Association of Adiponectin Receptors with Metabolic and Immune Homeostasis Parameters in Colorectal Cancer: In Silico Analysis and Observational Findings

Adiponectin (ADIPOQ) as both a regulator of metabolic homeostasis and a protein involved in immune response might be of particular interest to contemporary laboratory medicine, especially in terms of minimally invasive diagnostics. The diverse roles of ADIPOQ with regard to the immune and metabolic aspects of colorectal carcinogenesis have been proposed. However, the expression of its receptors ADIPOR1 and ADIPOR2 is scarcely explored in peripheral blood mononuclear cells (PBMCs). Moreover, ADIPORs’ relationships with the immune response mediator TNF-α have not been previously investigated in the PBMCs of CRC patients. This study used both in silico and observational case–control analyses with the aim of exploring the association of ADIPOR gene expression and ADIPOQ single nucleotide polymorphisms (SNPs) with the inflammatory marker TNF-α and lipid status parameters in patients with CRC. Publicly available transcriptomic datasets (GSE47756, GSE44076) obtained from analyses of monocytes and CRC tissue samples were employed for the in silico evaluation of ADIPORs’ specific genetic traits. GSE47756 and GSE44076 datasets were processed with GSEA software to provide a genetic fingertip of different signaling pathways associated with ADIPORs’ mRNA levels. The case–control aspect of the study included the PBMC samples of 73 patients diagnosed with CRC and 80 healthy volunteers. The PCR method was carried out for the PBMC gene expression analysis (ADIPOR1, ADIPOR2, TNF-α mRNA levels) and for the subjects’ genotyping (ADIPOQ rs266729, ADIPOR1 rs7539542). GSEA showed significant associations of ADIPOR mRNA expression with gene sets related to metabolic and immune homeostasis in both datasets. The case–control study revealed the association of ADIPOR1 rs7539542 with reduced lipid status parameters in CRC. In addition, PBMC ADIPOR1 mRNA levels decreased in CRC (p < 0.001), whereas ADIPOR2 mRNA did not differ between the groups (p = 0.442). A reduction in PBMC TNF-α mRNA levels was noted in CRC (p < 0.05). Our results indicate that ADIPOR1 and ADIPOR2 play a significant role in the alteration of both metabolic and immune homeostasis during the progression of CRC. For the first time, ADIPOR1 is shown to be a specific receptor for mediating ADIPOQ’s effects in the PBMCs of CRC patients

Significance of LDL and HDL subclasses characterization in the assessment of risk for colorectal cancer development

Introduction: Dyslipidaemia contributes to the occurrence of colorectal cancer (CRC). We hypothesized that qualitative changes of lipoproteins are associated with the risk for CRC development. This study analyses low-density lipoprotein (LDL) and high-density lipoprotein (HDL) diameters, as well as distribution of LDL and HDL subclasses in patients with CRC, with an aim to determine whether advanced lipid testing might be useful in predicting the risk for the onset of this malignancy. Materials and methods: This case-control study included 84 patients with newly diagnosed CRC and 92 controls. Gradient gel electrophoresis was applied for separation of lipoprotein subclasses and for LDL and HDL diameters determination. Lipid parameters were measured using routine enzymatic methods. Results: Total cholesterol, HDL and LDL-cholesterol were significantly lower in CRC patients compared to controls (4.47 mmol/L vs. 5.63 mmol/L; 0.99 mmol/L vs. 1.27 mmol/L; 2.90 mmol/L vs. 3.66 mmol/L; P lt 0.001, respectively). Patients had significantly smaller LDL (25.14 nm vs. 26.92 nm; P lt 0.001) and HDL diameters (8.76 nm vs. 10.17 nm; P lt 0.001) and greater proportion of small, dense LDL particles (54.0% vs. 52.9%; P = 0.044) than controls. Decreased LDL and HDL diameters were independent predictors of CRC (OR = 0.5, P = 0.001 and OR = 0.5, P = 0.008, respectively), and alongside with age and HDL-cholesterol concentrations formed the optimal cost-effective model, providing adequate discriminative abilities for CRC (AUC = 0.89) and correct patients classification (81%). Conclusions: Patients with CRC have decreased LDL and HDL diameters and increased proportion of smaller particles. LDL and HDL diameters determination could be useful in assessing the risk for CRC development

Uvođenje autohtonih ekotipova češnjaka in vitro pod utjecajem regulatora rasta i svjetlost

Garlic is valuable crop that is used not only for human consumption, but also in pharmaceutical, food and cosmetics industries. Indigenous cultivars have specific beneficial properties that could be permanently lost due to cultivation of new cultivars. Aim of this study was to established two indigenous garlic cultivars in vitro under influence of growth regulator and light. Garlic varieties Slavonian winter (Croatia) and Vincek (Slovenia) were introduced on medium supplemented with two different concentrations of BAP (1 and 1,5 mg/L) and grown under two types of light (FLUO and LED). Results showed there were no significant influence of light type but concentration of growth regulator significantly influenced in vitro development of garlic microshoots of both investigated cultivars. The best treatment for Vincek garlic explants was nutrient medium supplemented with 1.5 mg/L BAP and LED lights, while for Slavonian winter garlic the best treatment showed to be FLUO light and 1,5 mg/L BAP.Češnjak je dragocjena kultura koja se koristi osim za ljudsku prehranu, i u farmaceutskoj, prehrambenoj i kozmetičkoj industriji. Autohtone sorte imaju specifična korisna svojstva koja bi mogla biti trajno izgubljena uzgojem novih kultivara. Cilj ovog istraživanja bio je uspostaviti in vitro protokol za uzgoj dvije autohtone sorte češnjaka pod utjecajem regulatora rasta i svjetla. U in vitro kulturu uvedene su autohtone sorte češnjaka Slavonski ozimi (Hrvatska) i Vincek (Slovenija) na dvije različite varijante hranjive podloge (1 i 1,5 mg/L BAP-a) te su uzgajane pod dvije varijante osvjetljenja (FLUO i LED). Rezultati su pokazali da nije bilo značajnog utjecaja vrste svjetla, ali je koncentracija regulatora rasta značajno utjecala na in vitro razvoj mikroizdanaka češnjaka obje ispitivane sorte. Eksplantati češnjaka Vincek postigli su bolje rezultate na tretmanu hranjive podloge s dodatkom 1,5 mg/L BAP-a i LED svjetla, dok se za Slavonski ozimi češnjak pokazao najbolji tretman FLUO svjetlo i 1,5 mg/L BAP-a

Association among resistin, adenylate cyclase-associated protein 1 and high-density lipoprotein cholesterol in patients with colorectal cancer: a multi-marker approach, as a hallmark of innovative predictive, preventive, and personalized medicine

Background: Elevated concentrations of resistin have been reported in colorectal cancer (CRC), but its interactions with adenylate cyclase-associated protein 1 (CAP-1) are largely unexplored. We investigated resistin plasma concentration, peripheral blood mononuclear cells (PBMCs) resistin messenger ribonucleic acid (mRNA), and CAP-1 mRNA levels in CRC patients, as well as the impact of resistin gene polymorphism rs1862513 on the examined markers. We also explored associations of resistin with high-density lipoprotein cholesterol (HDL-C) and predictive potential of our parameters for CRC. Methods: Eighty-six patients with CRC and 75 healthy adults were included. Commercial ELISA kit was used for obtaining resistin’s concentrations, while polymerase chain reaction (PCR) method was applied for evaluation of resistin and CAP-1 mRNA levels and rs1862513 polymorphism. Results: Plasma resistin and CAP-1 mRNA levels were higher in CRC patients (p < 0.001 and p < 0.05, respectively), while resistin mRNA levels were lower (p < 0.001). Negative association existed among plasma resistin and HDL-C concentrations (ρ = − 0.280; p < 0.05). A model including age, body-mass index, HDL-C, low-density lipoprotein cholesterol (LDL-C), and plasma resistin concentrations as independent predictors of CRC showed very good diagnostic accuracy (AUC = 0.898). We found no associations of rs1862513 with the examined markers. Conclusions: Our study demonstrated increased plasma resistin and CAP-1 mRNA levels, implying their possible interaction in CRC. The association among plasma resistin and HDL-C might indicate that HDL-C is involved in alterations of resistin’s secretion process. As a hallmark of personalized medicine, multi-marker approach in determination of resistin-related parameters might be useful for prediction and prevention of CRC development

Efekat suplementacije propolisom i N-acetilcisteinom na raspodelu lipoproteinskih supklasa i aktivnosti paraoksonaze 1 u osoba sa akutnom respiratornom infekcijom

Background:Propolis and N-acetylcysteine have positiveimpact on respiratory tract health. Also, it has been sug-gested that they have beneficial effects on serum lipid andoxidative stress status, but the available data are limitedand mostly gained from animal models. In this study weevaluated the effects of propolis and N-acetylcysteine sup-plementation (PropoMucil®) on lipid status, lipoproteinsubclasses distribution and paraoxonase 1 activity in sub-jects with acute respiratory infection.Methods:Twenty subjects with acute respiratory infectionwere included. PropoMucil®granules for oral solution (80mg of dry propolis extract and 200 mg of N-acetylcysteine)were administered tree times per day for ten days. Serumlipid profile, paraoxonase 1 activity and low-density andhigh-density lipoprotein size and subclasses distributionwere assessed at baseline and after supplementation.Results:Following ten days of supplementation lipid statusremained unchanged, but a significant increase of low-density lipoprotein particle size and proportion of high-den-sity lipoprotein 3a particles were found (P<0.05).Moreover, supplementation with PropoMucil®significantlyimproved high-density lipoprotein particles distribution, particularly in those who smoke. There was a moderateincrease of paraoxonase 1 activity, but without statisticalsignificance.Conclusions:The presented study demonstrated that short-term supplementation with PropoMucil®has beneficialeffects on low-density and high-density lipoprotein sub-classes distribution and paraoxonase 1 activity in subjectswith acute respiratory infection particularly in those whosmoke.Uvod: Propolis i N-acetilcistein pozitivno utiču na zdravlje disajnih puteva. Takođe, sugeriše se da oni imaju blagotvorno dejstvo na lipidni i oksidativno-stresni status, ali podaci su ograničeni i dobijeni uglavnom na životinjskim modelima. U ovom istraživanju, procenili smo kombinovani efekat propolisa i N-acetilcisteina (PropoMucil®) na status lipida, raspodelu supklasa lipoproteina i aktivnost paraoksonaze 1 kod pacijenata sa akutnom respiratornom infekcijom (ARI). Metode: Uključeno je 20 ispitanika sa akutnom respiratornom infekcijom. Oralni rastvor praška PropoMucil® (80 mg suvog ekstrakta propolisa i 200 mg N-acetilcisteina) je aplikovan 3 puta dnevno tokom 10 dana. Serumski lipidni profil, aktivnost praoksonaze 1 i veličina i raspodela supfrakcija lipoproteina niske gustine i lipoproteina visoke gustine su određeni pre i nakon suplementacije. Rezultati: Nakon deset dana suplementacije, lipidni status je ostao nepromenjen, ali je utvrđeno značajno povećanje veličine lipoproteina niske gustine i relativnog udela lipoproteina visoke gustine 3a (P <0,05). Pored toga, suplementacija PropoMucil®-om značajno je poboljšala distribuciju lipoproteinskih čestica visoke gustine, posebno kod pacijenata koji puše. Došlo je do umerenog porasta aktivnosti paraoksonaze 1, ali bez statističke značajnosti. Zaključak: Studija je pokazala da kratkotrajna suplementacija PropoMucil®-om ima korisne efekte na distribuciju supklasa lipoproteina niske i visoke gustine i aktivnost paraoksonaze 1 kod ispitanika sa akutnom respiratornom infekcijom, posebno kod onih koji puše

Revealing the role of high-density lipoprotein in colorectal cancer

Colorectal cancer (CRC) is a highly prevalent malignancy with multifactorial etiology,which includes metabolic alterations as contributors to disease development. Studies have shownthat lipid status disorders are involved in colorectal carcinogenesis. In line with this, previous studieshave also suggested that the serum high-density lipoprotein cholesterol (HDL-C) level decreases inpatients with CRC, but more recently, the focus of investigations has shifted toward the explorationof qualitative properties of HDL in this malignancy. Herein, a comprehensive overview of availableevidences regarding the putative role of HDL in CRC will be presented. We will analyze existingfindings regarding alterations of HDL-C levels but also HDL particle structure and distribution inCRC. In addition, changes in HDL functionality in this malignancy will be discussed. Moreover,we will focus on the genetic regulation of HDL metabolism, as well as the involvement of HDL indisturbances of cholesterol trafficking in CRC. Finally, possible therapeutic implications related toHDL will be presented. Given the available evidence, future studies are needed to resolve all raisedissues concerning the suggested protective role of HDL in CRC, its presumed function as a biomarker,and eventual therapeutic approaches based on HDL

Povezanost metabolita holesterola i vitamina D sa rizikom za nastanak kolorektalnog karcinoma visokog gradusa

Background:Vitamin D deficiency is repeatedly reported in colorectal cancer (CRC). Since cholesterol and vitamin D share common precursor 7-dehydrocholesterol (7-DHC), it would be important to explore the associations of key vitamin D metabolites and serum lipid parameters in patients with high and low grade CRC. The aim of this study was toanalyze relationships between serum 25(OH)D3,24,25(OH)2D3 and 7-DHC levels and serum lipids inpatients with CRC, and to evaluate their potential for prediction of risk for development of high grade CRC. Methods:We recruited 82 patients CRC and 77 controls.7-DHC, 25(OH)D3 and 24,25(OH)2D3 were quantified by LC-MS/MS methods.Results:7-DHC, 25(OH)D3 and vitamin D metabolic ratio(VDMR) were significantly lower in CRC patients than in control group (P<0.001, P<0.010, P<0.050 and P<0.050, respectively). 25(OH)D3 levels were higher inpatients with grade I CRC when compared to grade II(P<0.050). All vitamin D metabolites positively correlated with total cholesterol (TC) concentration in CRC patients.25(OH)D3 was significant predictor of increased CRC risk(P<0.010). After adjustment for TC concentration,25(OH)D3 lost its predictive abilities. However, 25(OH)D3 remained significant predictor of poorly differentiated type of cancer (P<0.050). Conclusions:We found significant positive association between vitamin D status and serum total cholesterol.Although low 25(OH)D3 was found to be a significant risk factor for CRC development, the obtained results primarily suggest profound impact of cholesterol level on vitamin D status in CRC. However, our results suggest that low 25(OH)D3 might independently contribute to development of poorly differentiated tumor.Uvod: Deficijencija vitamina D je učestalo javlja kod obolelih od kolorektalnog karcinoma (CRC). Kako holesterol i vitamin D dele zajednički prekursor 7-dehidroholesterol (7-DHC), bilo bi značajno ispitati povezanost ključnih metabolita vitamin D i serumskih lipidnih parametara kod pacijenata sa CRC klasifikovanih na osnovu gradusa. U ovom radu ispitivali smo odnos između serumskih koncentracija 25(OH)D3, 24,25(OH)2D3 and 7-DHC i serumskih lipida kod pacijenata sa CRC, kao i doprinos metabolita vitamina D u predikciji rizika za nastanak CRC visokog gradusa. Metode: U studiji su učestvovala 82 pacijenta sa CRC i 77 zdravih ispitanika. 7-DHC, 25(OH)D3 i 24,25(OH)2D3 su kvantifikovani pomoću metode LC-MS/MS. Rezultati: 7-DHC, 25(OH)D3 i odnos metabolita vitamina D (VDMR) su bili značajno niži kod pacijenata sa CRC u odnosu na kontrolnu grupu (P<0,001, P<0,010, P<0,050 i P<0,050, redom). Koncentracije 25(OH)D3 su bile više kod pacijenata sa gradusom I u odnosu na pacijente sa gradusom II (P<0,050). Svi metaboliti vitamina D su pozitivno korelirali sa ukupnim holesterolom kod pacijenata sa CRC. 25(OH)D3 je bio značajan prediktor povećanog rizika za nastanak CRC (P<0,010). Nakon korekcije za koncentraciju ukupnog holesterola, 25(OH)D3 je izgubio prediktivni značaj. Međutim, 25(OH)D3 je ostao značajan prediktor slabo diferenciranog karcinoma (P<0,050). Zaključak: Utvrđena je značajna pozitivna korelacija iz među statusa vitamina D i serumskih koncentracija ukupnog holesterola. Iako je uočeno da je nizak 25(OH)D3 značajan faktor rizika za razvoj CRC, naši rezultati upućuju na dominantan uticaj holesterola na status vitamina D kod ovih pacijenata. Ipak, uočeno je da niski nivoi 25(OH)D3 mogu nezavisno doprineti razvoju slabo diferentovanih oblika CRC

Can non-cholesterol sterols indicate the presence of specific dysregulation of cholesterol metabolism in patients with colorectal cancer?

Colorectal cancer (CRC) is a highly prevalent malignancy. Previous studies suggested that cholesterol might play a signficant role in malignant transformation and proliferation. Non-cholesterol sterols (NCS), which are transported by serum lipoproteins alongside cholesterol, are regarded as cholesterol synthesis and absorption markers. Quantification of NCS in serum and HDL fraction (NCSHDL), could provide a better insight into the cholesterol metabolism. The aim of this study was to examine the status of cholesterol synthesis and cholesterol absorption markers in serum and HDL fraction and explore their interrelation in CRC patients. Current study was designed as observational, case-control study. The study included 73 CRC patients and 95 healthy subjects. NCS and NCSHDL concentrations were determined by HPLC-MS/MS. Based on NCS and NCSHDL concentrations, different cholesterol homeostasis indices were calculated. Patients had significantly lower NCS (P<0.001) and NCSHDL concentrations (P<0.001 for desmosterolHDL; P<0.05 for lathosterolHDL, P=0.001 for campesterolHDL, P<0.001 for β-sitosterolHDL). NCSHDL/NCS (P<0.005 for desmosterolHDL/desmosterol; P<0.05 for lathosterolHDL/lathosterol; P<0.001 for both β-sitosterolHDL/β-sitosterol and campesterolHDL/campesterol) and synthesis to absorption ratio (CSI/CAI) (P<0.005) were increased in CRC patients. Additionally, low serum concentrations of desmosterol (P<0.001; OR=0.329; 95%CI (0.199–0.542)) and campesterol (P<0.001; OR=0.540; 95%CI (0.424–0.687)) were independent predictors of CRC presence. Our data suggest that cholesterol homeostasis in CRC is shifted towards increased synthesis. Relative abundance of NCS in HDL particles is increased, suggesting the possible overproduction of cholesterol precursors in peripheral tissues

Changes in lecithin: cholesterol acyltransferase, cholesteryl ester transfer protein and paraoxonase-1 activities in patients with colorectal cancer

Background: Previous studies revealed decreased level of high-density lipoprotein cholesterol (HDL-C) as important factor for development of colorectal cancer (CRC). Quantity and structure of HDL particles depend on activities of lipid transfer proteins lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP), but this topic is largely unexplored in CRC. The main objective of this study was to investigate activities of LCAT and CETP in patients with CRC. Additionally, we analyzed activity of paraoxonase-1 (PON-1), as a main carrier of HDL-antioxidant function. Materials and methods: Ninety-nine CRC patients and 101 healthy individuals were included. LCAT and CETP activities were assessed by measuring rates of formation and transfer of cholesteryl esters. PON-1 paraoxonase and arylesterase activities were measured. Results: Lower levels of HDL-C (p lt .001) were observed in cohort of patients, alongside with decreased LCAT (p lt .050) and increased CETP activity (p lt .050). Both PON-1 activities were diminished in CRC (p lt .050 and p lt .001 respectively). Univariate logistic regression singled out HDL-C level (OR = 0.218, p lt .001), CETP activity (OR = 1.010, p lt .01) and mass (OR = 0.994, p lt .001) as possible markers of elevated CRC risk. CETP mass maintained its predictive significance when adjusted for traditional risk factors and level of oxidative stress (OR = 0.993, p lt .001; OR = 0.982, p lt .050, respectively). Conclusion: Our results demonstrated increased CETP and decreased LCAT and PON-1 activities in CRC patients. In preliminary analysis CETP mass was identified as potential significant predictor of CRC development, suggesting that alterations in HDL-C levels, alongside with changes in HDL structure might have a role in carcinogenesis

Relationship of short-course preoperative radiotherapy and serum albumin level with postoperative complications in rectal cancer surgery

Background/Aim. The identification of risk factors could play a role in improving early postoperative outcome for rectal cancer surgery patients. The aim of this study was to determine the relationship between short-course preoperative radiotherapy (RT), serum albumin level and the development of postoperative complications in patients after anterior rectal resection due to rectal cancer without creation of diverting stoma. Methods. This retrospective study included patients with histopathologically confirmed adenocarcinoma of the rectum by and the clinical stage of T2-T4 operated on between 2007 and 2012. All the patients underwent open anterior rectal resection with no diverting stoma creation. Preoperative serum albumin was measured in each patient. Tumor location was noted intraoperatively as the distance from the inferior tumor margin to the anal verge. Tumor size was measured and noted by the pathologist who assessed specimens. Some of the patients received short-course preoperative RT, and some did not. The patients were divided into two groups (group 1 with short-course preoperative RT, group 2 with no short-course preoperative RT). Postoperative complications included clinically apparent anastomotic leakage, wound infection, diffuse peritonitis and pneumonia. They were compared between the groups, in relation to preoperative serum albumin level, patients age, tumor size and location. Results. The study included 107 patients (51 in the group 1 and 56 in the group 2). There were no significant difference in age (p = 0.95), and gender (p = 0.12) and tumor distance from anal verge (p = 0.53). The size of rectal carcinoma was significantly higher in the group 1 than in the group 2 (51.37 ± 12.04 mm vs 45.57 ± 9.81 mm, respectively; p = 0.007). The preoperative serum albumin level was significantly lower in the group 1 than in the group 2 (34.80 ± 2.85 g/L vs 37.55 ± 2.74 g/L, respectively; p < 0.001). A significant correlation between the tumor size and the serum albumin level was found (p = 0.042). Overall, postoperative complications were observed in 13 (25.5%) patients in the group 1 and in 10 (17.8%) patients in the group 2 with significant difference between the groups (p = 0.18). A significantly lower level of serum albumin was found in patients postoperative complications and in those who died. A significant difference in anastomotic leakage occurrence between groups was also found (p = 0.039). Male gender and the lower level of serum albumin were significant predictors for anastomotic leakage occurrence (p = 0.05 and p = 0.002, respectively), but preoperative RT had no significant impact on it. Conclusions. A lower serum albumin level, but not short-course of preoperative RT, was significantly associated with postoperative complications development after rectal resection with no diverting stoma