Advances in management of metabolic dysfunction-associated steatotic liver disease: from mechanisms to therapeutics.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease that affects over 30% of the world's population. For decades, the heterogeneity of non-alcoholic fatty liver disease (NAFLD) has impeded our understanding of the disease mechanism and the development of effective medications. However, a recent change in the nomenclature from NAFLD to MASLD emphasizes the critical role of systemic metabolic dysfunction in the pathophysiology of this disease and therefore promotes the progress in the pharmaceutical treatment of MASLD. In this review, we focus on the mechanism underlying the abnormality of hepatic lipid metabolism in patients with MASLD, and summarize the latest progress in the therapeutic medications of MASLD that target metabolic disorders.

FSTL1: A double-edged sword in cancer development.

Flolistatin-related protein 1 (FSTL1), a secreted glycoprotein that is involved in many physiological functions, has attracted much interest and has been implicated in a wide range of diseases, including heart diseases and inflammatory diseases. In recent years, the involvement of FSTL1 in cancer progression has been implicated and researched. FSTL1 plays a contradictory role in cancer, depending on the cancer type as well as the contents of the tumor microenvironment. As reviewed here, the structure and distribution of FSTL1 are first introduced. Subsequently, the expression and clinical significance of FSTL1 in various types of cancer as a tumor enhancer or inhibitor are addressed. Furthermore, we discuss the functional role of FSTL1 in various processes that involve tumor cell proliferation, metastasis, immune responses, stemness, cell apoptosis, and resistance to chemotherapy. FSTL1 expression is tightly controlled in cancer, and a multitude of cancer-related signaling cascades like TGF-ß/BMP/Smad signaling, AKT, NF-κB, and Wnt-ß-catenin signaling pathways are modulated by FSTL1. Finally, FSTL1 as a therapeutic target using monoclonal antibodies is stated. Herein, we review recent findings showing the double-edged characteristics and mechanisms of FSTL1 in cancer and elaborate on the current understanding of therapeutic approaches targeting FSTL1.

Effect of nano-graphene lubricating oil on particulate matter of a diesel engine.

Nano-graphene lubricating oil with appropriate concentration shows excellent performance in reducing friction and wear under different working conditions of diesel engines, and has been widely concerned. Lubricating oil has a significant impact on particulate matter (PM) emissions. At present, there are few studies on the impact of nano-graphene lubricating oil on the physicochemical properties of PM. In order to comprehensively evaluate the impact of nano-graphene lubricating oil on diesel engines, this paper mainly focused on the effects of lubricating oil nano-graphene additives on the particle size distribution and physicochemical properties of PM. The results show that, compared with pure lubricating oil, the total number of nuclear PM and accumulated PM of nano-graphene lubricating oil is significantly increased. The fractal dimension of PM of nano-graphene lubricating oil increases and its structure becomes more compact. The average fringe separation distance of basic carbon particles decreases, the average fringe length increases. The degree of ordering and graphitization of basic carbon particles are higher. The fringe tortuosity of basic carbon particles decreases, and the fluctuation of carbon layer structure of basic carbon particles decreases. Aliphatic substances in PM are basically unchanged, aromatic components and oxygen functional groups increase. The initial PM oxidation temperature and burnout temperature increase, the maximum oxidation rate temperature and combustion characteristic index decrease, and the activation energy increases, making it more difficult to oxidize. This was mainly caused by the higher graphitization degree of PM of nano-graphene lubricating oil and the increased content of aromatic substances.

Performance evaluation of nano-graphene lubricating oil with high dispersion and low viscosity used in diesel engines.

The basic tribological experiments have reported that nano-graphene lubricating oil has excellent anti-friction and anti-wear properties, which has been widely concerned. However, the real anti-friction effect of nano-graphene lubricating oil and its impact on engine power performance, economic performance and emission performance remain to be proved. This has seriously hindered the popularization and application of nano-graphene lubricating oil in the engine field. In this paper, nano-graphene powder was chemically grafted to prepare nano-graphene lubricating oil with high dispersion stability. The influence of nano-graphene on physicochemical properties of lubricating oil was studied, and the influence of nano-graphene on engine power performance, economic performance and emission performance was explored. The results show that after modification, the dispersion of nano-graphene in lubricating oil is improved. Compared with pure lubricating oil, the addition of nano-graphene makes the kinematic viscosity of lubricating oil slightly lower, and has little effect on the density, flash point, pour point and total acid value of lubricating oil. The reversed towing torque of nano-graphene lubricating oil is reduced by 1.82-5.53%, indicating that the friction loss decreases. The specific fuel consumption of the engine is reduced, which indicates that the fuel economic performance is improved. Engine HC+NOX, CH4, CO2 emissions do not change much, but particulate matter (PM) emissions increase by 8.85%. The quantity concentration of nuclear particles, accumulated particles and total particles of nano-graphene lubricating oil are significantly higher than that of pure lubricating oil. And the increase of the quantity concentration of accumulated particles is more obvious than that of nuclear particles, and the larger the load, the more obvious this phenomenon. In order to apply nano-graphene lubricating oil to the engine, it is also necessary to further study its impact on the post-processing system, adjust the control strategy of the post-processing system and then test and calibrate.

Two decades of a protooncogene TBL1XR1: from a transcription modulator to cancer therapeutic target.

Transducin beta-like 1X-related protein 1 (TBL1XR1) was discovered two decades ago and was implicated as part of the nuclear transcription corepressor complex. Over the past 20 years, the emerging oncogenic function of TBL1XR1 in cancer development has been discovered. Recent studies have highlighted that the genetic aberrations of TBL1XR1 in cancers, especially in hematologic tumors, are closely associated with tumorigenesis. In solid tumors, TBL1XR1 is proposed to be a promising prognostic biomarker due to the correlation between abnormal expression and clinicopathological parameters. Post-transcriptional and post-translational modification are responsible for the expression and function of TBL1XR1 in cancer. TBL1XR1 exerts its functional role in various processes that involves cell cycle and apoptosis, cell proliferation, resistance to chemotherapy and radiotherapy, cell migration and invasion, stemness and angiogenesis. Multitude of cancer-related signaling cascades like Wnt-ß-catenin, PI3K/AKT, ERK, VEGF, NF-κB, STAT3 and gonadal hormone signaling pathways are tightly modulated by TBL1XR1. This review provided a comprehensive overview of TBL1XR1 in tumorigenesis, shedding new light on TBL1XR1 as a promising diagnostic biomarker and druggable target in cancer.

Dexrazoxane inhibits the growth of esophageal squamous cell carcinoma by attenuating SDCBP/MDA-9/syntenin-mediated EGFR-PI3K-Akt pathway activation.

Syndecan-binding protein (SDCBP) was reported to stimulate the advancement of esophageal squamous cell carcinoma (ESCC) and could potentially be a target for ESCC treatment. There is a growing corpus of research on the anti-tumor effects of iron chelators; however, very few studies have addressed the involvement of dexrazoxane in cancer. In this study, structure-based virtual screening was employed to select drugs targeting SDCBP from the Food and Drug Administration (FDA)-approved drug databases. The sepharose 4B beads pull-down assay revealed that dexrazoxane targeted SDCBP by interacting with its PDZ1 domain. Additionally, dexrazoxane inhibited ESCC cell proliferation and anchorage-independent colony formation via SDCBP. ESCC cell apoptosis and G2 phase arrest were induced as measured by the flow cytometry assay. Subsequent research revealed that dexrazoxane attenuated the binding ability between SDCBP and EGFR in an immunoprecipitation assay. Furthermore, dexrazoxane impaired EGFR membrane localization and inactivated the EGFR/PI3K/Akt pathway. In vivo, xenograft mouse experiments indicated that dexrazoxane suppressed ESCC tumor growth. These data indicate that dexrazoxane might be established as a potential anti-cancer agent in ESCC by targeting SDCBP.

Association of vitamin D deficiency and subclinical diabetic peripheral neuropathy in type 2 diabetes patients.

Background: Diabetic peripheral neuropathy (DPN) contributes to disability and imposes heavy burdens, while subclinical DPN is lack of attention so far. We aimed to investigate the relationship between vitamin D and distinct subtypes of subclinical DPN in type 2 diabetes (T2DM) patients. Methods: This cross-sectional study included 3629 T2DM inpatients who undertook nerve conduction study to detect subclinical DPN in Zhongshan Hospital between March 2012 and December 2019. Vitamin D deficiency was defined as serum 25-hydroxyvitamin D (25(OH)D) level < 50 nmol/L. Results: 1620 (44.6%) patients had subclinical DPN and they were further divided into subgroups: distal symmetric polyneuropathy (DSPN) (n=685), mononeuropathy (n=679) and radiculopathy (n=256). Compared with non-DPN, DPN group had significantly lower level of 25(OH)D (P < 0.05). In DPN subtypes, only DSPN patients had significantly lower levels of 25(OH)D (36.18 ± 19.47 vs. 41.03 ± 18.47 nmol/L, P < 0.001) and higher proportion of vitamin D deficiency (78.54% vs. 72.18%, P < 0.001) than non-DPN. Vitamin D deficiency was associated with the increased prevalence of subclinical DPN [odds ratio (OR) 1.276, 95% confidence interval (CI) 1.086-1.501, P = 0.003] and DSPN [OR 1. 646, 95% CI 1.31-2.078, P < 0.001], independent of sex, age, weight, blood pressure, glycosylated hemoglobin, T2DM duration, calcium, phosphorus, parathyroid hormone, lipids and renal function. The association between vitamin D deficiency and mononeuropathy or radiculopathy was not statistically significant. A negative linear association was observed between 25(OH)D and subclinical DSPN. Vitamin D deficiency maintained its significant association with subclinical DSPN in all age groups. Conclusions: Vitamin D deficiency was independently associated with subclinical DSPN, rather than other DPN subtypes.

Characteristics of changes in plasma proteome profiling after sleeve gastrectomy.

Bariatric surgery (BS), recognized as the most effective intervention for morbid obesity and associated metabolic comorbidities, encompasses both weight loss-dependent and weight loss-independent mechanisms to exert its metabolic benefits. In this study, we employed plasma proteomics technology, a recently developed mass spectrometric approach, to quantitatively assess 632 circulating proteins in a longitudinal cohort of 9 individuals who underwent sleeve gastrectomy (SG). Through time series clustering and Gene Ontology (GO) enrichment analysis, we observed that complement activation, proteolysis, and negative regulation of triglyceride catabolic process were the primary biological processes enriched in down-regulated proteins. Conversely, up-regulated differentially expressed proteins (DEPs) were significantly associated with negative regulation of peptidase activity, fibrinolysis, keratinocyte migration, and acute-phase response. Notably, we identified seven proteins (ApoD, BCHE, CNDP1, AFM, ITIH3, SERPINF1, FCN3) that demonstrated significant alterations at 1-, 3-, and 6-month intervals post SG, compared to baseline. These proteins play essential roles in metabolism, immune and inflammatory responses, as well as oxidative stress. Consequently, they hold promising potential as therapeutic targets for combating obesity and its associated comorbidities.

Association between fast eating speed and metabolic dysfunction-associated steatotic liver disease: a multicenter cross-sectional study and meta-analysis.

BACKGROUND: With the fast pace of modern life, people have less time for meals, but few studies have examined the association between the habit of fast eating and metabolic diseases. OBJECTIVE: Combining the results of the current study and the prior ones, we aimed to investigate the possible relationship between fast eating and the risk of metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: This is a sub-analysis of a multicenter cross-sectional study of 1965 participants investigated the association between fast eating and MASLD in Chinese. Fast eating was defined as meal time less than five minutes and participants were divided into three categories based on their self-reported frequency of fast eating: ≤1 time/month, ≤1 time/week and ≥2 times/week. We further conducted a literature search for available studies published before November, 2023 as well as a meta-analysis to investigate the association between fast eating and MASLD. RESULTS: The proportion of MASLD was 59.3%, 50.5%, and 46.2% in participants with fast eating ≥2 times/week, ≤1 time/week and ≤1 time/month, respectively (P for trend <0.001). The frequency of fast eating was independently associated with risk of MASLD after multiple adjustment for sex, age, demographics, smoking and drinking status, BMI and clinical metabolic parameters (OR, 1.29; 95%CI, 1.09-1.53). Participants who ate fast frequently (≥2 times/week) had 81% higher risk of MASLD (P = 0.011). A meta-analysis of five eligible studies confirmed that frequent fast eating was associated with increased risk of MASLD (pooled OR, 1.22; 95%CI, 1.07-1.39). CONCLUSIONS: Frequent fast eating was associated with an increased risk of MASLD.

Underlying Mechanism of Fluoride Inhibits Colonic Gland Cells Proliferation by Inducing an Inflammation Response.

The integrity of colonic gland cells is a prerequisite for normal colonic function and maintenance. To evaluate the underlying injury mechanisms in colonic gland cells induced by excessive fluoride (F), forty-eight female Kunming mice were randomly allocated into four groups and treated with different concentrations of NaF (0, 25, 50, and 100 mg F-/L) for 70 days. As a result, the integrity of the colonic mucosa and the cell layer was seriously damaged after F treatment, as manifested by atrophy of the colonic glands, colonic cell surface collapse, breakage of microvilli, and mitochondrial vacuolization. Alcian blue and periodic acid Schiff staining revealed that F decreased the number of goblet cells and glycoprotein secretion. Furthermore, F increased the protein expression of TLR4, NF-κB, and ERK1/2 and decreased IL-6, interfered with NF-κB signaling, following induced colonic gland cells inflammation. The accumulation of F inhibited proliferation via the JAK/STAT signaling pathway, as characterized by decreased mRNA and protein expression of JAK, STAT3, STAT5, PCNA, and Ki67 in colon tissue. Additionally, the expression of CDK4 was up-regulated by increased F concentration. In conclusion, excessive F triggered colonic inflammation and inhibited colonic gland cell proliferation via regulation of the NF-κB and JAK/STAT signaling pathways, leading to histopathology and barrier damage in the colon. The results explain the damaging effect of the F-induced inflammatory response on the colon from the perspective of cell proliferation and provide a new idea for explaining the potential mechanism of F-induced intestinal damage.