Biology subjects

Wang, H. J.

Publications and source records attributed to Wang, H. J..

3 recordsLinked to original sources

bioRxiv2026

Macrophage-Derived 25-Hydroxycholesterol Drives Statin-Associated Acute Kidney Injury

Although acute kidney injury (AKI) has been implicated as a potential adverse effect of statin therapy, experimental evidence supporting this association remains limited. Here, we investigated whether elevated levels of 25-hydroxycholesterol (25-HC), an oxysterol produced by activated macrophages and monocytes, increase susceptibility to statin-induced AKI. We found that atorvastatin and fluvastatin induced cell death in proximal tubular cells when combined with 25-HC. Consistently, administration of low-dose lipopolysaccharide triggered AKI in statin-treated mice. Mechanistically, impaired protein prenylation disrupted the autophagosome-lysosome pathway in proximal tubular cells. AKI was attenuated by mevalonate supplementation, which restored protein prenylation, and by macrophage/monocyte depletion, which reduced the cellular sources of 25-HC. Furthermore, combined exposure to fluvastatin and 25-HC increased kidney injury molecule-1 (KIM-1) expression in human induced pluripotent stem cell-derived kidney organoids. Together, these findings suggest that elevated macrophage-derived 25-HC under conditions of infection, inflammation, or major surgery may increase susceptibility to statin-induced AKI. Our study identifies a previously unrecognized interaction between statins and 25-HC and suggests potential strategies to mitigate kidney injury while preserving the therapeutic benefits of statins.

pharmacology and toxicology↗

bioRxiv2025

CCN1 forms a complex with GPC4 and heparin to fine-tune signaling activities for embryonic cortical neural stem cell maintenance

Radial glial cells (RGCs) are the neural stem cells (NSCs) in the developing brain, capable of self-renewing and generating neurons and glia in order. The developmental behaviors of NSCs are determined by extrinsic factors from the NSC niche, together with intrinsic factors. Here, we show that Cellular Communication Network 1 (CCN1), a secreted matricellular protein, is an autocrine factor derived from RGCs in the embryonic telencephalon. Loss of Ccn1 in RGCs leads to accelerated lineage progression of RGCs, and causes premature cell cycle exit and neuronal differentiation, resulting in a reduction in NSC pool size, and in turn, at the expense of the perinatal gliogenesis. Mechanistically, CCN1 interacts with an RGC-expressed membrane protein GPC4, one of the heparan sulfate proteoglycans (HSPGs), and is required for GPC4 to maintain NSCs through the Sonic Hedgehog (Shh) signaling pathway, depending on the binding of heparin to CCN1. Our work provides a potential mechanism for the dynamic and sophisticated interconnections of niche components that meet the needs of context-dependent maintenance, differentiation, and fate determination of NSCs.

developmental biology↗

bioRxiv2019

Acidic pH reduces Vibrio cholerae motility in mucus by weakening flagellar motor torque

Intestinal mucus is the first line of defense against intestinal pathogens. It acts as a physical barrier between the epithelial tissues and luminal microbes. Enteropathogens, such as Vibrio cholerae, must compromise or circumvent the mucus barrier to establish a successful infection. We investigated how motile V. cholerae is able to penetrate mucus using single cell tracking in unprocessed porcine intestinal mucus. We found that changes in pH within the range of what has been measured in the human small intestine indirectly affect V. cholerae flagellar motor torque, and consequently, mucus penetration. Microrheological measurements indicate that the viscoelasticity of mucus does not change substantially within the physiological pH range and that commercially available mucins do not form gels when rehydrated. Finally, we found that besides the reduction in motor torque, El Tor and Classical biotypes have different responses to acidic pH. For El Tor, acidic pH promotes surface attachment that is mediated by activation of the mannose-sensitive haemagglutinin (MshA) pilus without a measurable change in the total cellular concentration of the secondary messenger cyclic dimeric guanosine monophosphate (c-di-GMP). Overall, our results support that the high torque of V. cholerae flagellar motor is critical for mucus penetration and that the pH gradient in the small intestine is likely an important factor in determining the preferred site of infection. Author summaryThe diarrheal disease cholera is still a burden for populations in developing countries with poor sanitation. To develop effective vaccines and prevention strategies against Vibrio cholerae, we must understand the initial steps of infection leading to the colonization of the small intestine. To infect the host and deliver the cholera toxin, V. cholerae has to penetrate the mucus layer protecting the intestinal tissues. However, V. choleraes interactions with intestinal mucus has not been extensively investigated. In this report, we demonstrate using single cell tracking that V. cholerae is able to penetrate native intestinal mucus using flagellar motility. In addition, we found that a strong motor torque is required for mucus penetration and, that torque is weakened in acidic environments even though the motor is powered by a sodium potential. This finding has important implications for understanding the dynamics of infection because pH varies significantly along the small intestine, between individuals, and between species. Blocking mucus penetration by interfering with V. choleraes flagellar motility, reinforcing the mucosa, controlling intestinal pH, or manipulating the intestinal microbiome, will offer new strategies to fight cholera.

microbiology↗