Publications by authors named "Zhenhuan Luo"

8 Publications

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Can locally developed me-too drugs aid price negotiation? An example of cancer therapies from China.

Semin Oncol 2021 Apr 6. Epub 2021 Apr 6.

Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts, USA.

Rapid growth in pharmaceutical expenditures and high prices have greatly hampered access to medicines, especially targeted anticancer medicines. Confronted with such difficulties, the Chinese government has put more effort into supporting local research and development of cancer medicines, resulting in locally developed me-too drugs. Since 2016, the government has implemented a central reimbursement-linked drug price negotiation policy aimed at reducing the prices of expensive medicines. Locally developed me-too drugs marketed at lower prices may inject price competition and help negotiate reduced prices of similar internationally-developed products. As an example, we selected 3 tyrosine kinase inhibitors (TKIs) developed for the therapy of advanced non-small cell lung cancer harboring mutations in the epidermal growth factor receptor (EGFR). Descriptive analysis was applied to data from the Chinese Medical Economic Information database to describe the impact on the price and utilization of three TKIs after the introduction of icotinib, a locally developed me-too TKI and two national negotiations regarding the price of EGFR-TKIs in China. After two national negotiations, the daily costs of all three EGFR-TKIs were reduced to around $30. From the first quarter of 2013 to the second quarter of 2016, the market share of the purchasing volume of icotinib, China's locally developed TKI, increased from 13% to 40%, while the market shares of two internationally developed TKIs decreased from 35% to 15% and from 52% to 45%, for erlotinib and gefitinib, respectively. The prices of EGFR-TKIs decreased and China's locally developed TKI accounted for a considerable proportion of market share. Locally developed me-too drugs aid price negotiation by injecting price competition and helping negotiate reduced prices of similar internationally-developed products. Through efforts to develop me-too drugs, combined with national drug price negotiation and reimbursement policies, developing countries might improve access to more affordable targeted cancer therapies.
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http://dx.doi.org/10.1053/j.seminoncol.2021.03.001DOI Listing
April 2021

MiniCAFE, a CRISPR/Cas9-based compact and potent transcriptional activator, elicits gene expression in vivo.

Nucleic Acids Res 2021 04;49(7):4171-4185

Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.

CRISPR-mediated gene activation (CRISPRa) is a promising therapeutic gene editing strategy without inducing DNA double-strand breaks (DSBs). However, in vivo implementation of these CRISPRa systems remains a challenge. Here, we report a compact and robust miniCas9 activator (termed miniCAFE) for in vivo activation of endogenous target genes. The system relies on recruitment of an engineered minimal nuclease-null Cas9 from Campylobacter jejuni and potent transcriptional activators to a target locus by a single guide RNA. It enables robust gene activation in human cells even with a single DNA copy and is able to promote lifespan of Caenorhabditis elegans through activation of longevity-regulating genes. As proof-of-concept, delivered within an all-in-one adeno-associated virus (AAV), miniCAFE can activate Fgf21 expression in the liver and regulate energy metabolism in adult mice. Thus, miniCAFE holds great therapeutic potential against human diseases.
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http://dx.doi.org/10.1093/nar/gkab174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053112PMC
April 2021

N-methyldeoxyadenine and histone methylation mediate transgenerational survival advantages induced by hormetic heat stress.

Sci Adv 2021 01 1;7(1). Epub 2021 Jan 1.

Zhuhai Precision Medical Center, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Jinan University, Guangzhou, Guangdong 510632, China.

Environmental stress can induce survival advantages that are passed down to multiple generations, representing an evolutionarily advantageous adaptation at the species level. Using the nematode worm as a model, we found that heat shock experienced in either parent could increase the longevity of themselves and up to the fifth generation of descendants. Mechanistic analyses revealed that transcription factor DAF-16/FOXO, heat shock factor HSF-1, and nuclear receptor DAF-12/FXR functioned transgenerationally to implement the hormetic stress response. Histone H3K9me3 methyltransferases SET-25 and SET-32 and DNA N-methyl methyltransferase DAMT-1 participated in transmitting high-temperature memory across generations. H3K9me3 and N-methyladenine could mark heat stress response genes and promote their transcription in progeny to extend life span. We dissected the mechanisms responsible for implementing and transmitting environmental memories in descendants from heat-shocked parents and demonstrated that hormetic stress caused survival benefits could be transmitted to multiple generations through H3K9me3 and N-mA modifications.
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http://dx.doi.org/10.1126/sciadv.abc3026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775758PMC
January 2021

Influence of Government Price Regulation on the Price, Volume and Spending of Antibiotics in China: A Controlled Interrupted Time Series Study.

Int J Health Policy Manag 2020 Jul 18. Epub 2020 Jul 18.

International Research Center for Medicinal Administration (IRCMA), Peking University, Beijing, China.

Background: Chinese government established maximum retail prices for antibiotics listed in China's National Reimbursement List in February 2013. This study aimed to analyze the impact of pharmaceutical price regulation on the price, volume and spending of antibiotics in China.

Methods: An interrupted time series design with comparison series was used to examine impacts of the policy changes on average daily cost, monthly hospital purchase volume and spending of the 11 price-regulated antibiotics and 40 priceunregulated antibiotics in 699 hospitals. One intervention point was applied to assess the impact of policy.

Results: After government price regulation, compared to price-unregulated antibiotics, the average daily cost of the price-regulated group declined rapidly (β=-5.68, <.001). The average hospital monthly purchase spending of priceregulated antibiotics also decreased rapidly (β=-0.49, P<.010) and a positive trend change (β=0.04, <.001) in average hospital spending of price-unregulated antibiotics was found.

Conclusion: Government regulation can reduce the prices and spending of price-regulated antibiotics. To control increasing expenditure, besides price caps regulation, factors determining drug utilization also need to be considered in policy designing.
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http://dx.doi.org/10.34172/ijhpm.2020.113DOI Listing
July 2020

Health Care Utilization and Costs of Patients With Prostate Cancer in China Based on National Health Insurance Database From 2015 to 2017.

Front Pharmacol 2020 10;11:719. Epub 2020 Jun 10.

Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China.

Background: In terms of medical costs, prostate cancer is on the increase as one of the most costly cancers, posing a tremendous economic burden, but evidence on the health care utilization and medical expenditure of prostate cancer has been absent in China.

Objective: This study aimed to analyze health care utilization and direct medical costs of patients with prostate cancer in China.

Methods: Health care service data with a national representative sample of basic medical insurance beneficiaries between 2015 and 2017 were obtained from the China Health Insurance Association database. We conducted descriptive and statistical analyses of health care utilization, annual direct medical costs, and composition based on cancer-related medical records. Health care utilization was measured by the number of hospital visits and the length of stay.

Results: A total of 3,936 patients with prostate cancer and 24,686 cancer-related visits between 2015 and 2017 were identified in the database. The number of annual outpatient and inpatient visits per patient differed significantly from 2015 to 2017. There was no obvious change in length of stay and annual direct medical costs from 2015 to 2017. The number of annual visits per patient (outpatient: 3.0 vs. 4.0, P < 0.01; inpatient: 1.5 vs. 2.0, P < 0.001) and the annual medical direct costs per patient (US$2,300.1 vs. US$3,543.3, P < 0.001) of patients covered by the Urban Rural Resident Basic Medical Insurance (URRBMI) were both lower than those of patients covered by the Urban Employee Basic Medical Insurance (UEBMI), and the median out-of-pocket expense of URRBMI was higher than that of UEBMI (US$926.6 vs. US$594.0, P < 0.001). The annual direct medical costs of patients with prostate cancer in Western regions were significantly lower than those of patients in Eastern and Central regions (East: US$4011.9; Central: US$3458.6; West: US$2115.5) (P < 0.001).

Conclusions: There was an imbalanced distribution of health care utilization among regions in China. The direct medical costs of Chinese patients with prostate cancer remained stable, but the gap in health care utilization and medical costs between two different insurance schemes and among regions still needed to be further addressed.
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http://dx.doi.org/10.3389/fphar.2020.00719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299164PMC
June 2020

Uric acid induces stress resistance and extends the life span through activating the stress response factor DAF-16/FOXO and SKN-1/NRF2.

Aging (Albany NY) 2020 02 12;12(3):2840-2856. Epub 2020 Feb 12.

Zhuhai Precision Medical Center, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Jinan University, Guangdong 510632, Guangzhou, China.

Uric acid is a common metabolite found in mammals' serum. Recently, several metabolites have been identified that modulate aging, and uric acid levels are positively correlated with mammals' lifespan. However, the molecular mechanisms underlying this are largely undefined. Here we show that uric acid, an end product of purine metabolism, enhances the resistance of oxidative stress and extends the life span of . We show that uric acid enhances a variety of pathways and leads to the upregulation of genes that are required for uric acid-mediated life span extension. We find that the transcription factors DAF-16/FOXO, SKN-1/NRF2 and HSF-1 contribute to the beneficial longevity conferred by uric acid. We also show that uric acid induced life span extension by regulating the reproductive signaling and insulin/IGF-1 signaling (IIS) pathways. In addition, we find that mitochondrial function plays an important role in uric acid-mediated life span extension. Taken together, these data suggest that uric acid prolongs the life span of , in part, because of its antioxidative activity, which in turn regulates the IIS and the reproductive signaling pathways, thereby activating the function of the transcription factors DAF-16, HSF-1 and SKN-1.
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http://dx.doi.org/10.18632/aging.102781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041755PMC
February 2020

Hypotaurine promotes longevity and stress tolerance via the stress response factors DAF-16/FOXO and SKN-1/NRF2 in Caenorhabditis elegans.

Food Funct 2020 Jan;11(1):347-357

The First Affiliated Hospital, Biomedical Translational Research Institute, Jinan University, Guangzhou, Guangdong 510632, China.

Hypotaurine, an important sulfur-containing and nonpeptidic amino acid, is a precursor of taurine and an antioxidant. Our previous study indicated that hypotaurine levels are associated with the ageing of Caenorhabditis elegans (C. elegans). However, whether hypotaurine plays a role in the lifespan regulation of C. elegans and the mechanism remains undetermined. Here, we found that hypotaurine enhances oxidative stress resistance and ameliorates ageing in C. elegans. Our results show that hypotaurine regulates a variety of pathways and leads to the upregulation of some age-related genes to extend lifespan. We also found that the stress response-related transcription factors DAF-16/FOXO and SKN-1/NRF2 contribute to the beneficial longevity conferred by hypotaurine. Moreover, our results demonstrate that hypotaurine induced lifespan extension by regulating the insulin/IGF-1 signaling (IIS) pathway, the reproductive signaling pathway and DR-like mechanisms. Additionally, our results also indicated that mitochondrial function also plays a crucial role in the lifespan extension induced by hypotaurine. Taken together, these data indicate that hypotaurine delays the ageing of C. elegans, due, at least in part, to its antioxidant activity, which in turn regulates IIS, and reproductive and DR-related pathways, thereby inducing the activity of the transcription factors DAF-16 and SKN-1.
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http://dx.doi.org/10.1039/c9fo02000dDOI Listing
January 2020

Antiobesity Effect of Flaxseed Polysaccharide via Inducing Satiety due to Leptin Resistance Removal and Promoting Lipid Metabolism through the AMP-Activated Protein Kinase (AMPK) Signaling Pathway.

J Agric Food Chem 2019 Jun 14;67(25):7040-7049. Epub 2019 Jun 14.

Department of Food Science and Engineering , Jinan University , Guangzhou , 510632 Guangdong , China.

Obesity is a metabolic syndrome worldwide that causes many chronic diseases. Recently, we found an antiobesity effect of flaxseed polysaccharide (FP), but the mechanism remains to be elucidated. In this study, rats were first induced to develop obesity by being fed a high-fat diet. The obese rats were then fed a control diet, AIN-93M (group HFD), or a 10% FP diet (group FPD). The body weight, body fat, adipose tissue and liver sections, serous total triglycerides, levels of fasting blood glucose in serum, serous insulin, inflammatory cytokines in serum, and serous proteins within the leptin-neuropeptide Y (NPY) and AMP-activated protein kinase (AMPK) signaling pathway were determined and analyzed. FP intervention significantly reduced body weight and abdominal fat from 530 ± 16 g and 2.15% ± 0.30% in group HFD to 478 ± 10 g and 1.38% ± 0.48% in group FPD, respectively. This effect was achieved by removing leptin resistance possibly by inhibiting inflammation and recovering satiety through the significant downregulation of NPY and the upregulation of glucagon-like peptide 1. Adiponectin was then significantly upregulated probably via the gut-brain axis and further activated the AMPK signaling pathway to improve lipid metabolism including the improvement of lipolysis and fatty acid oxidation and the suppression of lipogenesis. This is the first report of the proposed antiobesity mechanism of FP, thereby providing a comprehensive understanding of nonstarch polysaccharides and obesity.
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http://dx.doi.org/10.1021/acs.jafc.9b02434DOI Listing
June 2019