Triglyceride to HDL Cholesterol Ratio for the Identification of MASLD in Obesity: A Liver Biopsy-Based Case-Control Study.

Associations between dyslipidemia and metabolic dysfunction-associated steatotic liver disease (MASLD) have been reported. Previous studies have shown that the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio may be a surrogate marker of MASLD, assessed by liver ultrasound. However, no studies have evaluated the utility of this ratio according to biopsy-proven MASLD and its stages. Therefore, our aim was to evaluate if the TG/HDL-C ratio allows for the identification of biopsy-proven MASLD in patients with obesity. We conducted a case-control study in 153 patients with obesity who underwent metabolic surgery and had a concomitant liver biopsy. Fifty-three patients were classified as no MASLD, 45 patients as metabolic dysfunction-associated steatotic liver-MASL, and 55 patients as metabolic dysfunction-associated steatohepatitis-MASH. A receiver operating characteristic (ROC) analysis was performed to assess the accuracy of the TG/HDL-C ratio to detect MASLD. We also compared the area under the curve (AUC) of the TG/HDL-C ratio, serum TG, and HDL-C. A higher TG/HDL-C ratio was observed among patients with MASLD, compared with patients without MASLD. No differences in the TG/HDL-C ratio were found between participants with MASL and MASH. The greatest AUC was observed for the TG/HDL-C ratio (AUC 0.747, p < 0.001) with a cut-off point of 3.7 for detecting MASLD (sensitivity = 70%; specificity = 74.5%). However, no statistically significant differences between the AUC of the TG/HDL-C ratio and TG or HDL-C were observed to detect MASLD. In conclusion, although an elevated TG/HDL-C ratio can be found in patients with MASLD, this marker did not improve the detection of MASLD in our study population, compared with either serum TG or HDL-C.

The role of PCSK9 in metabolic dysfunction-associated steatotic liver disease and its impact on bariatric surgery outcomes.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely tied to obesity. The degree ranges from steatosis (MASL) and steatohepatitis (MASH) to liver cirrhosis. PCSK9 controls cholesterol and lipid particle transport to the liver. PCSK9 might interfere with the pathophysiology of MASLD and bariatric surgery (BS) outcomes of patients with MASLD. OBJECTIVES: Evaluate the relationship between serum and hepatic PCSK9 levels with the degree of MASLD and the metabolic outcome of BS. SETTING: University Hospital, Spain. METHODS: A total of 110 patients with obesity undergoing BS were classified according to liver histology as controls, MAS, and MASH. PCSK9 levels in serum were measured before and 6 months after BS using enzyme-linked immunosorbent assay. PCSK9 protein and mRNA levels in liver tissue were analyzed by immunohistochemistry and reverse transcriptase-polymerase chain reaction, respectively. RESULTS: Hepatic PCSK9 protein levels were diminished in MASL and MASH compared with patients without MASLD and showed a strong negative association with MASLD severity scores. Liver PCSK9 mRNA was higher in MASH compared with controls and MASL and showed positive associations with MASLD severity scores. There were no differences in serum PCSK9 pre or postBS between the groups. Pre- and postsurgery serum PCSK9 positively correlated with cholesterol fold-changes and body mass index (BMI), cholesterol, and low-density lipoprotein -cholesterol fold-changes, respectively. PCSK9 fold-change positively correlated with BMI changes and was the sole variable explaining BMI fold changes in a regression model. CONCLUSIONS: PCSK9 mRNA and protein in the liver might be associated with the degree of MASLD. Serum PCSK9 may be associated with cholesterol and/or BMI fold changes. Serum changes of PCSK9 after BS could explain BMI loss outcome.

Lipidomic analysis reveals alterations in hepatic FA profile associated with MASLD stage in patients with obesity.

CONTEXT: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by the intracellular lipid accumulation in hepatocytes. Excess caloric intake and high-fat diets are considered to significantly contribute to MASLD development. OBJECTIVE: To evaluate the hepatic and serum fatty acid (FA) composition in patients with different stages of MASLD, and their relationship with FA dietary intake and MASLD-related risk factors. METHODS: This was a case-control study in patients with obesity undergoing bariatric surgery at a University Hospital between January 2020 and December 2021. Participants were distributed in three groups: no MASLD (n = 26), steatotic liver disease (n = 33), and metabolic dysfunction-associated steatohepatitis (n = 32). Hepatic and serum FAs levels were determined by GC-MS. The nutritional status was evaluated using validated food frequency questionnaires. The hepatic expression of genes involved in FA metabolism was analyzed by RT-qPCR. RESULTS: The hepatic, but not serum, FA profiles were significantly altered in patients with MASLD compared to those without MASLD. No differences were observed in FA intake between the groups. Levels of C16:0, C18:1, and the C18:1/C18:0 ratio were higher, while C18:0 levels and C18:0/C16:0 ratio were lower in patients with MASLD being significantly different between the three groups. Hepatic FA levels and ratios correlated with histopathological diagnosis and other MASLD-related parameters. The expression of genes involved in the FA metabolism was upregulated in patients with MASLD. CONCLUSION: Alterations in hepatic FA levels in MASLD patients were due to an enhancement of the de novo lipogenesis in the liver.

Hepatic and serum branched-chain fatty acid profile in patients with nonalcoholic fatty liver disease: A case-control study.

OBJECTIVE: Alterations in the hepatic lipidome are a crucial factor involved in the pathophysiology of nonalcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate the serum and hepatic profile of branched-chain fatty acids (BCFAs) in patients with different stages of NAFLD. METHODS: This was a case-control study performed in 27 patients without NAFLD, 49 patients with nonalcoholic fatty liver, and 17 patients with nonalcoholic steatohepatitis, defined by liver biopsies. Serum and hepatic levels of BCFAs were analyzed by gas chromatography-mass spectrometry. The hepatic expression of genes involved in the endogenous synthesis of BCFAs was analyzed by real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: A significant increase in hepatic BCFAs was found in subjects with NAFLD compared with those without NAFLD; no differences were observed in serum BCFAs between study groups. Trimethyl BCFAs, iso-BCFAs, and anteiso-BCFAs were increased in subjects with NAFLD (either nonalcoholic fatty liver or nonalcoholic steatohepatitis) compared with those without NAFLD. Correlation analysis showed a relationship between hepatic BCFAs and the histopathological diagnosis of NAFLD, as well as other histological and biochemical parameters related to this disease. Gene expression analysis in liver showed that the mRNA levels of BCAT1, BCAT2, and BCKDHA were upregulated in patients with NAFLD. CONCLUSIONS: These results suggest that the increased production of liver BCFAs might be related to NAFLD development and progression.

New challenges in cholangiocarcinoma candidates for elective surgery: harnessing the microbiome dysbiosis.

BACKGROUND: The gut microbiota, composed by several species of microorganisms, works to preserve the liver-gut homeostasis and plays an important role during digestion and absorption of nutrients, and in the immune response of the host. In this review, we analyzed the influence of microbiota in patients with cholangiocarcinoma (CCA) who were candidates for elective surgery. METHODS: A literature review was conducted to identify papers that provided empiric evidence to support that the altered microbiota composition (dysbiosis) is related also to CCA development. RESULTS: Bacteria such as Helicobacter pylori, Helicobacter hepaticus, and Opisthorchis viverrini increase the risk of CCA. The most abundant genera were Enterococcus, Streptococcus, Bacteroides, Klebsiella, and Pyramidobacter in CCA's biliary microbiota. Additionally, levels of Bacteroides, Geobacillus, Meiothermus, and Anoxybacillus genera were significantly higher. An enrichment of Bifidobacteriaceae, Enterobacteriaceae, and Enterococcaceae families has also been observed in CCA tumor tissue. Microbiota is related to postoperative outcomes in abdominal surgery. The combination of caloric restriction diets in liver cancer or CCA increases the effect of the chemotherapy treatment. CONCLUSION: The correct use of nutrition for microbiota modulation according to each patient's needs could be a therapeutic tool in combination with elective surgery and chemotherapy to diminish side effects and improve prognosis. Further investigations are needed to fully understand the mechanisms by which they are related.

Optimizing the Preparation of Silk Fibroin Nanoparticles and Their Loading with Polyphenols: Towards a More Efficient Anti-Inflammatory Effect on Macrophages.

Silk fibroin nanoparticles (SFN) have become a promising tool in drug delivery systems due to their physicochemical characteristics. SFN have shown their outstanding properties as an active vehicle for polyphenols, enhancing their antioxidant and anti-inflammatory effects on macrophages; therefore, it becomes necessary to have an easy, reproducible and scalable production method. In order to improve the production of nanoparticles, we performed direct precipitation of non-dialyzed silk fibroin solutions and evaluated the reproducibility of the method using dynamic light scattering. We also studied the loading efficiency of three different natural polyphenols using propylene glycol as a solvent. The loaded nanoparticles were fully characterized and used to treat human macrophage cells to assess the anti-inflammatory activity of these nanoparticles. The measured hydrodynamic characteristics of the SFN and the overall yield of the process showed that the new preparation method is highly reproducible and repeatable. Thus, we not only present a new scalable method to prepare silk nanoparticles but also how to improve the loading of natural polyphenolic compounds to the SFN, as well as the important anti-inflammatory effects of these loaded nanoparticles in a cell model of human macrophage cells.

Anti-Leukemic Activity of Brassica-Derived Bioactive Compounds in HL-60 Myeloid Leukemia Cells.

Acute myeloid leukemia (AML) is a cancer of the myeloid blood cells mainly treated with chemotherapy for cancer remission, but this non-selective treatment also induces numerous side effects. Investigations with bioactive compounds from plant-derived foods against cancer have increased in the last years because there is an urgent need to search for new anti-leukemic agents possessing higher efficacy and selectivity for AML cells and fewer negative side effects. In this study, we analyzed the anti-leukemic activity of several phytochemicals that are representative of the major classes of compounds present in cruciferous foods (glucosinolates, isothiocyanates, hydroxycinnamic acids, flavonols, and anthocyanins) in the human acute myeloid leukemia cell line HL-60. Our results revealed that among the different Brassica-derived compounds assayed, sulforaphane (SFN) (an aliphatic isothiocyanate) showed the most potent anti-leukemic activity with an IC50 value of 6 µM in dose-response MTT assays after 48 h of treatment. On the other hand, chlorogenic acid (a hydroxycinnamic acid) and cyanidin-3-glucoside (an anthocyanin) also displayed anti-leukemic potential, with IC50 values of 7 µM and 17 µM after 48 h of incubation, respectively. Importantly, these compounds did not show significant cell toxicity in macrophages-like differentiated cells at 10 and 25 µM, indicating that their cytotoxic effects were specific to AML cancer cells. Finally, we found that these three compounds were able to induce the NRF2/KEAP1 signaling pathway in a dose-dependent manner, highlighting SFN as the most potent NRF2 activator. Overall, the present evidence shed light on the potential for using foods and ingredients rich in anticancer bioactive phytochemicals from Brassica spp.

Dietary modulation of gut microbiota in patients with colorectal cancer undergoing surgery: A review.

Colorectal cancer (CRC) is the third most frequent malignancy and the second cause of cancer death worldwide. Several factors have been postulated to be involved in CRC pathophysiology, including physical inactivity, unhealthy dietary habits, obesity, and the gut microbiota. Emerging data suggest that the microbiome may play a key role in CRC prognosis and derived complications in patients undergoing colorectal surgery. On the other hand, dietary intervention has been demonstrated to be able to induce significant changes in the gut microbiota and related metabolites in different conditions; therefore, the manipulation of gut microbiota through dietary intervention may constitute a useful approach to improve perioperative dysbiosis and post-surgical outcomes in patients with CRC. In this article, we review the role of the gut microbiota in CRC surgery complications and the potential therapeutic modulation of gut microbiome through nutritional intervention in patients with CRC undergoing surgery.

Gut Microbiome Modification through Dietary Intervention in Patients with Colorectal Cancer: Protocol for a Prospective, Interventional, Controlled, Randomized Clinical Trial in Patients with Scheduled Surgical Intervention for CRC.

Colorectal cancer (CRC) is the third most common cancer and the second cause of cancer death worldwide. Several factors have been postulated to be involved in CRC pathophysiology, including heritable and environmental factors, which are the latest to be closely associated with nutritional habits, physical activity, obesity, and the gut microbiota. The latter may also play a key role in CRC prognosis and derived complications in patients undergoing surgery. This is a single-center, open, controlled, randomized clinical trial, in patients with scheduled surgical intervention for CRC. The primary objective is to assess whether a pre-surgical nutritional intervention, based on a high-fiber diet rich in polyunsaturated fatty acids (PUFAs), can reduce disturbances of the gut microbiota composition and, consequently, the rate of post-surgical complications in patients with CRC. Patients will be randomized in a 1:1 ratio after receiving a diagnosis of CRC. In the control arm, patients will receive standard nutritional recommendations, while patients in the intervention arm will be advised to follow a high-fiber diet rich in PUFAs before surgery. Participants will be followed up for one year to evaluate the overall rate of postsurgical complications, recurrences of CRC, response to adjuvant therapy, and overall/disease-free survival.

Leptin Signaling in Obesity and Colorectal Cancer.

Obesity and colorectal cancer (CRC) are among the leading diseases causing deaths in the world, showing a complex multifactorial pathology. Obesity is considered a risk factor in CRC development through inflammation, metabolic, and signaling processes. Leptin is one of the most important adipokines related to obesity and an important proinflammatory marker, mainly expressed in adipose tissue, with many genetic variation profiles, many related influencing factors, and various functions that have been ascribed but not yet fully understood and elucidated, the most important ones being related to energy metabolism, as well as endocrine and immune systems. Aberrant signaling and genetic variations of leptin are correlated with obesity and CRC, with the genetic causality showing both inherited and acquired events, in addition to lifestyle and environmental risk factors; these might also be related to specific pathogenic pathways at different time points. Moreover, mutation gain is a crucial factor enabling the genetic process of CRC. Currently, the inconsistent and insufficient data related to leptin's relationship with obesity and CRC indicate the necessity of further related studies. This review summarizes the current knowledge on leptin genetics and its potential relationship with the main pathogenic pathways of obesity and CRC, in an attempt to understand the molecular mechanisms of these associations, in the context of inconsistent and contradictory data. The understanding of these mechanisms linking obesity and CRC could help to develop novel therapeutic targets and prevention strategies, resulting in a better prognosis and management of these diseases.

Analysis of the anti-inflammatory potential of Brassica bioactive compounds in a human macrophage-like cell model derived from HL-60 cells.

BACKGROUND: Chronic inflammatory diseases are major causes of global morbidity and mortality. Acute inflammation is meant to protect the body against foreign agents, but it also plays a major role in tissue repairment. Several mediators are involved in this process, including pro-inflammatory cytokines produced by macrophages. Occasionally, if the inflammatory response is not resolved, the acute inflammatory process can evolve into a chronic inflammation. Natural compounds from vegetables are considered as an important source of active agents with potential to treat or prevent inflammatory related pathologies and could be used as an alternative of the therapeutic agents currently in use, such as non-steroidal anti-inflammatory drugs (NSAIDs), which present several side effects. METHODS: In this research work we evaluated in vitro the anti-inflammatory activity of a series of ten phytochemicals present in Brassica, measured as the potential of those compounds to reduce the production of key pro-inflammatory cytokines (TNF-α, IL-6 and IL-1ß) by a human macrophage-like cell model of HL-60 cells RESULTS: Most of the tested phytochemicals (including the most representative bioactive molecules of the major classes of compounds present in cruciferous foods such as glucosinolates, isothiocyanates, hydroxycinnamic acids, flavonols and anthocyanins) demonstrated significant anti-inflammatory activity at micromolar level in the absence of cytotoxic effects in this human macrophage-like cell model. CONCLUSION: These data confirm that phytochemicals commonly obtained from Brassica may be potential therapeutic leads to treat or prevent human chronic inflammation and related diseases.

Gut microbiota and related metabolites in the pathogenesis of nonalcoholic steatohepatitis and its resolution after bariatric surgery.

Nonalcoholic fatty liver disease (NAFLD) is increasing in parallel with the rising prevalence of obesity, leading to major health and socioeconomic consequences. To date, the most effective therapeutic approach for NAFLD is weight loss. Accordingly, bariatric surgery (BS), which produces marked reductions in body weight, is associated with significant histopathological improvements in advanced stages of NAFLD, such as nonalcoholic steatohepatitis (NASH) and liver fibrosis. BS is also associated with substantial taxonomical and functional alterations in gut microbiota, which are believed to play a significant role in metabolic improvement after BS. Interestingly, gut microbiota and related metabolites may be implicated in the pathogenesis of NAFLD through diverse mechanisms, including specific microbiome signatures, short chain fatty acid production or the modulation of one-carbon metabolism. Moreover, emerging evidence highlights the potential association between gut microbiota changes after BS and NASH resolution. In this review, we summarize the current knowledge on the relationship between NAFLD severity and gut microbiota, as well as the role of the gut microbiome and related metabolites in NAFLD improvement after BS.