Stroke is associated with elevation of several proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-8 that are correlated with central nervous system (CNS) injury. Anti-platelet therapies are important agents in stroke management. The role of antiplatelets as anti-inflammatory agents is not known in acute stroke patients. Furthermore, their effect on induction of potential cytokines as TNF-alpha and IL-8 in those patients is still not clear. Thus, we herein examined the induction of TNF-alpha and IL-8 in acute stroke patients and examined the effects of the antiplatelets drugs aspirin, clopidogrel and dipyridamole, and piracetam in their induction. Cytokines were detected intracellularly in leukocytes from patients who had first acute ischemic stroke and from matched controls by immunocytochemistry. The results showed significant increase of spontaneously produced TNF-alpha and IL-8 in patients compared to control. This induction was significantly inhibited differently by each drug and dual drug agents. The data of this work suggest that antiplatelets agents may have a role in inhibition of stroke mediated proinflammatory cytokine effects, which may initiate a new aspect of the role of antiplatelets in the treatment of acute ischemic stroke.
Background:RANTES (regulated on activation, normal T cell expressed and secreted) expression is increased in inflammatory bowel disease (IBD). RANTES is produced at higher levels in granulomatous conditions, so increased RANTES expression can be expected in Crohn’s disease compared with ulcerative colitis.Aim:To compare RANTES expression between intestinal biopsy specimens of patients with Crohn’s disease and those with ulcerative colitis.Materials and methods:A prospective study of patients presenting with lower gastrointestinal symptoms at the Bahrain Specialist Hospital from July 2004 to April 2005 was carried out. Endoscopic colonic biopsy specimens were taken from every patient and subjected to (a) routine haematoxylin and eosin staining examination by light microscopy, (b) immunohistochemistry for examination of RANTES protein expression by light microscopy and (c) in situ hybridisation for examination of RANTES mRNA expression by light microscopy. RANTES expression was assessed and quantified.Results:58 patients were enrolled to the study. Of them, 40 had IBD (21 had Crohn’s disease and 19 had ulcerative colitis), 15 were controls with normal colonic biopsy results or non-inflammatory lesions and 3 had colonic inflammatory lesions other than IBD. RANTES expression in lymphocytes or histiocytes was significantly higher (p = 0.04) in new patients with ulcerative colitis than in those with Crohn’s disease analysed by immunohistochemistry (IHC).Conclusion:RANTES expression in lymphocytes or histiocytes is significantly higher in patients with ulcerative colitis than in those with Crohn’s disease. Hence, RANTES IHC can be an effective method for distinguishing between biopsy specimens of patients with ulcerative colitis from those of patients with Crohn’s disease, where routine histological features are indeterminate. RANTES IHC may prove to be a useful technique for identifying early or equivocal granulomas.
Curcumin displays anticancer properties; however, some issues with the drug delivery mode limit its therapeutic use. Although reformulation and derivatization of curcumin have improved its bioavailability, curcumin derivatives may not retain the same anticancer properties as the parent compound. The present study investigated the anticancer properties of two curcumin complexes, the iron-curcumin [Fe(Cur) 3 ] and boron-curcumin [B(Cur) 2 ] complexes, in the MDA-MB-231 breast cancer cell line. The cellular localization of curcumin, B(Cur) 2 and Fe(Cur) 3 was determined by fluorescence microscopy. Cell proliferation, migration and invasion were also analysed. Furthermore, apoptosis-associated proteins were detected by using a proteome profiler array, and ion channel gene expression was analysed by reverse transcription-quantitative PCR. The results demonstrated that the three compounds were localized in the perinuclear and cytoplasmic regions of the cell, and displayed cytotoxicity with IC 50 values of 25, 35 and 8 µM for curcumin, B(Cur) 2 and Fe(Cur) 3 , respectively. In addition, the three compounds inhibited cell invasion, whereas only curcumin and B(Cur) 2 inhibited cell migration. Furthermore, cell exposure to curcumin resulted in an increase in the relative expression of the two key proapoptotic proteins, cytochrome c and cleaved caspase-3, as well as the antiapoptotic protein haem oxygenase-1. In addition, curcumin increased the expression levels of the voltage-gated potassium channels Kv2.1 and Kv3.2. Similarly, the expression levels of the chloride channel bestrophin-1 and the calcium channel coding gene calcium voltage-gated channel auxiliary subunit γ4 were increased following exposure to curcumin. Taken together, these results indicated that Fe(Cur) 3 and B(Cur) 2 may display similar anticancer properties as curcumin, suggesting that chemical complexation may be considered as a strategy for improving the potency of curcumin in the treatment of breast cancer.
Breast cancer is the most common cancer diagnosed among females worldwide. Although breast cancer survival has largely improved in the past 30 years, it remains highly heterogeneous in its response to treatment. Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks the expression of the estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor-2 (Her2). While TNBC may initially be responsive to chemotherapy, recurrence and subsequent high mortality rates are frequently reported. Studies have shown curcumin and its derivatives to be effective against TNBC cell lines in vitro. To improve its anti-cancer effects, we have synthesized Fe3+–curcumin (Fe–Cur3) and Cu2+–curcumin (CD) complexes and investigated them experimentally. Further, CD was encapsulated into a poly(styrene)-co-maleic acid (SMA) micelle to enhance its stability. We assessed the cytotoxicity of these formulations both in vitro and in vivo. SMA–CD demonstrated dose-dependent cytotoxicity and abolished TNBC tumor growth in vivo. The encapsulation of the curcumin–copper complex improved its anti-cancer activity without overt adverse effects in a murine model of TNBC. These results provide evidence and insights into the value of nanoformulations in enhancing drug-delivery and increasing the potential therapeutic efficacy of curcumin derivatives.
This study relates to a novel mediator signaling between the nervous system and the spleen following an immune challenge. Using enzyme-linked immunospot and cell proliferation assays, we found that supernatants of cultured splenocytes prepared from subcutaneously trypanosome-inoculated rats and mice spleens obtained immediately after inoculation and added to naive cells significantly stimulate interferon-c production and cell proliferation compared to phosphate-buffered saline-inoculated animals. This action was abrogated by surgical denervation of the spleen. Using the fluorescent differential display technology, the gene involved in this process was identified and further cloned and its sequence was mapped to chromosome 14 (GenBank accession number: EU552928). Protein expression revealed B15 kDa molecule with biological activities similar to the cultured supernatants of splenocytes obtained directly from parasite-inoculated animals. Antibodies raised against the protein blocked the activities of both the protein and the supernatant and also recognized a band in the active supernatant with the same molecular mass as the protein. Furthermore, the protein was able to reactivate experimentally immunosuppressed cells by regaining their ability to proliferate, suggesting that such a nervous system-induced immune system-released activating agent (ISRAA) may have a potential therapeutic benefit in immunocompromised situations and in further understanding the mechanism for innate immunity commencement and action. Keywords: CNS; cytokine; innate immunity; immunosuppression A bewildering array of infectious agents and parasites gain subsistence at the expense of their hosts. Although host-parasite interplay depends on the virulence of parasites and resistance of the host, the early events of innate immunity during host-parasite interactions are very important in directing the ultimate pattern of the immune response. These early events of the innate immune response are, however, much less well characterized than the later secondary immune responses.Immune responses are not isolated from other organ systems in the body, and indeed there are various means of communication between these organ systems and the immune system. Among these communications are regulatory interactions between the nervous and the immune systems.
Multiple sclerosis (MS) is an immune-mediated neurological, inflammatory disease of the central nervous system. Recent studies have suggested that genetic variants in mitochondrial DNA (mtDNA)-encoded complexes of respiratory chain, particularly, complex I (NADH dehydrogenase), contribute to the pathogenicity of MS among different ethnicities, and targeting mitochondrial function may represent a novel approach for MS therapy. In this study, we sequenced ND genes (ND1, ND2, ND3, ND4, ND4L, ND5 and ND6) encoding subunits of complex I in 124 subjects, 60 patients with relapsing-remitting MS and 64 healthy individuals, in order to identify potential novel mutations in these patients. We found several variants in ND genes in both the patients and controls, and specific variants only in patients with MS. While the majority of these variants were synonymous, 4 variants in the ND4 gene were identified as missense mutations in patients with MS. Of these, m.11150G>A was observed in one patient, whereas m.11519A>C, m.11523A>C and m.11527C>T were observed in another patient. Functional analysis predicted the mutations, m.11519A>C, m.11523A>C and m.11150G>A, as deleterious with a direct impact on ND4 protein stability and complex I function, whereas m.11527C>T mutation had no effect on ND4 protein stability. However, the 3 mutations, m.11519A>C, m.11523A>C and m.11527C>T, which were observed in the same patient, were predicted to cause a cumulative destabilizing effect on ND4 protein, and could thus disrupt complex I function. On the whole, this study identified 4 novel mutations in the mtDNA-encoded ND4 gene in patients with MS, which could lead to complex I dysfunction, and further confirmed the implication of mtDNA mutations in the pathogenicity of MS. The identified novel mutations in patients with MS may be ethnic-related and may prove to be significant in personalized treatment.
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