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Cancer Science Oct 2023Patients with nonalcoholic fatty liver disease (NAFLD) continue to increase with the epidemics of obesity, and NAFLD is estimated to become the most prevalent etiology... (Review)
Review
Patients with nonalcoholic fatty liver disease (NAFLD) continue to increase with the epidemics of obesity, and NAFLD is estimated to become the most prevalent etiology of hepatocellular carcinoma (HCC). Recently, NAFLD-HCC has been recognized to have clinico-histologically and molecularly distinct features from those from other etiologies, including a lower incidence rate of HCC and less therapeutic efficacy to immune checkpoint inhibitors (ICIs). Consistent with the clinical observations that up to 50% of NAFLD-HCC occurs in the absence of cirrhosis, the imbalance of pro- and antitumorigenic hepatic stellate cells termed as myHSC and cyHSC can contribute to the creation of an HCC-prone hepatic environment, independent of the absolute fibrosis abundance. Immune deregulations by accumulated metabolites in NAFLD-affected livers, such as a fatty-acid-induced loss of cytotoxic CD4 T cells serving for immune surveillance and "auto-aggressive" CXCR6+ CD8 T cells, may promote hepatocarcinogenesis and diminish therapeutic response to ICIs. Steatohepatitic HCC (SH-HCC), characterized by the presence of fat accumulation in tumor cells, ballooned tumor cells, Mallory-Denk body, interstitial fibrosis, and intratumor immune cell infiltration, may represent a metabolic reprogramming for adapting to a lipid-rich tumor microenvironment by downregulating CPT2 and leveraging its intermediates as an "oncometabolite." Genome-wide analyses suggested that SH-HCC may be more responsive to ICIs given its mutual exclusiveness with β-catenin mutation/activation that promotes immune evasion. Thus, further understanding of NAFLD-specific hepatocarcinogenesis and HCC would enable us to improve the current daily practice and eventually the prognoses of patients with NAFLD.
PubMed: 37545384
DOI: 10.1111/cas.15925 -
Phytomedicine : International Journal... Sep 2023To study the effect of ShenKang Injection (SKI) on the kidneys of DKD rats and its effect on oxidative stress mediated by the Keap1/Nrf2/Ho-1 signaling pathway through...
OBJECTIVE
To study the effect of ShenKang Injection (SKI) on the kidneys of DKD rats and its effect on oxidative stress mediated by the Keap1/Nrf2/Ho-1 signaling pathway through network pharmacology and in vivo and in vitro experiments.
METHODS
SKI drug targets were screened by TCMSP, DKD targets were screened by GenGards, OMIM, Drugbank, TTD, and Disgenet databases, and the two intersected for PPI network analysis and target prediction was performed by GO and KEGG. A total of 40 SD rats were randomly divided into 10 in the control group and 30 in the model group. After the model group was fed 8 W with high-sugar and high-fat diets, a DKD model was constructed by one-time intraperitoneal injection of streptozotocin (35 mg/kg). According to the weight, the model animals were randomly divided into three groups: 8 for model validation group, 8 for Irbesartan (25 mg/kg daily) group, and 8 for SKI group (5 ml/kg). Gavaged deionized water was given to the control group and the model validation group equally. The general conditions of the rats were observed, their body weights measured and their urine volumes recorded for 24 h. After the intervention of 16 W, serum was collected to detect Urea, Scr, blood lipids, and oxidative stress and lipid peroxidation indicators; Transmission electron microscopy, HE and Mallory staining were used to observe the pathological morphology of renal tissue. Immunohistochemistry and RT-PCR were used to detect the expression of Keap1, Nrf2, Ho-1, Gpx4 proteins and mRNA in rat kidney tissues. HK-2 cells were cultured in vitro and divided into: the control group, AGEs (200 μg/ml) group and AGEs + SKI group. The cell activity of the groups was detected using CCK-8 after 48 h of cell culture, and ROS were detected using fluorescent probes. Gpx4 expression was detected by immunofluorescence, while Keap1, Nrf2, Ho-1, and Gpx4 were detected by Western Blot.
RESULTS
Network pharmacological analysis predicted that SKI may delay DKD kidney injury by affecting redox-related signaling pathways and mitigating AGEs-induced oxidative stress. In the animal experiment, compared with the model validation group, the general state of rats in the SKI group was improved, and 24-hour urine protein levels were significantly reduced, and the Scr in the serum was reduced. A decreasing trend was seen in Urea, and TC, TG, and LDL levels significantly decreased and the levels of ROS, LPO and MDA were significantly lowered. Pathological staining showed that renal interstitial fibrosis was significantly improved, and electron microscopy showed that foot process effacement was alleviated. Immunohistochemistry and RT-PCR showed decreased expression of Keap1 protein and mRNA in kidney tissues of the SKI group. Additionally, Nrf2, Ho-1, and Gpx4 proteins and mRNA were expressed significantly. In the cell experiment, after 48 h treatment with AGEs, ROS in HK-2 cells increased significantly and cell activity decreased significantly, while cell activity in AGEs + SKI group increased significantly and ROS decreased. The expression of Keap1 protein in HK-2 cells in the AGEs + SKI group decreased, while the expression of Nrf2, Ho-1 and Gpx4 proteins increased significantly.
CONCLUSION
SKI can protect kidney function in DKD rats, delay DKD progression, inhibit AGEs-induced oxidative stress damage in HK-2 cells, and the mechanism of SKI to improve DKD may be achieved by activating the Keap1/Nrf2/Ho-1 signal transduction pathway.
Topics: Rats; Animals; Reactive Oxygen Species; Diabetic Nephropathies; Rats, Sprague-Dawley; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Network Pharmacology; Oxidative Stress; Signal Transduction; Urea; Glycation End Products, Advanced; Diabetes Mellitus
PubMed: 37392674
DOI: 10.1016/j.phymed.2023.154915 -
The American Journal of Pathology Oct 2023Sequestosome 1 (SQSTM1/p62; hereafter p62) is an autophagy receptor protein for selective autophagy primarily due to its direct interaction with the microtubule light... (Review)
Review
Sequestosome 1 (SQSTM1/p62; hereafter p62) is an autophagy receptor protein for selective autophagy primarily due to its direct interaction with the microtubule light chain 3 protein that specifically localizes on autophagosome membranes. As a result, impaired autophagy leads to the accumulation of p62. p62 is also a common component of many human liver disease-related cellular inclusion bodies, such as Mallory-Denk bodies, intracytoplasmic hyaline bodies, α-antitrypsin aggregates, as well as p62 bodies and condensates. p62 also acts as an intracellular signaling hub, and it involves multiple signaling pathways, including nuclear factor erythroid 2-related factor 2, NF-κB, and the mechanistic target of rapamycin, which are critical for oxidative stress, inflammation, cell survival, metabolism, and liver tumorigenesis. This review discusses the recent insights of p62 in protein quality control, including the role of p62 in the formation and degradation of p62 stress granules and protein aggregates as well as regulation of multiple signaling pathways in the pathogenesis of alcohol-associated liver disease.
Topics: Humans; Sequestosome-1 Protein; Signal Transduction; Liver Neoplasms; NF-kappa B; Liver Diseases, Alcoholic; Autophagy
PubMed: 36906265
DOI: 10.1016/j.ajpath.2023.02.015