Biology subjects

Li, Z.-H.

Publications and source records attributed to Li, Z.-H..

8 recordsLinked to original sources

bioRxiv2026

ANKS1B in the Nucleus Accumbens controls escalated cocaine self-administration via regulating CBP-FoxO3 complex

The transition from controlled to escalated drug intake is a core feature of cocaine use disorder (CUD), yet the molecular mechanisms underlying this behavioral escalation remain poorly defined. Our prior genome-wide association study (GWAS) identified ANKS1B as a significant shared genetic risk factor for heroin, methamphetamine, and alcohol dependence, suggesting a broad role in addiction vulnerability. However, the specific function of ANKS1B in cocaine addiction and its associated neural mechanisms were unknown. Here, we found that ANKS1B expression level in the Nucleus Accumbens (NAc) was downregulated after extended cocaine use, and manipulating ANKS1B could selectively influence the escalation of cocaine intake and the subsequent cocaine-seeking behavior in the long-access cocaine self-administration rat model. Molecular experiments reveal that ANKS1B interacts with the histone acetyltransferase CBP to control H3K27 acetylation and extended cocaine intake, via epigenetically repressing the transcription factor FoxO3. Overall, these findings suggest that ANKS1B is a crucial factor influencing the escalation of cocaine use. The ANKS1B-CBP-FoxO3 signaling pathway presents a promising target for potential therapeutic interventions for controlling extended cocaine use.

neuroscience↗

bioRxiv2025

SLC44A1 deficiency impedes myelin development in the central nervous system

Axon-wrapping myelin sheath is essential for the proper functioning of the central nervous system (CNS). Defects in myelination occur in various neurodevelopmental disorders. Human deficiency of the solute carrier 44A1 (SLC44A1) causes a new type of childhood-onset neurodegeneration with leukoencephalopathy. Currently, there is no effective treatment for this devastating disease, and little is known about its pathological mechanisms. In this study we identified that SLC44A1 is enriched in oligodendrocytes and required for myelin development in the CNS of zebrafish and rodents, which is crucial for normal motor coordination and cognitive function. Defective oligodendroglial maturation and myelinogenesis can be visualized by in vivo time-lapse imaging in the spinal cord of zebrafish with Slc44a1b deficiency. Mechanistically, SLC44A1 deficiency disrupts the expression of genes involved in phosphatidylcholine production pathway, and subsequently inhibiting phospholipid biosynthesis and disturbing the lipid composition of myelin sheaths. More importantly, supplementation with citicoline, a natural choline metabolite, restores developmental myelination in SLC44A1-deficient animals. These findings demonstrate that SLC44A1 is essential for CNS myelination and citicoline supplementation represents a potential therapeutic strategy to address the developmental hypomyelination.

neuroscience↗

bioRxiv2024

Calcium tunneling through the entoplasmic reticulum and transfer to other organelles for optimal signaling in Toxoplasma gondii

Ca2+ signaling in cells begins with the opening of Ca2+ channels in either the plasma membrane (PM) or endoplasmic reticulum (ER), leading to a sharp increase of the physiologically low (<100 nM) cytosolic Ca2+ level. The temporal and spatial regulation of Ca{superscript 2} is crucial for the precise activation of key biological processes. In the apicomplexan parasite Toxoplasma gondii, which infects approximately one-third of the global population, Ca{superscript 2} signaling governs essential aspects of the parasites infection cycle. T. gondii relies on Ca{superscript 2} signals to regulate pathogenic traits, with several Ca{superscript 2}-signaling components playing critical roles. Ca2+ entry from the extracellular environment has been demonstrated in T. gondii for both, extracellular parasites, exposed to high Ca2+, and intracellular parasites, which acquire Ca{superscript 2} from host cells during host Ca{superscript 2} signaling events. Active egress, an essential step of the parasites infection cycle, is preceded by a large increase in cytosolic Ca2+, most likely initiated by release from intracellular stores. However, extracellular Ca2+ is also necessary to reach a cytosolic Ca2+ threshold required for timely egress. In this study, we investigated the mechanism of Ca{superscript 2} intracellular store replenishment and identified a central role for the SERCA-Ca2+-ATPase in maintaining Ca{superscript 2} homeostasis not only within the ER but also in other organelles. We demonstrate mitochondrial Ca2+ uptake, which occurs by transfer of Ca2+ from the ER, likely through membrane contact sites. Our findings suggest that the T. gondii ER plays a key role in sequestering and redistributing Ca{superscript 2} to intracellular organelles following Ca{superscript 2} influx at the PM. HIGHLIGHTSThe T. gondii ER takes up Ca2+ that enters the cytosol from the extracellular milieu. Filling of acidic stores in T. gondii depends on ER Ca{superscript 2} content. The mitochondrion of T. gondii has no direct access to extracellular Ca{superscript 2} but can take it up via transfer from the ER and/or acidic stores. The absence of SERCA activity results in reduced Ca{superscript 2} levels in the ER as well as in other organelles

cell biology↗

bioRxiv2024

The ameliorative effect of C-Kit pos hepatic endothelial Mertk deficiency on nonalcoholic steatohepatitis

Recently, Mer tyrosine kinase (Mertk) and KIT proto-oncogene (C-Kit) were reported play a role in liver sinusoidal endothelial cells (LSECs) in patients with nonalcoholic steatohepatitis (NASH). In this study, lower levels of C-Kit and higher levels of Mertk/p-Mertk were confirmed in steatotic LSECs and in the livers of patients and mice with NASH. C-Kit was suggested to negatively regulate Mertk signaling in steatotic LSECs. The steatotic LSECs in which Mertk was knocked down displayed high fenestration and reduced expression of procapillarized CD31/VN; showed antiangiogenic features and decreased expression of proangiogenic VEGF/ERK1/2; and exhibited intact mitophagy and upregulation of the Pink1/Parkin pathway. Bone marrow transplantation (BMT) of C-Kitpos-BMCssh-Mertk to MCD mice could equivalently protect endothelial functions. Steatotic hepatocytes (HCs) or hepatic stellate cells (HSCs) cocultured with LSECssh-Mertk exhibited diminished lipid deposition; decreased expression of prolipogenic LXR/SREBP-1c, proinflammatory TNF-/IL-6 and profibrotic -SMA/ColI; and increased expression of prolipolytic FXR/ADPN. Similarly, the BMT of C-Kitpos-BMCssh-Mertk to MCD mice ameliorated NASH. C-Kitpos-LSECs that underwent Mertk cleavage were found to limit NASH progression. Therefore, Mertk deficiency should be a novel therapeutic agent for restoring LSECs in patients with NASH.

molecular biology↗

bioRxiv2022

De novo mapping of the apicomplexan Ca2+-responsive proteome

Apicomplexan parasites cause persistent mortality and morbidity worldwide through diseases including malaria, toxoplasmosis, and cryptosporidiosis. Ca2+ signaling pathways have been repurposed in these eukaryotic pathogens to regulate parasite-specific cellular processes governing the transition between the replicative and lytic phases of the infectious cycle. Despite the presence of conserved Ca2+-responsive proteins, little is known about how specific signaling elements interact to impact pathogenesis. We mapped the Ca2+-responsive proteome of the model apicomplexan T. gondii via time-resolved phosphoproteomics and thermal proteome profiling. The waves of phosphoregulation following PKG activation and stimulated Ca2+ release corroborate known physiological changes but identify specific proteins operating in these pathways. Thermal profiling of parasite extracts identified many expected Ca2+-responsive proteins, such as parasite Ca2+-dependent protein kinases. Our approach also identified numerous Ca2+-responsive proteins that are not predicted to bind Ca2+, yet are critical components of the parasite signaling network. We characterized protein phosphatase 1 (PP1) as a Ca2+-responsive enzyme that relocalized to the parasite apex upon Ca2+ store release. Conditional depletion of PP1 revealed that the phosphatase regulates Ca2+ uptake to promote parasite motility. PP1 may thus be partly responsible for Ca2+-regulated serine/threonine phosphatase activity in apicomplexan parasites.

microbiology↗

bioRxiv2022

Toxoplasma gondii Coq1 is a heptaprenyl diphosphate synthase and its inhibition by a lipophilic bisphosphonate protects mice against T. gondii infection

Prenyldiphosphate synthases catalyze the reaction of allylic diphosphates with one or more isopentenyl diphosphate molecules to form compounds such as farnesyl diphosphate, used in e.g. sterol biosynthesis and protein prenylation, as well as longer "polyprenyl" diphosphates, used in ubiquinone and menaquinone biosynthesis. Quinones play an essential role in electron transport and are associated with the inner mitochondrial membrane due to the presence of the polyprenyl group. In this work, we investigated the synthesis of the polyprenyl diphosphate that alkylates the ubiquinone ring precursor in Toxoplasma gondii, an opportunistic pathogen that causes serious disease in immunocompromised patients and the unborn fetus. The enzyme that catalyzes this early step of the ubiquinone synthesis is Coq1 (TgCoq1), and we show that it produces the C35 species, heptaprenyl diphosphate. TgCoq1 localizes to the mitochondrion, and is essential for in vitro T. gondii growth. We demonstrate that the growth defect of a T. gondii TgCoq1 mutant is rescued by complementation with a homologous TgCoq1 gene or with a (C45) solanesyl diphosphate synthase from Trypanosoma cruzi (TcSPPS). We find that a lipophilic bisphosphonate (BPH-1218) inhibits T. gondii growth at low nM concentrations, while overexpression of the TgCoq1 enzyme dramatically reduced growth inhibition by the bisphosphonate. Both the severe growth defect of the mutant and the inhibition by BPH-1218 were rescued by supplementation with a long chain (C30) ubiquinone (UQ6). Importantly, BPH-1218 also protected mice against a lethal T. gondii infection. TgCoq1 thus represents a potential drug target that could be exploited for improved chemotherapy of toxoplasmosis. ImportanceMillions of people are infected with Toxoplasma gondii and the available treatment for toxoplasmosis is not ideal. Most of the drugs currently used are only effective for the acute infection and treatment can trigger serious side-effects requiring changes in the therapeutic approach. There is, therefore, a compelling need for safe and effective treatments for toxoplasmosis. In this work, we characterize an enzyme of the mitochondrion of T. gondii that can be inhibited by an isoprenoid pathway inhibitor. We present evidence that demonstrate that inhibition of the enzyme is linked to parasite death. In addition, the drug is able to protect mice against a lethal dose of T. gondii. Our results thus reveal a promising chemotherapeutic target for the development of new medicines for toxoplasmosis.

microbiology↗

bioRxiv2020

The Role of Host Calcium Signaling in Toxoplasma gondii egress

Toxoplasma gondii, an obligate intracellular parasite, is capable of invading virtually any nucleated cell. Ca2+ signaling is universal and both T. gondii and its mammalian host cell will utilize Ca2+ signaling to stimulate diverse cellular functions. Egress of T. gondii from the host cell is an essential step for the infection cycle of T. gondii and a cytosolic Ca2+ increase initiates the Ca2+ signaling cascade that culminates in stimulation of motility and egress. In this work we demonstrate that intracellular T. gondii is capable of taking up Ca2+ from the host cytoplasm when this concentration is increased during host signaling events. Both intracellular and extracellular Ca2+ sources are important to reach a threshold of cytosolic Ca2+ needed for a successful egress. Two peaks of Ca2+ were observed in single parasites that egressed with the second peak resulting from Ca2+ influx. We patched infected host cells to allow a precise delivery of exact concentrations of Ca2+ for stimulating motility and egress. Using this approach, we found that low potassium concentration modulates but do not trigger host cell egress. This is the first study using whole-cell patches to study the role of ions such as K+ and Ca2+ in T. gondii egress.

microbiology↗

bioRxiv2017

Allopatric divergence, local adaptation, and multiple Quaternary refugia in a long-lived tree (Quercus spinosa) from subtropical China

O_LIThe complex geography and climatic changes occurring in subtropical China during the Tertiary and Quaternary might have provided substantial opportunities for allopatric speciation. To gain further insight into these processes, we reconstruct the evolutionary history of Quercus spinosa, a common evergreen tree species mainly distributed in this area.\nC_LIO_LIForty-six populations were genotyped using four chloroplast DNA regions and 12 nuclear microsatellite loci to assess genetic structure and diversity, which was supplemented by divergence time and diversification rate analyses, environmental factor analysis, and ecological niche modeling of the species distributions in the past and at present.\nC_LIO_LIThe genetic data consistently identified two lineages: the western Eastern Himalaya-Hengduan Mountains lineage and the eastern Central-Eastern China lineage, mostly maintained by populations environmental adaptation. These lineages diverged through climate/orogeny-induced vicariance during the Neogene and remained separated thereafter. Genetic data strongly supported the multiple refugia (per se, interglacial refugia) or refugia within refugia hypotheses to explain Q. spinosa phylogeography in subtropical China.\nC_LIO_LIQ. spinosa population structure highlighted the importance of complex geography and climatic changes occurring in subtropical China during the Neogene in providing substantial opportunities for allopatric divergence.\nC_LI

evolutionary biology↗