Biology subjects

Zhang, C. C.

Publications and source records attributed to Zhang, C. C..

6 recordsLinked to original sources

bioRxiv2025

DLK inhibition has sex-specific effects on neuroprotection and locomotor recovery after spinal cord injury

Spinal cord injury (SCI) causes devastating functional deficits, in part due to neuroinflammation, oxidative stress, and excitotoxicity that drive death of lesion-adjacent viable neurons. Dual leucine zipper kinase (DLK) is a neuron-enriched kinase that responds to cellular stress by activating the c-Jun N-terminal kinase (JNK) pathway, driving both stress-responsive gene expression and neuronal apoptosis. We hypothesized that SCI would robustly activate DLK signaling and that acute pharmacological inhibition of DLK would suppress JNK pathway activation, thereby enhancing neuroprotection and locomotor recovery in our mouse model of moderate contusion SCI. Using western blotting, we observed that SCI induced strong and sustained activation of the JNK pathway in the injured spinal cord starting at 4 hours post-injury through 7 days. Complementary analysis of single-nucleus RNA-seq revealed that DLK expression is highly enriched in neurons across all injury phases. Following SCI, neurons exhibited robust, time-dependent upregulation of multiple DLK-responsive transcripts, consistent with sustained pathway activation during the acute and subacute periods. Systemic treatment with the selective DLK inhibitor IACS-52825 effectively suppressed intraspinal JUN activation in a dose-dependent manner. However, unexpectedly, treatment delayed functional recovery and expanded lesion volume by 71% in male mice with no significant effect in females. These findings highlight the complex roles of DLK signaling after SCI, revealing a need to understand the sex-specific molecular mechanisms that modulate injury outcomes. Future studies should further optimize timing, location, and cellular targeting of DLK therapeutic strategies to improve neuroprotection and neurologic recovery after SCI.

neuroscience↗

bioRxiv2024

Diversification mitigates pesticide but not microplastic effects on bees without compromising rapeseed yield in China

Humanity depends on agriculture for food, fiber and energy provisioning, but input-intensive agricultural production is impacting ecosystem services such as pollination. Pollution effects from neonicotinoid insecticides on pollinators receive much attention, but nothing is known on the synergistic effects with emerging plastic contaminants and the mitigation potential of agricultural diversification. Here, we conduct the first large-scale and full-factorial mesocosm study to understand two-generation effects of diversified floral resources (diversification treatment), neonicotinoid and microplastic pollution (pollution treatments) on Osmia cornifrons bees in 72 mesocosms. In our three-year experiment, we found that diversification can mitigate individual neonicotinoid effects. We did not find any individual or synergistic effects of microplastic on reproductive performance of solitary bees. None of our treatments affected rapeseed yield. Our results confirm the benefits of diversified flower resources to mitigate pesticide effects on bees in China and suggest that microplastics have no acute individual or interaction toxicity in semi-natural environment at realistic exposure levels. Diversified flower resources in Chinese agricultural landscapes to mitigate pesticide pollution effects on pollinators is an important policy argument for pollinator protection with downstream implications for food security.

ecology↗

bioRxiv2024

Synergistic and antagonistic drug-drug interactions are prevalent but not conserved across acute myeloid leukemia cell lines

Acute myeloid leukemia (AML) is the most prevalent type of leukemia in adults. Despite advancements in medicine, the standard treatment that utilizes a combination of cytarabine and daunorubicin for AML has remained the same for decades. Combination drug therapies are proven to be an effective way to achieve targeted efficacy while minimizing drug dosage along with the unintended side effects. However, a systematic survey of synergistic potential of drug-drug interactions in the context of AML pathology is currently lacking. Here we examine the interactions between 15 frequently used cancer drugs across distinct AML cell lines and demonstrate that synergistic and antagonistic drug-drug interactions are widespread but not conserved across these cell lines. Notably, enasidenib (AG-221) and venetoclax (ABT-199), recently approved anticancer agents, exhibited the highest counts of synergistic interactions and the fewest antagonistic ones. In contrast, 6-Thioguanine (6-TG), a purine analog, was involved in the highest number of antagonistic interactions. The interactions we report here cannot be attributed solely to the inherent synergistic or antagonistic natures of these three drugs, as each drug we examined was involved in several synergistic or antagonistic interactions in the cell lines we tested. Moreover, we observed that these drug-drug interactions are not conserved across cell lines, suggesting that the success of combination therapies might vary depending on AML genotypes. For instance, we found that a single mutation in the TF1 cell line could dramatically alter drug-drug interactions, even turning synergistic interactions into antagonistic ones, as seen with AG-221 and cladribine A (2CdA). Our findings provide a preclinical survey of the potential synergistic effects revealing the complexity of the problem in vitro. However, the exploitable synergistic regimes in clinical scenarios remain to be explored. We anticipate these results to be an insightful guideline for future clinical studies, aiming to refine chemotherapy regimens and ultimately enhance patient outcomes.

cancer biology↗

bioRxiv2023

Modeling kidney development, disease, and plasticity with clonal expandable nephron progenitor cells and nephron organoids

Nephron progenitor cells (NPCs) self-renew and differentiate into nephrons, the functional units of the kidney. Here we report manipulation of p38 and YAP activity creates a synthetic niche that allows the long-term clonal expansion of primary mouse and human NPCs, and induced NPCs (iNPCs) from human pluripotent stem cells. Cultured iNPCs resemble closely primary human NPCs, generating nephron organoids with abundant distal convoluted tubule cells, which are not observed in published kidney organoids. The synthetic niche reprograms differentiated nephron cells into NPC state, recapitulating the plasticity of developing nephron in vivo. Scalability and ease of genome-editing in the cultured NPCs allow for genome-wide CRISPR screening, identi-fying novel genes associated with kidney development and disease. A rapid, efficient, and scala-ble organoid model for polycystic kidney disease was derived directly from genome-edited NPCs, and validated in drug screen. These technological platforms have broad applications to kidney development, disease, plasticity, and regeneration.

developmental biology↗

bioRxiv2021

Lung adenocarcinoma cell-derived exosomal miR-328 promote osteoclastogenesis by targeting Nrp2

Bone metastasis of lung cancer and detailed mechanisms are still elusive, and the roles of exosomes derived from lung adenocarcinoma cells in this process have attracted much attention. In this study, we found that A549 cell-derived exosomes (A549-Exos) promoted osteogenesis and bone resorption in vitro. Furthermore, A549-Exos target bone in vivo and promoted bone resorption in vivo. Mechanistically, A549-Exosomal miR-328 promoted bone resorption by targeting Nrp2 and A549-ExosmiR-328 Inhibitors inhibited bone resorption in vivo. Thus, A549-Exosomal miR-328 promote osteoclastogenesis by targeting Nrp2 and A549-ExosmiR-328 Inhibitors may serve as a potential nanomedicine for the treatment of bone metastasis.

cancer biology↗

bioRxiv2020

Interaction network of SARS-CoV-2 with host receptome through spike protein

Host cellular receptors are key determinants of virus tropism and pathogenesis. Virus utilizes multiple receptors for attachment, entry, or specific host responses. However, other than ACE2, little is known about SARS-CoV-2 receptors. Furthermore, ACE2 cannot easily interpret the multi-organ tropisms of SARS-CoV-2 nor the clinical differences between SARS-CoV-2 and SARS-CoV. To identify host cell receptors involved in SARS-CoV-2 interactions, we performed genomic receptor profiling to screen almost all human membrane proteins, with SARS-CoV-2 capsid spike (S) protein as the target. Twelve receptors were identified, including ACE2. Most receptors bind at least two domains on S protein, the receptor-binding-domain (RBD) and the N-terminal-domain (NTD), suggesting both are critical for virus-host interaction. Ectopic expression of ASGR1 or KREMEN1 is sufficient to enable entry of SARS-CoV-2, but not SARS-CoV and MERS-CoV. Analyzing single-cell transcriptome profiles from COVID-19 patients revealed that virus susceptibility in airway epithelial ciliated and secretory cells and immune macrophages highly correlates with expression of ACE2, KREMEN1 and ASGR1 respectively, and ACE2/ASGR1/KREMEN1 (ASK) together displayed a much better correlation than any individual receptor. Based on modeling of systemic SARS-CoV-2 host interactions through S receptors, we revealed ASK correlation with SARS-CoV-2 multi-organ tropism and provided potential explanations for various COVID-19 symptoms. Our study identified a panel of SARS-CoV-2 receptors with diverse binding properties, biological functions, and clinical correlations or implications, including ASGR1 and KREMEN1 as the alternative entry receptors, providing insights into critical interactions of SARS-CoV-2 with host, as well as a useful resource and potential drug targets for COVID-19 investigation.

microbiology↗