Yao Yang

Sun Yat-sen University

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Xiaowei Zeng

Sun Yat-sen University

Lin Mei

Chinese Academy of Medical Sciences & Peking Union Medical College

Hongzhong Chen

Sun Yat-sen University

Zimu Li

Sun Yat-sen University

Jinyuan Li

Second Affiliated Hospital of Nanchang University

Nansha Gao

Sun Yat-sen University

Xin Pan

Sun Yat-sen University

Chuanbin Wu

Jinan University

Zhengwei Huang

Jinan University

Ying Huang

Beijing Radiation Center

Cooperative Institutions

Sun Yat-sen University

Shanghai Jiao Tong University

Qingdao University

Chinese Academy of Sciences

Chinese Academy of Medical Sciences & Peking Union Medical College

Army Medical University

Peking University

Novartis (Switzerland)

Chongqing Medical University

Affiliated Hospital of Qingdao University

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Shikonin Mediates Apoptosis through G Protein-Coupled Estrogen Receptor of Ovarian Cancer Cells

Evidence-based Complementary and Alternative Medicine (2022)

Xinyue Liu Yao Yang Xuefei Tang Li Guo Xinhui Tang

This study was intended to establish the predictive target of Shikonin (SK) against ovarian cancer using network pharmacology and to clarify the potential mechanism of SK in promoting apoptosis in ovarian cancer. Cell Counting Kit-8 assay, plate clone assays, LDH assay, flow cytometric analysis of Annexin V-fluorescein isothiocyanate/propidium iodide staining, and western blotting were used to assess the effect of SK on apoptosis of ovarian cancer cell lines (SKOV3 and A2780). Pharmacodynamic targets were used to predict the targets of SK and ovarian cancer. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment analyses were used to analyze the biological functions and signal pathways of these targets. SK promoted apoptosis in ovarian epithelioid adenocarcinoma cells. SK-ovarian cancer pharmacodynamic target analysis screened 17 related genes. GO and KEGG analyses showed that SK affected the estrogen signaling pathway. SK inhibited the expression of GPER in SKOV3 and A2780 cells and downregulated the expression of EGFR, p-EGFR, PI3K, and p-AKT in a concentration-dependent manner. The apoptosis-promoting effect of SK was enhanced by GPER-specific agonist G1 and inhibited by the specific inhibitor G15. The expression of EGFR, p-EGFR, PI3K, and p-AKT was decreased by G1 and reversed by G15. SK also inhibited tumor growth in the SKOV3 xenograft model, and it acted synergistically with G1. However, the effect can be attenuated by G15 in vivo. In summary, SK may affect the apoptosis of ovarian cancer cells through GPER/EGFR/PI3K/AKT, and GPER may be a key target of SK in ovarian cancer cell apoptosis.

GPER

Propidium iodide

KEGG

10.1155/2022/6517732

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Citations (3)

[p53 mutations and protein overexpression in primary colorectal cancer and its liver metastasis].

PubMed (1999)

Yao Yang Xia Qin Fang Lian

To compare p53 status between primary and hepatic metastatic colorectal cancer in 34 patients.p53 gene status (exon 5-9) was examined by PCR, denaturing gradient gel electrophoresis (DGGE) and automated sequencing. p53 protein was detected by immunohistochemistry using monoclonal antibody DO-7.p53 mutations were found in exons 5 through 9 in 21 of 34 patients (61.8%). Among them, 5 patients had mutation in liver metastasis but not in their primary tumor while in the other 4 patients the same mutations were found in both primary and metastatic colorectal cancers. In no patients was p53 mutation exclusively found in the primary colorectal tumor. Moreover, additional mutation was detected in the metastatic lesions in two cases. Of the 37 mutations within the exons examined, 73% was missense mutation and 16% was nonsense mutation. There were 4 microinsertions. p53 protein was overexpressed in both primary and metastatic colorectal cancers with p53 gene mutations. The presence of p53 mutations significantly correlated with p53 protein accumulation (r = 0.96, P < 0.001). However, in 4 patients with p53 nonsense mutation, immunohistochemical staining was negative. In three patients who showed no p53 mutation of the primary tumor, p53 protein was consistently over-expressed.In colorectal cancer, p53 gene mutation usually appears first in the primary tumor and maintains as such but more prominent when metastasized to the liver. However, p53 gene mutation may occur only after being metastasized. Although p53 gene mutation and p53 protein overexpression correlate with each other, either parameter examined alone may lead to false positive results.

Nonsense mutation

Primary tumor

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Citations (1)

Streptococcal toxic shock syndrome complicating varicella in children.

PubMed (1997)

Yao Yang Ching Chuan Liu Shih Min Wang Chao Huang Jiunn Jong Wu

Lethargy

Chicken Pox

Fulminant

Toxic shock syndrome

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Charge-reversal nanomedicine based on black phosphorus for the development of A Novel photothermal therapy of oral cancer

Drug Delivery (2021)

Zimu Li Qingyun Liu Yi Zhang Yao Yang Xiaomin Zhou

Driven by the lifestyle habits of modern people, such as excessive smoking, drinking, and chewing betel nut and other cancer-causing foods, the incidence of oral cancer has increased sharply and has a trend of becoming younger. Given the current mainstream treatment means of surgical resection will cause serious damage to many oral organs, so that patients lose the ability to chew, speak, and so on, it is urgent to develop new oral cancer treatment methods. Based on the strong killing effect of photothermal therapy on exposed superficial tumors, we developed a pH-responsive charge reversal nanomedicine system for oral cancer which is a kind of classic superficial tumor. With excellent photothermal properties of polydopamine (PDA) modified black phosphorus nanosheets (BP NSs) as basal material, then used polyacrylamide hydrochloride-dimethylmaleic acid (PAH-DMMA) charge reversal system for further surface modification, which can be negatively charged at blood circulation, and become a positive surface charge in the tumor site weakly acidic conditions due to the breaking of dimethylmaleic amide. Therefore, the uptake of oral cancer cells was enhanced and the therapeutic effect was improved. It can be proved that this nanomedicine has excellent photothermal properties and tumor enrichment ability, as well as a good killing effect on oral cancer cells through in vitro cytotoxicity test and in vivo photothermal test, which may become a very promising new model of oral cancer treatment.

Black Phosphorus

10.1080/10717544.2021.1909176

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Citations (23)

Smart materials for drug delivery and cancer therapy

View (2020)

Yao Yang Weiwei Zeng Ping Huang Xiaowei Zeng Lin Mei

Abstract Until now, enormous smart materials have been engineered with endogenous stimulators such as pH, reactive oxygen species, glutathione, hypoxia and enzyme, or exogenous stimulators such as temperature, light, ultrasound, radiation, and magnetic field in drug delivery. As footstone of stimuli‐responsive nanocarriers, endogenous/exogenous responsive smart materials possess many properties, such as responding ability to specific triggers, controlled drug release, long blood circulation, increased tumor accumulation, “ON‐OFF” switch activities, enhanced diagnostic accuracy, and therapeutic efficacy. Smart materials have attracted considerable attention because they provide likelihood strategy for individualized and comprehensive therapy. In this review, significant research achievements of smart materials responsive to different triggers including their synthesis and formulation mechanism, responsive mechanism, applications, multiple functions are summarized and discussed separately. We primarily focus on the studies in the past few years (2017‐2020). The current situation and remaining challenges of stimuli‐sensitive materials‐based nanocarriers for clinical translation are discussed rationally at the end. It is hope that this timely and overall review would provide some helpful information for researchers in this field.

Nanocarriers

Targeted drug delivery

10.1002/viw.20200042

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Citations (137)

Polymeric microneedle‐mediated sustained release systems: Design strategies and promising applications for drug delivery

Asian Journal of Pharmaceutical Sciences (2021)

Yang Li Yao Yang Hongzhong Chen Lin Mei Xiaowei Zeng

Parenteral sustained release drug formulations, acting as preferable platforms for long-term exposure therapy, have been wildly used in clinical practice. However, most of these delivery systems must be given by hypodermic injection. Therefore, issues including needle-phobic, needle-stick injuries and inappropriate reuse of needles would hamper the further applications of these delivery platforms. Microneedles (MNs) as a potential alternative system for hypodermic needles can benefit from minimally invasive and self-administration. Recently, polymeric microneedle-mediated sustained release systems (MN@SRS) have opened up a new way for treatment of many diseases. Here, we reviewed the recent researches in MN@SRS for transdermal delivery, and summed up its typical design strategies and applications in various diseases therapy, particularly focusing on the applications in contraception, infection, cancer, diabetes, and subcutaneous disease. An overview of the present clinical translation difficulties and future outlook of MN@SRS was also provided.

Hypodermic needle

Delivery system

Clinical Practice

10.1016/j.ajps.2021.07.002

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Citations (57)

Invasive fungal infections in pediatric patients with leukemia: emphasis on pulmonary and dermatological manifestations.

PubMed (2005)

Shih Min Wang Yao Yang Jiann Shiuh Chen Hui‐Chen Lin Chia Yu

Patients of hematological malignancies with neutropenia form one of the most susceptible host groups for microbial infection. In this study, we concentrated on the pulmonary and cutaneous manifestations of invasive fungal infections in leukemic children, aiming to make early diagnosis and intervention. Clinical, laboratory, radiological, and histopathological findings concerning 13 leukemic children who had invasive fungal infection between 1997 and 2002 were retrospectively reviewed. Seventy-seven percent (10/13) of diagnoses were made by fungal cultures and/or by histopathological evidence from various specimens, four from cutaneous lesions and six from pulmonary tissues. Candidiasis was the most common infection (69%), followed by mucormycosis (15%), fusariosis (8%), and aspergillosis (8%). Three episodes of fungemia (23%) were identified. Lung (69%) and skin (69%) were the two most common sites of disseminated fungal infections. A premortem diagnosis was documented in 92% of the patients. Pathogens other than Candida albicans (85%) accounted for the great majority of cases. The case-fatality rate was 31% of disseminated fungal infections. A vigilant assessment of any suspicious lesion by physical and radiological examinations, including a biopsy of the lesions for microbiological and histopathological studies, may provide helpful for early diagnosis of disseminated fungal infections in leukemic children.

Histopathology

Fungemia

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Citations (5)

Homozygous deletions, mutation and abnormal expression of p16 gene in ovarian carcinoma

Rongjian Su Yao Yang Liang Shi Changlong Lu YU Cheng-guo

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Inhibition of Notch1 Signaling Alleviates Endotoxin-Induced Inflammation Through Modulating Retinal Microglia Polarization

Frontiers in Immunology (2019)

Zhixing Cheng Yao Yang Fang Duan Bingsheng Lou Jieting Zeng

Microglial cells are resident immune cells and play an important role in various cerebral and retinal inflammatory diseases. Notch1 signaling is involved in the microglia polarization and the control of cerebral inflammatory reactions. However, its role in endotoxin-induced uveitis (EIU) remains unknown. This study aimed to investigate the role of Notch1 signaling on retinal microglia polarization and inflammation in the cultured retinal microglial cells and EIU rat model. We found that Notch1 signaling blockade with N-[N-(3, 5-difluorophenacetyl)-1-alany1-S-phenygly -cine t-butyl ester (DAPT) shifted retinal microglia phenotype from pro-inflammatory M1 phenotype (COX2+ and iNOS+) to anti-inflammatory M2 phenotype (Arg-1+) and reduced the release of pro-inflammatory cytokines both in vivo and in vitro. Moreover, DAPT treatment contributed to prevent retinal ganglion cells from apoptosis, reduce the intraocular infiltrating cells, and attenuate the impairment of retinal function. Taken together, these results suggest that inhibition of Notch1 signaling could alleviate the inflammatory response in EIU rat mainly through regulating the polarization of retinal microglia. Therefore, Notch1 signaling might be a promising therapeutic target in the treatment of ocular inflammatory diseases.

10.3389/fimmu.2019.00389

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Toward a Scalable Synthesis and Process for EMA401, Part I: Late Stage Process Development, Route Scouting, and ICH M7 Assessment

Organic Process Research & Development (2020)

Leo A. Hardegger Franck Mallet Barbara Bianchi Chunlong Cai Alexandre Grand‐Guillaume Perrenoud

We present the enantioselective synthesis of sodium (3S)-5-(benzyloxy)-2-(diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (EMA401, olodanrigan), an angiotensin II type 2 antagonist. The manuscript features the process optimizations of the end game used for late phase clinical supplies, an overview of synthetic strategies identified in a route scouting exercise to a key intermediate phenylalanine derivative, and the analytical control strategy of the potentially formed highly toxic impurity bis(chloromethyl) ether (BCME). Starting from the phenylalanine derivative, we describe the optimizations of the end game from early phase to late phase processes with consequent improvements in the PMI factor. This sequence includes a Pictet–Spengler cyclization and an amide coupling as the last bond-forming steps, and the manufacturing process was successfully implemented on a 175 kg scale in a pilot plant setup. The modified process conditions eliminated one step by in situ activation of the carboxylic acid, avoided the REACH listed solvent DMF, and resulted in a PMI improvement by a factor of 3. In the final crystallization, a new, thermodynamically more stable modification of the drug substance was found in the complex solid-state landscape of EMA401 during an extensive polymorph screening. A process suitable for large-scale production was developed to prepare the new polymorph, avoiding the need of any special equipment such as fluidized bed drying required in the early phase process. In the second section, some of the synthetic approaches investigated for the route scouting of the phenylalanine derivative key intermediate are presented. To conclude, we discuss the analytical control strategy for BCME, the formation of which, due to the simultaneous presence of HCl and CH2O in the Pictet–Spengler cyclization, could not be ruled out. The BCME purge factor calculations using the tools of ICH M7 control option 4 are compared to actual results from spiking experiments.

Derivative (finance)

Peptide bond

Peptide Synthesis

10.1021/acs.oprd.0c00215

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Citations (7)