Biology subjects

Tao, J.

Publications and source records attributed to Tao, J..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Kidney collecting duct cell type composition is regulated by Notch signaling via modulation of mTORC1

The plasticity and diversity of cell types with specialized functions likely defines the capacity of multicellular organisms to adapt to physiologic stressors. The kidney collecting ducts contribute to water, electrolyte, and pH homeostasis and are composed of mature intermingled epithelial cell types that are susceptible to transdifferentiate. The conversion of kidney collecting duct principal cells to intercalated cells is actively inhibited by Notch signaling to ensure urine concentrating capability. Here we identify Hes1, a target of Notch signaling, allows for maintenance of functionally distinct epithelial cell types within the same microenvironment by regulating mechanistic target of rapamycin complex 1 (mTORC1) activity. Hes1 directly represses the expression of insulin receptor substrate 1 (Irs1), an upstream component of mTOR pathway and suppresses mTORC1 activity in principal cells. Genetic inactivation of tuberous sclerosis complex 2 (Tsc2) to increase mTORC1 activity in mature principal cells is sufficient to promote acquisition of intercalated cell properties, while inhibition of mTORC1 in adult kidney epithelia suppresses intercalated cell properties. Considering that mTORC1 integrates environmental cues, the linkage of functionally distinct epithelial cell types to mTORC1 activity levels likely allows for cell plasticity to be regulated by physiologic and metabolic signals and the ability to sense/transduce these signals.

developmental biology↗

bioRxiv2024

Partitioning changes in ecosystem productivity by effects of species interactions in biodiversity experiments

Species interactions affect ecosystem productivity. Positive interactions (resource partitioning and facilitation) increase productivity while negative interactions (species interference) decrease productivity relative to the null expectations defined by monoculture yields. Effects of competitive interactions (resource competition) can be either positive or negative. Distinguishing effects of species interactions is therefore difficult, if not impossible, with current biodiversity experiments involving mixtures and full density monocultures. To partition changes in ecosystem productivity by effects of species interactions, we modify null expectations with competitive growth responses, i.e., proportional changes in individual size (biomass or volume) expected in mixture based on species differences in growth and competitive ability. We use partial density (species density in mixture) monocultures and the competitive exclusion principle to determine maximum competitive growth responses and full density monoculture yields to measure species ability to achieve maximum competitive growth responses in mixture. Deviations of observed yields from competitive expectations represent the effects of positive/negative species interactions, while the differences between competitive and null expectations reflect the effects of competitive interactions. We demonstrate the effectiveness of our competitive partitioning model in distinguishing effects of species interactions using both simulated and experimental species mixtures. Our competitive partitioning model enables meaningful assessments of species interactions at both species and community levels and helps disentangle underlying mechanisms of species interactions responsible for changes in ecosystem productivity and identify species mixtures that maximize positive effects.

ecology↗

bioRxiv2024

Dual Targeting of STING and PI3Kγ Eliminates Regulatory B Cells to Overcome STING Resistance for Pancreatic Cancer Immunotherapy

The immune suppression in tumors and lymph nodes of pancreatic ductal adenocarcinoma (PDAC), regulated by suppressive myeloid cells and regulatory B (Breg) cells, hinders the effectiveness of immunotherapy. Although STING agonists activate myeloid cells to overcome immune suppression, it expands Breg cells, conferring STING resistance in PDAC. We discovered that blocking PI3K{gamma} during STING activation abolished IRF3 phosphorylation to eliminate Breg cells, while PI3K{gamma} inhibition sustained STING-induced IRF3 phosphorylation to preserve STING function in myeloid cells. Therefore, we developed a dual functional compound SH-273 and its albumin nanoformulation Nano-273, which stimulates STING to activate myeloid cells and inhibits PI3K{gamma} to eliminates Breg cells overcoming STING resistance. Nano-273 achieved systemic antitumor immunity through intravenous administration, which decreases Breg cells and remodels microenvironment in tumors and lymph nodes. Nano-273, combined with anti-PD-1, extended median survival to 200 days in transgenic KPC PDAC mice (KrasG12D-P53R172H-Cre), offering potential for PDAC treatment.

pharmacology and toxicology↗

bioRxiv2023

Post-translational regulation of Platelet-derived growth factor receptor β is critical for fracture repair in aged mice

Increased protein ubiquitination was observed in fracture callus and particularly in aged mice. Treatment of proteasome inhibitor enhanced fracture repair in young and mice by increasing the number of mesenchymal progenitor cells (MPCs). However, the protein targets of proteasome inhibitor are still not known. Ub-proteomics identifies the top ub-proteins in MPCs and osteoblasts. Among them, PDGFR{beta} plays important roles both in osteogenesis and angiogenesis, which were reduced in callus of aged mice. We examine the dramatic decrease of PDGFR{beta} protein level, increased Ub-PDGFR{beta}, but mild decrease of mRNA in callus of aged mice, suggesting dys-regulated protein modification is the major cause of decreased PDGFR{beta} level. Decreased PDGFR{beta} results in the failure of PDGF-BB enhanced MPCs proliferation and fracture repair in aged mice. Co-treatment with proteasome inhibitor rescues the ability of PDGF-BB on MPC proliferation and fracture repair. Our findings not only discover the protein target of proteasome inhibitor in MPCs, but importantly connect the compromised effect of PDGF treatment on diseases with PDGFR{beta} proteasomal degradation. We open a new avenue for the treatment of fracture repair in elderly with the combination of PDGF-BB and proteasome inhibitor.

cell biology↗

bioRxiv2023

Prickle and Ror modulate Dishevelled-Vangl interaction to regulate non-canonical Wnt signaling during convergent extension

Convergent extension (CE) is a fundamental morphogenetic process where oriented cell behaviors lead to polarized extension of diverse tissues. In vertebrates, regulation of CE requires both non-canonical Wnt, its co-receptor Ror, and several "core members" of the planar cell polarity (PCP) pathway. PCP was originally identified as a mechanism to coordinate the cellular polarity in the plane of static epithelium, where core proteins Frizzled (Fz)/ Dishevelled (Dvl) and Van Gogh-like (Vangl)/ Prickle (Pk) partition to opposing cell cortex. But how core PCP proteins interact with each other to mediate non-canonical Wnt/ Ror signaling during CE is not clear. We found previously that during CE, Vangl cell-autonomously recruits Dvl to the plasma membrane and keeps Dvl inactive. In this study, we show that non-canonical Wnt induces Dvl to transition from Vangl to Fz. Pk inhibits the transition, and functionally synergize with Vangl to suppress Dvl during CE. Conversely, Ror is required for the transition, and functionally antagonizes Vangl. Biochemically, Vangl interacts directly with both Ror and Dvl. Ror and Dvl do not bind directly, but can be cofractionated with Vangl. Collectively, we propose that Pk assists Vangl to function as an unconventional adaptor that brings Dvl and Ror into a complex to serves two functions: 1) simultaneously preventing both Dvl and Ror from ectopically activating non-canonical Wnt signaling; and 2) relaying Dvl to Fz for signaling activation upon non-canonical Wnt induced dimerization of Fz and Ror.

developmental biology↗

bioRxiv2023

Discovery of reactive peptide inhibitors of human papillomavirus oncoprotein E6

Human papillomavirus (HPV) infections account for nearly all cervical cancer cases, which is the fourth most common cancer in women worldwide. High-risk variants, including HPV16, drive tumorigenesis in part by promoting the degradation of the tumor suppressor p53. This degradation is mediated by the HPV early protein 6 (E6), which recruits the E3 ubiquitin ligase E6AP and redirects its activity towards ubiquitinating p53. Targeting the protein interaction interface between HPV E6 and E6AP is a promising modality to mitigate HPV-mediated degradation of p53. In this study, we designed a covalent peptide inhibitor, termed reactide, that mimics the E6AP LXXLL binding motif by selectively targeting cysteine 58 in HPV16 E6 with quantitative conversion. This reactide provides a starting point in the development of covalent peptidomimetic inhibitors for intervention against HPV-driven cancers.

molecular biology↗

bioRxiv2023

Transcriptome mining of RNA viruses (family Totiviridae) in Eimeria necatrix and Eimeria stiedai

Coccidian protozoa from the genus Eimeria are widespread parasites of vertebrates, causing serious disease (coccidiosis) and economic loss most notably in poultry. Several species of Eimeria are themselves infected with small RNA viruses assigned to the family Totiviridae. In this study, the sequences of two such viruses were newly determined, one of which represents the first complete protein-coding sequence of a virus from E. necatrix, an important pathogen of chickens, and the other of which is from E. stiedai, an important pathogen of rabbits. Sequence features of the newly identified viruses, compared with those of ones reported previously, provide several insights. Phylogenetic analyses suggest that these eimerian viruses constitute a well-demarcated clade, probably deserving of recognition as a distinct genus.

microbiology↗

bioRxiv2023

Excess PrPC inhibits muscle cell differentiation via miRNA-enhanced liquid-liquid phase separation implicated in myopathy

The cellular prion protein (PrPC), a glycoprotein existing in membrane-bound and cytoplasmic forms, has functional importance in skeletal muscle, but the mechanism behind the phenomenon remains poorly understood. Here we report that PrPC is overexpressed and located in the cytoplasm of the skeletal muscle of six myopathy patients; cytoplasmic PrPC strongly inhibits skeletal muscle cell autophagy and blocks myoblast differentiation. PrPC selectively binds to a subset of miRNAs during myoblast differentiation, and the co-localization of PrPC with miR-214-3p was clearly observed in the skeletal muscle of six myopathy patients but not in that of four age-matched controls. We demonstrate that PrPC is overexpressed in skeletal muscle cells under pathological conditions and inhibits muscle cell differentiation via physically interacting with a subset of miRNAs to significantly inhibit autophagy-related protein 5-dependent autophagy, and selectively recruits these miRNAs into phase-separated condensates in living myoblasts, which in turn greatly enhances liquid-liquid phase separation (LLPS) of PrPC and results in the subsequent PrP aggregation and muscle bundle formation in myopathy patients characterized by incomplete muscle regeneration. Our findings show how excess PrPC can inhibit muscle cell differentiation via miRNA-enhanced LLPS implicated in myopathy.

biochemistry↗

bioRxiv2023

Calponin 2 harnesses metabolic reprogramming to determine kidney fibrosis

In the fibrotic kidneys, the extent of a formed deleterious microenvironment is determined by cellular mechanical forces. This process requires metabolism for energy; however, how cellular mechanics and metabolism are connected remains unclear. Our proteomics revealed that actin filament binding and cell metabolism are the two most dysregulated events in the fibrotic kidneys. As a prominent actin stabilizer, Calponin 2 (CNN2) is predominantly expressed in fibroblasts and pericytes. CNN2 knockdown preserves kidney function and alleviates fibrosis. Global proteomics profiled that CNN2 knockdown enhanced the activities of the key rate-limiting enzymes and regulators of fatty acid oxidation (FAO) in diseased kidneys. Inhibiting carnitine palmitoyltransferase 1 in the FAO pathway results in lipid accumulation and extracellular matrix deposition in the fibrotic kidneys, which were restored after CNN2 knockdown. In patients, increased serum CNN2 levels are correlated with lipid content. Bioinformatics and chromatin immunoprecipitation showed that CNN2 interactor, estrogen receptor 2 (ESR2) binds peroxisome proliferator-activated receptor- (PPAR) to transcriptionally regulate FAO downstream target genes expression amid kidney fibrosis. In vitro, ESR2 knockdown repressed the mRNA levels of PPAR and the key genes in the FAO pathway. Conversely, activation of PPAR reduced CNN2-induced matrix inductions. Our results suggest that balancing cell mechanics and metabolism is crucial to develop therapeutic strategies to halt kidney fibrosis.

pathology↗

bioRxiv2022

Metal-driven anaerobic oxidation of methane as an important methane sink in methanic cold seep sediments

Anaerobic oxidation of methane (AOM) coupled with reduction of metal oxides is supposed to be a globally important bioprocess in marine sediments. However, the responsible microorganisms and their contributions to methane budget are not clear in deep sea cold seep sediments. Here, we combined geochemistry, muti-omics and numerical modeling to study metal-dependent AOM in methanic cold seep sediments in the northern continental slope of the South China Sea. Geochemical data based on methane concentrations, carbon stable isotope, solid-phase sediment analysis and pore water measurements indicate the occurrence of anaerobic methane oxidation coupled to metal oxides reduction in the methanic zone. The 16S rRNA gene amplicons and transcripts, along with metagenomic and metatranscriptomic data suggest that diverse ANME groups actively mediated methane oxidation in the methanic zone either independently or in syntrophy with e.g. ETH-SRB1 as potential metal reducers. Modeling results suggest that the estimated rates of methane consumption via Fe-AOM and Mn-AOM were both 0.3 mol cm-2 yr-1, which account for [~]3% of total CH4 removal in sediments. Overall, our results highlight metal-driven anaerobic oxidation of methane as an important methane sink in methanic cold seep sediments.

microbiology↗

bioRxiv2022

Kinetochore-fiber lengths are maintained locally but coordinated globally by poles in the mammalian spindle

At each cell division, nanometer-scale components self-organize to build a micron-scale spindle. In mammalian spindles, microtubule bundles called kinetochore-fibers attach to chromosomes and focus into spindle poles. Despite evidence suggesting that poles can set spindle length, their role remains poorly understood. In fact, many species do not have spindle poles. Here, we probe the poles contribution to mammalian spindle length, dynamics, and function by inhibiting dynein to generate spindles whose kinetochore-fibers do not focus into poles, yet maintain a metaphase steady-state length. We find that unfocused kinetochore-fibers have a mean length indistinguishable from control, but a broader length distribution, and reduced length coordination between sisters and neighbors. Further, we show that unfocused kinetochore-fibers, like control, can grow back to their steady-state length if acutely shortened by drug treatment or laser ablation: they recover their length by tuning their end dynamics, albeit slower due to their reduced baseline dynamics. Thus, kinetochore-fiber dynamics are regulated by their length, not just pole-focusing forces. Finally, we show that spindles with unfocused kinetochore-fibers can segregate chromosomes but fail to correctly do so. We propose that mammalian spindle length emerges locally from individual k-fibers while spindle poles globally coordinate k-fibers across space and time.

cell biology↗

bioRxiv2022

Machine-guided cell-fate engineering

AO_SCPLOWBSTRACTC_SCPLOWThe creation of induced pluripotent stem cells (iPSCs) has enabled scientists to explore the derivation of many types of cells. While there are diverse general approaches for cell-fate engineering, one of the fastest and most efficient approaches is transcription factor (TF) over-expression. However, finding the right combination of TFs to over-express to differentiate iPSCs directly into other cell-types is a difficult task. Here were describe a machine-learning (ML) pipeline, called CellCartographer, for using chromatin accessibility data to design multiplex TF pooled-screens for cell type conversions. We validate this method by differentiating iPSCs into twelve diverse cell types at low efficiency in preliminary screens and then iteratively refining our TF combinations to achieve high efficiency differentiation for six of these cell types in < 6 days. Finally, we functionally characterized engineered iPSC-derived cytotoxic T-cells (iCytoT), regulatory T-cells (iTReg), type II astrocytes (iAstII), and hepatocytes (iHep) to validate functionally accurate differentiation.

developmental biology↗

bioRxiv2022

Evolution of m6A related genes in insects and function of METTL3 in embryonic development of silkworm.

N6-methyladenosine (m6A), the most prevalent modification in eukaryotic RNAs, plays a key role in biological processes. However, the evolutionary relationships and function of m6A related genes in insects are still largely unknown. Here, we analyzed the phylogenetics of m6A related genes among 207 insects and find that m6A related genes are evolutionarily conserved in insects. We apply the lepidopteran model insect Bombyx. mori as a study system. Subcellular localization experiments in BmN cells confirmed that YTHDF3 localizes in the cytoplasm, METTL3, METTL14 and YTHDC localize in the nucleus, while FL2D localizes in both nucleus and cytoplasm. We also detected expression pattern of m6A related genes during the embryonic development of B. mori and found that m6A related genes expression pattern is temporally specific. To elucidate the function of METTL3 during embryonic stage, RNA sequencing was performed to measure differential expressions of mRNA from silkworm eggs after METTL3 knockdown, and METTL3-overexpressing BmN cells. The global transcriptional pattern showed that METTL3 knockdown affected multiple cellular processes, including oxidoreductase activity, transcription regulator activity, cation binding and fundamental many metabolism processes, such as carbon metabolism, purine metabolism, biosynthesis of amino acids, and the citrate cycle, were affected. In addition, METTL3 knockdown significantly affected Wnt and Toll/Imd pathways in embryonic stage. The results suggest that METTL3 plays an important role during the embryonic development of B. mori. This study deepens our understanding of the function of m6A related genes in insects.

evolutionary biology↗

bioRxiv2022

HIV positive patients on antiretroviral therapy have an altered mucosal intestinal but not oral microbiome

This study characterized compositional and functional shifts in the intestinal and oral microbiome in HIV-positive patients compared to uninfected individuals. 79 specimens were collected from 5 HIV-positive and 12 control subjects from five locations (colon brush, colon wash, TI brush, TI wash and saliva) during colonoscopy and at patient visits. Microbiome composition was characterized using 16S rRNA sequencing and microbiome function was predicted using bioinformatics tools (PICRUSt and Bugbase). Our analysis indicated that the {beta} diversity of all intestinal samples (colon brush, colon wash, TI brush, TI wash) from patients with HIV was significantly different from patients without HIV, as measured by weighted UniFrac distances. Specifically, bacteria from genera Prevotella, Fusobacterium, Eubacterium, Megasphaera, Mogibacterium and Mitsuokella were more abundant in samples from HIV-positive patients. On the other hand, bacteria from genera Ruminococus, Blautia, and Clostridium were more abundant in samples from HIV-negative patients. Additionally, HIV-positive patients had higher abundances of biofilm-forming and pathogenic bacteria. Furthermore, pathways related to translation and nucleotide metabolism were elevated in HIV-positive patients whereas pathways related to lipid and carbohydrates metabolism and membrane transport were positively correlated with samples from HIV-negative patients. Our analyses further showed variations in microbiome composition in HIV-positive and negative patients by sampling site, with samples from colon wash, colon brush and TI wash significant between groups while samples from TI brush and saliva were not significant. Taken together, here we report altered intestinal microbiome composition and function in patients with HIV compared to uninfected patients, though we found no changes in the oral microbiome. Author summaryOver 37 million people worldwide are living with HIV. Although the availability of antiretroviral therapy has significantly reduced the number of AIDS-related deaths, individuals living with HIV are at increased risk for opportunistic infections. We now know that HIV interacts with the trillions of bacteria, fungus, and viruses in the human body termed the microbiome. The advent of next generation sequencing has allowed us to characterize the composition of the microbiome and how HIV changes the microbiome composition to influence disease severity and progression. Previous studies have examined changes in the microbiome in HIV-positive and negative individuals. However, only a limited number of studies have compared variations in the oral and gastrointestinal microbiome with HIV infection. Furthermore, very few studies have looked at how the microbiome in HIV infection may vary by sampling site. Here, we detail how the oral and gastrointestinal microbiome changes with HIV infection and use 5 different sampling sites to gain a more comprehensive view of these changes by location. Our results show site-specific changes in the intestinal microbiome associated with HIV infection. Additionally, we show that while there are significant changes in the intestinal microbiome, there are no significant changes in the oral microbiome.

microbiology↗

bioRxiv2022

GTEM cell design for controlled exposure to electromagnetic fields in biological system

This study describes a structure design of the Gigaherz Transverse Electromagnetic (GTEM) cell for electromagnetic tests in biological systems. Using electromagnetic simulation software we show that the optimization of final structure assures the criteria imposed on a low level of reflection towards the radio frequency generator, and a fairly uniform field in the test zone. A sensitivity study was also conducted when the cell was loaded with a few samples under test. We report that the level of reflection remains adequate as long as the test volume remains limited in relation to the size of the cell. The first estimation results on the SAR values are consistent with the distribution of the fields in the cell. A cell was fabricated with the design data, and tested for the reflection level. The measurements confirm the results of simulations.

biophysics↗

bioRxiv2022

Odysseia: Genetic Regulatory Feature Analysis with Interpretable Classification Machine Learning Models

As rapid progress in sequencing technology since last decade, numerous mechanisms underlying cell functions and developmental processes have been revealed as complex regulations of gene expressions. Since single-cell RNA sequencing (scRNA-seq) made high-resolution transcriptomic view increasingly accessible, precise identification of gene regulatory network (GRN) describing cell types and cell states became achievable. However, extracting key regulatory elements, including gene regulatory pathways (GRPs), transcription factors (TFs), and targetomes, that accurately and completely reflects functionality changes in biological phenomena remains challenging. Herein, we describe AGEAS, an semi-supervised automated machine learning (AutoML) based genetic regulatory element extraction system that assesses importances of GRPs in resulting biological phenomena, such as cell type differentiation, physiological and pathological development, and reconstructs GRNs with extracted important GRPs for comprehensive inference. With several case studies in divergent research areas, we show that AGEAS can indeed extract informative regulatory elements and reconstruct networks to indicate regulatory changes in biological phenomena of interest. Availability and implementationThe AGEAS code is available at https://github.com/JackSSK/Ageas.

bioinformatics↗

bioRxiv2022

Western diet unmasks transient low-level vinyl chloride exposure-induced tumorigenesis; potential role of the (epi-)transcriptome

Background & AimsVinyl chloride (VC) monomer is a volatile organic compound commonly used in industry to produce polyvinyl chloride (PVC). At high exposure levels, VC causes liver cancer and toxicant-associated steatohepatitis. However, lower exposure levels (i.e., < regulatory exposure limits) that do not directly damage the liver, enhance injury caused by Western diet (WD). Although these lower exposure levels are considered safe, it is unknown if the long-term impact of transient low-concentration VC enhances the risk of liver cancer development. Low-concentration VC is especially a concern given that fatty liver disease is in and of itself a risk factor for the development of liver cancer. MethodsC57Bl/6J mice were fed WD or control diet (CD) for 1 year. During the first 12 weeks of feeding only, mice were also exposed to VC via inhalation at sub-regulatory limit concentrations (<1 ppm) or air for 6 hours/day, 5 days/week. ResultsFeeding WD for 1 year caused significant hepatic injury, including steatohepatitis and moderate fibrosis, which was exacerbated by VC. Additionally, VC increased the number of tumors which ranged from moderately to poorly differentiated hepatocellular carcinoma (HCC). Transcriptomic analysis demonstrated VC-induced changes in metabolic but also ribosomal processes. Epitranscriptomic analysis showed a VC-induced shift of the modification pattern that has been associated with metabolic disease, mitochondrial dysfunction, and cancer. ConclusionsThese data indicate that VC sensitizes the liver to other stressors (e.g., WD), resulting in enhanced tumorigenesis. These data raise concerns about a potential interaction between VC exposure and WD. Furthermore, it also emphasizes that current safety restrictions may be insufficient to account for other factors that can influence hepatotoxicity.

cancer biology↗

bioRxiv2021

Serum Amyloid A promotes Acetaminophen-induced liverinjury by damaging sinusoidal endothelial cell and exacerbating platelet aggregation in liver

BackgroundAcetaminophen (APAP) is the most commonly used non-prescription antipyretic and analgesic drugs. Overuse of APAP can cause hepatotoxicity. Liver sinusoidal endothelial cells (LSECs) damage is an important early event in APAP-induced liver injury. Serum amyloid A (SAA) is an acute phase protein that mainly produced by hepatocytes, and promotes endothelial dysfunction via a pro-inflammatory and pro-thrombotic effect in atherosclerosis and renal disease. However, the role of SAA in APAP-induced liver injury remains unclear. MethodsIn this study, we used neutralizing antibody (anti-SAA) or antagonistic small peptide derived from sequence of human SAA1/2 (SAA-pep) to block the functional activity of Saa1/2 in mouse serum. Immunohistochemistry staining, Evans blue and platelet adhesion assays were performed to examine the liver damage, the integrity of sinusoidal endothelium and platelets accumulation in APAP-induce liver injury. ResultsOur study showed that in the early stage of APAP-induced acute liver injury in mice, the intrahepatic and serum Saa1/2 levels were significantly increased within 24 hours, and then gradually reduced to normal level from 3 days. Neutralization of Saa1/2 by antibodies or peptides effectively prevented the destruction of hepatic sinusoids, reduced the intrahepatic hemorrhage and platelet accumulation in liver, as well as increased the survival rate of mice treated with lethal dose of APAP. In vitro experiments showed that Saa1/2 aggravated LSECs death induced by APAP. Moreover, Saa1/2 promoted platelets adhesion on LSECs via Tlr2/Vcam-1 axis. ConclusionOur findings suggest that Saa1/2 promotes APAP-induced liver injury by damaged LSECs and exacerbated platelets aggregation. This study provides a potential target for intervention of acute liver injury/failure caused by hepatotoxic drugs such as APAP.

pharmacology and toxicology↗