Expression Levels Of P53 Research Articles

Effect of propolis supplementation on cadmium toxicity associated with renal and hepatic dysfunction in rats.

Cadmium (Cd), one of the toxic heavy metals, is of great importance for public health due to its use in many industrial areas. Propolis is a natural product with antioxidant and anti-inflammatory properties collected from plants by honey bees. The aim of this study was to investigate the protective role of propolis against the potential toxic effects of cadmium chloride in blood, liver and kidney tissues. For this purpose, rats were divided into four groups. Control group, propolis (150 mg/kg b.w.) treated group, cadmium chloride (1.76 mg/kg b.w. 1/50 LD50) treated group and cadmium chloride plus propolis (1.76 mg/kg b.w. and 150 mg/kg b.w. respectively) treated group. The substances were given to rats by gavage for 28 days. After 28 days of treatment, a statistically significant change was observed in serum biochemical parameters such as ALT, AST, BUN, LDH, urea, uric acid and creatinine, hematological parameters such as erythrocyte, hemoglobin and hematocrit, and IL-1β and IL-6 cytokine levels of cadmium chloride treated rats compared to the control group. In addition, significant changes were observed in mRNA expression levels of Casp-3, p53 and Tnf-α genes, HSP70, HSP90 and GRP78 protein levels and histopathological/immunohistochemical examinations. Improvement in biochemical and hematologic parameters, cytokines, mRNA expression, heat shock proteins and immunohistochemistry changes were observed in cadmium plus propolis treated group compared to cadmium treated group.

Curcumin nanoparticles alleviate brain mitochondrial dysfunction and cellular senescence in γ-irradiated rats

Despite the diverse applications of γ radiation in radiotherapy, industrial processes, and sterilization, it causes hazardous effects on living organisms, such as cellular senescence, persistent cell cycle arrest, and mitochondrial dysfunction. This study evaluated the efficacy of curcumin nanoparticles (CNPs) in mitigating mitochondrial dysfunction and cellular senescence induced by γ radiation in rat brain tissues. Four groups of male Wistar albino rats (n = 8 per group) were included: (Gr1) the control group; (Gr2) the CNPs group (healthy rats receiving oral administration of curcumin nanoparticles at a dose of 10 mg/kg/day, three times per week for eight weeks); (Gr3) the irradiated group (rats exposed to a single dose of 10 Gy head γ irradiation); and (Gr4) the irradiated + CNPs group (irradiated rats treated with CNPs). The data obtained demonstrated that oral administration of CNPs for eight weeks attenuated oxidative stress in γ-irradiated rats by lowering the brain’s lipid peroxidation level [malondialdehyde (MDA)] and enhancing antioxidant markers [superoxide dismutase (SOD), reduced glutathione (GSH), and total antioxidant capacity (TAC)] (P < 0.05). In addition, CNPs significantly increased mitochondrial function by improving complex I, complex II, and ATP production levels compared to the irradiated group. In irradiated rats, CNPs also showed anti-neuroinflammatory effects by reducing brain interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), and nuclear factor-kappa B (NF-ĸB) levels (P < 0.05). Moreover, CNPs administered to irradiated rats significantly reduced brain β-galactosidase activity and the expression levels of p53, p21, and p16 genes (P < 0.05) while concurrently inducing a significant increase in AMPK mRNA expression compared to the irradiated group. In conclusion, CNPs ameliorated the neurotoxicity of γ radiation and hold promise as a novel agent to delay cellular senescence via their combined antioxidant, anti-inflammatory, and mitochondrial-enhancing properties.

Forsythiaside A Ameliorates Inflammation by Regulating the Autophagy in Methotrexate-induced Intestinal Mucositis.

Methotrexate (MTX) effectively eliminates cancerous cells but can also cause inflammation intestinal, known as mucositis. Forsythiaside A (FTA) from Forsythia suspensa has shown promise in relieving mucositis by targeting the NLRP3 pathways. Since NLRP3 inflammasome activation is negatively regulated by autophagy, this study explores how FTAmediated autophagy affects NLRP3 inflammasome in treating MTX-induced intestinal inflammation. Intestinal mucositis was induced in rats with MTX. FTA's impact was assessed using HE staining and ELISA. The mechanism was studied using immunofluorescence, western blot, and ELISA. FTA treatment resulted in reduced levels of D-lactic acid and diamine oxidase (DAO) in MTX-treated rats. Western blot and immunofluorescence analyses revealed up-regulation of Beclin- 1 and LC3II/I, accumulation of LC3, and down-regulation of p62 expression levels in MTXtreated rats following 40 or 80 mg/kg FTA intervention. However, when the autophagy inhibitor 3-MA was used, the intestinal pathology was exacerbated, the inflammatory scores increased, and serum levels of TNF-α, IL-1β, and IL-18 were elevated. Western blotting indicated decreased LC3II/I expression, while NLRP3, cleaved caspase 1, and cleaved IL-1β expressions were upregulated. These findings suggested that FTA alleviated MTX-treated intestinal mucositis by activating autophagy, which in turn inhibits the NLRP3 inflammasome.

Rationale for Testing TP53 Mutations in Thyroid Cancer—Original Data and Meta-Analysis

The p53 protein is a tumor-suppressing transcription factor that is critical in tumorigenesis. While TP53 mutations are rare in differentiated thyroid cancer (DTC), they are significantly more common in anaplastic thyroid cancer (ATC). This study presents original results and a meta-analysis reevaluating the prognostic value of TP53 mutations in thyroid cancer, including surrogate markers such as immunohistochemical p53 expression and serum p53-Abs levels. TP53 mutations were analyzed using SSSP and direct sequencing in a DTC group (15 patients), an ATC group (3 patients), and a control group (25 patients). The immunohistochemical p53 expression was assessed in tissue samples. A meta-analysis of 14 eligible studies identified through the PubMed, Scopus, Google Scholar, and Cochrane databases was conducted. Our results showed TP53 mutations in all ATC cases, 6.67% of DTC cases (1 out of 15), and none in the control group. Immunohistochemical p53 overexpression was observed in 4 out of 15 DTC (26.67%) and all ATC cases but absent in controls. A meta-analysis confirmed that TP53 mutations are significantly more frequent in ATC than controls (OR 8.95; 95% CI: 1.36–58.70; p = 0.02) but not in DTC vs. controls (OR 1.87; 95% CI: 0.53–6.58; p = 0.33). p53 overexpression was significantly higher in both DTC and ATC vs. controls (OR 7.99; 95% CI: 5.11–12.51; p &lt; 0.01 and OR 64.37; 95% CI: 27.28–151.89; p &lt; 0.01, respectively). The serum p53-Abs positivity was also elevated in patients with PTC vs. controls (OR 2.07; 95% CI: 1.24–3.47; p &lt; 0.01). TP53 mutations are frequent events in the pathogenesis of ATC. In DTC, further prospective studies are needed to determine the prognostic value of TP53 mutations and related surrogate markers (immunohistochemical p53 expression, p53-Abs positivity).

Synergistic Anticancer Activity of Quercetin Combined with Luteolin in MCF-7 Breast Cancer Cells via Induction of Apoptosis

Cancer is a major public health problem with its increasing incidence and mortality. The striking role of phytochemicals in the prevention and treatment of cancer is undeniable in studies. In this study, the effects of the combination of quercetin (QUR) and luteolin (LTN) on the MCF-7 human breast cancer cell line were investigated in vitro. WST-1 cell cytotoxicity assay was used to determine cytotoxic activity. The effects on colony survival and cell migration were determined by clonogenic assay and wound scratch assay, respectively. For the determination of apoptosis, AO/EB dual staining, and Caspase-3 ELISA analysis, and genomic analyses revealing p53, Bcl-2, and Bax expression levels were performed. As a result of the analyses, it was seen that especially QUR plus LTN treatment exhibited a great cytotoxic activity in cells. It was determined that the combination treatment suppressed colony survival and significantly inhibited cell migration. Quantitative analysis results show that QUR+LTN treatment triggers cellular apoptosis by upregulating Caspase-3, p53, and Bax, and downregulating Bcl-2. Supporting these findings with further in vitro and in vivo analyses may contribute significantly to revealing the promising efficacy of combined phytochemical treatment approaches on cancer.

Lingguizhugan decoction enhances autophagy of Alzheimer’s disease via regulating the mTOR/ p70s6K pathway in vivo and in vitro

IntroductionLingguizhugan decoction (LGZG) has been reported to treat Alzheimer’s disease (AD) by anti-inflammatory and transporting amyloid-β (Aβ).MethodsUsing APP/PS1 transgenic mice as in vivo model and gave LGZG decoction by oral gavage. Using Aβ25-35-induced SH-SY5Y cells as in vitro model and then added LGZG medicated serum (LMS) to observe the regulatory effect of LGZG on AD autophagy-related pathways. Morris water maze (MWM) was used to evaluate the mice’s learning and memory ability. Mice’s hippocampus tissue sections were stained immunohistochemically to observe hippocampal Aβ deposition. Transmission electron microscopy monitored autophagosomes and autolysosomes. Western blot analysis measured protein expression levels of beclin-1, p62 and light chain 3II (LC3 II) and mTOR signaling. Results: LGZG could greatly improve learning and memory ability of APP/PS1 mice, and enhance autophagy in vitro and in vivo. LGZG increased the levels of beclin-1 and LC3 II and decreased the levels of p62.ConclusionLGZG enhanced autophagy and showed therapeutic potential in AD by inhibiting mTOR/p70s6K signaling.

Combination effects of Pistachio hull and carfilzomib on NF-κB p65, MDR1, MRP1, and Caspase3 gene expression in breast cancer cell line

ObjectiveThis study aimed to investigate the synergistic effects of the chemotherapy drug Carfilzomib (CFZ) and Pistachio hull extract on the SK-BR3 breast cancer cell line.MethodsIn this experimental study, we evaluated the effect of Pistachio hull extract and CFZ as standalone treatments on cell viability using the MTT assay at 24- and 48-hours post-treatment. Following this, we conducted combination therapy analyses to assess the potential synergistic relationship between Pistachio hull extract and CFZ after 24- and 48-hours of treatment on both the SK-BR3 breast cancer cell line and the MCF10A normal cell line. We utilized real-time PCR to measure the expression levels of MDR1, MRP1, NF-κB p65, and Caspase3 genes. Additionally, the NF-κB p65 transcription factor was evaluated using ELISA after 24- and 48-hours.ResultsThe MTT assay revealed IC50 values of 2.014 mg/mL and 1.031 mg/mL in the SK-BR3 cell line, and 3.265 mg/mL and 2.994 mg/mL in the MCF10A cell line at 24- and 48-hours post-treatment with Pistachio hull extract. CFZ concentrations of 0.181 × 10− 3 mg/mL and 0.0057 × 10− 3 mg/mL in the SK-BR3 cell line, as well as 5.54 × 10− 3 mg/mL and 2.51 × 10− 3 mg/mL in the MCF10A cell line, inhibited growth by up to 50%. The analysis of combination therapy indicated a synergistic effect between the two treatments after both 24- and 48-hours of exposure. Real-time PCR results demonstrated significant alterations in the expression of MDR1, MRP1, NF-κB p65, and Caspase3 genes, along with changes in NF-κB p65 protein levels in both cell lines following treatment with Pistachio hull extract, CFZ, or their combination compared to the control group (p < 0.05).ConclusionThe findings highlight the effectiveness of CFZ as a proteasome inhibitor when used in conjunction with Pistachio hull extract in breast cancer cell lines. Therefore, both CFZ and Pistachio hull extract, whether administered alone or in combination, represent promising molecular targets for breast cancer treatment.

Ischemic Area-Targeting and Self-Monitoring Nanoprobes Ameliorate Myocardial Ischemia/Reperfusion Injury by Scavenging ROS and Counteracting Cardiac Inflammation.

Precise and effective management of myocardial ischemia/reperfusion injury (MIRI) is still a formidable challenge in clinical practice. Additionally, real-time monitoring of drug aggregation in the MIRI region remains an open question. Herein, a drug delivery system, hesperadin and ICG assembled in PLGA-Se-Se-PEG-IMTP (HI@PSeP-IMTP), is designed to deliver hesperadin and ICG to the MIRI region for in vivo optical imaging tracking and to ameliorate MIRI. The peak aggregation of nanoprobes in the MIRI region is monitored by near-infrared fluorescence and photoacoustic imaging. The maximal fluorescence and photoacoustic signals of the HI@PSeP-IMTP group in the MIRI region rise ≈32% and 40% respectively compared with that of HI@PSeP group. Moreover, HI@PSeP-IMTP effectively mitigates MIRI due to a synergistic integration of diselenide bonds and hesperadin, which can eliminate ROS and suppress cardiac inflammation. Specifically, the expression levels of p-CaMKII, p-IκBα, and p65 in the MIRI region in the HI@PSeP-IMTP group demonstrate a reduction of 30%, 46%, and 42% respectively compared to that of the PBS group. Collectively, HI@PSeP-IMTP provides new insights into the development of drugs integrating diagnosis and treatment for MIRI.

Synephrine Inhibits Oxidative Stress and H2O2-Induced Premature Senescence.

Synephrine, a protoalkaloid found in Citrus aurantium (CA) peels, exerts lipolytic, anti-inflammatory, and vasoconstrictive effects; however, its antioxidant activity remains unclear. In this study, electron spin resonance spectroscopy revealed that synephrine scavenged both hydroxyl and superoxide anion radicals. Several external stimuli, such as H2O2, X-rays, and ultraviolet (UV) radiation, cause stress-induced premature senescence (SIPS). As oxidative stress induces SIPS, we hypothesized that synephrine, an antioxidant, would suppress H2O2-induced premature senescence in WI-38 cells. Synephrine significantly decreased the reactive oxygen species levels induced by H2O2, thereby reducing lipid peroxidation, and oxidative DNA damage and preventing SIPS. Additionally, synephrine inhibited mitochondrial dysfunction in H2O2-treated WI-38 cells. The expression levels of p53, p21, and p16-INK4A, which are involved in the induction of cell cycle arrest in SIPS, were significantly lower in synephrine-treated cells than in untreated cells. Our results indicate that synephrine inhibits H2O2-induced oxidative stress and mitochondrial dysfunction, suppressing premature senescence by inhibiting activation of the p53-p21 and p16-INK4A-pRB pathways.

Taxifolin Protects Against 5-Fluorouracil-Induced Cardiotoxicity in Mice Through Mitigating Oxidative Stress, Inflammation, and Apoptosis: Possible Involvement of Sirt1/Nrf2/HO-1 Signaling.

Although 5-fluorouracil (5-FU) is widely utilized in cancer treatment, its side effects, including cardiotoxicity, limit its use. Taxifolin (TAX) is a bioactive anti-inflammatory and antioxidant flavonoid. This study aimed to elucidate the protective effect of TAX against 5-FU-induced cardiac injury in male mice. Mice were treated with TAX (25 and 50mg/kg, orally) for 10days and a single dose of 150mg/kg 5-FU at day 8. Mice intoxicated with 5-FU showed increased creatine kinase-MB and lactate dehydrogenase activities and troponin I levels, with multiple cardiac histopathological changes. They also showed a significant increase in cardiac malondialdehyde (MDA) and nitric oxide (NO) and decreases in myocardial reduced glutathione (GSH) content and superoxide dismutase (SOD) and catalase (CAT) activities (P < 0.001). Pretreatment of 5-FU-injected mice with TAX suppressed cardiac injury, decreased MDA and NO contents (P < 0.001), and boosted antioxidant defenses in the myocardium. Moreover, TAX attenuated cardiac inflammatory response, as evidenced by the decreased expression levels of cardiac NF-κB p65,inducible nitric oxide synthase (iNOS), and pro-inflammatory cytokines (P < 0.001). Largely, TAX ameliorated the decrease in Bcl-2 expression and the increase in BAX and caspase-3 in the heart. It also restored the cardiac Sirt1/Nrf2/HO-1 signaling pathway. In conclusion, TAX showed significant cardioprotective effects on 5-FU-induced cardiac injury and might represent a promising adjuvant in preventing cardiac injury associated with oxidative stress and inflammation.

Tianxiangdan suppresses foam cell formation by enhancing lipophagy and reduces the progression of atherosclerosis.

The aim of this study is to assess the impact of Tianxiangdan (TXD) on lipophagy in foam cells and its underlying mechanism in treating atherosclerosis, particularly focusing on its efficacy in lowering blood lipids. In vivo, ApoE-/- atherosclerosis mouse models were established for group intervention. Blood lipid levels of the mice were measured, lipid deposition and autophagy levels in atherosclerotic plaques were assessed, and co-localization of lipid droplets and autophagosomes was examined. In vitro, human THP-1 cells were induced into macrophages and then transformed into foam cells using ox-LDL induction. Different intervention groups were established. Total cellular cholesterol (TC), free cholesterol (FC), and autophagy levels were assessed, while the morphology and distribution of lipid droplets and autophagosomes in cells were observed using transmission electron microscopy. Western blot analysis was performed to evaluate the expression levels of PI3K, Akt, mTOR, TFEB, LC3II/I, ULK1, ABCA1, and p62. TXD effectively lowers blood lipid levels in ApoE-/- atherosclerotic mice, enhances lipophagy, and reduces lipid accumulation in foam cells and arterial lipid plaques. It achieves this by suppressing the expression of p85, Akt, and mTOR, while activating downstream autophagy signals such as TFEB, LC3II/I, and ULK1. Additionally, TXD reduces the expression of p62 and enhances the expression of the cholesterol transport molecule ABCA1. Our findings indicate that TXD activates lipophagy via the PI3K/Akt/mTOR pathway, leading to a reduction in lipid deposition within foam cells and plaques, thereby mitigating atherosclerosis.

High glucose induces renal tubular epithelial cell senescence by inhibiting autophagic flux.

Autophagy, a cellular degradation process involving the formation and clearance of autophagosomes, is mediated by autophagic proteins, such as microtubule-associated protein 1 light chain 3 (LC3) and sequestosome 1 (p62), and modulated by 3-methyladenine (3-MA) as well as chloroquine (CQ). Senescence, characterised by permanent cell cycle arrest, is marked by proteins such as cyclin-dependent kinase inhibitor 1 (p21) and tumour protein 53 (p53). This study aims to investigate the relationship between cell senescence and renal function in diabetic kidney disease (DKD) and the effect of autophagy on high-glucose-induced cell senescence. We categorised 46 patients with DKD diagnosed by renal biopsy into classes I, IIa, IIb, III and IV and used four normal kidney specimens from patients with renal trauma as controls. We evaluated pathological changes, LC3 and p21. We used streptozotocin-induced DKD models in rats and 35mM glucose-cultured human proximal tubular epithelial cells (HK-2) with or without 3-MA and CQ. We assessed p53, p21, LC3 and p62. We observed autophagosomes and detected senescence-associated galactosidase (SA-β-gal) activity. In patients with DKD, p21 and LC3 expression levels increased over time and correlated positively with blood creatinine and proteinuria. In DKD rats and HK-2 cells, p21, p53, LC3 and p62 expression levels were higher than in the controls, as were SA-β-gal-positive cells, renal tubular autophagosomes and co-expression of p21 and LC3. The 3-MA reduced p16, p21 and p53 expression compared with the high glucose group, whereas CQ had the opposite effect. These results suggest that renal tubular cell senescence is associated with the progression of DKD. Additionally, autophagic flux may play a role in mediating high-glucose-induced senescence in renal tubular cells.

Herbal Munziq Ameliorates Myocardial Ischemia-Reperfusion Injury by Inhibiting Inflammation.

The objective of this study was to investigate the cardioprotective effects of Munziq on abnormal body fluid myocardial ischemia-reperfusion injury (MIRI) and its underlying mechanism.Normal rats and rats with abnormal body fluid (ABF) were pre-treated with Munziq for 21 days. Following this, MIRI models were established. Histopathological changes and myocardial ultrastructure changes were observed by Hematoxylin and Eosin (HE)staining and transmission electron microscopy to observe pathological manifestations of myocardial injury. Serum CK-MB, cTn-T, and ICAM-1 levels were detected by Enzyme-Linked Immunosorbent Assay (ELISA) to observe myocardial injury-related markers. The levels of IL-1β, IL-6, and TNF-α in serum and myocardial tissue were also detected by ELISA to observe the anti-inflammatory effect. The expression levels of NF-κB signaling pathway-related proteins NIK, IKKα, Pikα, and p65 were detected by Western blot analysis. The results showed that myocardial injury in the ABF MIRI group was more severe compared to the control MIRI group. Munziq pretreatment has the potential to mitigate the pathological changes induced by ischemia-reperfusion injury and could protect cardiac function. Protein levels of the NF-κB pathway and downstream effectors IL-1β, IL-6, and TNF-α were significantly up-regulated in the MIRI group while down-regulated in the Munziq group. Interestingly, there was more activation of the NF-κB signaling pathway and higher levels of downstream inflammatory cytokines in the ABF MIRI group. The results suggest that MIRI was more severe in ABF. Munziq has cardioprotective effects in ischemia and reperfusion injury. This protective effect may be acted by suppressing the NF-κB signaling pathway.

MiR-507 Acts as a Tumor Suppressor in Renal Cell Carcinoma Cells by Targeting STEAP3.

In recent years, there has been a rise in the incidence of renal cell carcinoma (RCC), with metastatic RCC being a prevalent and significant contributor to mortality. While a regulatory role for microRNAs (miRNAs) in the development and progression of RCC has been recognized, their precise functions, molecular mechanisms, and potential clinical implications remain inadequately elucidated. Hence, this study aimed to explore the role of miR-507 in RCC and identify STEAP3 as a downstream target of miR-507. Bioinformatics analysis was used to analyze the expression of miR-507 and STEAP3 in RCC specimens. CCK-8, Transwell, and flow cytometry assays were used to assess the function of miR-507 in RCC cells. The connection between miR-507 and STEAP3 was confirmed through a luciferase reporter assay. The expression level of STEAP3, p53, and xCT was analyzed by western blotting. Bioinformatics analysis showed that miR-507 was expressed at low levels in RCC tissues and was linked to poor overall survival. STEAP3 was found to be significantly upregulated in RCC. Further, STEAP3 was shown to be targeted by miR-507. High levels of miR-507 reduced the expression of STEAP3, leading to stagnant cell viability, apoptosis, and migrative capacity. Whereas miR-507 knockdown reverted such a tendency. The study also discovered that miR-507 exerted its inhibitory effect through the op53/xCT pathway. Within RCC, miR-507 modulates the expression of SETAP3/p53/xCT axis, exhibiting a tumor suppressive effect. These discoveries offer present prospective biomarkers for both surveillance and treatment of RCC.

SQSTM1/p62 predicts prognosis and upregulates the transcription of CCND1 to promote proliferation in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a rare, highly invasive non-Hodgkin's lymphoma. The main pathogenesis of MCL is associated with the formation of the IgH/CCND1 fusion gene and nuclear overexpression of cyclin D1, which accelerates the cell cycle, leading to tumorigenesis. The prognosis with current standard chemotherapy is still unsatisfactory. SQSTM1/p62 is a multifunctional adaptor that plays an important role in various tumors. Here, we found that the expression of p62 in MCL tissues was higher than that in hyperplastic lymphadenitis patients. Patients with low p62 expression in MCL cells had better overall survival and progression-free survival rates than those with high expression (p = 0.024 and p = 0.025, respectively). Multivariate Cox analysis indicated that the calculated death risk (hazard ratio [HR]) in patients with high expression levels of p62 increased to 2.742 (95% confidence interval (CI) of 1.268-5.852, p = 0.01), which was higher than those with low levels. Silencing p62 impaired Jeko-1 and Granta519 cell proliferation while downregulating CCND1 mRNA and protein expression, thereby inducing G0/G1 cell cycle arrest. However, silencing p62 does not affect the fusion of IgH and CCND1. Luciferase reporter gene analysis and chromatin immunoprecipitation analysis demonstrated that p62 may regulate CCND1 gene expression through Nrf2. These results provide evidence that p62 can predict poor prognosis in MCL. The precise targeting of p62 therapy reduces the promoting effect of Nrf2 on CCND1, thereby preventing cell cycle progression and effectively inhibiting tumor proliferation. Therefore, p62 may provide a potential target for MCL.

Ponatinib alleviates non-alcoholic steatohepatitis through TFEB-mediated autophagy.

Non-alcoholic steatohepatitis (NASH) is a progressive liver disease with lipid accumulation, inflammation, and liver fibrosis. Ponatinib, a third-generation tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia, was found to improve metabolic disorders in mice. However, the role of ponatinib in liver inflammation and fibrosis remains to be elucidated. Here we aimed to determine the effect of ponatinib in non-alcoholic steatohepatitis. We explored the function and mechanism of ponatinib using a mouse model of NASH induced by a methionine and choline deficient (MCD) diet and LO2 cells cultured in MCD mimic medium. Here, we found that ponatinib reduced liver lipid deposition, fibrosis, and inflammation induced by MCD diet without affecting body weight and blood glucose. Meanwhile, we found that ponatinib attenuated steatohepatitis and inflammation in LO2 cells induced by MCD mimic medium. We further discovered that the expression levels of LC3II and lysosomal associated membrane protein 1 (LAMP1) were reduced and the expression level of p62 was upregulated in both mouse and cell models, suggesting that autophagy was inhibited, which was restored by ponatinib treatment. In addition, transcription factor EB (TFEB) is a major regulator of autophagy and lysosome biogenesis and the transcription and protein expression levels of TFEB were decreased in steatosis hepatocytes, which could be ameliorated by ponatinib treatment. These results revealed that the beneficial effects of ponatinib on NASH via TFEB-mediated autophagy.

Portulaca oleracea L. (purslane) extract ameliorates intestinal inflammation in diet-induced obese mice by inhibiting the TLR4/NF-κB signaling pathway.

Portulaca oleracea L. (purslane) is a dietary plant and a botanical drug with antioxidant, antidiabetic, and anti-inflammatory activities. However, the effects of purslane against intestinal-inflammation-associated obesity are yet to be studied. In the present study, we hypothesized that purslane extract could reduce intestinal inflammation associated with metabolic disorder. Male C57BL/6J mice were fed a high-fat diet (HFD, 60% kcal% of fat) for a total duration of 14 weeks to establish an obesity model; further, the treatment group was orally administered purslane extract (200mg/kg/day) during the last 4 weeks. Then, intestinal tissues were detached from the mice for detecting protein expressions through Western blot and immunohistochemical analyses. Pro-inflammatory cytokines were determined using ELISA kits, whereas the components of purslane extract were detected by ultra performance liquid chromatography/electrospray ionization quadrupole time-of-flight mass spectrometry. Chronic oral administration of purslane extract ameliorated colon shortening syndrome and reduced bowel inflammation in HFD-induced obese mice through suppression of the toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway to downregulate TLR4, myeloid differentiation factor 88 (MyD88), Ser32 phosphorylation of NF-κB inhibitor alpha (IκBα), and Ser536 phosphorylation of NF-κB p65 expression levels, thereby inhibiting the pro-inflammatory cytokines, tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels. The present study supports the anti-inflammatory potential of purslane extract for modulating bowel inflammation under obesity through inhibition of the TLR4/NF-κB signaling pathway.

USP38 exacerbates myocardial injury and malignant ventricular arrhythmias after ischemia/reperfusion by promoting ferroptosis through the P53/SLC7A11 pathway

IntroductionMyocardial ischemia–reperfusion (I/R) leads to myocardial injury and malignant ventricular arrhythmias (VAs). Ferroptosis is a novel form of cell death that plays a role in myocardial injury after I/R. Ubiquitin-specific protease 38 (USP38), a member of the deubiquitinating enzyme family, is involved in regulating the progression of inflammation and tumors, but its role in myocardial I/R and ferroptosis is unclear. ObjectivesHerein, we explored whether USP38 regulates myocardial I/R-induced ferroptosis and the development of malignant arrhythmias and underlying mechanisms. MethodsIn this study, cardiac I/R mice model was established by ligating/loosening the left anterior descending artery, and the effects of USP38 on I/R-induced ferroptosis and VAs susceptibility were investigated using USP38 cardiac conditional knockout (USP38-CKO) mice and USP38 cardiac specific overexpression (USP38-TG) mice. In addition, an in vitro I/R model was constructed by hypoxia/reoxygenation for further validation. ResultsOur study showed that USP38 expression was significantly increased after I/R. USP38-CKO significantly inhibited I/R-induced iron overload, ROS production, and lipid peroxidation. In addition, USP38-CKO ameliorates post-I/R electrophysiologic abnormalities and reduces susceptibility to VAs. USP38-TG showed the opposite effect, exacerbating ferroptosis and increasing susceptibility to VAs after I/R. In vivo experiments similarly demonstrated that USP38 significantly exacerbated H/R-induced ferroptosis. Mechanistically, USP38 directly interacts with P53 and regulates the ubiquitination level of P53 and downstream SLC7A11 expression. ConclusionWe found that ferroptosis was significantly associated with VAs after I/R. USP38 can modulate myocardial injury and VAs susceptibility by affecting ferroptosis, which may be related to the P53/SLC7A11 pathway.

Anthracosis, epidemiology, gene and cancer: An updated mini-review.

It is believed that anthracosis is one of the most important occupational diseases, mainly seen in the residents of industrial areas and coal mine workers. This bronchial disease is more common in Asia's rural areas, particularly in the Middle East. In this study, we examined the epidemiology and genetic factors affecting this disease and its relationship with different types of cancer. In this review article, we searched four databases (Pubmed, the Cochrane Database of Systematic Reviews, Embase and Scopus) up to June 3, 2022, for published articles on anthracosis, epidemiology, gene, and cancer. Non-published studies, studies not published in indexed journals or without peer review, and studies not available in English were all excluded. The relationship between this disease and tobacco, smoking, air pollution, mycobacterium tuberculosis, gender, and indoor smoke was researched, and its prevalence was cited. Mutations in tumour suppressor genes such as P16 and P53 and expression levels of P16, CDH1, LUNX and RASSF1A genes were researched. Finally, this article discussed the relationship between anthracosis and cancers. According to the studied literature, antracotic people are more susceptible to pulmonary adenocarcinoma, hepatic nodules, renal cell carcinoma, and esophageal cancer.

MiR- 146b-5p inhibits Candida albicans-induced inflammatory response through targeting HMGB1 in mouse primary peritoneal macrophages.

Candida albicans (C. albicans) is one of the most common pathogens associated with deep fungal infection, which represents a serious threat to human health. Although high mobility group box 1 (HMGB1) plays a key role in C. albicans infection, its mechanism is unclear. We aimed to explore the regulation of small-molecule non-coding RNA (miRNA) for HMGB1 in C. albicans infection. Mouse primary peritoneal macrophages (MPMs) were isolated successfully. The optimum conditions for C. albicans infection were selected by Western blot and ELISA. The miRNA differential expression profiles of C. albicans infection were screened and verified by 6 miRNA gene chips and qRT-PCR. The direct regulation of the target gene HMGB1 by mmu-miR-146b-5p was confirmed through a dual-luciferase assay. The levels of mmu-miR-146b-5p, HMGB1, inflammatory mediators, p-IKK, IKK, p-IκBα, IκBα and NF-κB p65 were tested by qRT-PCR, Western blot, and ELISA. The nuclear and cytoplasm translocation of HMGB1 and NF-κB p65 were detected by Western blot and laser confocal microscopy. After siHMGB1 transfection, the expression levels of HMGB1, inflammatory mediators, p-IKK, IKK, p-IκBα, IκBα and NF-κB p65 were assessed using Western blot, qRT-PCR and ELISA. In our study, MPMs were successfully extracted and infected with C. albicans at optimum conditions of 1.5×107CFU/mL for 36h. Through miRNA gene chips analysis, 40 differential genes were screened. mmu-miR-146b-5p could directly and negatively regulate the expression and translocation of HMGB1, inhibit the expression of inflammatory mediators, and might participate in the NF-κB signaling pathway in a HMGB1-dependent manner under C. albicans infection. mmu-miR-146b-5p may play an anti-inflammatory role in treating C. albicans infection and provide a novel target for it.