Cytokine and Chemokine Receptor Profiles in Adipose Tissue Vasculature Unravel Endothelial Cell Responses in HIV.

Chronic systemic inflammation contributes to a substantially elevated risk of myocardial infarction in people living with HIV (PLWH). Endothelial cell dysfunction disrupts vascular homeostasis regulation, increasing the risk of vasoconstriction, inflammation, and thrombosis that contribute to cardiovascular disease. Our objective was to study the effects of plasma from PLWH on endothelial cell (EC) function, with the hypothesis that cytokines and chemokines are major drivers of EC activation. We first broadly phenotyped chemokine and cytokine receptor expression on arterial ECs, capillary ECs, venous ECs, and vascular smooth muscle cells (VSMCs) in adipose tissue in the subcutaneous adipose tissue of 59 PLWH using single cell transcriptomic analysis. We used CellChat to predict cell-cell interactions between ECs and other cells in the adipose tissue and Spearman correlation to measure the association between ECs and plasma cytokines. Finally, we cultured human arterial ECs (HAECs) in plasma-conditioned media from PLWH and performed bulk sequencing to study the direct effects ex-vivo. We observed that arterial and capillary ECs expressed higher interferon and tumor necrosis factor (TNF) receptors. Venous ECs had more interleukin (IL)-1R1 and ACKR1 receptors, and VSMCs had high significant IL-6R expression. CellChat predicted ligand-receptor interactions between adipose tissue immune cells as senders and capillary ECs as recipients in TNF-TNFRSF1A/B interactions. Chemokines expressed largely by capillary ECs were predicted to bind ACKR1 receptors on venous ECs. Beyond the adipose tissue, the proportion of venous ECs and VSMCs were positively plasma IL-6. In ex-vivo experiments, HAECs cultured with plasma-conditioned media from PLWH expressed transcripts that enriched for the TNF-α and reactive oxidative phosphorylation pathways. In conclusion, ECs demonstrate heterogeneity in cytokine and chemokine receptor expression. Further research is needed to fully elucidate the role of cytokines and chemokines in EC dysfunction and to develop effective therapeutic strategies.

Human Heart Failure Alters Mitochondria and Fiber 3D Structure Triggering Metabolic Shifts.

This study, utilizing SBF-SEM, reveals structural alterations in mitochondria and myofibrils in human heart failure (HF). Mitochondria in HF show changes in structure, while myofibrils exhibit increased cross-sectional area and branching. Metabolomic and lipidomic analyses indicate concomitant dysregulation in key pathways. The findings underscore the need for personalized treatments considering individualized structural changes in HF.

More Physical Exercise is Required for Overweight or Obese Women with Gestational Diabetes Mellitus to Achieve Good Plasma Glucose Control During Pregnancy: Finding from a Prospective Cohort in Shanghai.

Objective: This study was based on a gestational diabetes mellitus (GDM) cohort in Shanghai to examine the association between physical exercise and plasma glucose control among GDM women with and determine what the effects of pre-pregnancy body mass index (BMI). Methods: In this study, GDM was diagnosed if the plasma glucose values at any of the following time points reached the diagnostic threshold: fasting blood glucose (5.1 mmol/L), 1-hour blood glucose (10.0 mmol/L), and 2-hour blood glucose (8.5 mmol/L) by 75 g oral glucose tolerance test (OGTT). Information on GDM women was extracted from the hospital's health records and prenatal examination forms and was obtained through face-to-face interviews after delivery. A restricted cubic spline curve with four knots was used to flexibly model the relationship between the duration of moderate-intensity physical exercise and the percentage of abnormal plasma glucose among GDM patients with different BMI values. In this study, a P-value less than 0.05 (two-tailed) was considered as statistical significance. Results: Among 1139 GDM women with GDM, the median percentage of abnormal plasma glucose (PG) was 40.0% (interquartile range (IQR): 20.0-66.7%), and the difference between overweight-obese group and underweight-normal group was statistically significant (50.0% vs 40.0%, P <0.001). In this study, engaging in more physical exercise during pregnancy contributed to a higher prevalence of satisfactory glycemic control, and women with BMI <25 kg/m2 should engage in no less than 90 minutes of moderate-intensity physical activity per day to achieve satisfactory glycemic control (prevalence of abnormal PG <35%). However, over 120 minutes of daily moderate-intensity physical activity is required for GDM women with a BMI ≥25 kg/m2 to achieve satisfactory glycemic control. Conclusion: Overweight or obese women with GDM have a higher risk of poor glycemic control and require a longer duration of physical exercise to achieve the same level of blood glucose control.

Molecular characterization of a novel cytorhabdovirus infecting Plumbago indica L.

In 2021, Plumbago indica plants with necrotic spots on their leaves were observed in Beijing, China. Through high-throughput sequencing, we discovered a putative novel member of the genus Cytorhabdovirus, which was provisionally named "plumbago necrotic spot-associated virus" (PNSaV). The full-length negative-sense single-stranded RNA genome of this virus is 13,180 nucleotides in length and contains eight putative open reading frames (ORFs), in the order 3' leader-N-(P')-P-P3-M-G-P6-L-5' trailer. Phylogenetic analysis and pairwise comparisons suggested that PNSaV is most closely related to pastinaca cytorhabdovirus 1, with 59.2% nucleotide sequence identity in the complete genome and 56.4% amino acid sequence identity in the L protein. These findings suggest that PNSaV should be considered a new member of the genus Cytorhabdovirus.

The impact of green technology innovation and firm default risk: benefit effect or risk effect?-evidence from the panel data on Chinese manufacturing firms.

In the context of China's strategic goal of carbon neutrality, the realization of green technology innovation to reduce the risk of manufacturing default will help promote the green transformation of firms and achieve high-quality economic development. The study explored the relationship between green technology innovation and default risk by taking the manufacturing industry of listed enterprises in China from 2001 to 2020 as research samples. The results showed that green technology innovation is negatively correlated with default risk. Moreover, the heterogeneity analysis showed that the benefit effect of heavy-polluting enterprises, state-owned enterprises, and large-scale enterprises was more significant. The mechanism analysis showed that green technology innovation can reduce default risk through market position and capital structure. In addition, the study further distinguished that environmental protection tax was conducive to green technology innovation to reduce the occurrence of default risk. In theory, the study expanded the research paradigm between green technology innovation and default risk in theory, and provided new evidence and enlightenment for reducing the default risk of enterprises and supported the green and sustainable development of enterprises in practice.

Efficient Fe3C-CF Cathode Catalyst Based on the Formation/Decomposition of Li2-xO2 for Li-O2 Batteries.

Lithium-oxygen batteries have attracted considerable attention in the past several years due to their ultra-high theoretical energy density. However, there are still many serious issues that must be addressed before considering practical applications, including the sluggish oxygen redox kinetics, the limited capacity far from the theoretical value, and the poor cycle stability. This study proposes a surface modification strategy that can enhance the catalytic activity by loading Fe3C particles on carbon fibers, and the microstructure of Fe3C particle-modified carbon fibers is studied by multiple materials characterization methods. Experiments and density functional theory (DFT) calculations show that the discharge products on the Fe3C carbon fiber (Fe3C-CF) cathode are mainly Li2-xO2. Fe3C-CF exhibits high catalytic ability based on its promotion of the formation/decomposition processes of Li2-xO2. Consequently, the well-designed electrode catalyst exhibits a large specific capacity of 17,653.1 mAh g-1 and an excellent cyclability of 263 cycles at a current of 200 mA g-1.

Distinct CD3 + CD14 + T Cell-Monocytes are dynamic complexes that harbor HIV and are increased with glucose intolerance.

Persistent systemic inflammation in persons with HIV (PWH) is accompanied by an increased risk of metabolic disease. Yet, changes in the innate and adaptive immune system in PWH who develop metabolic disease remain poorly defined. Using unbiased approaches, we show that PWH with prediabetes/diabetes have a significantly higher proportion of circulating CD14 + monocytes complexed to T cells. The complexed CD3 + T cells and CD14 + monocytes demonstrate functional immune synapses, increased expression of proinflammatory cytokines, and greater glucose utilization. Furthermore, these complexes harbor more latent HIV DNA compared to CD14 + monocytes or CD4 + T cells. Our results demonstrate that circulating CD3 + CD14 + T cell-monocyte pairs represent functional dynamic cellular interactions that likely contribute to inflammation and, in light of their increased proportion, may have a role in metabolic disease pathogenesis. These findings provide an incentive for future studies to investigate T cell-monocyte immune complexes as mechanistic in HIV cure and diseases of aging. Highlights: Persons with HIV and diabetes have increased circulating CD3 + CD14 + T cell-monocyte complexes. CD3 + CD14 + T cell-monocytes are a heterogenous group of functional and dynamic complexes. We can detect HIV in T cell-monocyte complexes. The proportion of CD3 + CD14 + T cell-monocyte complexes is positively associated with blood glucose levels and negatively with plasma IL-10 and CD4 + T regulatory cells.

Identification and Analysis of Long Non-Coding RNAs Related to UV-B-Induced Anthocyanin Biosynthesis During Blood-Fleshed Peach (Prunus persica) Ripening.

Blood flesh is a key fruit trait in peaches (Prunus persica) and can be attributed to the accumulation of anthocyanins. The roles of long non-coding RNAs (lncRNAs) have been highlighted by multiple studies in regulating fruit ripening, anthocyanin accumulation, and abiotic stress responses in many flowering plants. Such regulatory functions of lncRNAs in Prunus persica, nonetheless, have not been reported. In this research, we sequenced and analyzed the complete transcriptome of C3-20 (a blood-fleshed peach) fruit at four developmental stages. Analyses of the correlated genes and differentially expressed lncRNA target genes helped to forecast lncRNAs' possible functions. The RNA-seq data were generated using high-throughput sequencing. In total, 17,456 putative lncRNAs, including 4,800 intergenic lncRNAs, 2,199 antisense lncRNAs, and 10,439 intronic lncRNAs were discovered, of which 4,871 differentially expressed lncRNAs (DE-lncRNAs) were annotated in the fruit developmental processes. The target genes of these DE-lncRNAs and their regulatory relationship identifying 21,795 cis-regulated and 18,271 trans-regulated targets of the DE-lncRNAs were in a similar way predicted by us. The enriched GO terms for the target genes included anthocyanin biosynthesis. Flavonoid biosynthesis and plant hormone signal transduction were also included in the enriched KEGG pathways. Co-expression network construction demonstrated that the highly expressed genes might co-regulate multiple other genes associated with auxin signal transduction and take effect in equal pathways. We discovered that lncRNAs, including LNC_000987, LNC_000693, LNC_001323, LNC_003610, LNC_001263, and LNC_003380, correlated with fruit that ripened and could take part in ethylene biosynthesis and metabolism and the ABA signaling pathway. Several essential transcription factors, such as ERFs, WRKY70, NAC56, and NAC72, may in a similar way regulate fruit ripening. Three DE-lncRNAs, XLOC_011933, XLOC_001865, and XLOC_042291, are involved in UV-B-induced anthocyanin biosynthesis and positively regulating UVR8 and COP10, were identified and characterized. Our discovery and characterization of XLOC_011933, XLOC_001865, and XLOC_042291 provide a more precise understanding and preliminarily establishes a theoretical framework for UV-B-induced flesh anthocyanin biosynthesis. This phenomenon might encourage more in-depth investigations to study the molecular mechanisms underlying peach flesh coloring.

Direct Synthesis of Biphenyl-2-carbonitriles by Rh(III)-Catalyzed C-H Hiyama Cross-Coupling in Water.

This method represents an efficient rhodium(III)-catalyzed o-C-H arylation of readily available benzimidate derivatives with diverse arylsilanes in water as a sustainable solvent, enabling the straightforward synthesis of potentially useful biphenyl-2-carbonitrile derivatives. This silicon-based protocol employs benzimidates as both an efficacious directing group and the source of a nitrile group.

The Collagen Receptor Discoidin Domain Receptor 1b Enhances Integrin ß1-Mediated Cell Migration by Interacting With Talin and Promoting Rac1 Activation.

Integrins and discoidin domain receptors (DDRs) 1 and 2 promote cell adhesion and migration on both fibrillar and non fibrillar collagens. Collagen I contains DDR and integrin selective binding motifs; however, the relative contribution of these two receptors in regulating cell migration is unclear. DDR1 has five isoforms (DDR1a-e), with most cells expressing the DDR1a and DDR1b isoforms. We show that human embryonic kidney 293 cells expressing DDR1b migrate more than DDR1a expressing cells on DDR selective substrata as well as on collagen I in vitro. In addition, DDR1b expressing cells show increased lung colonization after tail vein injection in nude mice. DDR1a and DDR1b differ from each other by an extra 37 amino acids in the DDR1b cytoplasmic domain. Interestingly, these 37 amino acids contain an NPxY motif which is a central control module within the cytoplasmic domain of ß integrins and acts by binding scaffold proteins, including talin. Using purified recombinant DDR1 cytoplasmic tail proteins, we show that DDR1b directly binds talin with higher affinity than DDR1a. In cells, DDR1b, but not DDR1a, colocalizes with talin and integrin ß1 to focal adhesions and enhances integrin ß1-mediated cell migration. Moreover, we show that DDR1b promotes cell migration by enhancing Rac1 activation. Mechanistically DDR1b interacts with the GTPase-activating protein (GAP) Breakpoint cluster region protein (BCR) thus reducing its GAP activity and enhancing Rac activation. Our study identifies DDR1b as a major driver of cell migration and talin and BCR as key players in the interplay between integrins and DDR1b in regulating cell migration.

A galacturonan from Dioscorea opposita Thunb. regulates fecal and impairs IL-1 and IL-6 expression in diarrhea mice.

Antibiotic-associated diarrhea (AAD) is a common side-effect of antibiotic treatment resulting from an imbalance in the colonic bacteria. The hypothesis of this study is to ask whether polysaccharide from the rhizome of Dioscorea opposita which is recorded as conventional herbs and food for diarrhea treatment in Southeast Asia, may be an active compound against diarrhea induced by antibiotics. To address, firstly, a homogenous polysaccharide, DOP0.2-S-3 was characterized as a homogalacturonan containing linear repeating units of → 4)-α-D-GalAp(1 → 4)-α-D-GalAp(1 → with the average molecular weight of 14 kDa. DOP0.2-S-3 significantly reduced the water content and defecation times caused by AAD in mice, while it also remarkably attenuated the cytokines of IL-1ß and IL-6 expression in mice colon tissues. DOP0.2-S-3 decreased potential pathogen and increased Bacteroidetes in the mice gut. These results suggested DOP0.2-S-3 might be a new leading compound for the functional foods or drug candidate development against AAD partially through regulating gut flora.

DDR1 contributes to kidney inflammation and fibrosis by promoting the phosphorylation of BCR and STAT3.

Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase activated by collagen, contributes to chronic kidney disease. However, its role in acute kidney injury and subsequent development of kidney fibrosis is not clear. Thus, we performed a model of severe ischemia/reperfusion-induced acute kidney injury that progressed to kidney fibrosis in WT and Ddr1-null mice. We showed that Ddr1-null mice had reduced acute tubular injury, inflammation, and tubulointerstitial fibrosis with overall decreased renal monocyte chemoattractant protein (MCP-1) levels and STAT3 activation. We identified breakpoint cluster region (BCR) protein as a phosphorylated target of DDR1 that controls MCP-1 production in renal proximal tubule epithelial cells. DDR1-induced BCR phosphorylation or BCR downregulation increased MCP-1 secretion, suggesting that BCR negatively regulates the levels of MCP-1. Mechanistically, phosphorylation or downregulation of BCR increased ß-catenin activity and in turn MCP-1 production. Finally, we showed that DDR1-mediated STAT3 activation was required to stimulate the secretion of TGF-ß. Thus, DDR1 contributes to acute and chronic kidney injury by regulating BCR and STAT3 phosphorylation and in turn the production of MCP-1 and TGF-ß. These findings identify DDR1 an attractive therapeutic target for ameliorating both proinflammatory and profibrotic signaling in kidney disease.

Crataegus pinnatifida polysaccharide alleviates colitis via modulation of gut microbiota and SCFAs metabolism.

Inflammatory bowel disease (IBD) afflicted individual and most medications have side-effects. Crataegus pinnatifida (Hawthorn), which is a safe medicine and food homolog plant, has been reported to prevent colitis in murine. Yet the bioactivity component and the underlying molecular mechanism remain unclear. Here, we established a direct link between colitis induced by dextran sulphate sodium (DSS) in mice and polysaccharide HAW1-2 isolated from hawthorn. Our results showed HAW1-2 restored the pathological lesions in colon and inhibited the expression of inflammatory cytokines including IL-1ß, IL-6 and TNF-α. Meanwhile, IKKα/ß, IκBα, NF-κB and the phosphorylation levels were inhibited significantly. These findings suggested HAW1-2 could alleviate the inflammation of colon. Further, we found the composition of gut microbiota was modified and Bacteroides including Alistipes and Odoribacter were significantly enriched. Besides, we showed Alistipes and Odoribacter were positively co-related with acetic acid and propionic acid while were negatively co-related with inflammatory cytokines. Finally, we demonstrated the anti-inflammation activity of HAW1-2 might be induced by acetic acid. Together, the present data revealed HAW1-2 could directly modify the gut microbiota, especially for Bacteroides, and generate SCFAs to inhibit colitis. It also implies microbiota-directed intervention in IBD patients should be particularly given more attention.

Isolation and Identification of Bovine Preadipocytes and Screening of MicroRNAs Associated with Adipogenesis.

The elucidation of the mechanisms of preadipocyte differentiation and fat accumulation in adipocytes is a major work in beef cattle breeding. As important post-transcriptional regulators, microRNAs (miRNAs) take part in cell proliferation, differentiation, apoptosis, and fat metabolism through binding seed sites of targeting mRNAs. The aim of this study was to isolate and identify bovine preadipocytes and screen miRNAs associated with adipogenesis. Bovine preadipocytes were isolated from subcutaneous fatty tissue and induced to differentiate into adipocytes. Verification of preadipocytes and adipocytes was performed by qRT-PCR (real-time quantitative reverse transcription PCR), Oil Red O staining, and immunofluorescence staining. Total RNA was extracted for small RNA sequencing. The sequencing data showed that 131 miRNAs were highly expressed in adipocytes, and 119 miRNAs were highly expressed in preadipocytes. Stem-loop qPCR (stem-loop quantitative real-time PCR) results showed that the expression patterns of 11 miRNAs were consistent with the sequencing results (miR-149-5p, miR-24-3p, miR-199a-5p, miR-33a, etc.). According to KEGG pathway and Gene Ontology (GO) analyses, multiple predicted target genes were associated with lipid metabolism. In summary, this study provides a protocol of isolating bovine preadipocytes and screening various differently expressed miRNAs during preadipocyte differentiation.

Analysis of the Bovine DLK1 Gene Polymorphism and Its Relation to Lipid Metabolism in Chinese Simmental.

In this study, we precisely constructed and transfected the overexpression and interference vectors in BFFs to evaluate the role of DLK1 gene on lipid metabolism in vitro. The expression of of DLK1 in the mRNA and protein level tended to reduce, and TGs were significantly increased in the pGPU6-shDLK1 group compared to the control group (p < 0.05). The expression of DLK1 in the mRNA and protein level were increased in the pBI-CMV3-DLK1 group compared to the control group, and the TGs content showed a significant decrease in the pBI-CMV3-DLK1 group (p < 0.05). Meanwhile, we used the restriction fragment length polymorphism (RFLP-PCR) detection method to screen SNPs further to explore and analyze the relationship between the gene and the economic traits of 28-month-old Chinese Simmental and the fatty acids composition of cattle longissimus muscle. The result showed that two SNPs, IVS3 + 478 C>T and IVS3 + 609 T>G, were identified as being significantly associated with carcass and meat quality traits in Chinese Simmental, such as the carcass fat coverage rate, loin eye muscle area, and fat color score. In summary, our results indicated that DLK1 can affect lipid metabolism in bovine and these two SNPs might be applied as genetic markers of meat quality traits for beef cattle breeding.

Clinical Effect of Low Molecular Weight Heparin Sodium Combined with Magnesium Sulfate in the Treatment of Patients with Severe Preeclampsia.

OBJECTIVE: To investigate the effect of low molecular weight heparin sodium combined with magnesium sulfate in the treatment of patients with severe preeclampsia. STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: The Department of Obstetrics and Gynecology, The Affiliated Hospital, North China University of Science and Technology, from April 2016 to July 2017. METHODOLOGY: Patients with severe preeclampsia were randomly divided into observation group (52 cases) and control group (51 cases). In the control group, magnesium sulfate were used, but in observation group low molecular weight heparin sodium were added. After treatment of 7 days, serum TGF-ß1, VCAM-1, ES levels and endothelial function markers of NO and ET-1 changes were compared between the two groups.The delivery status after treatment was observed in both groups. RESULTS: After treatment of 7 days, serum TGF-ß1 and NO levels in the observation group were higher than those in control group (both p<0.001), and VCAM-1, ES, ET-1, ET-1/NO levels in observation group were lower than those in control group (all p<0.001). Among the patients who delivered live births, observation group had a longer delivery gestation age after treatment than that of control group (p=0.038); placental quality, body mass and 1 minute Apgar score of surviving newborns in observation group were all higher than those in control group (all p<0.001). CONCLUSION: Low molecular weight heparin sodium combined with magnesium sulfate may improve the.

Exploration of binding and inhibition mechanism of a small molecule inhibitor of influenza virus H1N1 hemagglutinin by molecular dynamics simulation.

Influenza viruses are a major public health threat worldwide. The influenza hemagglutinin (HA) plays an essential role in the virus life cycle. Due to the high conservation of the HA stem region, it has become an especially attractive target for inhibitors for therapeutics. In this study, molecular simulation was applied to study the mechanism of a small molecule inhibitor (MBX2329) of influenza HA. Behaviors of the small molecule under neutral and acidic conditions were investigated, and an interesting dynamic binding mechanism was found. The results suggested that the binding of the inhibitor with HA under neutral conditions facilitates only its intake, while it interacts with HA under acidic conditions using a different mechanism at a new binding site. After a series of experiments, we believe that binding of the inhibitor can prevent the release of HA1 from HA2, further maintaining the rigidity of the HA2 loop and stabilizing the distance between the long helix and short helices. The investigated residues in the new binding site show high conservation, implying that the new binding pocket has the potential to be an effective drug target. The results of this study will provide a theoretical basis for the mechanism of new influenza virus inhibitors.

Hepatocyte ERBB3 and EGFR are required for maximal CCl4-induced liver fibrosis.

Epidermal growth factor receptor (EGFR) and its ligands have been implicated in liver fibrosis. However, it has not been directly shown that hepatocellular genetic ablation of either this receptor tyrosine kinase or ERBB3, its interactive signaling partner, affects hepatic fibrosis. Carbon tetrachloride (CCl4)-induced liver fibrosis in hepatocyte-specific (HS) mouse models of EGFR and ERBB3 ablation was evaluated in both single gene knockouts and an HS-EGFR-ERBB3 double knockout (DKO). Loss of hepatocellular EGFR or ERBB3 did not impact cytochrome P450-2E1 expression, the extent of centrilobular injury, or the initial regenerative response, but it did diminish liver fibrosis induced by chronic intraperitoneal administration of CCl4 The reduction of liver fibrosis correlated with reduced α-smooth muscle actin expression. Maximal impact to fibrogenesis occurred in the ERBB3 and EGFR-ERBB3 DKO models, suggesting that EGFR-ERBB3 heterodimeric signaling in damaged hepatocytes may play a more important role in liver fibrosis than EGFR-EGFR homodimeric signaling. Immunohistochemical analyses of phospho-EGFR and phospho-ERBB3 isoforms revealed clear staining in hepatocytes, activated stellate cells, and macrophages. Our results support a role for the hepatocellular ERBB tyrosine kinases in fibrogenesis and suggest that pharmacologic inhibition of EGFR-ERBB3 signaling may reverse or retard hepatic fibrosis.

Loss of hepatocyte ERBB3 but not EGFR impairs hepatocarcinogenesis.

Epidermal growth factor receptor (EGFR) and ERBB3 have been implicated in hepatocellular carcinogenesis (HCC). However, it is not known whether altering the activity of either EGFR or ERBB3 affects HCC development. We now show that Egfr(Dsk5) mutant mice, which have a gain-of-function allele that increases basal EGFR kinase activity, develop spontaneous HCC by 10 mo of age. Their tumors show increased activation of EGFR, ERBB2, and ERBB3 as well as AKT and ERK1,2. Hepatocyte-specific models of EGFR and ERBB3 gene ablation were generated to evaluate how the loss of these genes affected tumor progression. Loss of either receptor tyrosine kinase did not alter liver development or regenerative liver growth following carbon tetrachloride injection. However, using a well-characterized model of HCC in which N-nitrosodiethylamine is injected into 14-day-old mice, we discovered that loss of hepatocellular ERBB3 but not EGFR, which occurred after tumor initiation, retarded liver tumor formation and cell proliferation. We found no evidence that this was due to increased apoptosis or diminished phosphatidylinositol-3-kinase activity in the ERBB3-null cells. However, the relative amount of phospho-STAT3 was diminished in tumors derived from these mice, suggesting that ERBB3 may promote HCC through STAT3 activation.

Loss of hepatocyte EGFR has no effect alone but exacerbates carbon tetrachloride-induced liver injury and impairs regeneration in hepatocyte Met-deficient mice.

The role(s) of the epidermal growth factor receptor (EGFR) in hepatocytes is unknown. We generated a murine hepatocyte specific-EGFR knockout (KO) model to evaluate how loss of hepatocellular EGFR expression affects processes such as EGF clearance, circulating EGF concentrations, and liver regeneration following 70% resection or CCl4-induced centrilobular injury. We were able to disrupt EGFR expression effectively in hepatocytes and showed that the ability of EGF and heregulin (HRG) to phosphorylate EGFR and ERBB3, respectively, required EGFR. Loss of hepatocellular EGFR impaired clearance of exogenous EGF from the portal circulation but paradoxically resulted in reduced circulating levels of endogenous EGF. This was associated with decreased submandibular salivary gland production of EGF. EGFR disruption did not result in increased expression of other ERBB proteins or Met, except in neonatal mice. Liver regeneration following 70% hepatectomy revealed a mild phenotype, with no change in cyclin D1 expression and slight differences in cyclin A expression compared with controls. Peak 5-bromo-2'-deoxyuridine labeling was shifted from 36 to 48 h. Centrilobular damage and regenerative response induced by carbon tetrachloride (CCl4) were identical in the KO and wild-type mice. In contrast, loss of Met increased CCl4-induced necrosis and delayed regeneration. Although loss of hepatocellular EGFR alone did not have an effect in this model, EGFR-Met double KOs displayed enhanced necrosis and delayed liver regeneration compared with Met KOs alone. This suggests that EGFR and Met may partially compensate for the loss of the other, although other compensatory mechanisms can be envisioned.