Biology subjects

zhao, j.

Publications and source records attributed to zhao, j..

7 recordsLinked to original sources

bioRxiv2026

Dronedarone hydrochloride reverses obesity-related metabolic syndrome while preserving skeletal muscle mass

Obesity-driven metabolic syndrome poses a critical global threat, yet standard therapies like GLP-1 receptor agonists trigger substantial lean mass wasting, with muscle loss accounting for up to 40% of reduced weight. Here we identify a non-canonical metabolic application for dronedarone hydrochloride, an anti-arrhythmic benzofuran derivative. In diet-induced and ob/ob obese mice, short-term dronedarone hydrochloride administration dose-dependently reduces food intake, clears visceral and subcutaneous adiposity, and reverses steatohepatitis. Head-to-head trials show that dronedarone hydrochloride achieves glycemic control and fat clearance non-inferior to semaglutide, tirzepatide, and empagliflozin, but uniquely and completely preserves skeletal muscle mass. Mechanistically, dronedarone hydrochloride operates independently of central hypothalamic appetite-regulating neuropeptides and the peripheral leptin pathway. By decoupling fat reduction from sarcopenia, our findings establish dronedarone hydrochloride as a muscle-sparing therapeutic candidate for metabolic syndrome.

pharmacology and toxicology↗

bioRxiv2024

Complex genetic architecture underlying the plasticity of tobacco leaf width provides insight into across-environment genomic prediction

Phenotypic plasticity refers to the ability of a given genotype to produce multiple phenotypes in response to changing environmental conditions. Understanding the genetic basis of phenotypic plasticity and developing predictive models for agronomic traits are crucial for future agricultural adaptation to climate change. In this study, we investigated the genetic basis of leaf width mean (LWm) and plasticity (LWp) in a tobacco multiparent advanced generation inter-cross (MAGIC) population which consisting of 594 individuals. We identified 14 quantitative trait loci (QTLs) significantly associated with LWm, 43 with LWp. Our findings suggest that dynamic changes in QTL effects across environments, along with polygenic effects, may underlie the genetic basis of leaf width plasticity. Among them, qLW14 was narrowed down to a 3 Mb structural variation region. When this fragment was deleted in tobacco, plants exhibited increased leaf width, but only under specific environmental conditions. This finding suggests that the key gene within qLW14 may act as a negative regulator of leaf width through interactions with specific environmental factors. By integrating genetic diversity, environments variation, and their interactions into a GEAI model, we were able to build a framework for cross-environment prediction, improving prediction accuracy by 8.7% when compared to traditional model. Overall, this study highlights the complex genetic basis underlying LWp, involving multiple alleles and genotype-environment interactions. These findings provide valuable insights into the role of phenotypic plasticity in plant adaptation to environmental changes.

genetics↗

bioRxiv2024

Single-cell RNA sequencing of peripheral blood mononuclear cells reveals complex cellular signalling signatures of metformin treatment type 2 diabetes mellitus

ObjectiveType 2 diabetes mellitus (T2DM) is a complex polygenic disease. The onset of the disease is related to autoimmunity. However, how immune cells function in the peripheral blood remains to be elucidated. Metformin is the first-line treatment. Exploring biomarkers of T2DM based on single-cell sequencing technology can provide new insights for the discovery of metformin treatment T2DM in molecular mechanisms. MethodsWe profiled 43,971 cells and 20,228 genes from peripheral blood mononuclear cells (PBMCs) of T2DM patients and healthy controls by single-nucleotide RNA sequencing. ResultsB cells, T cells, monocytes/macrophages, platelets, neutrophils, NK cells and cDC2s were grouped into 7 subclusters. Furthermore, T cells and monocytes/macrophages might be significantly correlated with the clinical characteristics of T2DM patients. RPL27 and AC018755.4 expression were strongly negative correlated with HbA1c. CD4+ T cells are mainly in the memory activation stage, and CD8+ T cells are effectors. The 50 genes whose expression varied with developmental time were associated with cytoplasmic translation, cell-cell adhesion mediated by integrin, and the regulation of the inflammatory response. Monocytes/macrophages include classic monocytes and nonclassical monocytes. The GSEA results showed that the marker genes were enriched in the HALLMARK_INTERFERON_GAMMA_RESPONSE and HALLMARK_TNFA_SIGNALING_VIA_NFKB. The WGCNA results showed 14 modules. Meanwhile, TNFRSF1A is the most core genes in network interaction. Further analysis revealed ligand-receptor pairs, including MIF-(CD74 + CD44), MIF-(CD74 + CXCR4), ANXA1-FPR1 and LGALS9-CD45. ConclusionsOur study revealed that the transcriptional map of immune cells from PBMCs provided a framework for understanding the immune status of T2DM patients with metformin treatment via scRNA-seq analysis.

immunology↗

bioRxiv2020

The mechanism of analgesia in Nav1.7 null mutants

Deletion of SCN9A encoding the voltage-gated sodium channel NaV1.7 in humans leads to profound pain insensitivity and anosmia. Conditional deletion of NaV1.7 in sensory neurons of mice also abolishes pain suggesting the locus of analgesia is the nociceptor. Here we demonstrate that NaV1.7 knockout mice have essentially normal nociceptor activity using in vivo calcium imaging and extracellular recording. However, glutamate and substance P release from nociceptor central terminals in the spinal cord is greatly reduced by an opioid-dependent mechanism. Analgesia is also substantially reversed by central but not peripheral application of opioid antagonists. In contrast, the lack of neurotransmitter release from olfactory sensory neurons is opioid-independent. Male and female humans with NaV1.7 null mutations show naloxone reversible analgesia. Thus opioid-dependent inhibition of neurotransmitter release is the principal mechanism of NaV1.7 null analgesia in mice and humans.

neuroscience↗

bioRxiv2019

The Structural Basis for Glycerol Permeation by human AQP7

Human glycerol channel AQP7 conducts glycerol release from adipocyte and entry into the cells in pancreatic islets, muscles and kidney tubule, and thus regulate glycerol metabolism in those tissues. Compared with other human aquaglyceroporins, AQP7 shows a less conserved "NPA" motif in the center cavity, and a pair of aromatic residues at Ar/R selectivity filter. To understand the structural basis for the glycerol conductance, we crystallized the human AQP7 and determined the structure at 3.7 [A]. A substrate binding pocket was found near to the Ar/R filter and the bound glycerol molecule stabilized by R229. In vivo functional assay on human AQP7 as well as AQP3 and AQP10 demonstrated strong glycerol transportation activities at physiological condition. The human AQP7 structure reveals a fully closed conformation with its permeation pathway strictly confined by Ar/R filter at the exoplasmic side and the gate at the cytoplasmic side, and the dislocation of the residues at narrowest parts of glycerol pathway in AQP7 play a critical role in controlling the glycerol flux.

molecular biology↗

bioRxiv2019

Anlotinib overcomes multiple drug resistant of the colorectal cancer cells via inactivating PI3K/AKTpathway

BackgroundAnlotinib is a multi-tyrosine kinase inhibitor that has been reported to have activity against colorectal cancer. However, the functional mechanisms whereby anlotinib mediates against deadly drug-resistant colorectal cancer (CRC) has not been fully described-specifically, the potential mechanisms that inhibit proliferation and induce apoptosis remain largely unknown. MethodsMTT assays were used to detect cell viability and calculate the resistance index. Colony formation was used to evaluate the proliferation of resistant cells. DAPI staining was used to detect cell apoptosis morphologically. Annexin V-FITC with PI staining was used to detect early and late-stage apoptosis of cells. Cell cycle distribution was determined by Flow cytometry. Transwell assays were performed to examine the ability of migration and invasion. Cyclin D1 Survivin, CDK4, Bcl-2, Bax and changes of PI3K/AKT pathway were detected by Western blotting. Compared as a single agent or combined with anlotinib or LY294002, PI3K inhibitor (LY294002) was used to verify whether it inhibited drug-resistant CRC cells by lowering PI3K/AKT. ResultsHCT-8/5-FU cells showed multiple drug resistance. Drug resistance index of 5-FU, ADM and DDP were 390.27, 2.55 and 4.57, respectively. Anlotinib was shown to inhibit cell viability on HCT-8/5-FU and HCT-8 cells for 24 h and 48 h in a dosage- and time-dependent pattern. Compared with 48 h, intervened with anlotinib (0 M, 10 M, 20 M and 40 M) for 24 h, the HCT-8/5-FU cells were sensitive to anlotinib, and their sensitivity was greater than that of the parent cell line (HCT-8) at 24 h. Further, anlotinib inhibited the number of cloned cells significantly and had a significant inhibitory effect on cell cycle, mainly by blocking G1 transferring to S phase. Moreover, anlotinib could down-regulate the expression of survivin, cyclin D1, CDK4, caspase-3, Bcl-2, MMP-2, vimentin, MMP-9, and N-cadherin, while up-regulating cleaved-caspase-3, Bax and E-cadherin. Anlotinib inhibited the activity of the PI3K/AKT pathway and induced apoptosis in HCT-8/5-FU cells. Using LY294002, a specific PI3K inhibitor, our experiment found anlotinib can inhibit drug-resistant CRC cells by reducing PI3K and p-AKT activity-induce apoptosis. ConclusionsAnlotinib inhibited the proliferation, metastasis and induced apoptosis of HCT-8 / 5-FU cells; and the mechanism could be that anlotinib overcomes multiple drug resistant of the colorectal cancer cells via inactivating PI3K/AKT pathway.

pharmacology and toxicology↗

bioRxiv2019

The transmission of Hand, Foot, and Mouth Disease in East and Southeast Asia

Hand Foot and Mouth Disease (HFMD) is in endemic in many countries in East and Southeast Asia, including those in the tropical or subtropical climate zones. To substantially reduce HFMD, it is necessary to design effective control measures, which is based on a deep understanding of the disease transmission. However, the transmission mechanism of HFMD was rarely studied. The cyclic pattern of HFMD incidence is believed to be related to climatic factors, rather than school terms as observed from childhood infectious diseases in developed countries in the prevaccination era. Furthermore, the association of incidence and climatic factors in different locales in China are inconsistent and even contradictory. Here we selected countries or regions in typical climatic zones in East and Southeast Asia to study the transmission rate and its seasonality for HFMD. Countries or regions selected representing temperate, subtropical and tropical zones are Japan, Hong Kong SAR, Macau SAR and Singapore. Comparatively, we chose provinces in mainland China in three climate zones and contrast them with above selected regions or countries. We used Time Series Susceptible Infected Recovered (TSIR) model to estimate the HFMD transmission rate. The parameters in the TSIR model were estimated by Markov Chain Monte Carlo (MCMC). We then used a linear regression model to analyze the effects of climate factors, seasonal contact rate in children (and seasonal contact rate in population for provinces in China) on the transmission rate of HFMD in selected regions. We found that: 1) transmission rate of HFMD is highly seasonal in the studied countries, SARs and provinces of mainland China, except Singapore; 2) the HFMD transmission rate can be affected by the climatic factors as well as the seasonal contact rate of population, depending on which factor is dominant; 3) The transmission rate in provinces in China increased dramatically during the time period of Chinese Spring Travel Rush that has higher population contact; 4) transmission rate seasonality in Japan, Hong Kong SAR and Macau SAR is affected by climatic factors.\n\nAuthor SummaryHand, Foot and Mouth Disease (HFME) is endemic in East and Southeast Asia with reported cases of more than two million every year. The epidemic patterns such as annual cyclic pattern of reported HFMD cases have been observed and studied for the purpose of understanding the disease. The mechanisms that describe how a disease is transmitted cannot be observed, however they lead to the observed epidemic patterns of the disease. We analyzed the transmission rate (that help to understand the transmission mechanism) of HFMD in selected countries or regions that represent territories in tropical, subtropical and temperate climatic zones in East and Southeast Asia and compared the HFMD transmission in these regions. We also analyzed the possible driving factors of the seasonal transmission of HFMD. The transmission of HFMD can be affected by both social behavior and climatic factors, however either of them can dominant the effect on HFMD transmission depending on regions or countries. In mainland China, high population contact rate is the dominant factor to have high HFMD transmission; while in Japan, Hong Kong SAR and Macau SAR, climatic factors have the dominant effect. These findings can help design effective control measures.

epidemiology↗