Toll-like receptor-4 (TLR-4) is a member of evolutionarily conserved type I transmembrane proteins that can initiate sterile inflammatory cascade in the pancreas. Expression of TLR-4 is up-regulated in pancreatic tissue, as well as, on peripheral blood innate immune cells in human and experimental models of acute pancreatitis. TLR-4 plays important pro-inflammatory roles during development of acute pancreatitis: it recognize alarmins released from injured acinar cells and promotes activation and infiltration of innate immune cells after the premature and intraacinar activation of tripsinogen. Galectin-3 is β-galactoside-binding lectin that plays pro-inflammatory roles in a variety autoimmune diseases, acute bacterial infections and during tumorigenesis. It is reported that Galectin-3 is alarmin in experimental models of neuroinflammation and binds to TLR-4 promoting the pro-inflammatory phenotype of microglia. Also, in experimental model of acute pancreatitis Galectin-3 is colocalized with TLR-4 on innate inflammatory cells resulted in enhanced production of inflammatory cytokines, TNF-α and IL-1β, increased infiltration of pro-inflammatory N1 neutrophils, macrophages and dendritic cells and increased damage of pancreatic tissue. This review paper discusses the role of TLR-4/Gal-3 axis in the pathogenesis of acute pancreatitis.
B cells play a dual role in the pathogenesis of autoimmune diseases. In experimental autoimmune encephalomyelitis (EAE), an experimental model for multiple sclerosis, B cells contribute to disease progression, while their regulatory role predominates in the initial phases of disease development. Several studies have identified different subsets of regulatory B cells, mostly in the spleen, which are all sources of IL-10. However, peritoneal regulatory B cells are also important producers of IL-10, can migrate towards inflammatory stimuli, and could have an immunoregulatory function. As we have observed expansion of regulatory B cells in the peritoneum of resistant mice after EAE induction, herein we discuss the regulatory roles of B cells in EAE pathogenesis and the possible role of peritoneal regulatory B cells in resistance to EAE induction.
Pustular psoriasis is an uncommon form of psoriasis consisting of widespread pustules on an erythematous background. Very rarely pustular psoriasis represent a paraneoplastic dermatosis. In this report we describe a case of generalized pustular psoriasis (GPP) associated with advanced, inoperable, metastatic squamous cell carcinoma of the hypopharynx. We suggest that physicians should be alert for the worsening of existing psoriasis or formation of novel psoriasiform eruptions and should undertake clinical evaluation of possible neoplastic disease.
Metals are essential components in indispensable biochemical processes for living organisms. This review article highlights the metals zinc and gold in the development and treatment of breast cancer. Metal compounds off er many advantages as therapeutics due to their ability to coordinate ligands in a three-dimensional configuration. In aqueous solution, they form positively charged ions that can bind to negatively charged biological molecules. Metal complexes that contain metal ions such as zinc(II) and gold have received considerable attention as potential anticancer agents. Zinc is an essential trace element that plays a critical role in a wide range of cellular processes that include structural, signalling, catalytic and regulatory functions. Zinc acts as a key structural component in many proteins and enzymes, including transcription factors, cellular signalling proteins, and DNA repair enzymes, and perturbed levels of zinc in tissues may play a role in cancer aetiology and outcome. Unlike zinc, gold is feasible as a component of compounds for effective anticancer therapy. Some progress in anticancer therapy may include interactions between zinc and gold.
Since the discovery of the antitumor activity of cisplatin by Rosenberg and co-workers, the use of metal complexes in cancer treatment has caused a huge interest. Today, platinum-based drugs are part of standard chemotherapy in the management of a variety of ca ncers, germ cell tumours, sarcomas, and lymphomas. Unfortunately, toxicity and drug resistance are major obstacles to wider clinical application of these drugs. Their use is greatly limited by severe side effects such as nephrotoxicity, ototoxicity, and neurotoxicity. Although cisplatin is one of the most successful anticancer drugs to date, its biochemical mechanism of action is still unclear. Cisplatin is generally accepted as having the ability to interact with the purine bases on the DNA, causing DNA damage, interfering with DNA repair mechanisms, and subsequently inducing apoptosis in cancer cells.
Chronic lymphocytic leukaemia is a neoplastic B cell lymphoproliferative disease characterized by a highly variable clinical course. Clinical stage at the diagnosis and biological prognostic factors are the important predictors for survival. The Rai and Binet staging systems describe three major prognostic subgroups. Commonly used prognostic biomarkers in chronic lymphocytic leukaemia can be divided into genotypic, DNA-level changes and phenotypic, expression-level changes. For chronic lymphocytic leukaemia, substantial progress in therapy has not been made over the past 40 years. The main goal of future scientific research is to find new platinum complexes that have better efficacy in cancer treatment, the ability to be administered orally, without developing a cancer-drug resistance, and reduced toxic side effects.
Viral infection has been identified as the most likely environmental trigger of multiple sclerosis (MS). There are conflicting data regarding the role of cytomegalovirus (CMV) in MS pathogenesis.
We utilised experimental autoimmune encephalomyelitis (EAE)-resistant BALB/c mice and murine cytomegalovirus (MCMV), the murine homolog of CMV, to examine the mechanism by which viral infection enhances autoimmune neuroinflammation. Mice subjected to latent neonatal MCMV infection developed the typical characteristics of EAE. Similar to MS, the MCMV-infected EAE-induced mice developed infiltrates in the central nervous system (CNS) composed of similar percentages of CD4+ and CD8+ T cells. The influx of both Th 1 and Th 17 cells into the CNS of MCMV- infected EAE-induced mice was observed. Interestingly, the development of autoimmune neuroinflammation after latent MCMV infection was accompanied by a significant influx of Tc17 cells (CD8+IL-17+ and CD8+RoRγt+) but not Tc1, cells. Our results suggest that latent MCMV infection affects the development of inflammatory lymphocytes that exhibit encephalitogenic potential, thereby mediating increased CNS pathology following EAE induction, and that CMV represents a possible environmental factor in the pathogenesis of MS and other autoimmune diseases
Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver that is, characterised by destruction of the intrahepatic bile ducts and the presence of antimitochondrial antibodies (AMAs). Several murine models of PBC, with similar serological, biochemical, and histological features to human PBC, have been developed in recent years. These animal models enable investigators to study the etiology and pathophysiologic mechanism of PBC. Immune response in PBC is directed towards E2 components of the 2-oxo-acid dehydrogenase family of enzymes, which is in located in mitochondria and is an immunodominant epitope (a lipoylated peptide sequence shared by enzymes). Immunisation of mice with 2-octynoic acid coupled to bovine serum albumin (2-OA-BSA) (which is an antigen that is structurally related to the E2 subunit of the pyruvate dehydrogenase complex [PDC-E2]) produces histologic features similar to those found in human PBC. Th is model of xenobiotic induced PBC is suitable for studying the early events in PBC pathogenesis and for developing new therapeutics in PBC.
The design of platinum based drugs is not a new field of interest. Platinum complexes are widely used as anticancer agents and currently, approximately 30 platinum(II) and platinum(IV) entered into some of the phases of clinical trials. A special place in today’s research belongs to platinum complexes with diammine ligands. A large number of edda (ethylenediamine- N, N’-diacetate)-type ligands and their corresponding metal complexes has been successfully synthesized. This article summarizes recent progress in research on edda-type-platinum complexes. Some of these agents achieves better effect compared to the gold standard (cisplatin). It has been shown that there is a possible relationship between the length of the ligand ester group carbon chain and its cytotoxic effect. In most cases the longer the ester chain is the greater is the antitumor activity. Of particular interest are the noticeable effects of some new platinum compound with edda-type ligand on cell lines that are known to have a high level of cisplatin-resistance. Exanimate complexes appear to have a different mode of mechanism of action compared with cisplatin which includes apoptotic and necrotic cell death. There are indications that further investigations of these compounds may be very useful in overcoming the problems associated global cancer statistic.
Copper serves as a limiting factor for multiple steps of tumour progression, including angiogenesis, growth and metastasis. High levels of copper have been found in a wide spectrum of human cancers. Antitumour activities of copper-chelating drugs have been reported in animal models. Organosulfur compounds (diallyl sulfide, DAS; diallyl disulfide, DADS; S-ethylcysteine, SEC; N-acetylcysteine, NAC) derived from garlic exhibit marked copper-chelating activity. We analysed a mixture of fifteen n-propyl polysulfides (DPPS) for potential antitumour activity against several murine tumour cell lines, including colon carcinoma (CT26), mammary carcinoma (4T1) and melanoma cell lines (B16F10), and compared the effects with the antiproliferative effect in highly proliferative murine mesenchymal stem cells (mMSCs). The effects of the mixture of n-propyl polysulfides (100%) on cell viability were determined using MTT assays. Cell apoptosis was analysed using Annexin V-FITC/PI assays.
The results of the MTT assays indicate that this standardized mixture of n-propyl polysulfides has a strong, dose-dependent cytotoxic effect against all three of the tested tumour cell lines (CT26, 4T1, B16F10). The cytotoxic effect of the n-propyl polysulfide mixture against the CT26 and B16F10 cell lines was much stronger than that of cisplatin and was significantly weaker in mMSCs, which are non-cancerous and highly proliferative cells, than in cancer cells. Flow cytometric analysis of CT26 and 4T1 cells revealed that apoptosis was not the dominant mechanism of cell death induced by the n-propyl polysulfide mixture. The n-propyl polysulfide mixture exerted highly cytotoxic activity against murine colon carcinoma and melanoma cell lines, but its antiproliferative activity against mMSCs was significantly lower than that of cisplatin.
New complexes of copper(II) with S-alkenyl derivatives of thiosalicylic acid (alkenyl = propenyl-(L1), isobutenyl-(L2)) have been synthesized and characterized by microanalysis, infrared spectra, magnetic measurements, and by NMR spectra. The cytotoxic activity of two newly synthesized precursor S-alkenyl derivatives of thiosalicylic acid were tested using an MTT colorimetric technique on HCT-116 human colon carcinoma cells. The cytotoxic effect of the copper(II)- complexes were higher compared to the cytotoxicity of the corresponding ligand (for concentrations from 31.25 to 250 μM). Copper(II)-complexes showed a slightly lower cytotoxicity compared to cisplatin. Complexes of copper(II) with S-alkenyl derivatives of thiosalicylic acid (at concentrations from 250 to 1000 μM) had a cytotoxic effect on HCT-116 cells compared to cisplatin.