Biology subjects

wang, d.

Publications and source records attributed to wang, d..

7 recordsLinked to original sources

bioRxiv2024

AKR1C mediates the acquired resistance to T-Dxd in a HER-2 positive gastric cancer line

Trastuzumab deruxtecan (T-Dxd), an anti-HER2 antibody-drug conjugate, has significantly enhanced clinical outcomes for patients as a HER2-directed therapy compared to previous standards of care. However, acquired resistance is always a concern, necessitating further investigation into the underlying resistance mechanism. In this study, we successfully established T-Dxd-resistant cell line (N87-R) by exposing HER2-positive N87 gastric cancer cells to increasing concentrations of T-Dxd, and demonstrated its resistance phenotype both in vitro and in vivo. While there were no changes in HER2 expression or T-Dxd binding in N87-R, a signature of drug metabolism genes were found upregulated, among which AKR1C played a critical role in the resistance mechanism. The resistance phenotype of N87-R cells was mitigated by both siRNA-mediated knockdown of AKR1C and pharmacological inhibition of its enzymatic activity. Our preclinical study underscores the critical role of AKR1C function in mediating T-Dxd resistance and suggests potential therapeutic innovation for combating T-Dxd resistance.

cancer biology↗

bioRxiv2024

Apelin-13 in the paraventricular nucleus protects myocardium from ischemia via V1a receptor of the paraventricular nucleus and GABAA receptor γ2 of the nucleus tractus solitarii in rats

BackgroundApelin system plays a significant role in central blood pressure regulation, but its role in neural control of myocardial injury protection is poorly understood. Thus, this study was undertaken to evaluate the effects of apelin-13 in the paraventricular nucleus (PVN) on myocardial infarction (MI) and ischemia/reperfusion (I/R). MethodsThe cardiac functions were assessed after microinjecting or transferring the apelin-13 gene into the paraventricular nucleus (PVN) of rat models with myocardial infarction (MI) or ischemia/reperfusion (I/R). ResultsIn MI rats, we showed that apelin-13 expression decreased in PVN, V1a receptor expression increased in PVN and nucleus tractus solitarii (NTS), and GABAA receptor (GAR) {gamma}2 expression increased in NTS. In primary cultured hypothalamus and medulla oblongata neurons, V1a receptor expression was downregulated by APJ receptor antagonist or GAR agonist, indicating that there are interactions between these receptors in neurons. Apelin-13 overexpression in PVN significantly improved cardiac function of MI and I/R rats, including left-ventricular end-diastolic diameter, left-ventricular end-systolic diameter, left-ventricular ejection fraction, and left-ventricular fractions shortening, accompanied by decreased noradrenaline and increased vasopressin plasma levels. Myocardial ischemia-related apoptotic and inflammatory pathway markers (Bcl-1, Bax, TGF-{beta}1, CCR5, Smad2) were downregulated and four neuropeptides of the parasympathetic endocrine system (somatostatin, cholecystokinin, glucagon-like peptide 1, vasoactive intestinal peptide) were increased in serum correspondingly with cardiac function improving. V1a receptor antagonist in PVN or NTS and GAR agonist in NTS decreased the effects of apelin-13 overexpression on cardiac function of MI and I/R rats. ConclusionsOverexpression of apelin-13 in PVN leads to cardiac function improvement via V1a receptor in PVN and NTS, and GAR{gamma}2 in NTS. Parasympathetic endocrine system and myocardial ischemia-related apoptotic and inflammation signaling pathways are involved in apelin-13 in PVN-mediated cardiac function regulation, which provides evidence for neural regulation of cardiovascular diseases.

neuroscience↗

bioRxiv2024

Comparative metabolomics of wild and cultivated yew: insights into metabolic diversity and environmental adaptability

Taxus cuspidata is a well-known gymnosperm with great ornamental and medicinal value. The study aims to reveal the metabolic differences between wild and cultivated species of T. cuspidata, and to analyze the genetic and ecological factors behind these differences. This study conducted a comparative metabolomics analysis of wild and cultivated T. cuspidata based on LC-MS/MS technology. The results showed: (1) A total of 7030 metabolites were identified, primarily including flavonoids, organic acids, phenolic acids, amino acids and their derivatives, lipids, and alkaloids, among others; (2) 2381 differential metabolites were confirmed: 949 higher in cultivated species and 1432 higher in wild species, which suggesting wild species have more advantageous metabolites. (3) Through KEGG annotation, 20 significant metabolic pathways were identified, with sugar metabolism, photosynthesis, and sulfur metabolism were significantly higher in wild species. In contrast, pathways related to most amino acids and their derivatives, flavonoids, terpenoids, polyphenols, alkaloids, and plant hormones were significantly higher in cultivated species. In conclusion, the wild species are inferior to cultivated species in terms of drought resistance, growth rate, and medicinal value for cancer treatment. However, the advantage of wild species lies in their significantly higher diversity of upregulated secondary metabolites due to their rich genetic resources, which exhibit greater metabolic diversity and environmental adaptability, which enhances their survival capability. Furthermore, the wild species exhibit significantly higher efficiency in photosynthesis and sugar metabolism compared to cultivated species, enabling them to better withstand low-temperature stress. This study has provided the direction for research into the mechanisms of stress resistance in T. cuspidata and has also established a theoretical basis for formulating scientifically and reasonable conservation strategies for wild species.

molecular biology↗

bioRxiv2024

Adipocyte microRNA-802 promotes adipose tissue inflammation and insulin resistance by modulating macrophages in obesity

Adipose tissue inflammation is now considered to be a key process underlying metabolic diseases in obese individuals. However, it remains unclear how adipose inflammation is initiated and maintained or the mechanism by which inflammation develops. We found that microRNA-802 (miR-802) expression in adipose tissue is progressively increased with the development of dietary obesity in obese mice and humans. The increasing trend of miR-802 preceded the accumulation of macrophages. Adipose tissue-specific knockout of miR-802 lowered macrophage infiltration and ameliorated systemic insulin resistance. Conversely, the specific overexpression of miR-802 in adipose tissue aggravated adipose inflammation in mice fed a high-fat diet. Mechanistically, miR-802 activates noncanonical and canonical NF-{kappa}B pathways by targeting its negative regulator, TRAF3. Next, NF-{kappa}B orchestrated the expression of chemokine and SREBP1, which translated into strong recruitment and M1-like polarization of macrophages. Our findings indicate that miR-802 endows adipose tissue with the ability to recruit and polarize macrophages, which underscores miR-802 as an innovative and attractive candidate for miRNA-based immune therapy for adipose inflammation.

immunology↗

bioRxiv2020

CPEB2 m6A Methylation Regulates BTB Permeability via Affecting Splicing Factor SRSF5 Stability

The existence of the blood tumor barrier (BTB) severely hinders the delivery of anti-tumor drugs to gliomas, affecting the targeted therapeutic effects of drugs. Therefore, BTB selective opening has become a hot spot for glioma treatment. This study found that the up-regulated METTL3 and IGF2BP3 in GECs increase the stability of CPEB2 mRNA through m6A methylation of CPEB2 mRNA; CPEB2 binds and increases the stability of splicing factor SRSF5 mRNA; SRSF5 promotes the ETS1 exon inclusion; P51-ETS1 promotes the transcriptional expression of tight junction related proteins ZO-1, occludin and claudin-5, regulating BTB permeability. CPEB2, SRSF5 and P51-ETS1 alone or in combination can effectively enhance the role of Dox in promoting glioma cell apoptosis through BTB. The results of this study provide a new theoretical and experimental basis for the molecular regulation of BTB from the perspective of epigenetics, as well as new ideas for the comprehensive treatment of glioma.

cancer biology↗

bioRxiv2020

Allantoin induces pruritus by activating MrgprD in chronic kidney disease

Chronic kidney disease is a disease with decreased, irreversible renal function. Pruritus is the most common skin symptom in patients with chronic kidney disease, especially in end-stage renal disease (AKA chronic kidney disease-associated pruritus [CKD-aP]); however, the underlying molecular and neural mechanism of the CKD-aP in patients remains obscure. Our data show that the level of allantoin increases in the serum of CKD-aP and CKD model mice. Allantoin could induce scratching behavior in mice and active DRG neurons; the calcium influx and the action potential were significantly reduced in DRG neurons of MrgprD KO or TRPV1 KO mice. U73122, an antagonist of PLC, could also block calcium influx in DRG neurons induced by allantoin. Thus, our results concluded that allantoin plays an important role in CKD-aP, mediated by MrgprD and TrpV1, in CKD patients.

pathology↗

bioRxiv2018

A preliminary study of the calcification reason of pit mud

Pit mud play a key role in the brewing process of Chinese Strong-flavour liquor. In this study, the organic acids and metal ions was determinated by Ion Chromatograph and Inductively Coupled Plasma Mass Spectrometry, respectively. The diversities and structures in pit mud were analyzed by using high-throughput sequencing based on Illumina Miseq platform. The results showed that the lactic acid in calcified pit mud was about 10 times higher than quality pit mud, and the calcium ions was about 20 times higher than quality pit mud. It could found a strange phenomenon, the calcified pit mud had more pyruvic acid and quality pit mud basically does not had this kind of material. The data analysis shown that the pit mud were detected prokaryotes 908 strains and the eukaryotes 226 strains. It was found that the Lactobacillus and Prevotella in calcified pit mud (the total of both increase 11 times) had a higher percentage. It can be guess that the lactic acid and metal ions would form lactic acid salt compounds and those compounds could affect the growth and reproduction of microbes in pit mud. This study provided a good comparison of physical and chemical properties between the calcified pit mud and the quality pit mud, which was significant for the maintenance of pit mud and the quality of liquor. Because of the first study for pit mud by using high-throughput sequencing, it could provide theoretical basis for improving microbes in pit mud.

microbiology↗