Biology subjects

Cao, N.

Publications and source records attributed to Cao, N..

9 recordsLinked to original sources

bioRxiv2026

S-nitrosylation of protein kinase A is required for its activation by GPCRs

Stimulation of many G protein-coupled receptors (GPCRs) increases cyclic adenosine monophosphate (cAMP) and nitric oxide (NO). While cAMP-dependent activation of protein kinase A (PKA) is a central regulatory mechanism, a parallel role for NO in GPCR transduction has not been established. Here we show that upon stimulation of multiple GPCRs in heart, brain, and fat, the regulatory subunits of PKA undergo enzymatic S-nitrosylation by SNO-CoA-assisted nitrosylase (SCAN). S-nitrosylation by SCAN is required for dissociation of PKA holoenzymes and activation of PKA. In transgenic and cardiovascular disease models, impaired adrenergic stimulation is identified with deficient S-nitrosylation of PKA, which can be rescued by the drug sodium nitroprusside. Our work suggests a new understanding of GPCR physiology with direct application to the clinical setting.

physiology↗

bioRxiv2026

A quantitative proteomics dataset for assessment and prediction of low dose X-ray radiation exposure in mice.

Ionizing radiation induces molecular responses that may be used to estimate exposure when physical dosimeters are unavailable. Here we present two large-scale proteomics datasets generated from mouse dorsal skin punch samples collected following controlled X-ray exposures spanning multiple doses, dose rates, and post-exposure time points. Experiment 1 comprised 96 samples (including 16 reference samples) collected 6 days after exposure to 0-75 cGy delivered at either 30 or 300 cGy/min. Experiment 2 comprised 936 samples (including 236 reference samples) exposed to 0-100 cGy at either 3 or 28 cGy/min dose rates and harvested between 7 and 150 days post-exposure. All samples were processed using a standardized workflow involving automated bead-based digestion and data-independent acquisition mass spectrometry. The datasets include multiple pooled reference sample types, process controls, and system suitability standards ensuring high quality data. All data presented are available via ProteomeXchange at several levels of processing, from raw files through normalized peptide- and protein-level abundance matrices suitable for biomarker discovery and machine learning applications. This dataset will facilitate generation of new insights into the biological changes and molecular signatures resulting from X-ray exposure in mice and may also help inform future studies in humans.

biochemistry↗

bioRxiv2024

Berberine is a novel mitochondrial calcium uniporter (MCU) inhibitor that disrupts MCU-EMRE assembly

The mitochondrial calcium uniporter (MCU) complex mediates Ca2+ entry into mitochondrial, which plays a crucial role in regulating cellular energy metabolism and apoptosis. Dysregulation of MCU is implicated in various diseases, such as neurodegenerative disorders, cardiac diseases and cancer. Despite its importance, developing specific and clinically viable MCU inhibitors has been challenging. Here, we identify Berberine, a well-established drug with a documented safety profile, as a potent MCU inhibitor through a virtual screening of an FDA-approved drug library. Berberine localizes within mitochondria and directly binds to the juxtamembrane loop domain of MCU. This binding disrupts the interaction of MCU with its essential regulator, EMRE, thereby inhibiting rapid Ca2+ entry into the mitochondria. Notably, Berberine pretreatment reduces mitochondrial Ca2+ overload and mitigate ischemia/reperfusion-induced myocardial injury in mice. Our findings establish Berberine as a potent MCU inhibitor, offering a safe therapeutic strategy for diseases associated with dysregulated mitochondrial calcium homeostasis.

cell biology↗

bioRxiv2022

BCAA catabolism drives adipogenesis via an intermediate metabolite and promotes subcutaneous adipose tissue expansion during obesity

Branched-chain amino acids (BCAAs, including leucine, isoleucine, and valine) have emerged as major players in metabolic health and diseases, but the underlying mechanisms remain obscure. Here, we report that BCAA catabolism drives adipogenesis via an intermediate metabolite of leucine and promotes subcutaneous white adipose tissue (sWAT) expansion during obesity. Genetic analyses of humans and mice reveal that the BCAA catabolic pathway in WAT is strongly correlated with adipose physiology and obesity traits. Altering BCAA catabolism in mature adipocytes exerts minor effects on adiposity in mice. However, enhancing adipose BCAA catabolism via FABP4-Cre-mediated Bckdk deletion promotes diet-induced obesity while blocking adipose BCAA catabolism through Bckdha ablation does the opposite. Intriguingly, the catabolism of BCAAs elicits fat depot-specific responses and promotes sWAT extension and adipogenesis in a cell-autonomous manner. Mechanistically, BCAA catabolism drives adipocyte differentiation via an intermediate metabolite of leucine, which activates mTORC1 and polyamine synthesis from methionine to promote the expression of adipogenic master regulators. Together, these results demonstrate that BCAA catabolism promotes adipogenesis and sWAT expansion during obesity. The crosstalk between leucine and methionine metabolism driven by the catabolic intermediate highlights an unexpected regulatory role of amino acids in metabolic health and diseases.

physiology↗

bioRxiv2022

The Mediator complex regulates enhancer-promoter interactions

Enhancer-mediated gene activation generally requires physical proximity between enhancers and their target gene promoters. However, the molecular mechanisms by which interactions between enhancers and promoters are formed are not well understood. Here, we investigate the function of the Mediator complex in the regulation of enhancer-promoter interactions, by combining rapid protein depletion and high-resolution MNase-based chromosome conformation capture approaches. We show that depletion of Mediator leads to reduced enhancer-promoter interaction frequencies, which are associated with a strong decrease in gene expression. In addition, we find increased interactions between CTCF-binding sites upon Mediator depletion. These changes in chromatin architecture are associated with a re-distribution of the Cohesin complex on chromatin and a reduction in Cohesin occupancy specifically at enhancers. Our results indicate that enhancer-promoter interactions are dependent on an interplay between the Mediator and Cohesin complexes and provide new insights into the molecular mechanisms by which communication between enhancers and promoters is regulated.

molecular biology↗

bioRxiv2021

Differential effects of high versus low linear energy transfer (LET) radiation on type-I interferon (IFNβ) and TREX1 responses

PurposeCancer cells produce innate immune signals following radiation damage, with STING pathway signaling as a critical mediator. High linear energy transfer (LET) radiations create larger numbers of DNA double-strand breaks (DSBs) per unit dose than low-LET radiations and may therefore be more immunogenic. We studied the dose response characteristics of pro-immunogenic type-I interferon, interferon-beta (IFN{beta}), and its reported suppressor signal, three-prime repair exonuclease 1 (TREX1), in vitro with low-LET x-rays and high-LET fast neutrons. MethodsMerkel cell carcinoma cells (MCC) were irradiated by graded doses of x-rays (1-24 Gy) or fast neutrons (1-8 Gy). IFN{beta} was measured as a function of dose via ELISA assay, and exonuclease TREX1 expression via immunofluorescence microscopy. The Monte Carlo damage simulation (MCDS) was used to model fast neutron relative biological effectiveness for DSB induction (RBEDSB) and compared to laboratory measurements of the RBE for IFN{beta} production (RBEIFN{beta}) and TREX1 upregulation (RBETREX1). RBEIFN{beta} models were also applied to radiation transport simulations to quantify the potential secretion of IFN{beta} in representative clinical beams. ResultsPeak IFN{beta} secretion occurred at 5.7 Gy for fast neutrons and at 14.0 Gy for x-rays, i.e., an effective RBEIFN{beta} of 2.5 {+/-} 0.2. The amplitude (peak value) of secreted IFN{beta} signal did not significantly differ between x-rays and fast neutrons (P > 0.05). TREX1 signal increased linearly with absorbed dose, with a four-fold higher upregulation per unit dose for fast neutrons relative to x-rays (RBETREX1 of 4.0 {+/-} 0.1). Monte Carlo modeling of IFN{beta} suggests Bragg peak-to-entrance ratios of IFN{beta} production of 40, 100, and 120 for proton, alpha, and carbon ion beams, respectively, a factor of 10-20-fold higher compared to their corresponding physical dose peak-to-entrance ratios. The spatial width of the Bragg peak for IFN{beta} production is also a factor of two smaller. ConclusionHigh-LET fast neutrons initiate a larger IFN{beta} response per unit absorbed dose than low-LET x-rays (i.e., RBEIFN{beta} value of 2.5). The RBE value for IFN{beta} is quite similar to data reported in the literature for DSB induction and cellular, post-irradiation micronucleation formation for neutrons and x-rays. The increased IFN{beta} release after high-LET radiation may be a contributing factor in stimulating a systemic anti-tumor, adaptive immune response (abscopal effect). However, our results indicate that TREX1 anti-inflammatory signaling in vitro for MCC cells is larger per unit dose for fast neutrons than for x-rays (RBETREX1 of 4.0). Given these competing effects, additional studies are needed to clarify whether or not high-LET radiations are therapeutically advantageous over low-LET radiation for pro-inflammatory immune signaling in other cell lines in vitro and for in vivo cancer models.

cancer biology↗

bioRxiv2020

Coordinated regulation of ribosomes and proteasomes by PRMT1 in the maintenance of neural stemness of cancer cells and neural stem cells

Our studies suggest that neural stemness contributes to cell tumorigenicity. The basic cell physiological machineries and developmental programs, such as cell cycle, ribosomes, proteasomes, epigenetic factors, etc., which are upregulated in and promote cancers, are enriched in embryonic neural cells. How these machineries are coordinated is unknown. Here, we show that loss of neural stemness in cancer cells or neural stem cells leads to simultaneous downregulation of components of ribosomes and proteasomes, which are responsible for protein synthesis and degradation, respectively, and downregulation of major epigenetic factors. Inhibition of PRMT1 causes neuron-like differentiation, downregulation of a similar set of proteins, and alteration of subcellular localization of ribosome and proteasome components. PRMT1 interacts with these components, catalyzes arginine methylation of them and protects them from degradation, thereby maintaining a high level of expression of epigenetic factors that maintain neural stemness. PRMT1 inhibition results in repression of cell tumorigenicity. Therefore, PRMT1 coordinates ribosomes and proteasomes to match the needs for high protein production and protein homeostasis in cells with fast cell cycle and proliferation.

cell biology↗

bioRxiv2020

Airway bacterial and fungal microbiome in chronic obstructive pulmonary disease

BackgroundLittle is known about airway mycobiome, and its relationship with bacterial microbiome in chronic obstructive pulmonary disease (COPD). MethodsHere we report the first simultaneous characterization of sputum bacterial and fungal microbiome in 84 stable COPD and 29 healthy subjects, using 16S ribosomal DNA and fungal internal transcribed spacer DNA sequencing. ResultsAscomycota predominated over Basidiomycota in fungal microbiome both in COPD patients and healthy controls. Meyerozyma, Candida, Aspergillus and Schizophyllum were most abundant at the genus level. There was a significant inverse correlation between bacterial and fungal microbial diversity, both of which altered in opposite directions in COPD patients versus controls, and in frequent versus non-frequent exacerbators. An enhanced bacterial-fungal ecological interaction was observed in COPD patients, which was characterized by higher proportion of co-occurrence intrakingdom interactions and co-exclusive interkingdom interactions. In COPD, four mutually co-occurring fungal operational taxonomic units (OTUs) in Candida palmioleophila, Aspergillus and Sordariomycetes exhibited co-exclusive relationships with other fungal OTUs, which was specifically present in frequent exacerbators but not in non-frequent exacerbators. Conversely, the mutual co-occurrence interactions between bacterial OTUs in Rothia mucilaginosa, Streptococcus, Veillonella and Prevotella, showed up in non-frequent exacerbators but not in frequent exacerbators. The perturbed bacterial-fungal interactions in COPD were associated with increased airway inflammatory mediators such as IL-6 and IL-8. InterpretationThe disruption of airway bacterial-fungal community balance, characterized by the loss of commensal bacterial taxa and enriched pathogenic fungal taxa, is implicated in COPD. The airway mycobiome is an important cofactor mediating COPD pathogenic infection and host inflammation. Clinical Trial Registrationwww.clinicaltrials.gov (NCT 03240315).

microbiology↗

bioRxiv2019

Genome-wide variations analysis of special waxy sorghum cultivar Hongyingzi for brewing Moutai liquor

AbstractsHongyingzi is a special waxy sorghum (Sorghum bicolor L. Moench) cultivar for brewing Moutai liquor. For an overall understanding of the whole genome of Hongyingzi, we performed whole-genome resequencing technology with 56.10 X depth to reveal its comprehensive variations. Compared with the BTx623 reference genome, 2.48% of genome sequences were altered in the Hongyingzi genome. Among these alterations, there were 1885774 single nucleotide polymorphisms (SNPs), 309381 small fragments insertions and deletions (Indels), 31966 structural variations (SVs), and 217273 copy number variations (CNVs). These alterations conferred 29614 genes variations. It was also predicted that 35 genes variations were related to the multidrug and toxic efflux (MATE) transporter, chalcone synthase (CHS), ATPase isoform 10 (AHA10) transporter, dihydroflavonol-4-reductase (DFR), the laccase 15 (LAC15), flavonol 3'-hydroxylase (F3'H), flavanone 3-hydroxylase (F3H), O-methyltransferase (OMT), flavonoid 3'5' hydroxylase (F3'5'H), UDP-glucose:sterol-glucosyltransferase (SGT), flavonol synthase (FLS), and chalcone isomerase (CHI) involved in the tannin synthesis. These results would provide theoretical supports for the molecular markers developments and gene function studies related to the liquor-making traits, and the genetic improvement of waxy sorghum based on the genome editing technology.

genomics↗