underpinned by good clinical judgment and shared decision making with patients and families. Models of care for FH need to be adapted to local and regional health care needs and available resources. A comprehensive and realistic implementation strategy, informed by further research, including assessments of cost-benefit, will be required to ensure that this new guidance benefits all Australian families with or at risk of FH.
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http://dx.doi.org/10.1016/j.hlc.2020.09.943DOI Listing
March 2021

MRI-Based radiomics nomogram for differentiation of benign and malignant lesions of the parotid gland.

Eur Radiol 2020 Nov 19. Epub 2020 Nov 19.

Department of Radiology, The Affiliated Hospital of Qingdao University, No.16, Jiangsu Road, Qingdao, 266000, China.

Objectives: Preoperative differentiation between benign parotid gland tumors (BPGT) and malignant parotid gland tumors (MPGT) is important for treatment decisions. The purpose of this study was to develop and validate an MRI-based radiomics nomogram for the preoperative differentiation of BPGT from MPGT.

Methods: A total of 115 patients (80 in training set and 35 in external validation set) with BPGT (n = 60) or MPGT (n = 55) were enrolled. Radiomics features were extracted from T1-weighted and fat-saturated T2-weighted images. A radiomics signature model and a radiomics score (Rad-score) were constructed and calculated. A clinical-factors model was built based on demographics and MRI findings. A radiomics nomogram model combining the Rad-score and independent clinical factors was constructed using multivariate logistic regression analysis. The diagnostic performance of the three models was evaluated and validated using ROC curves on the training and validation datasets.

Results: Seventeen features from MR images were used to build the radiomics signature. The radiomics nomogram incorporating the clinical factors and radiomics signature had an AUC value of 0.952 in the training set and 0.938 in the validation set. Decision curve analysis showed that the nomogram outperformed the clinical-factors model in terms of clinical usefulness.

Conclusions: The above-described radiomics nomogram performed well for differentiating BPGT from MPGT, and may help in the clinical decision-making process.

Key Points: • Differential diagnosis between BPGT and MPGT is rather difficult by conventional imaging modalities. • A radiomics nomogram integrated with the radiomics signature, clinical data, and MRI features facilitates differentiation of BPGT from MPGT with improved diagnostic efficacy.
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http://dx.doi.org/10.1007/s00330-020-07483-4DOI Listing
November 2020

Lipoprotein(a) in Patients With Type 2 Diabetes and Premature Coronary Artery Disease in the Coronary Care Unit.

Heart Lung Circ 2021 May 12;30(5):734-740. Epub 2020 Nov 12.

Medical School, The University of Western Australia, Perth, WA, Australia; Departments of Internal Medicine and Cardiology, Royal Perth Hospital, Perth, WA, Australia; Department of Clinical Biochemistry, PathWest Laboratory Medicine WA, Royal Perth and Fiona Stanley Hospitals, Perth, WA, Australia; Department of Biochemistry, Clinipath Pathology, Perth, WA, Australia.

Introduction: Lipoprotein(a) [Lp(a)] and diabetes are independently associated with premature coronary artery disease (pCAD). However, there is an inverse relationship between Lp(a) concentration and type 2 diabetes (T2D) risk. We examine whether Lp(a) distribution in patients with pCAD differs between those with or without T2D, and whether elevated Lp(a) is associated with pCAD in patients with T2D.

Methods: Lp(a) concentration was measured in consecutive acute coronary syndrome (ACS) patients in two coronary care units (study one: ACS with or without diabetes, study two: ACS and diabetes). Elevated Lp(a) mass concentration was defined as ≥0.5 g/L and pCAD where CAD was diagnosed age <60 years. The association between elevated Lp(a) and pCAD was assessed using logistic regression.

Results: Of 449 patients, 233 (51.9%) had pCAD and 278 (61.9%) had T2D. In patients with pCAD, those with T2D had a significantly lower median Lp(a) concentration (0.13 g/L versus 0.27 g/L, p=0.004). In patients with T2D, elevated Lp(a) was significantly associated with pCAD (OR 2.419, 95% CI 1.513-3.867, p<0.001). After adjusting for gender, smoking, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides, elevated Lp(a) remained significantly associated with pCAD (OR 2.895, 95% CI 1.427-5.876, p=0.003) in patients with T2D.

Conclusions: In coronary care patients with pCAD, patients with T2D had lower Lp(a) concentrations than those without T2D. Despite this, elevated Lp(a) remained predictive of pCAD in patients with T2D. Measurement of Lp(a) should be considered in younger adults with T2D to identify who may benefit from earlier preventative therapies to reduce pCAD burden.
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http://dx.doi.org/10.1016/j.hlc.2020.09.932DOI Listing
May 2021

Under-Reporting of Family History of Premature Coronary Artery Disease in Patients Discharged From Coronary Care: Implications for the Detection of Familial Hypercholesterolaemia.

Heart Lung Circ 2021 Feb 26;30(2):e48-e49. Epub 2020 Oct 26.

School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia; Lipid Disorders Clinic, Cardiometabolic Services, Department of Cardiology, Royal Perth Hospital, Perth, WA, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.hlc.2020.09.930DOI Listing
February 2021

High-resolution MRI assessment of optic nerve sheath diameter in adults: optic nerve sheath variation and a new diagnostic tool for intracranial hypertension.

Acta Radiol 2020 Oct 21:284185120966715. Epub 2020 Oct 21.

Department of Radiology, The Affiliated Hospital of Qingdao University, Qingdao, PR China.

Background: Assessment of optic nerve sheath diameter (ONSD) is a non-invasive measure of intracranial pressure (ICP). However, it is not clear whether healthy individuals exhibit ONSD variation or whether factors other than ICP affect the ONSD.

Purpose: To investigate whether ONSD was correlated with age, sex, height, weight, eyeball transverse diameter (ETD), or body mass index (BMI), and to develop a new diagnostic model to increase the diagnostic accuracy of intracranial hypertension (IH).

Material And Methods: A total of 145 relatively healthy adults and 40 patients with acute IH who underwent high-resolution magnetic resonance imaging (MRI) were enrolled in this study. Linear regression analyses were used to determine the relationship between ONSD and these variables. If correlations were identified, an index ONSD removing variables effects was calculated. ROC analysis was used to assess the IH predictive value of ONSD in terms of sensitivity and specificity.

Results: In relatively healthy adults, there was a correlation between ONSD and BMI ( = 0.002), which can be presented as an index ONSD. The ONSD model better predicted IH than the ONSD model ( = 0.035), with a sensitivity of 70.00%, a specificity of 71.72%, and an AUC of 0.755.

Conclusion: A correlation between ONSD and body mass index (BMI) was found using high-resolution MRI. This result indicates that the effects of BMI should be considered along with the ONSD during ICP monitoring. Meanwhile, the index ONSD was better than the ONSD in predicting IH and could be used to obtain a more precise estimation of ICP.
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http://dx.doi.org/10.1177/0284185120966715DOI Listing
October 2020

The combined antibacterial effects of sodium new houttuyfonate and berberine chloride against growing and persistent methicillin-resistant and vancomycin-intermediate Staphylococcus aureus.

BMC Microbiol 2020 10 19;20(1):317. Epub 2020 Oct 19.

Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.

Background: Infections caused by drug-resistant Staphylococcus aureus, especially vancomycin-intermediate Staphylococcus aureus (VISA), leave clinicians with limited therapeutic options for treatment. Persister cells is a leading cause of recalcitrant infection and antibiotic treatment failure, and there is no drug in clinical use that specifically targets persister cells currently. Here, we report a promising combination therapy of sodium new houttuyfonate (SNH) and berberine chloride (BBR) which is able to eradicate both growing and persistent drug-resistant Staphylococcus aureus.

Results: The susceptibility test showed SNH exhibited anti-MRSA activity with MIC at 64 μg/mL, while BBR showed weak anti-MRSA activity with MIC at 512 μg/mL. MICs of BBR in combination with 1/2 MIC SNH decreased by 4 to 64 folds compared with MICs of BBR alone. The results of time-killing assays revealed that the combined use of sub-MIC SNH and BBR offered an in vitro synergistic action against growing MRSA (including pathogenic MRSA) and VISA strains. More importantly, the combination of SNH and BBR was able to eradicate VISA Mu50 and pathogenic MRSA persister cells. The synergistic effect is likely related to the interruption of the cell membrane caused by SNH, which is confirmed by scanning electron microscope and membrane potential and permeability analysis.

Conclusions: Our study provide a promising clinical curative strategy for combating drug-resistant S. aureus infections, especially for recalcitrant infections caused by persister cells.
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http://dx.doi.org/10.1186/s12866-020-02003-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574187PMC
October 2020

Rho GTPase ROP1 Interactome Analysis Reveals Novel ROP1-Associated Pathways for Pollen Tube Polar Growth in Arabidopsis.

Int J Mol Sci 2020 Sep 24;21(19). Epub 2020 Sep 24.

Center for Plant Cell Biology, Institute of Integrative Genome Biology, and Department of Botany and Plant Sciences, University of California, Riverside, CA 92508, USA.

ROP (Rho-like GTPases from plants) GTPases are polarly localized key regulators of polar growth in pollen tubes and other cells in plants. However, how ROP GTPases are regulated and how they control polar growth remains to be fully understood. To gain new insights into ROP-dependent mechanisms underlying polar cell growth, we characterized the interactome of ROP1 GTPase that controls Arabidopsis pollen tube (PT) tip growth, an extreme form of polar cell growth. We established an efficient method for culturing Arabidopsis pollen tubes in liquid medium, which was used for immunoprecipitation/mass spectrometry-based identification of ROP1-associated proteins. A total of 654 candidates were isolated from the ROP1 interactome in Arabidopsis pollen tubes, and GO (Gene Ontology) classification and pathway analysis revealed multiple uncharacterized ROP1-dependent processes including translation, cell wall modification, post transcriptional modification, and ion homeostasis, in addition to known ROP1-dependent pathways. The ROP1-interactome data was further supported by the co-expression of the candidate interactors in highly mature pollen with PT germination and growth defects being discovered in 25% (8/32) of the candidate mutant genes. Taken together, our work uncovers valuable information for the identification and functional elucidation of ROP-associated proteins in the regulation of polar growth, and provides a reliable reference to identify critical regulators of polar cell growth in the future.
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http://dx.doi.org/10.3390/ijms21197033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582345PMC
September 2020

Low Prevalence of Among Clinical Enterobacteriaceae Isolates and Co-transfer of and from Separate Donors.

Microb Drug Resist 2021 Apr 15;27(4):476-484. Epub 2020 Sep 15.

Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

and co-harboring isolates have been reported, usually reside on different plasmids, suggesting co-transfer possibility of the two genes from separate donors to the same recipient strain. This study aims at screening and characterization of carrying Enterobacteriaceae in Northern China, and studying the transfer ability of alone and in company with from a second donor. Three strains and one strain carrying gene were screened out from 1992 isolates in our study. Co-existence of multiple resistance genes was found in the -carrying strains, but none of them carried . One demonstrated an single nucleotide polymorphism (SNP) (A-G) at -10 region of , and one showed 2 SNPs (G-T and G-A) in the Shine-Dalgarno sequence-like region of . The gene was located on plasmids of about 33-276 kb, and capable of transferring alone in three out of four -positive isolates by conjugation. Co-transfer ability analysis demonstrated that from 13-68, which could not be transferred alone to C600, was successfully transferred in company with from ATCC BAA-2146. showed low incidence in our Enterobacteriaceae isolates. Co-transfer ability of and NDM-1 from separate donors provides direct evidence for the emergence of the and bla co-harboring isolates.
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http://dx.doi.org/10.1089/mdr.2020.0212DOI Listing
April 2021

The economic impact of familial hypercholesterolemia on productivity.

J Clin Lipidol 2020 Nov - Dec;14(6):799-806.e3. Epub 2020 Aug 17.

School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

Background: Familial hypercholesterolemia (FH) is a common inherited cause for premature coronary artery disease that increases suffering and disability in affected people. However, the extent to which FH impacts work productivity at a population level is unclear.

Objective: We aimed to quantify the burden of heterozygous FH (HeFH) in terms of productivity-adjusted life years (PALYs) lost to HeFH in Australia.

Methods: A life-table model was constructed to quantify years of life and PALYs lived by Australians with HeFH (prevalence 1 in 300) and of working age (aged 20-69 years). Follow-up was simulated until age 70 years. The model was then resimulated, but assuming the cohort did not have HeFH. Increased cardiovascular mortality and reduction in productivity attributable to HeFH were sourced from published data. Differences in total years of life, quality-adjusted life years, and PALYs lived by the "HeFH cohort" and the same cohort without HeFH ("non-HeFH cohort") reflected the quality-adjusted life years and PALYs lost due to HeFH. All future costs and outcomes were discounted by 5% annually.

Results: In 2017, an estimated 51,587 people of working age in Australia (0.33%) had HeFH. Over their working lifetime, we predicted that 2950 excess cardiovascular deaths occurred in the current Australian population of working age individuals with HeFH, resulting in a loss of 24,727 years of life. In terms of productivity, HeFH led to the loss of 24,954 PALYs over the working lifetime. Based on gross domestic product (GDP) per full-time equivalent worker, this equated to a total of AUD 5.23 billion in lost GDP over the working lifetime, with an average of AUD 101,366 lost per person. A relative reduction of 20% in cardiovascular deaths (as can be achieved with adequate cholesterol control) would lead to 1113 PALYs and AUD 233 million in GDP saved in the HeFH cohort.

Conclusion: The impact of HeFH on work productivity is significant. Screening and prevention strategies tailored early in life are likely to exert not only a positive impact on health but also the economy.
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http://dx.doi.org/10.1016/j.jacl.2020.08.004DOI Listing
August 2020

KHK-A promotes the proliferation of oesophageal squamous cell carcinoma through the up-regulation of PRPS1.

Arab J Gastroenterol 2021 Mar 11;22(1):40-46. Epub 2020 Sep 11.

Department of Gastroenterology, The Second Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China.

Background And Study Aims: The metabolism of dietary fructose by ketohexokinase (KHK) is an important step in glucose metabolism in various tumour types. However, the expression, function and underlying mechanisms of KHK in oesophageal squamous cell carcinoma (ESCC) remain largely unclear. The objective of this study was to investigate the effects of KHK-A, a peripheral isoform of KHK, on the proliferation of ESCC cell lines.

Material And Methods: The function and mechanism of KHK-A in ESCC cells were investigated by constructing stable KHK-A-knockdown and -overexpressing ESCC cell lines (KYSE410 and KYSE150, respectively). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, flow cytometry and colony formation assays were used to analyse the effects of KHK-A on cell proliferation, cell cycle and colony formation, respectively. KHK-A and phosphoribosyl pyrophosphate synthetase isoform 1 (PRPS1) mRNA and protein expressions in several ESCC cell lines were determined using routine reverse transcription-polymerase chain reaction and immunoblotting, respectively. KHK and PRPS1 expressions in ESCC tumour tissues and corresponding adjacent non-tumour tissues were evaluated according to the gene expression omnibus (GEO) database (GSE20347).

Results: In vitro experiments showed that KHK-A significantly promoted cell proliferation by modulating the G1/S phase transition in the cell cycle, which was probably regulated by PRPS1 expression. GEO database-based analysis showed that KHK levels were significantly higher in the ESCC tissues than in the corresponding adjacent non-tumour tissues. Pearson's correlation coefficient analysis showed that KHK expression in ESCC cell lines and tissues was significantly positively associated with the up-regulation of PRPS1, suggesting that KHK-A levels regulate PRPS1 expression in ESCC.

Conclusion: KHK-A may serve as a driving gene in ESCC for the activation of PRPS1, resulting in the up-regulation of PRPS1. This could lead to enhanced nucleic acid synthesis for tumourigenesis. Our study showed that KHK-A is a potential target for ESCC diagnosis and therapy.
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http://dx.doi.org/10.1016/j.ajg.2020.08.007DOI Listing
March 2021

Gaps in the Care of Familial Hypercholesterolaemia in Australia: First Report From the National Registry.

Heart Lung Circ 2021 Mar 29;30(3):372-379. Epub 2020 Aug 29.

School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia; Department of Cardiology, Calvary Cardiac Centre, Calvary Health Care, Hobart, Tas, Australia. Electronic address:

Background: Familial hypercholesterolaemia (FH) is under-diagnosed and under-treated worldwide, including Australia. National registries play a key role in identifying patients with FH, understanding gaps in care and advancing the science of FH to improve care for these patients.

Methods: The FH Australasia Network has established a national web-based registry to raise awareness of the condition, facilitate service planning and inform best practice and care services in Australia. We conducted a cross-sectional analysis of 1,528 FH adults enrolled in the registry from 28 lipid clinics.

Results: The mean age at enrolment was 53.4±15.1 years, 50.5% were male and 54.3% had undergone FH genetic testing, of which 61.8% had a pathogenic FH-causing gene variant. Only 14.0% of the cohort were family members identified through cascade testing. Coronary artery disease (CAD) was reported in 28.0% of patients (age of onset 49.0±10.5 years) and 64.9% had at least one modifiable cardiovascular risk factor. The mean untreated LDL-cholesterol was 7.4±2.5 mmol/L. 80.8% of patients were on lipid-lowering therapy with a mean treated LDL-cholesterol of 3.3±1.7 mmol/L. Among patients receiving lipid-lowering therapies, 25.6% achieved an LDL-cholesterol target of <2.5 mmol/L without CAD or <1.8 mmol/L with CAD.

Conclusion: Patients in the national FH registry are detected later in life, have a high burden of CAD and risk factors, and do not achieve guideline-recommended LDL-cholesterol targets. Genetic and cascade testing are under-utilised. These deficiencies in care need to be addressed as a public health priority.
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http://dx.doi.org/10.1016/j.hlc.2020.07.012DOI Listing
March 2021

The Knowns and Unknowns of Contemporary Statin Therapy for Familial Hypercholesterolemia.

Curr Atheroscler Rep 2020 09 1;22(11):64. Epub 2020 Sep 1.

School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia.

Purpose Of Review: Statins are first-line therapy for lowering low-density lipoprotein (LDL) cholesterol in familial hypercholesterolemia (FH), particularly in heterozygous patients. We review advances and new questions on the use of statins in FH.

Recent Findings: Cumulative evidence from registry data and sub-analyses of clinical trials mandates the value of statin therapy for prevention of atherosclerotic cardiovascular disease (ASCVD) in FH. Statins are safe in children and adolescents with FH, with longer term cardiovascular benefits. The potentially toxic effects of statins in pregnancy need to be considered, but no association has been reported in prospective cohort studies with birth defects. There is no rationale for discontinuation of statins in elderly FH unless indicated by adverse events. FH is undertreated, with > 80% of statin-treated FH patients failing to attain LDL cholesterol treatment targets. This may relate to adherence, tolerability, and genetic differences in statin responsiveness. Statin treatment from childhood may reduce the need for stringent cholesterol targets. Combination of statins with ezetimibe and PCSK9 inhibitors significantly improves the efficacy of treatment. Whether statin use could improve the clinical course of FH patients with COVID-19 and other respiratory infections remains an unsolved issue for future research. Statins are the mainstay for primary and secondary prevention of ASCVD in FH. Sustained long-term optimal statin treatment from an early age can effectively prevent ASCVD over decades of life. Despite their widespread use, statins merit further investigation in FH.
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http://dx.doi.org/10.1007/s11883-020-00884-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459268PMC
September 2020

EZH2 expression and its role in spermatogonial stem cell self-renewal in goats.

Theriogenology 2020 Oct 22;155:222-231. Epub 2020 Jun 22.

Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing, 210095, China. Electronic address:

Enhancer of zeste homolog 2 (EZH2) is a histone H3 lysine 27 (H3K27) methyltransferase that plays vital roles in mouse spermatogenesis. However, the expression pattern and role of EZH2 in goat spermatogonial stem cells (SSCs) is unknown. In the present study, we investigated EZH2 expression in the testis of postpubertal goats and its effect on the biological characteristics of goat SSCs. We found that EZH2 mRNA (P < 0.01) and protein (P < 0.05) expression was increased in the testes of postpubertal goats compared to that of prepubertal goats. Moreover, EZH2 was more highly expressed in goat SSCs than in Leydig cells (P < 0.01) and Sertoli cells (P < 0.01) as determined by qPCR, Western blot, and immunofluorescence. Compared to a negative control (NC), cell proliferation (P < 0.01) and viability (P < 0.01) were decreased in SSCs in which EZH2 was knocked down, and the G2/M phase of the cell cycle was blocked (P < 0.01), as determined by Edu staining, CCK-8 assay, and flow cytometry analysis. Additionally, the expression of CASP3, CASP9, and BAX was significantly increased (P < 0.01) while BCL2 expression was decreased (P < 0.01) in EZH2 knockdown SSCs. Notably, the expression of GDNF, a SSCs marker gene, and DAZL, a spermatogenesis-related gene, were significantly decreased (P < 0.01) while GFRA1 expression was significantly up-regulated (P < 0.01) in EZH2 knockdown SSCs. Our data suggest that EZH2 plays a pivotal role in the self-renewal of goat SSCs, and knockdown of EZH2 might impair spermatogenesis in goats.
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http://dx.doi.org/10.1016/j.theriogenology.2020.06.013DOI Listing
October 2020

Coronary artery disease and the risk-associated LPA variants, rs3798220 and rs10455872, in patients with suspected familial hypercholesterolaemia.

Clin Chim Acta 2020 Nov 16;510:211-215. Epub 2020 Jul 16.

School of Medicine, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Australia; Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Perth, Australia. Electronic address:

Background: The rs3798220 and rs10455872 single nucleotide polymorphisms (SNPs) in LPA are associated with increased plasma concentrations of lipoprotein(a) [Lp(a)] and coronary artery disease (CAD).

Methods: We investigated the association between rs3798220 and rs10455872 and prevalent CAD in 763 patients with suspected familial hypercholesterolaemia (FH). The rs3798220 and rs10455872 SNPs in LPA were detected using a SEQUENOM platform.

Results: Both LPA SNPs were significantly associated with CAD, but only rs3798220 after adjustment for other risk factors (odds ratio [OR] 2.05; 95% confidence interval [CI] 1.02-4.12; p = 0.045), and neither after adjustment for Lp(a) concentrations. Both SNPs were positively and independently associated with increased Lp(a) (rs3798220: OR 1.27; 95% CI 0.96-1.57; p < 0.001. rs10455872: OR 1.41; 95% CI 1.24-1.58; p < 0.001). Plasma concentrations of Lp(a) were independently associated with prevalent CAD (OR 1.28; 95% CI 1.08-1.52, p = 0.005) after adjustment for LPA SNPs and other cardiovascular risk factors. While both the rs3798220 and rs10455872 SNPs were associated with Lp(a) concentrations and prevalent CAD in patients with suspected FH, this was not independent of Lp(a) concentration.

Conclusions: Quantification of Lp(a) is more likely to be useful than assessment of these Lp(a)-associated SNPs to augment CAD risk prediction.
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http://dx.doi.org/10.1016/j.cca.2020.07.029DOI Listing
November 2020

Characterization of Camptotheca acuminata 10-hydroxygeraniol oxidoreductase and iridoid synthase and their application in biological preparation of nepetalactol in Escherichia coli featuring NADP - NADPH cofactors recycling.

Int J Biol Macromol 2020 Nov 26;162:1076-1085. Epub 2020 Jun 26.

Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, 9 Section 4, Renmin Road South, Chengdu 610041, People's Republic of China; State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, People's Republic of China. Electronic address:

Nepetalactol, an iridoid with four chiral carbons, is a crucial component of aphid sex pheromones that have been employed with great success to control the insect-related diseases. Despite of agricultural usage as end products, iridoids are fundamental biosynthetic intermediates for pharmaceutically important monoterpenoid indole alkaloids such as camptothecin (CAM) and vinca alkaloids. Herein we characterized 10-hydroxygeraniol oxidoreductase (10HGO) and iridoid synthase (IS) from Camptotheca acuminata, a CAM-producing plant, and reported their application in biological preparation of nepetalactol. Ca10HGO and CaIS were respectively cloned from C. acuminata, overexpressed in Escherichia coli, and purified to homogeneity. Ca10HGO catalyzes the oxidation of 10-hydroxygeraniol into 10-oxogeranial, in which NADP was reduced to NADPH. CaIS catalyzes nepetalactol formation from 10-oxogeranial using NADPH cofactor. The net outcome of the two reactions generate nepetalactol from 10-hydroxygeraniol efficiently, indicating NADP - NADPH recycling. Ca10HGO and CaIS were co-overexpressed in E. coli under optimized fermentation conditions to prepare cell-based catalysts that catalyze the conversion of 10-hydroxygeraniol into nepetalactol. The present work shows the enzymatic conversion of 10-hydroxygeraniol into nepetalactol involved in CAM biosynthesis. Co-overexpression of Ca10HGO and CaIS in E. coli is an alternative valuable cell-based biotransformation process with regenerating recycling of NADP - NADPH cofactors for nepetalactol preparation.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.06.223DOI Listing
November 2020

Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: Many happy returns on investment?

Atherosclerosis 2020 07 20;304:1-8. Epub 2020 May 20.

The University of Western Australia, Faculty of Health and Medical Sciences, Internal Medicine, Perth, Australia.

Background And Aims: There are no studies that have specifically investigated the cost-effectiveness of cascade screening of children for heterozygous familial hypercholesterolemia (FH) and treatment of affected individuals with statins to prevent coronary heart disease (CHD). This study explores the cost-effectiveness of this strategy from the perspective of the Australian public healthcare system.

Methods: A lifetime Markov model with four health states (Alive without CHD, Alive with CHD, Dead from fatal CHD, and Dead from other causes) was developed to simulate the progression of ten-year-old children screened for FH and treated immediately with statins if found to have FH. The underlying prevalence of FH in this target population was assumed to be 56.8%, and the sensitivity and specificity of testing were 100%. The comparator was usual care, which assumed that subjects started statins spontaneously at a later point or when they experienced a cardiovascular event. The effect of reducing low-density lipoprotein cholesterol (LDL-C) on the risk of a first event at each age assumed that risk was proportional to total lifetime exposure and was implemented using Mendelian randomisation analysis data. Cost and other outcome data were sourced from published sources. Outcome of interests were costs in Australian dollars (AUD), life years gained (LYG) and quality-adjusted life years (QALYs) gained, as well as incremental cost-effectiveness ratios (ICERs) of costs per LYG and per QALY gained. All future costs and outcomes were discounted by 5% annually.

Results: Undiscounted results showed that compared with usual care, cascade screening of ten year-old children for FH and initiation of treatment of affected individuals saved 7.77 LYG and 7.53 QALYs per person over a lifetime. With 5% annual discounting, there were 0.97 LYG and 1.07 QALYs gained per person, at net reduction cost of -$1134. The cascade screening of ten-year-old children for FH and initiation of treatment compared to usual case was a cost saving approach. In 51.2% of iterations, screening and initiation with statin were cost saving and in 48.8% of iterations were cost-effective. In most of the one-way sensitivity and scenario analyses, the ICER stayed within the accepted Australian threshold.

Conclusions: Compared to usual care, cascade screening of ten-year-old children for FH and treating affected individuals are likely to be cost saving.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.05.007DOI Listing
July 2020

Radiotherapy Enhancement for Human Pancreatic Carcinoma Using a Peptide-Gold Nanoparticle Hybrid.

J Biomed Nanotechnol 2020 Mar;16(3):352-363

Pancreatic ductal adenocarcinoma (PDAC) is radioresistant. Due to their strong X-ray absorption capacity, gold nanoparticles (AuNPs) have been used as radiosensitizers for cancer therapeutics. Herein, we describe a novel conjugate complex consisting of a peptide for targeting plectin-1 (PTP) specifically expressed on the PDAC cell membrane and AuNPs, termed AuNP-PTP, to be used for PDAC radiotherapy and . Previous studies revealed that compared with unmodified AuNPs, AuNP-PTP along with relevant low-energy X-ray irradiation of 6 MV at a dose of 2 Gy (RF) increased the targeting efficiency and induced apoptosis in treated PANC-1 cells and tumours. Importantly, extensive histopathological examination did not reveal evidence of acute or chronic injury in mice due to AuNPs or AuNP-PTP for up to six weeks despite the presence of X-ray exposure. The delicate AuNP-PTP hybrid provides a novel strategy to enhance radiotherapy efficiency in PDAC treatment.
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http://dx.doi.org/10.1166/jbn.2020.2898DOI Listing
March 2020

ZIF-Induced d-Band Modification in a Bimetallic Nanocatalyst: Achieving Over 44 % Efficiency in the Ambient Nitrogen Reduction Reaction.

Angew Chem Int Ed Engl 2020 Sep 27;59(39):16997-17003. Epub 2020 Jul 27.

Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore, 637371, Singapore.

The electrochemical nitrogen reduction reaction (NRR) offers a sustainable solution towards ammonia production but suffers poor reaction performance owing to preferential catalyst-H formation and the consequential hydrogen evolution reaction (HER). Now, the Pt/Au electrocatalyst d-band structure is electronically modified using zeolitic imidazole framework (ZIF) to achieve a Faradaic efficiency (FE) of >44 % with high ammonia yield rate of >161 μg mg  h under ambient conditions. The strategy lowers electrocatalyst d-band position to weaken H adsorption and concurrently creates electron-deficient sites to kinetically drive NRR by promoting catalyst-N interaction. The ZIF coating on the electrocatalyst doubles as a hydrophobic layer to suppress HER, further improving FE by >44-fold compared to without ZIF (ca. 1 %). The Pt/Au-N interaction is key to enable strong N adsorption over H atom.
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http://dx.doi.org/10.1002/anie.202006071DOI Listing
September 2020

CT-Based Radiomics Nomogram: A Potential Tool for Differentiating Hepatocellular Adenoma From Hepatocellular Carcinoma in the Noncirrhotic Liver.

Acad Radiol 2020 May 5. Epub 2020 May 5.

Department of Radiology, the Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao 266000, Shandong, China. Electronic address:

Rationale And Objectives: To evaluate the value of a radiomics nomogram for preoperative differentiating hepatocellular adenoma (HCA) from hepatocellular carcinoma (HCC) in the noncirrhotic liver.

Materials And Methods: One hundred and thirty-one patients with HCA (n = 46) and HCC (n = 85) were divided into a training set (n = 93) and a test set (n = 38). Clinical data and CT findings were analyzed. Radiomics features were extracted from the triphasic contrast CT images. A radiomics signature was constructed with the least absolute shrinkage and selection operator algorithm and a radiomics score was calculated. Combined with the radiomics score and independent clinical factors, a radiomics nomogram was developed by multivariate logistic regression analysis. The performance of the radiomics nomogram was assessed by calibration, discrimination and clinical usefulness.

Results: Gender, age, and enhancement pattern were the independent clinical factors. Three thousand seven hundred and sixty-eight features were extracted and reduced to 7 features as the optimal discriminators to build the radiomics signature. The radiomics nomogram (area under the curve [AUC], 0.96; 95% confidence interval [CI], 0.93-0.99) and the clinical factors model (AUC, 0.93; 95%CI, 0.88-0.99) showed better discrimination capability (p = 0.001 and 0.047) than the radiomics signature (AUC, 0.83; 95%CI, 0.74-0.92) in the training set. In the test set, the radiomics nomogram (AUC, 0.94; 95%CI, 0.87-1.00) performed better (p = 0.013) than the radiomics signature (AUC, 0.75; 95%CI, 0.59-0.91). Decision curve analysis showed the radiomics nomogram outperformed the clinical factors model and the radiomics signature in terms of clinical usefulness.

Conclusion: The CT-based radiomics nomogram has the potential to accurately differentiate HCA from HCC in the noncirrhotic liver.
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http://dx.doi.org/10.1016/j.acra.2020.04.027DOI Listing
May 2020

Design, development and deployment of a web-based patient registry for rare genetic lipid disorders.

Pathology 2020 Jun 7;52(4):447-452. Epub 2020 Apr 7.

Department of Clinical Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital and Fiona Stanley Hospital Network, Perth, WA, Australia; School of Medicine, University of Western Australia, Nedlands, WA, Australia. Electronic address:

Rare genetic lipid disorders comprise all the monogenic disorders of lipoprotein metabolism with the exception of heterozygous familial hypercholesterolaemia (FH). The creation and maintenance of patient registries is critical for disease monitoring, improving clinical best practice, facilitating research and enabling the development of novel therapeutics, but very few disease-specific rare genetic lipid disorder registries currently exist. Our aim was to design, develop and deploy a web-based patient registry for rare genetic lipid disorders. The Rare Genetic Lipid Disorders Registry is based on the FH Australasia Network (FHAN) Registry, which has been operating since 2015. The Rare Genetic Lipid Disorders Registry was deployed utilising the open-source Rare Disease Registry Framework (RDRF), which enables the efficient customisation and sustainable deployment of web-based registries. The Registry has been designed to capture longitudinal data on 13 rare genetic lipid disorders, with the ability to add more if required in the future. Recruitment of volunteers into the Registry is currently through the Royal Perth Hospital Lipid Disorders Clinic in Western Australia. Although in essence a clinic-based patient registry, the web-based design allows for expansion and distribution across Australia and beyond. Data collated by the Registry may ultimately improve the diagnosis, management and treatment of these conditions.
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http://dx.doi.org/10.1016/j.pathol.2020.02.002DOI Listing
June 2020

[Effect of electroacupuncture at governor vessel on learning-memory ability and serum level of APP, Aβ in patients with Alzheimer's disease].

Zhongguo Zhen Jiu 2020 Apr;40(4):375-8

Third Ward of Rehabilitation Department, Second Clinical Medical College of Heilongjiang University of CM, Harbin 150001.

Objective: To compare the therapeutic effect of electroacupuncture (EA) combined with donepezil hydrochloride and donepezil hydrochloride alone on improving learning-memory ability in patients with Alzheimer's disease (AD), and to explore its action mechanism.

Methods: Sixty patients of AD were randomly divided into an observation group and a control group, 30 cases in each group. The patients in the observation group were treated with EA at governor vessel (GV) combined with donepezil hydrochloride. EA was applied at Baihui (GV 20) and Fengfu (GV 16) with dilatational wave (10 Hz/50 Hz of frequency, 0.5 to 5.0 mA of intensity), and the needles were kept for 40 min, EA was given once a day; the donepezil hydrochloride tablet was taken orally, 5 mg, once a day, and after 4 weeks the dosage might be increased to 10 mg per day according to the specific situation. All the treatment was given for 8 weeks. The patients in the control group were only treated with donepezil hydrochloride with the identical procedure as the observation group. The Montreal cognitive assessment (MoCA) and Alzheimer's disease assessment scale cognitive part (ADAS-Cog) were evaluated before and after treatment; P300 (latency and amplitude of N2 and P3) was detected by EEG/ERP system brain event related potential instrument, and amyloid precursor protein (APP) and β-amyloid protein 1-42 (Aβ) were detected by ELISA.

Results: Compared before treatment, the MoCA scores were increased after treatment in the two groups (<0.05), and the MoCA score in the observation group was higher than that in the control group (<0.05). Compared before treatment, the ADAS-Cog scores were decreased after treatment in the two groups (<0.05), and the ADAS-Cog score in the observation group was lower than that in the control group (<0.05). Compared before treatment, the latency of N2 and P3 was shortened and the amplitude was increased after treatment in the two groups (<0.05); after treatment, the latency of N2 and P3 in the observation group was shorter than that in the control group and the amplitude was higher than that in the control group (<0.05). Compared before treatment, the serum levels of APP and Aβ were lower after treatment in the two groups (<0.05), and the serum levels of APP and Aβ in the observation group were lower than those in the control group (<0.05).

Conclusion: EA at Baihui (GV 20) and Fengfu (GV 6) combined with donepezil hydrochloride can effectively reduce the serum levels of APP and Aβ and improve the scores of MoCA and ADAS-Cog and the levels of N2 and P3 of P300 in AD patients, which has superior effect to donepezil hydrochloride alone in improving the learning-memory of AD patients.
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http://dx.doi.org/10.13703/j.0255-2930.20190728-0003DOI Listing
April 2020

PCSK9 Inhibition with alirocumab increases the catabolism of lipoprotein(a) particles in statin-treated patients with elevated lipoprotein(a).

Metabolism 2020 06 30;107:154221. Epub 2020 Mar 30.

Faculty of Medicine and Health, University of New England, Armidale, Australia.

Background: Lipoprotein(a) (Lp(a)) is a low-density lipoprotein (LDL) particle containing apolipoprotein(a) (apo(a)) covalently linked to apolipoprotein B-100 (apoB). Statin-treated patients with elevated Lp(a) have an increased risk of atherosclerotic cardiovascular disease (ASCVD). Recent trials show that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition decreases Lp(a) and cardiovascular events, particularly in high risk patients with elevated Lp(a). We investigated the kinetic mechanism whereby alirocumab, a PCSK9 inhibitor, lowers Lp(a) in statin-treated patients with high Lp(a) and ASCVD.

Methods: The effects of 12-week alirocumab treatment (150 mg every 2 weeks) on apo(a) kinetics were studied in 21 patients with elevated Lp(a) concentration (>0.5 g/L). Apo(a) fractional catabolic rate (FCR) and production rate (PR) were determined using intravenous D3-leucine administration, mass spectrometry and compartmental modelling. All patients were on long-term statin treatment.

Results: Alirocumab significantly decreased plasma concentrations of total cholesterol (-39%), LDL-cholesterol (-67%), apoB (-56%), apo(a) (-25%) and Lp(a) (-22%) (P< 0.001 for all). Alirocumab also significantly lowered plasma apo(a) pool size (-26%, P <0.001) and increased the FCR of apo(a) (+28%, P< 0.001), but did not alter apo(a) PR, which remained significantly higher relative to a reference group of patients on statins with normal Lp(a) (P< 0.001).

Conclusions: In statin-treated patients, alirocumab lowers elevated plasma Lp(a) concentrations by accelerating the catabolism of Lp(a) particles. This may be consequent on marked upregulation of hepatic receptors (principally for LDL) and/or reduced competition between Lp(a) and LDL particles for these receptors; the mechanism could contribute to the benefit of PCSK9 inhibition with alirocumab on cardiovascular outcomes.
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http://dx.doi.org/10.1016/j.metabol.2020.154221DOI Listing
June 2020

Synthesis and Structure-Activity Relationship of Palmatine Derivatives as a Novel Class of Antibacterial Agents against .

Molecules 2020 Mar 16;25(6). Epub 2020 Mar 16.

Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

Taking palmatine (PMT) as the lead, 20 new PMT derivatives were synthesized and examined for their antibacterial activities against six tested metronidazole (MTZ)-resistant () strains. The structure-activity relationship (SAR) indicated that the introduction of a suitable secondary amine substituent at the 9-position might be beneficial for potency. Among them, compound exhibited the most potent activities against MTZ-resistant strains, with minimum inhibitory concentration (MIC) values of 4-16 μg/mL, better than that of the lead. It also exhibited a good safety profile with a half-lethal dose (LD) of over 1000 mg/kg. Meanwhile, might exert its antimicrobial activity through targeting urease. These results suggested that PMT derivatives might be a new family of anti- components.
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http://dx.doi.org/10.3390/molecules25061352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146163PMC
March 2020

An age-matched computed tomography angiographic study of coronary atherosclerotic plaques in patients with familial hypercholesterolaemia.

Atherosclerosis 2020 04 6;298:52-57. Epub 2020 Mar 6.

School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia; Department of Cardiology, Royal Perth Hospital, Perth, Western Australia, Australia. Electronic address:

Background And Aims: Familial hypercholesterolaemia (FH) is characterised by a high, but variable risk of premature coronary artery disease (CAD). Cardiac computed tomography angiography (CCTA) can be employed to assess subclinical coronary atherosclerosis. We investigated the features and distribution of coronary artery plaques in asymptomatic patients with and without genetically confirmed heterozygous FH.

Methods: We undertook an aged-matched case-control study of asymptomatic phenotypic FH patients with (cases, M+) and without (controls, M-) an FH-causing mutation. Coronary atherosclerosis was assessed by CCTA and calcium scoring. Coronary segments were evaluated for global and vessel-level coronary plaques and degree of stenosis.

Results: We studied 104 cases and 104 controls (mean age 49.9 ± 10.4 years), who had a similar spectrum of non-cardiovascular risk factors. Pre-treatment plasma LDL-cholesterol was higher in the M+ than M- group (7.8 ± 2.1 vs 6.2 ± 1.2 mmol/L, p<0.001). There was a greater proportion of patients with mixed and calcified plaque, as well as a higher coronary artery calcium score and segment stenosis score (all p<0.05), in the M+ compared with the M- group. M+ patients also had a significantly higher frequency of coronary artery calcium in the left main and anterior descending and right coronary arteries (all p<0.05), but not in the left circumflex.

Conclusions: Among patients with phenotypic FH, those with a genetically confirmed diagnosis had a higher frequency and severity of coronary atherosclerotic plaques, and specifically more advanced calcified plaques.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.03.001DOI Listing
April 2020