Role of Adipose Tissue Hormones in Pathogenesis of Cryptoglandular Anal Fistula.

The cryptoglandular perianal fistula is a common benign anorectal disorder that is managed mainly with surgery and in some cases may be an extremely challenging condition. Perianal fistulas are often characterized by significantly decreased patient quality of life. Lack of fully recognized pathogenesis of this disease makes it difficult to treat it properly. Recently, adipose tissue hormones have been proposed to play a role in the genesis of cryptoglandular anal fistulas. The expression of adipose tissue hormones and epithelial-to-mesenchymal transition (EMT) factors were characterized based on 30 samples from simple fistulas and 30 samples from complex cryptoglandular perianal fistulas harvested during surgery. Tissue levels of leptin, resistin, MMP2, and MMP9 were significantly elevated in patients who underwent operations due to complex cryptoglandular perianal fistulas compared to patients with simple fistulas. Adiponectin and E-cadherin were significantly lowered in samples from complex perianal fistulas in comparison to simple fistulas. A negative correlation between leptin and E-cadherin levels was observed. Resistin and MMP2 levels, as well as adiponectin and E-cadherin levels, were positively correlated. Complex perianal cryptoglandular fistulas have a reduced level of the anti-inflammatory adipokine adiponectin and have an increase in the levels of proinflammatory resistin and leptin. Abnormal secretion of these adipokines may affect the integrity of the EMT in the fistula tract. E-cadherin, MMP2, and MMP9 expression levels were shifted in patients with more advanced and complex perianal fistulas. Our results supporting the idea of using mesenchymal stem cells in the treatment of cryptoglandular perianal fistulas seem reasonable, but further studies are warranted.

The role of bidirectional communication between the adipokines and the endogenous opioid system in an experimental mouse model of colitis-associated colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the leading causes of death globally. Multiple factors may contribute to the pathogenesis of CRC, including the abnormalities in the functioning of the endogenous opioid system (EOS) or adiponectin-related signaling. The aim of our study was to evaluate if differences in the expression of opioid receptors (ORs) influence the development of CRC and if modulation of adiponectin receptors using AdipoRon, a selective AdipoR1 receptor agonist, affects colorectal carcinogenesis. METHODS: Naltrexone, an opioid receptor antagonist, was injected intraperitoneally every second day for 2 weeks, at the dose of 1 mg/kg in healthy Balb/C mice to induce changes in ORs expression. CRC was induced by a single intraperitoneal injection of azoxymethane (AOM) and the addition of dextran sodium sulfate (DSS) into drinking water in three-week cycles. The development of CRC was assessed using macro- and microscopic scoring and molecular analysis (RT qPCR, ELISA) after 14 weeks. RESULTS: Naltrexone significantly increased the mRNA expression of Oprm1, Oprd1, and Oprk1 in the mouse colon and in the brain (non-significantly). The pretreatment of mice with naltrexone aggravated the course of CRC (as indicated by tumor area, colon thickness, and spleen weight). The level of circulatory adiponectin was lowered in mice with CRC and increased in the colon as compared with healthy mice. The ß-endorphin level was increased in the plasma of mice with CRC and decreased in the colon as compared to healthy mice. AdipoRon, AdipoR1 agonist, worsened the CRC development, and pretreatment with naltrexone enhanced this negative effect in mice. CRC did not affect the expression of the Adipor1 gene, but the Adipor1 level was increased in mice pretreated with naltrexone (AOM/DSS and healthy mice). AdipoRon did not influence the expression of opioid receptors at the mRNA level in the colon of mice with CRC. The mRNA expression of Ptgs2, Il6, Nos2, Il1b, Il18, Gsdmd, and Rela was increased in mice with CRC as compared to the healthy colon. AdipoRon significantly decreased mRNA expression of Ptgs2, Il6, Il1b, and Il18 as compared to CRC mice. CONCLUSION: EOS and adiponectin-related signaling may play a role in the pathogenesis of CRC and these systems may present some additivity during carcinogenesis.

New gold(III) complexes TGS 121, 404, and 702 show anti-tumor activity in colitis-induced colorectal cancer: an in vitro and in vivo study.

BACKGROUND: Chronic inflammation in the course of inflammatory bowel disease may result in colon cancer, or colitis-associated colorectal cancer (CACRC). It is well established that CACRC is associated with oxidative stress and secretion of multiple pro-inflammatory cytokines, e.g. tumor necrosis factor-α. Recently, we proved that the administration of gold(III) complexes resulted in the alleviation of acute colitis in mice. The aim of the current study was to assess the antitumor effect of a novel series of gold(III) complexes: TGS 121, 404, 512, 701, 702, and 703. MATERIALS: Analyzed gold(III) complexes were screened in the in vitro studies using colorectal cancer and normal colon epithelium cell lines, SW480, HT-29, and CCD 841 CoN, and in vivo, in the CACRC mouse model. RESULTS: Of all tested complexes, TGS 121, 404, and 702 exhibited the strongest anti-tumor effect in in vitro viability assay of colon cancer cell lines and in in vivo CACRC model, in which these complexes decreased the total number of colonic tumors and macroscopic score. We also evidenced that the mechanism of action was linked to the enzymatic antioxidant system and inflammatory cytokines. CONCLUSIONS: TGS 121, 404, and 702 present anti-tumor potential and are an attractive therapeutic option for colorectal cancer.

Current status of Complementary and Alternative Medicine Interventions in the Management of Pancreatic Cancer - An Overview.

OPINION STATEMENT: Pancreatic cancer (PC) remains the deadliest cancer worldwide. Most patients are diagnosed at the advanced or metastatic stage, leading to a poor prognosis. Awareness of the limitations of current therapy and accompanying pain, depression, malnutrition, and side effects of chemoradiotherapy may lead patients and physicians towards complementary and alternative medicine (CAM). CAM refers to a diverse set of medical and healthcare practices, products, and systems that are not part of conventional Western medicine. Despite the low-quality evidence supporting the efficacy of these methods, they remain appealing due to patients' beliefs, fear of death, and the slow development of conventional therapy. Hence, the possibility of using natural products for pancreatic cancer is increasing. CAM options such as: medical cannabis, plants, fungi, herbal formulas, and injections, which originate primarily from traditional Chinese or Japanese medicine i.e. Curcuma longa, Panax ginseng, Poria cocos, Hochuekkito, Juzentaihoto, and Rikkunshito, Shi-quan-da-bu-tang/TJ-48, Huang-qin-tang, Shuangbai San, Wen Jing Zhi Tong Fang, Xiang-Sha-Liu-jun-zi-tang, Aidi injection, Brucea javanica oil emulsion/Yadanziyouru injection, Compound Kushen injection, Huachansu injection, Kangai injection and Kanglaite injections are becoming promising candidates for the management of pancreatic cancer. The abovementioned substances/medications are the most popular or potentially effective in PC treatment and consequently CAM-based adjuvant therapy through improving patients' quality of life, might be a useful addition in the treatment of pancreatic cancer patients.

Correlations between the symptoms of insomnia, depression, sleep quality, antitumor necrosis factor therapy, and disrupted circadian clock gene expression in inflammatory bowel disease.

INTRODUCTION: Inflammatory bowel disease (IBD) might be accompanied by emotional disturbances. Circadian rhythm genes, such as brain and muscle ARNT­Like 1 (BMAL1), circadian locomotor output cycles kaput (CLOCK), neuronal PAS domain protein 2 (NPAS2), or nuclear receptor subfamily 1 group D member 1 (NR1D1) are related to inflammation and psychiatric symptoms that might modulate their expression. OBJECTIVES: The study aimed to compare the expression of the BMAL1, CLOCK, NPAS2, NR1D1 mRNA in IBD patients and healthy controls (HCs). We evaluated the association between the gene expression and the disease severity, antitumor necrosis factor (TNF) therapy, sleep quality, insomnia, and depression. PATIENTS AND METHODS: A total of 81 IBD patients and 44 HCs were recruited and classified according to the disease activity and IBD type (ulcerative colitis [UC] or Crohn disease [CD]). The participants filled out questionnaires assessing their sleep quality, daytime sleepiness, insomnia, and depression. Venous blood samples were collected, and the IBD patients on the anti­TNF therapy had their blood drawn before and after 14 weeks of the treatment. RESULTS: In comparison with HCs, the IBD group had decreased expression of all studied genes apart from the BMAL1 gene. UC individuals with exacerbation had decreased expression of the CLOCK and the NPAS2 genes, as compared with the remission group. UC severity negatively correlated with the CLOCK, NPAS2, and NR1D1 mRNA levels. The IBD participants with depression symptoms had a decreased expression of the CLOCK and the NR1D1 genes, as compared with those without mood disturbances. Poor sleep quality was associated with a decreased expression of the NR1D1 gene. Biologic treatment decreased the expression of the BMAL1 gene. CONCLUSIONS: Disruption of the clock gene expression might constitute a molecular background of sleep disorders and depression in IBD and might contribute to UC exacerbation.

The clinical relevance of the adhesion G protein-coupled receptor F5 for human diseases and cancers.

Among the numerous adhesion G protein-coupled receptors (GPCRs), adhesion G protein-coupled estrogen receptor F5 (ADGRF5) contains unique domains in the long N-terminal tail which can determine cell-cell and cell-matrix interaction as well as cell adhesion. Nevertheless, the biology of ADGRF5 is complex and still poorly explored. Accumulating evidence suggests that the ADGRF5 activity is fundamental in health and disease. For instance, ADGRF5 is essential in the proper function of lungs and kidney as well as the endocrine system, and its signification in vascularization and tumorigenesis has been demonstrated. The most recent studies have provided findings about the diagnostic potential of ADGRF5 in osteoporosis and cancers, and ongoing studies suggest other diseases as well. Here, we elaborate on the current state of knowledge about the ADGRF5 in the physiology and pathophysiology of human diseases and highlight its high potential as a novel target in various therapeutic areas.

Relation between Selected Sleep Parameters, Depression, Anti-Tumor Necrosis Factor Therapy, and the Brain-Derived Neurotrophic Factor Pathway in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) patients often have sleep and mood disorders. Brain-derived neurotrophic factor (BDNF) and proBDNF were shown to modulate interactions between the central nervous system and the gastrointestinal tract, possibly contributing to psychological issues. Anti-tumor necrosis factor (TNF) therapy in IBD can alter BDNF expression and further affect the brain-gut axis. Eighty IBD patients and 44 healthy controls (HCs) were enrolled and divided into subsets based on disease activity and condition (ulcerative colitis (UC)/Crohn's disease (CD)). Questionnaires evaluating sleep parameters and depression as well as venous blood were collected. The IBD group had a lower expression of BDNF mRNA, but higher proBDNF and BDNF protein concentration than HCs. The UC group had a higher BDNF protein concentration than the CD. BDNF protein was positively correlated to sleep efficiency in the IBD group. Depression severity was associated positively with BDNF mRNA and negatively with BDNF protein in the remission group. Anti-TNF therapy enhanced BDNF mRNA expression. The BDNF pathway might be disturbed in IBD, linking it to sleep disorders and depression. Systemic inflammation could be the main cause of this disruption. BDNF mRNA is a more reliable parameter than protein due to numerous post-translational modifications.

New gold (III) cyanide complex TGS 121 induces ER stress, proteasome inhibition and death of Ras-hyperactivated cells.

Metal-based agents in cancer therapy, like cisplatin and its derivates, have established clinical applications but also can induce serious side effects. Thus, metallotherapeutic alternatives for platinum derivatives are developed and intensively studied. Platinum is replaced by several transition metals including gold. Especially gold (III) complexes can have the same square-planar structure and are isoelectric with platinum (II). Hence, they are developed as potential anti-cancer drugs. Thus, our group projected and developed a group of novel cyanide-based gold (III) complexes. Within this work, we aimed to characterize the safety and effectivity of one of them, TGS 121. TGS 121 in our preliminary work was selective for Ras-hyperactivated cells. Here we studied the effects of the novel complex in cancerous Ras-3 T3 and non-cancerous NIH-3 T3 cells. The complex TGS 121 turned out to be non-toxic for NIH-3 T3 cells and to induce death and alternations in Ras-hyperactivated cells. We found induction of ER stress, mitochondria swelling, proteasome inhibition, and cell cycle block. Moreover, TGS 121 inhibited cell migration and induced the accumulation of perinuclear organelles that was secondary to proteasome inhibition. Results presented in this report suggest that stable gold-cyanide TGS 121 complex is non-toxic, with a targeted mechanism of action and it is promising in anticancer drug discovery.

Increased GPR35 expression in human colorectal and pancreatic cancer samples: A preliminary clinical validation of a new biomarker.

BACKGROUND: G protein-coupled receptor 35 (GPR35) is involved in carcinogenesis; however, limited experimental data are available on its actual expression in patients with colorectal cancer (CRC) and pancreatic adenocarcinoma (PDAC). OBJECTIVES: We aimed to measure the relative expression of GPR35 in samples from patients with CRC or PDAC. MATERIAL AND METHODS: Using real-time polymerase chain reaction (RT-PCR), we have examined GPR35 expression in surgery samples from 40 CRC and 17 PDAC patients, and performed analysis of the results. RESULTS: The analysis of GPR35 expression in patients with CRC revealed correlations between relative GPR35 mRNA expression and several tumor characteristics, with statistical significance for higher American Joint Committee on Cancer (AJCC) stages, T stages and histological grades. GPR35 expression was significantly higher in tumor samples compared to the paired healthy samples collected from the same patient. Similar, although not statistically significant trends were found in PDAC tumor samples for sex (lower expression in women) and for samples with no nodal involvement (lower expression). Samples with higher tumor T stages and higher histological grades or considered inoperable had higher GPR35 expression. CONCLUSIONS: We have identified correlations which confirm our expectation of high GPR35 expression in CRC and PDAC. Our findings suggest the prognostic value of GPR35 testing in patients with an increased risk of CRC or PDAC development, and warrant further clinical confirmation.

Complex-Forming Properties of the Anti-Inflammatory Sialorphin Derivative Palmitic Acid-Lysine-Lysine-Glutamine-Histidine-Asparagine-Proline-Arginine with Cu(II) Ions in an Aqueous Solution.

The present work describes the complexation of the anti-inflammatory sialorphin derivative Pal-Lys-Lys-Gln-His-Asn-Pro-Arg (palmitic acid-lysine-lysine-glutamine-histidine-asparagine-proline-arginine) with Cu(II) ions in an aqueous solution, at a temperature of 25.0 ± 0.1 °C, over the whole pH range. The complexing properties were characterized by potentiometric and UV-Vis spectrophotometric methods. The potentiometric method was used to calculate the logarithms of the overall stability constants (log ß) and the values of the stepwise dissociation constants (pKa) of the studied complexes. The percentage of each species formed in an aqueous solution was estimated from the species distribution curve as a function of pH. The absorbance (A) and molar absorption coefficient (ε) values for the Cu(II)-sialorphin derivative system were determined with UV-Vis spectroscopy. Our studies indicate that the sialorphin derivative forms stable complexes with Cu(II) ions, which may lead to future biological and therapeutic applications.

The Expression Pattern of Adhesion G Protein-Coupled Receptor F5 Is Related to Cell Adhesion and Metastatic Pathways in Colorectal Cancer-Comprehensive Study Based on In Silico Analysis.

Adhesion G protein-coupled receptor F5 (ADGRF5) is involved inthe neoplastic transformation of some cancer types. However, the significance of ADGRF5 expression signature and the impact of signaling pathways mediated by ADGRF5 during neoplastic transformation of the colon and colorectal cancer (CRC) progression has been poorly examined. Using Gene Expression Omnibus and The Cancer Genome Atlas datasets, we showed that ADGRF5 is overexpressed in the colons of patients with CRC. In line, combined analysis of ADGRF5 expression with clinical characterization revealed an increased expression of ADGRF5 in patients with more advanced stages of CRC compared to patients with early stages of CRC. The Spearman correlation analysis documented numerous genes positively and negatively correlated with the expression pattern of ADGRF5 in the colon of patients with CRC. In the colon of CRC patients, the expression signature of ADGRF5 was associated with genes participating in phosphatidylinositol 3-kinase/Akt, focal adhesion, cell adhesion molecules, and ribosome signaling pathways. Of note, ADGRF5 expression correlated with the levels of tumor-infiltrating immune cells in the colon of CRC patients. Moreover, we found that CRC patients with high expression of ADGRF5 had a significantly lower probability of overall survival and disease-free survival. In conclusion, our results support the prognostic value of ADGRF5 and its potent therapeutic implication in CRC.

N-Terminally Lipidated Sialorphin Analogs-Synthesis, Molecular Modeling, In Vitro Effect on Enkephalins Degradation by NEP and Treatment of Intestinal Inflammation in Mice.

Pharmacotherapy for inflammatory bowel disease (IBD) is difficult, and some patients do not respond to currently available treatments. Therefore, the discovery of novel anti-IBD agents is imperative. Our aim was the synthesis of lipidated analogs of sialorphin and the in vitro characterization of their effect on the degradation of Met-enkephalin by neutral endopeptidase (NEP). We also investigated in vivo whether the most active inhibitor (peptide VIII) selected in the in vitro studies could be a potential candidate for the treatment of colitis. Peptides were synthesized by the solid-phase method. Molecular modeling technique was used to explain the effect of fatty acid chain length in sialorphin analogs on the ligand-enzyme interactions. The anti-inflammatory effect was evaluated in the dextran sulphate sodium (DSS)-induced model of colitis in mice. Peptide VIII containing stearic acid turned out to be in vitro the strongest inhibitor of NEP. We have also shown that the length of the chain of stearic acid fits the size of the grove of NEP. Peptides VII and VIII exhibited in vivo similar anti-inflammatory activity. Our results suggest that lipidation of sialorphin molecule is a promising direction in the search for NEP inhibitors that protect enkephalins.

Evening primrose seed extract rich in polyphenols modulates the invasiveness of colon cancer cells by regulating the TYMS expression.

Natural polyphenols are plant metabolites exhibiting a broad range of biological activities. Among them, anticancer properties seem to be very desirable. This study examined the anticancer and anti-metastatic properties of the polyphenol-rich extract from the evening primrose seeds (EPE). In vitro and in vivo studies performed in colorectal cancer (CRC) cell lines and AOM-DSS-induced colitis-associated colon cancer in mice revealed the EPE anticancer properties. Furthermore, we studied the EPE activity on metastatic abilities and showed that the EPE inhibited invasiveness in the following models (cells isolated from patients with different invasive stages and cells with induced invasion by either Snail overexpression or CAF stimulation). More importantly, we also demonstrated that the EPE decreases the cell invasiveness of 5-fluorouracil (5-FU) resistant CRC cells. The inhibition of metastasis correlated with a decrease in thymidylate synthetase (TYMS), which has recently been associated with metastatic phenotype development. Our results indicate that the EPE might be an effective anticancer agent in suppressing colon cancer metastasis regardless of the invasiveness cause. Based on these findings, we concluded that the used EPE extract rich in polyphenols inhibits cell invasion by TYMS downregulation.

The lack of transcriptionally active Nrf2 triggers colon dysfunction in female mice - The role of estrogens.

BACKGROUND AND AIM: The proper functioning of the gastrointestinal system relies on an intricate crosstalk between a plethora of cell types and signaling pathways. Recently we identified that the lack of NRF2 transcriptional activity (NRF2 tKO) triggers significant colon microscopical alterations, still they do not affect the general functioning of mice. Therefore, in this study, we aimed to address the gender-dependent impact of NRF2 transcriptional deficiency on colon function, and relate them to an established model of inflammatory bowel disease (IBD). METHODS: In the study we subjected 3- and 6-month old mice deficient in IL-10 and NRF2 transcriptional activity and wild-type counterparts to tests assessing colon functionality, and histological analyses. To address the role of estrogens, we attempted to rescue the phenotype by the delivery of 17ß-estradiol through subcutaneous implants. RESULTS: In females, NRF2 transcriptional abrogation, like IL-10 deficiency, triggers a functional and microscopic phenotype, that resembles IBD. The females are significantly more affected by the dysfunctional phenotype, and the functional impairmentdecreases with age. We found that NRF2 transcriptional activity influences 17ß-estradiol level and the estrogen receptors expression and location. Exogenous delivery of 17ß-estradiol normalized colon motility in the NRF2 tKO mice, which is related to enhanced ERß signaling. CONCLUSIONS: Summing up, in this study, we underline that NRF2 transcriptional deficiency or the lack of IL-10 results in pronounced GI functional decline in young females. Mechanistically, we show that the impaired distal colon motility is dependent on ERß signaling. Targeting estrogen signaling seems a promising therapeutic strategy to counteract colonic dysfunction.

The role of kappa opioid receptors in immune system - An overview.

Opioids are one of the most effective anti-nociceptive agents used in patients with cancer pain or after serious surgery in most countries. The endogenous opioid system participates in pain perception, but recently its role in inflammation was determined. κ-opioid receptors (KOP receptors), a member of the opioid receptor family, are expressed in the central and peripheral nervous system as well as on the surface of different types of immune cells, e.g. T cells, B cells and monocytes. In this review, we focused on the involvement of KOP receptors in the inflammatory process and described their function in a number of conditions in which the immune system plays a key role (e.g. inflammatory bowel disease, arthritis, subarachnoid hemorrhage, vascular dysfunction) and inflammatory pain. We summed up the application of known KOP ligands in pathophysiology and we aimed to shed new light on KOP receptors as important elements during inflammation.

Characterization of Specific Signatures of the Oral Cavity, Sputum, and Ileum Microbiota in Patients With Crohn's Disease.

Background: Crohn's disease (CD) is a chronic nonspecific inflammatory bowel disease (IBD) with an increasing incidence worldwide. The etiology of CD is still obscure, but microbial dysbiosis has been recognized as an essential factor contributing to CD. However, few studies have revealed the microbiome's signatures and reciprocal correlations between multiple sites in patients with CD over different disease stages. This study investigated the specific microbial architectures of the oral cavity, sputum, and ileum in patients with CD in the active and remission stages. Methods: Microbial samples from the oral cavity, sputum, and ileum were collected from patients with CD in the active and remission stages and healthy controls. The microbial composition was assessed by 16S ribosomal RNA (rRNA) gene sequencing. In addition, bioinformatics methods were used to demonstrate the microbial signatures, functional changes, and correlations between microbiota and clinical data in CD. Results: Compared with healthy controls, a distinct microbiota dysbiosis in the oral cavity, sputum, and ileum of patients with CD was identified, characterized by alterations in microbiota biodiversity and composition. The oral cavity and sputum microbiota showed significantly lower microbial diversity in patients with CD than in healthy controls. In terms of microbiota composition, the microbiota changes in the oral cavity of patients with CD were similar to those in the sputum, while they were different from those in the ileum. In the oral cavity and sputum of patients with CD, a lower relative abundance of Firmicutes and Actinobacteria was observed compared to healthy controls, which was most prominent in the active stage. In contrast, an increased relative abundance of Fusobacteria, Porphyromonas, and Haemophilus was observed in patients with CD. The predicted metabolic pathways involved in the oral cavity, sputum, and ileum were similar, predominantly involving metabolism, environmental information processing, and genetic information processing. Conclusion: The results revealed the alterations of microbiota architecture in the oral cavity, sputum, and ileum of patients with CD, which varied across disease stages. Studying microbiota dysbiosis may bring new insights into the etiology of CD and lead to novel treatments.

The GPR35 expression pattern is associated with overall survival in male patients with colorectal cancer.

BACKGROUND: G protein-coupled receptor 35 (GPR35) is involved in the carcinogenesis; however, limited data exist on its relevance for overall survival (OS) and disease-specific survival (DSS) in patients with cancer. METHODS: We have examined The Cancer Genome Atlas dataset to check the relations between GPR35 expression pattern and OS or DSS of patients with colorectal cancer (CRC). RESULTS: The performed analysis showed a negative association between positive GPR35 expression Z score and OS in males, which remains statistically significant in advanced stages of colon (COAD) and rectal (READ) adenocarcinoma combined. CONCLUSIONS: These findings suggest the prognostic value of early testing of GPR35 in male patients with an increased risk of CRC development and warrant further clinical confirmation.

The Anti-Inflammatory Effect of Acidic Mammalian Chitinase Inhibitor OAT-177 in DSS-Induced Mouse Model of Colitis.

Inflammatory bowel diseases (IBD) are chronic and relapsing gastrointestinal disorders, where a significant proportion of patients are unresponsive or lose response to traditional and currently used therapies. In the current study, we propose a new concept for anti-inflammatory treatment based on a selective acidic mammalian chitinase (AMCase) inhibitor. The functions of chitinases remain unclear, but they have been shown to be implicated in the pathology of various inflammatory disorders regarding the lung (asthma, idiopathic pulmonary fibrosis) and gastrointestinal tract (IBD and colon cancer). The aim of the study is to investigate the impact of AMCase inhibitor (OAT-177) on the dextran sulfate sodium (DSS)-induced models of colitis. In the short-term therapeutic protocol, OAT-177 given intragastrically in a 30 mg/kg dose, twice daily, produced a significant (p < 0.001) anti-inflammatory effect, as shown by the macroscopic score. Additionally, OAT-177 significantly decreased TNF-α mRNA levels and MPO activity compared to DSS-only treated mice. Intraperitoneal administration of OAT-177 at a dose of 50 mg/kg caused statistically relevant reduction of the colon length. In the long-term therapeutic protocol, OAT-177 given intragastrically in a dose of 30 mg/kg, twice daily, significantly improved colon length and body weight compared to DSS-induced colitis. This is the first study proving that AMCase inhibitors may have therapeutic potential in the treatment of IBD.

Gold (III) Derivatives in Colon Cancer Treatment.

Cancer is one of the leading causes of morbidity and mortality worldwide. Colorectal cancer (CRC) is the third most frequently diagnosed cancer in men and the second in women. Standard patterns of antitumor therapy, including cisplatin, are ineffective due to their lack of specificity for tumor cells, development of drug resistance, and severe side effects. For this reason, new methods and strategies for CRC treatment are urgently needed. Current research includes novel platinum (Pt)- and other metal-based drugs such as gold (Au), silver (Ag), iridium (Ir), or ruthenium (Ru). Au(III) compounds are promising drug candidates for CRC treatment due to their structural similarity to Pt(II). Their advantage is their relatively good solubility in water, but their disadvantage is an unsatisfactory stability under physiological conditions. Due to these limitations, work is still underway to improve the formula of Au(III) complexes by combining with various types of ligands capable of stabilizing the Au(III) cation and preventing its reduction under physiological conditions. This review summarizes the achievements in the field of stable Au(III) complexes with potential cytotoxic activity restricted to cancer cells. Moreover, it has been shown that not nucleic acids but various protein structures such as thioredoxin reductase (TrxR) mediate the antitumor effects of Au derivatives. The state of the art of the in vivo studies so far conducted is also described.

Adipocyte Fatty Acid Binding Protein (A-FABP) as a Potential New Therapeutic Target for the Treatment of Obesity - Associated Cancers.

Fatty acid binding protein A (A-FABP) is one of FABPs isoforms found mainly in adipose tissue and macrophages. It works through many integrated pathways, regulating inflammation and lipid metabolism, promoting glucose production, impairing insulin function, and contributing to diseases such as atherosclerosis and diabetes. A-FABP is upregulated in the adipose tissue of obese patients and its increased release into the bloodstream is positively associated with body mass index. Consequently, A-FABP plays a key role in regulating metabolism in obese people. Recent studies in mouse models and humans demonstrated the role of A-FABP in increasing the risk of obesity-related cancers. Here we summarized the state of research on the link between obesity, cancer and A-FABP as a new potential therapeutic target for the treatment of obesity - associated cancers.