Journal of physiology and biochemistry最新文献

Excess adiposity contributes to the development of colon carcinoma (CC). Interleukin (IL)-1β is a pro-inflammatory cytokine relevant in obesity-associated chronic inflammation and tumorigenic processes. We herein aimed to study how obesity and CC affects the expression of IL1B, and to determine the impact of IL-1β on the regulation of metabolic inflammation and gut barrier function in the context of obesity and CC. Samples from 71 volunteers were used in a case-control study and a rat model of diet-induced obesity (DIO). Furthermore, bariatric surgery was used to determine the effect of weight loss on the intestinal gene expression levels of Il1b. To evaluate the effect of IL-1β and obesity in CC, we treated the adenocarcinoma cell line HT-29 with IL-1β and the adipocyte-conditioned medium (ACM) from patients with obesity. We showed that obesity (P < 0.05) and CC (P < 0.01) upregulated the transcript levels of IL1B in visceral adipose tissue as well as in the colon from patients with CC (P < 0.01). The increased expression of Il1b in the ileum and colon in DIO rats decreased after weight loss achieved by either sleeve gastrectomy or caloric restriction (both P < 0.05). ACM treatment on HT-29 cells upregulated (P < 0.05) the transcripts of IL1B and CCL2, while reducing (P < 0.05) the expression of the anti-inflammatory ADIPOQ and MUC2 genes. Additionally, IL-1β upregulated (P < 0.01) the expression of CCL2 and TNF whilst downregulating (P < 0.01) the transcript levels of IL4, ADIPOQ and TJP1 in HT-29 cells. We provide evidence of the important role of IL-1β in obesity-associated CC by directly promoting inflammation.

Recent studies have focused on genetic polymorphisms that may influence athlete status. This meta-analysis aimed to investigate the association between athlete status and specific candidate genetic polymorphisms (AGTR2 rs11091046, FTO rs9939609, GALNTL6 rs558129, GNB3 rs5443, MCT1 rs1049434, NOS3 rs2070744). Only case-control studies collected from PubMed and Web of Science databases, published between 2009 and 2022, were included. A total of 23 studies were included in the meta-analysis according to the criteria of the research, and analyses were performed using random or fixed effects models. Effect size, odds ratio, or risk ratio were evaluated with a suitable 95% confidence interval. The results showed that the GALNTL6 rs558129 T/T genotype, MCT1 rs1049434 T/T genotype, and NOS3 rs2070744 T allele and T/T genotype were more prevalent in power athletes than in controls (p < 0.05). Conversely, the GALNTL6 rs558129 C allele, C/C genotype, and AGTR2 rs11091046 C allele and C/C genotype were more common in the control group. These findings indicate that some genetic polymorphisms may be important markers in athlete status and should be supported by future studies.

Cardiovascular diseases (CVDs) constitute a major global health problem, being the leading cause of death. Several risk factors for CVDs have been identified, including tobacco use, unhealthy diet, and physical inactivity. However, the role of genetic factors in CVDs remains unclear. Recent studies suggest that vitamin D deficiency is associated with an increased risk of CVDs. Therefore, the aim of this study is to assess the impact of 13 single nucleotide polymorphisms (SNPs) located in genes involved in vitamin D metabolism (VDR, GC, CYP27B1, CYP2R1, and CYP24A1) on the risk of developing CVDs. A retrospective case-control study was conducted in 766 Caucasian individuals from southern Spain: 383 diagnosed with CVDs and 383 without cardiovascular complications, matched based on age and sex. The 13 SNPs were identified by real-time PCR using TaqMan™ probes at the Virgen de las Nieves University Hospital and the University of Granada. According to statistical analysis the allele G and genotype GG of the SNP CYP2R1 rs10741657 and the allele C and CC genotype of the SNP CYP27B1 rs3782130 are associated with a decreased risk of CVDs and diabetes in three of the five heritage models studied. Thus, it can be concluded that CYP2R1 rs10741657 and CYP27B1 rs3782130 could be used as risk biomarkers for CVDs in the future, although studies with a larger number of participants are needed.

Mitochondrial dysfunction plays an important role in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). Transient receptor potential ankyrin-1 (TRPA1) activation improves mitochondrial dysfunction in a variety of cells. The present study tested the effects of Trpa1 knockout and activation in diet-induced MASLD in mice and palmitate-induced lipid deposition in HepG2 cells. Mice were fed with a high-fat diet (HFD) for 24 weeks to establish the animal model of MASLD. TRPA1 was downregulated in the liver of mice with MASLD and in HepG2 cells with palmitate-treated steatosis. Compared with HFD-fed wild-type mice, Trpa1^-/- mice on HFD demonstrated exacerbated lipid deposition and mitochondrial damage in hepatocytes. AMP-activated protein kinase (AMPK) and carnitine palmitoyl transferase 1 A (CPT1A) in the liver were downregulated by HFD and to a greater extent in Trpa1^-/- mice. Similarly, knockdown of Trpa1 worsened palmitate-induced lipid accumulation, mitochondrial morphological damage, mitochondrial ATP reduction and dysfunction, and downregulation of AMPK and CPT1A in HepG2 cells. Oral administration of cinnamaldehyde significantly reduced lipid deposition and improved mitochondrial damage in hepatocytes, which were abolished by HC030031, a TRPA1 antagonist. In HepG2 cells, cinnamaldehyde remarkably attenuated palmitate-induced lipid accumulation, mitochondrial damage, ATP reduction, and mitochondrial dysfunction, which were blunted by HC030031. Cinnamaldehyde reversed downregulation of AMPK and CPT1A in the liver of HFD-fed mice and palmitate-treated HepG2 cells through activating TRPA1. In conclusion, these findings suggest that the downregulation of TRPA1 may be involved in the pathogenesis of MASLD and activation of TRPA1 holds potential in the prevention and treatment of MASLD.

An association between type 2 diabetes (T2D) and breast cancer risk has been reported. This association can be potentially explained by alteration of the insulin/IGF system. Therefore, we aimed to prospectively investigate whether a previously reported Dietary-Based Diabetes Risk Score (DDS) inversely associated with T2D was also associated with breast cancer risk in the SUN ("Seguimiento Universidad de Navarra") cohort. We followed up 10,810 women (mean age = 35 years, SD = 11 years) for an average of 12.5 years during which 147 new cases of invasive breast cancer were diagnosed. A validated 136-item FFQ was administered at baseline and after 10 years of follow-up. The DDS (range: 11 to 55 points) positively weighted vegetables, fruit, whole cereals, nuts, coffee, low-fat dairy, fiber, PUFA; while it negatively weighted red meat, processed meats, and sugar-sweetened beverages. The DDS was categorized into tertiles. Self-reported medically diagnosed breast cancer cases were confirmed through medical records. We found a significant inverse association between the intermediate tertile of the DDS score and overall breast cancer risk (Hazard ratio, HR_{T2 vs. T1}= 0.55; 95% CI: 0.36-0.82) and premenopausal breast cancer risk (HR_T2= 0.26; 95% CI: 0.13-0.53), but not for the highest tertile. This association was stronger among women with a BMI < 25 kg/m² (p_interaction: 0.029). In conclusion, moderate adherence to the DDS score was associated with a lower risk of breast cancer, especially among premenopausal women and women with a lower BMI. These findings underscore the importance of antidiabetic diet in reducing the risk of breast cancer.

Background: Soluble Alpha-Klotho (S-αklotho) protein and 25-Hydroxyvitamin D (25-OH-D) have emerged as potential modulators for activating and recruiting Brown Adipose Tissue (BAT). The present study aimed to investigate whether circulating S-αklotho and 25-OH-D levels are related to BAT volume, ¹⁸Fluorine-Fluorodeoxyglucose (¹⁸F-FDG) uptake, and BAT radiodensity in young healthy adults.

Methods: A total of 128 participants (68% women) aged 18-25 years old participated in this cross-sectional study. Serum levels of S-αklotho were determined by a solid-phase sandwich enzyme-linked immunosorbent assay kit and 25-OH-D serum levels were analyzed using a competitive chemiluminescence immunoassay, both in blood samples collected after an overnight fast. All participants underwent a personalized cold exposure to determine their BAT volume, ¹⁸F-FDG uptake, and radiodensity, using a static positron emission tomography combined with computed tomography scan.

Results: After adjusting for multiple covariates, serum levels of S-αklotho (all R² ≤ 0.228 and P ≥ 0.364), 25-OH-D as continuous (all R² ≤ 0.242 and P ≥ 0.088) or by vitamin D status (all R² ≤ 0.767 and P ≥ 0.061) were not associated with either BAT volume and ¹⁸F-FDG uptake, or BAT radiodensity.

Conclusion: Serum S-αklotho and 25-OH-D levels within the physiological range are not related to BAT-related variables in young healthy adults. Further studies are needed to fully understand the underlying mechanisms involved in BAT metabolism in humans. (ACTIBATE; ClinicalTrials.gov identifier: not applicable).

This erratum addresses corrections to the article titled 'miR-9 inhibits the metastatic ability of hepatocellular carcinoma via targeting beta galactoside alpha-2,6-sialyltransferase 1' published in Journal of physiology and biochemistry on 13 July 2018. In the original article, the transwell microscope images presented in Fig. 4C of the Hca-P mimic group and Fig. 5E of Hca-P PF group were accidentally misused during the assembly of the figures. These errors have now been corrected and does not change the conclusions of the study. The authors apologize for this oversight and any confusion it may have caused.

This Special Issue contains 7 contributions elaborated in the context of the workshop "Frontiers in Cancer, Obesity and metabolism" organized by the Journal of Physiology and Biochemistry (Pamplona, Spain, 2022). It contains basic, translational and epidemiological research that sheds light in our understanding of the molecular mechanisms underlying how the excess of adipose tissue in obesity promotes tumor growth and progression, and highlights the role of nutrition in preventing tumor development and improving treatment outcomes in cancer patients with obesity and related comorbidities. Two review articles and one systematic review are included in this special issue, which describe the effects of nutrient deprivation that potentially enhance cancer immunotherapy, reveal the importance of the glucose transporter GLUT12 in obesity and cancer, and analyze recently described molecular mechanisms that connect obesity and the development of different types of cancer. Additionally, four original articles demonstrate a metabolic inflammatory pathway in patients with obesity in which dysfunctional adipose tissue alters the tumor microenvironment favoring tumor progression, offers mechanistic support for exploring low-fat ketogenic diets as adjuvant therapy in obesity-related breast cancer prevention or therapy by linking nutritional ketosis to epigenetic regulation of cancer‑related genes, indicate the use of genes related to amino acid metabolism as prognostic biomarkers in breast cancer, and associate a moderate adherence to a dietary-based diabetes-risk score to a lower risk of breast cancer among premenopausal women and women with low body mass index. Globally, the articles included in this special issue contribute to better understand the molecular mechanisms beyond nutritional aspects linked to obesity and cancer development.

Sorafenib resistance is a significant hurdle in the treatment landscape of hepatocellular carcinoma (HCC). Lipocalin 2 (LCN2), a secretory glycoprotein that transports lipophilic molecules across cell membranes, is thought to affect the s therapeutic efficacy of sorafenib. Despite its importance, the detailed regulatory pathways involving LCN2 are still being deciphered. We probed the correlation between LCN2 expression and sorafenib resistance in HCC cells. Through the modulation of LCN2 levels, we investigated its role in cell proliferation, apoptosis, and its regulatory effects on autophagy-driven ferroptosis. With the aid of hTFtarget and JASPAR databases, ESR1 was pinpointed as a transcriptional inhibitor of LCN2. The impact of the ESR1-LCN2 axis on sorafenib resistance in HCC was then examined in vitro and validated in a xenograft tumor mouse model. In HCC cells, elevated LCN2 levels were found to be associated with resistance to sorafenib. Depletion of LCN2 resulted in attenuated HCC cell growth and elevated rates of apoptosis and ferroptosis. Overexpression of LCN2 had the opposite effect, promoting cell proliferation and suppressing cell death pathways, a response that could be overridden by autophagy agonists. ESR1 suppressed LCN2 transcription, which in turn activated autophagy-mediated ferroptosis, mitigating sorafenib tolerance in HCC and enhancing the therapeutic index. ESR1 targets LCN2 transcription to initiate autophagy-driven ferroptosis, thereby reducing sorafenib resistance in HCC cells.

Hepatocytes are the primary functional cells in the liver, and the malignant transformation of hepatocytes significantly contributes to hepatocellular carcinoma (HCC) progression. Liver fibrosis and cirrhosis caused by extracellular matrix (ECM) remodeling during liver lesions is a pivotal driver of HCC. However, the impact of matrix stiffness on hepatocytes and the underlying molecular mechanisms are not fully understood. Herein, using gelatin/sodium alginate hydrogels with different stiffnesses to simulate the change of matrix stiffness during liver lesions, we found that matrix stiffening leads to a notable decrease in the expression of hepatocyte nuclear factor 4α (HNF4α) and functional hepatocyte genes and a significant increase in the expression of interleukin 6 (IL‒6) in human hepatocyte line L‒02 cells, indicating obvious damage of hepatocyte function. In addition, matrix stiffening causes extensive DNA damage to L‒02 cells. Mechanistically, matrix stiffening upregulates piezo‒type mechanosensitive ion channel component 1 (Piezo1) expression and activates extracellular signal‒regulated kinase 1/2 (ERK1/2) signaling. Piezo1 knockdown suppresses matrix stiffening‒induced functional impairment and DNA damage in L‒02 cells. Moreover, Piezo1 knockdown blocks matrix stiffening‒activated ERK1/2 signaling in L‒02 cells. U0126 (a selective inhibitor of ERK1/2 activation) treatment could rescue matrix stiffening‒induced functional impairment and DNA damage. Taken together, these findings demonstrate that matrix stiffening induces functional impairment and DNA damage in L‒02 cells via the Piezo1‒ERK1/2 signaling pathway, which provides evidence for a better understanding of the hepatocyte function damage caused by tissue mechanical microenvironment change in liver diseases and the mechanotransduction in this process.