Biology subjects

huang, j.

Publications and source records attributed to huang, j..

6 recordsLinked to original sources

bioRxiv2025

Non-planar perylene diimides dual-targeting mitochondrial membrane potential and mitochondrial DNA transcription for an-titumor Therapy

Mitochondrial DNA (mtDNA) transcription is an emerging target in cancer therapy. While enzyme-targeted inhibitors such as IMT1B block POLRMT, their organelle specificity remains unclear. Here, we report a distinct strategy using non-planar perylene diimide derivatives (PDIs). The fluorescent lead compound PDIC-BL combines mitochondrial membrane potential ({Delta}{Psi}m) dependent accumulation (validated in cells and isolated mitochondria), and with direct intercalation into mtDNA (Kd = 32 M), as demonstrated by single-molecule stretching assays. This dual-targeting mechanism leads to selective inhibition of mitochondrial transcription, ROS generation and triggers apoptosis. PDIC-BL exhibits superior antitumor efficacy in breast cancer cell lines (MCF-7, MDA-MB-231) and significantly supresses tumor growth in vivo, with good tolerability in cancer xenograft model in nude mice. This work not only elucidates the structure-activity relationship of non-planar PDIs, but also offers a generalizable strategy for developing organelle-selective DNA binding therapeutics.

cancer biology↗

bioRxiv2025

A new nitrogen biochemical process: Oxidization of ammonium into nitrogen gas using nitrate

The nitrifying bacteria oxidize ammonium into nitrite or nitrate under aerobic conditions, while the anaerobic ammonia-oxidizing bacteria utilize nitrite to oxidize ammonium into nitrogen gas under anaerobic conditions. There is no biochemical process that can directly oxidize ammonium into nitrogen gas using nitrate under anaerobic conditions. In this study, mature anaerobic ammonium oxidation (anammox) granular sludge was inoculated in an anaerobic nitrogen-removal system, while nitrate and ammonium were used as the influent substrates. The experiment was conducted for 537 days at a temperature of 30-32{degrees}C and a pH of 8.0-9.0. The transformation from nitrite-anammox to nitrate-anammox was stably achieved on the 350th day. The experimental results showed that, nitrate directly oxidized ammonium into nitrogen gas under anaerobic conditions. The produced gas consisted of 96.3% nitrogen and 3.7% carbon dioxide. The removal ratio of ammonium to nitrate was approximately 1.67:1, and the total inorganic nitrogen removal rate reached up to 290.20 mg/(L{middle dot}d). Unlike the nitrite-anammox reaction, this reaction was accompanied by an acid production process, which caused a decrease in pH. When the substrate was changed to nitrite and ammonium, the total nitrogen removal rate of only 1.1-1.3 mg/(L{middle dot}d) was achieved. This new biochemical reaction of nitrogen was defined as nitrate-anammox. The study reveals a new pathway of nitrogen transformation, providing novel insights into the global nitrogen cycle.

microbiology↗

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

Ligand-independent c-Met activation by HHLA2 drives hepatocellular carcinoma and predicts c-MET inhibitor efficacy

The HGF/c-Met signaling pathway facilitates the initiation, progression, and metastasis of hepatocellular carcinoma (HCC). c-Met activation, however, is complex and not solely dependent on HGF, hindering targeted therapy development. This study identifies a critical oncogenic role for HHLA2, a B7 family member, in HCC and highlights its potential as a therapeutic target. We demonstrate that HHLA2 directly interacts with and activates c-Met through N-glycosylation, triggering sustained signaling and promoting aggressive HCC features. Mechanistically, we identified the pro-tumorigenic role of HHLA2 required downstream upregulation of MMP9 and VEGFA, both implicated in tumor progression. In multiple mouse models, HHLA2 overexpression accelerated tumor progression, metastasis, and reduced liver NK cell infiltration, all of which were reversed by c-Met inhibition. In a cohort of 176 HCC patients, HHLA2 expression strongly correlated with c-Met phosphorylation, advanced tumor stage, and poor prognosis. Importantly, HHLA2 expression predicted sensitivity to c-Met inhibitors in cell lines and patient-derived organoids and could be detected in patient serum, suggesting its potential as a prognostic biomarker. Collectively, our findings reveal an HHLA2-mediated mechanism of c-Met activation and provide a strong rationale for targeting the HHLA2-c-Met axis as a novel therapeutic strategy, with HHLA2 serving as a potential prognostic biomarker. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=173 SRC="FIGDIR/small/622557v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@8b10dforg.highwire.dtl.DTLVardef@b43dorg.highwire.dtl.DTLVardef@394c4aorg.highwire.dtl.DTLVardef@1bfbc8c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Cadmium Disrupts Blood-Testis Barrier (BTB) via An Oxidative Stress-Dependent Autophagy in Prepubertal Rats

Blood testis barrier (BTB) is an important target of cadmium (Cd) toxicology, but the mechanism underlying the Cd-induced impairment of BTB function remains fully elucidated. The mammalian target of rapamycin (mTOR) complex 2 (mTOR2) regulates BTB function via its effects on cellular junctions and the cytoskeleton of Sertoli cells. In this study, we investigated whether mTOR2 was involved in the effects of Cd exposure on BTB integrity. A Cd exposure model in vivo was established in prepubertal male rats using a single intraperitoneal injection of Cadmium Chloride (CdCl2). A Cd exposure model of Sertoli cell was established using a CdCl2-treated TM4 cell line. The Acute cadmium exposure decreased the activity of mTOR2 signaling and adhesin proteins which is linked to the induction of oxidative stress-induced autophagy. In the presence of CdCl2, mTOR, the catalytic subunit of the mTOR2 complex, exhibits a reduction in levels of phosphorylation, accompanied by decreased adhesin proteins and Rictor, the key component of the mTOR2 complex. CdCl2 treatment also drives a process of oxidative stress-induced autophagy, evidenced by alterations in cellular markers for oxidative stress and autophagy. Pharmaceutical inhibition of oxidative stress and/or autophagy alleviates the alternations in mTOR2 signaling and adhesin proteins upon CdCl2 treatment in TM4, a Sertoli cell line. This work is the first to examine the effects of cadmium exposure on rictor/mTOR2 signaling pathways. Our results suggest that Cadmium might exert testicular toxicology via the perturbation in mTOR2 signaling, which can be associated with the cellular stress-related protolysis in Sertoli cells.

pharmacology and toxicology↗

bioRxiv2020

Genome-wide analyses of chromatin interactions after the loss of Pol I, Pol II and Pol III

BackgroundThe relationship between transcription and the 3D genome organization is one of the most important questions in molecular biology, but the roles of transcription in 3D chromatin remain controversial. Multiple groups showed that transcription affects global Cohesin binding and genome 3D structures. At the same time, several studies have indicated that transcription inhibition does not affect global chromatin interactions. ResultsHere, we provide the most comprehensive evidence to date to demonstrate that transcription plays a marginal role in organizing the 3D genome in mammalian cells: 1) degraded Pol I, Pol II and Pol III proteins in mESCs, and showed their loss results in little or no changes of global 3D chromatin structures for the first time; 2) selected RNA polymerases high abundance binding sites-associated interactions and found they still persist after the degradation; 3) generated higher resolution chromatin interaction maps and revealed that transcription inhibition mildly alters small loop domains; 4) identified Pol II bound but CTCF and Cohesin unbound loops and disclosed that they are largely resistant to transcription inhibition. Interestingly, Pol II depletion for a longer time significantly affects the chromatin accessibility and Cohesin occupancy, suggesting RNA polymerases are capable of affecting the 3D genome indirectly. So, the direct and indirect effects of transcription inhibition explain the previous confusing effects on the 3D genome. ConclusionsWe conclude that Pol I, Pol II, and Pol III loss only mildly alter chromatin interactions in mammalian cells, suggesting the 3D chromatin structures are pre-established and relatively stable.

genomics↗