Mechanism of matrix metalloproteinase-14 (mmp-14) regulation during atherosclerosis

"December 2006"The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file.Vita.Thesis (Ph. D.) University of Missouri-Columbia 2006.Atherosclerosis is characterized by the narrowing of the arterial lumen due to formation of the plaque within the intimal layer of the arterial wall resulting in the impaired flow of blood to the target organs. Most severe consequences of atherosclerosis arise due to the rupture of the atherosclerotic plaque, which is the cause of stroke, myocardial infarction, etc. Rupture of the plaque occurs due to the thinning of the fibrous cap of the plaque. Increased expression of matrix metalloproteinases (MMPs), including MMP-14, the enzymes which can cause degradation of many components of the extracellular matrix, is the cause of thinning and rupture of the fibrous cap of the atherosclerotic plaque. Increased expression of MMP-14 is due to its transcriptional upregulation during inflammatory conditions such as atherosclerosis. In a recent study, we have shown that serum amyloid A-activating factor-1 (SAF-1) is involved in the increased expression of MMP-14 in the atherosclerotic lesion area. This discovery is a major breakthrough in understanding the regulation of MMP-14 gene expression during inflammatory conditions. However, we still do not have a clear understanding of the regulatory processes that are involved in the expression of MMP-14 during physiological and pathological conditions. We here show that another transcription factor, octamer binding protein-1 (Oct-1) may be involved in the regulation of MMP-14. We have here shown that there is physical interaction between SAF-1 and Oct-1, and Oct-1 may be involved in controlling SAF-1 mediated expression ofMMP-14 gene. The crucial finding that Oct-1 is a downreguator of MMP-14 gene may be an important target for developing new therapeutic measures for the treatment of atherosclerosis.Includes bibliographical reference

Prospective study of clinical profile of acute ischemic stroke in a tertiary care hospital of North India

Background: Owing to the recent demographic shifts and negative lifestyle changes, stroke is one of the leading causes of mortality across every income group in most of the countries. It is of the utmost importance to devolve into the clinical profile, etiology and management of patients with acute ischaemic stroke.Methods: It is a prospective case control study. Data was collected using a pre-tested pro forma meeting the objectives of the study. Patients who consented were divided into two groups and complete examination and investigations were carried out.Results: There were 94 patients with AIS enrolled for the study. The mean age was 56.2 years, of which 68.08% were males and 31.92% were females. The mean time for these patients to reach the health facility was 12.6 hours and only 36.17% of patients reached in the window period of 4.5 hours and were eligible for thrombolysis. Hypertension, Diabetes and smoking were the most common risk factors in this order among others.Conclusions: There is poor awareness regarding identification of stroke related symptoms and warning signs as majority of patients were unable to reach the hospital in the window period making them ineligible for thrombolysis. The leading etiology runs in the direction of modifiable risk factors which can be corrected at a primary prevention level

Dietary Phytochemicals: As a Natural Source of Antioxidants

Since time immemorial, plants are used as the source of food and medicine. It can be traced back to the start of humanity. Bringing plant-based food, such as fruits, vegetables, and whole grains, rich in phytochemicals, with beneficial nutrients, opens the door for healthy living. The health benefits are partly attributed to the compounds which possess antioxidants. Several epidemiological observations have shown an opposite relationship between consumption of plant-based foods, rich in phytochemicals, and many diseases including cancer. The majority of the ailments are related to oxidative stress induced by free radicals. Free radicals are extremely unstable with a very short half-life, highly reactive molecule which leads to oxidative damage to macromolecules such as proteins, DNA, and lipids. Free radical induced cellular inflammation appears to be a major contributing factor to cause aging, and degenerative diseases such as cancer, cardiovascular diseases, diabetes, hepatic diseases, renal ailments, and brain dysfunction. Free radicals have been caught up in the pathogenesis of several diseases. Providentially, free radical formation is controlled naturally by phytochemicals, through their antioxidant potential which plays a key role in preventing many diseases including cancer by suppressing oxidative stress-induced DNA damage. Keeping these facts in mind, an attempt has been made to highlight the oxidative stress, enzymatic and non-enzymatic antioxidant, dietary phytochemicals and their role of in disease prevention and cure

In vitro investigation of phytochemicals, Antioxidant and Hepatoprotective activity of Selaginella bryopteris

The present study investigated the total phenolic content, free radical scavenging activity and hepatoprotective effect of Selaginella bryopteris (SB) against acetaminophen (APAP) and carbon tetrachloride (CCl4) induced hepatotoxicity on HepG2 cell lines. The preliminary phytochemicals screening of SB aqueous and ethanolic extract confirmed the presence of phytochemical constituents and total phenolic contents. Both extracts exhibited radical scavenging activities in dose dependent manner (100-500 μg/mL). The maximum concentration (500 μg/mL) showed highest DPPH, ABTS and H2O2 free radical scavenging activity in ethanolic extract of SB followed by aqueous extract. Hepatoprotective activity was assessed by MTT assay which confirmed that SB extracts at three doses (25μg/mL, 50μg/mL and 100μg/mL) appeared to have considerable cellular protection (72- 88%) against CCl4 and APAP induced toxicity in HepG2 cell line in dose-dependent manner. At 100μg/mL, the cell viability rate was found to be higher in SB ethanolic extract compared to the aqueous extract. No adverse effect was observed in the SB treated HepG2 cell line. LDH leakage assay also confirmed that SB extract significantly reduced the level of cellular LDH leakage into the cell culture medium. The results indicate that Selaginella bryopteris extract has significant hepatoprotective activity against APAP and CCL4-inducedtoxicity which might be due to its free radical scavenging activity

Oct1 and OCA-B are selectively required for CD4 memory T cell function

Epigenetic changes are crucial for the generation of immunological memory. Failure to generate or maintain these changes will result in poor memory responses. Similarly, augmenting or stabilizing the correct epigenetic states offers a potential method of enhancing memory. Yet the transcription factors that regulate these processes are poorly defined. We find that the transcription factor Oct1 and its cofactor OCA-B are selectively required for the in vivo generation of CD4+ memory T cells. More importantly, the memory cells that are formed do not respond properly to antigen reencounter. In vitro, both proteins are required to maintain a poised state at the Il2 target locus in resting but previously stimulated CD4+ T cells. OCA-B is also required for the robust reexpression of multiple other genes including Ifng. ChIPseq identifies ∼50 differentially expressed direct Oct1 and OCA-B targets. We identify an underlying mechanism involving OCA-B recruitment of the histone lysine demethylase Jmjd1a to targets such as Il2, Ifng, and Zbtb32. The findings pinpoint Oct1 and OCA-B as central mediators of CD4+ T cell memory