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Biomedical subjects

Hasan Mukhtar

Publications and source records attributed to Hasan Mukhtar.

65 records · Page 4Linked to original sources
PubMed2002

Green tea constituent epigallocatechin-3-gallate inhibits angiogenic differentiation of human endothelial cells.

Several independent research studies have shown that consumption of green tea reduces the development of cancer in many animal models. Epidemiological observations, though inconclusive, are suggesting that green tea consumption may also reduce the risk of some cancers in humans. These anti-carcinogenic effects of green tea have been attributed to its constituent polyphenols. Angiogenesis is a crucial step in the growth and metastasis of cancers. We have investigated the effect of the major polyphenolic constituent of green tea, epigallocatechin-3-gallate (EGCG), on the tube formation of human umbilical vein endothelial cells (HUVEC) on matrigel. Tube formation was inhibited by treatment both prior to plating and after plating endothelial cells on matrigel. EGCG treatment also was found to reduce the migration of endothelial cells in matrigel plug model. The role of matrix metalloproteinases (MMP) has been shown to play an important role during angiogenesis. Zymography was performed to determine if EGCG had any effect on MMPs. Zymographs of EGCG-treated culture supernatants modulated the gelatinolytic activities of secreted proteinases indicating that EGCG may be exerting its inhibitory effect by regulating proteinases. These findings suggest that EGCG acts as an angiogenesis inhibitor by modulating protease activity during endothelial morphogenesis.

Animals↗
PubMed2002

Botanical antioxidants for chemoprevention of photocarcinogenesis.

The incidence of non-melanoma skin cancer, consisting of basal- and squamous- cell carcinoma, continues to increase in the United States and elsewhere. Solar ultraviolet (UV) B radiation has been implicated as its main cause. This adverse effect of UVB has become a major human health concern. Therefore, development of novel strategies to reduce the occurrence of skin cancer is a highly desirable goal. Because UV radiation is known to cause excessive generation of reactive oxygen species (ROS) thereby resulting in an oxidative stress condition, the approaches aimed at counteracting ROS production may be useful for the prevention of skin cancer. One approach to reduce its occurrence is through 'Photochemoprotection', which we define as 'the use of agents capable of ameliorating the adverse effects of UVB on the skin'. Among many photochemoprotective agents, botanical antioxidants are showing promise. We propose that the use of botanical antioxidants, in combination with the use of sunscreens and educational efforts to avoid excessive sun exposure, may be an effective strategy for reduction of incidence of skin cancer and other UV-mediated damage in humans.

Anticarcinogenic Agents↗
PubMed2002

Role of the retinoblastoma (pRb)-E2F/DP pathway in cancer chemopreventive effects of green tea polyphenol epigallocatechin-3-gallate.

Because of the demonstrated role of green tea polyphenol epigallocatechin-3-gallate (EGCG) in cancer chemoprevention, there is considerable emphasis in understanding its mechanism of action. In this study, we assessed the involvement of the retinoblastoma (pRb)-E2F/DP pathway as an important contributor in the antiproliferative effects of EGCG. As shown by immunoblot analysis, EGCG treatment of A431 cells resulted in a dose- as well as time-dependent decrease in the total pRb with a relative increase in the hypophosphorylated form of pRb. EGCG also resulted in serine-780 phosphorylation of pRb in these cells. Further, EGCG was found to downregulate the protein expression of other members of the pRb family, viz. p130 and p107, in a dose- as well as time-dependent manner. This response was accompanied by downregulation in the protein expression of the E2F (1 through 5) family of transcription factors and their heterodimeric partners DP1 and DP2. Taken together, our study suggests that EGCG causes a downregulation of hyperphosphorylated pRb protein with a relative increase in hypophosphorylated pRb that, in turn, compromises with the availability of "free" E2F. This series of events leads to stoppage of cell cycle progression at the G1-->S phase transition thereby causing G0/G1 arrest and subsequent apoptotic cell death. This, to our knowledge, is the first study showing the involvement of the pRb-E2F/DP pathway in antiproliferative and apoptotic effects of EGCG.

Antineoplastic Agents↗
PubMed2002

Green tea and prostate cancer.

Many laboratory studies and human epidemiological data suggest that most prostate cancer deaths are attributable to lifestyle, including nutritional factors where diet plays a major role in initiation as well as subsequent progression of the disease. Under these circumstances, chemoprevention seems to be a logical and obvious strategy. Because of its long latency and high incidence, prostate cancer is an ideal disease for chemoprevention. The suitable agent(s) for prostate cancer chemoprevention should be the one(s) that has efficacy in the laboratory experiments on one hand, and also possesses proven epidemiological basis on the other hand. In this article, we address the use of green tea for prostate cancer chemoprevention. Experimental as well as the epidemiological basis for this possibility is provided.

Animals↗
PubMed2002

Chemoprevention of skin cancer: current status and future prospects.

Chemoprevention represents a relatively new and promising strategy whereby the use of natural or synthetic agents the process of carcinogenesis can be slowed, reversed or completely halted. Especially for the skin cancer, chemoprevention could be an important armamentarium because of increasing incidence of such cancers and because skin is continuously exposed to various environmental carcinogens that include both chemical agents and solar ultraviolet radiations. A wide range of compounds, both synthetic and naturally occurring has been shown to possess cancer chemopreventive effects in murine skin carcinogenesis models. Only a limited number of these agents have been tested for their efficacy in the human population. Here, we provide a brief review on the skin cancer chemopreventive potential and mechanism of action of various synthetic and natural agents. Many of these agents are present in daily diet and are supplemented or topically applied against prevention of various stages of skin cancer. We will also discuss the current status and future prospects of these agents for development as promising chemopreventive agents against skin cancer.

Animals↗
PubMed2002

Cyclooxygenase-2 expression in murine and human nonmelanoma skin cancers: implications for therapeutic approaches.

Inflammatory stimuli result in the production of cutaneous eicosanoids, which are known to contribute to the process of tumor promotion. Cyclooxygenase (COX), the rate-limiting enzyme for the production of prostaglandins (PG) from arachidonic acid, exists in at least two isoforms, COX-1 and COX-2. COX-1 is constitutively expressed in most tissues and plays various physiological roles, whereas increased COX-2 expression is known to occur in several types of epithelial neoplasms. Enhanced PG synthesis is a potential contributing factor in UVB-induced nonmelanoma skin cancers (NMSC). Increased COX-2 staining occurs in murine skin neoplasms after chronic exposure to carcinogenic doses of UVB. In this study, immunohistochemical and Western blot analyses were employed to assess longitudinally COX-2 expression in a standard mouse UVB complete carcinogenesis protocol and in human basal cell carcinomas (BCC) and squamous cell carcinomas (SCC). During UVB irradiation of mice, COX-2 expression consistently increased in the hyperplastic skin, the benign papillomas and the SCC. COX-2 expression was also increased in human actinic keratoses, SCC and BCC as well as in murine SCC and BCC. The pattern of COX-2 expression was quite variable, occurring in a patchy distribution in some lesions with staining confined mainly to suprabasal cell layers. In general, COX-2 expression progressively became more extensive in benign papillomas and well-differentiated murine SCC. The staining was predominantly cytoplasmic and perinuclear in some focal areas in tissue stroma around both murine and human tumors. Western blot analysis confirmed negative COX-2 expression in normal skin, whereas acute UVB exposure resulted in increased enzyme expression, which continued to increase in developing papillomas and SCC. Because of the evidence indicating a pathogenic role for eicosanoids in murine and human skin neoplasms, we performed studies to assess the anti-inflammatory and anticarcinogenic effects of green tea extracts, which are potent antioxidants. Acute exposure of the human skin to UVB (minimum erythema dose x 4) caused a transient enhancement of the COX-2 expression, which reverted to baseline within hours; however, in murine skin the expression persisted for several days. Pretreatment with the topically applied green tea extract (1 mg/cm2) largely abrogated the acute COX-2 response to UVB in mice or humans. In summary, enhanced COX-2 expression serves as a marker of epidermal UVB exposure for murine and human NMSC. These results suggest that COX-2 inhibitors could have potent anticarcinogenic effects in UVB-induced skin cancer.

Adult↗
PubMed2002

A high-efficiency translational control element with potential for cancer gene therapy.

An active internal ribosome entry sequence (IRES) that efficiently mediates cap (m7pppGN)-independent translation in human carcinoma cells could be an effective device for gene co-transduction in cancer gene therapy. In this study using the cytomegalovirus (CMV) promoter, a remarkable internal translation activity was observed and mediated by the sequence localized to the 183-653 region of 5' NF-kappaB repressor mRNA (NFR183IRES). To test the potential of such sequence for therapeutic application, we carried out in vitro functional assays using the dicistronic constructs that internally expressed human PTEN tumor suppressor. The PTEN expression mediated by NFR183IRES was found to result in growth inhibition of carcinoma cells more effectively than the expression by NFR1IRES that contained the 1-653 region. When compared to the internal translation driven by the picornaviral IRES element of the encephalomyocarditis virus (EMCV) or the foot-and-mouth disease virus (FMDV), NFR183IRES consistently exhibited a higher activity in the human carcinoma cells, HeLa, LNCaP and MCF7. Such high-efficiency translational control element may prove useful for cancer gene therapy.

5' Untranslated Regions↗
PubMedDate not supplied

Photochemoprevention by botanical antioxidants.

The trend towards an increase in incidence and higher prevalence of skin cancer makes identification of effective chemopreventive agents an urgent priority. Excessive exposure to solar ultraviolet (UV) B radiation has been implicated as its main cause. Since these trends are likely to continue in the foreseeable future, the adverse effect of UVB has become a major human health concern. Therefore, the development of novel strategies to reduce the occurrence of skin cancer has become a highly desirable goal. Because UV radiation is known to cause excessive generations of reactive oxygen species (ROS) which in turn results in a situation known as oxidative stress, the approaches aimed at counteracting ROS production may be useful for the prevention of skin cancer. One approach to reduce its occurrence is through 'photochemoprotection', which we define as 'the use of agents capable of ameliorating the adverse effects of UVB on the skin'. Among many photochemoprotective agents, botanical antioxidants are showing promise. This review focuses on photochemopreventive effects of selected botanical antioxidants. We suggest that the use of botanical antioxidants in combination with the use of sunscreens and educational efforts to avoid excessive sun exposure may be an effective strategy for reducing incidence of skin cancer and other UV-mediated damages in humans.

Animals↗
PubMedDate not supplied

Pomegranate fruit extract modulates UV-B-mediated phosphorylation of mitogen-activated protein kinases and activation of nuclear factor kappa B in normal human epidermal keratinocytes paragraph sign.

Excessive exposure of solar ultraviolet (UV) radiation, particularly its UV-B component, to humans causes many adverse effects that include erythema, hyperplasia, hyperpigmentation, immunosuppression, photoaging and skin cancer. In recent years, there is increasing use of botanical agents in skin care products. Pomegranate derived from the tree Punica granatum contains anthocyanins (such as delphinidin, cyanidin and pelargonidin) and hydrolyzable tannins (such as punicalin, pedunculagin, punicalagin, gallagic and ellagic acid esters of glucose) and possesses strong antioxidant and anti-inflammatory properties. Recently, we have shown that pomegranate fruit extract (PFE) possesses antitumor promoting effects in a mouse model of chemical carcinogenesis. To begin to establish the effect of PFE for humans in this study, we determined its effect on UV-B-induced adverse effects in normal human epidermal keratinocytes (NHEK). We first assessed the effect of PFE on UV-B-mediated phosphorylation of mitogen-activated protein kinases (MAPK) pathway in NHEK. Immunoblot analysis demonstrated that the treatment of NHEK with PFE (10-40 microg/mL) for 24 h before UV-B (40 mJ/cm(2)) exposure dose dependently inhibited UV-B-mediated phosphorylation of ERKl/2, JNK1/2 and p38 protein. We also observed that PFE (20 microg/mL) inhibited UV-B-mediated phosphorylation of MAPK in a time-dependent manner. Furthermore, in dose- and time-dependent studies, we evaluated the effect of PFE on UV-B-mediated activation of nuclear factor kappa B (NF-kappaB) pathway. Using Western blot analysis, we found that PFE treatment of NHEK resulted in a dose- and time-dependent inhibition of UV-B-mediated degradation and phosphorylation of IkappaBalpha and activation of IKKalpha. Using immunoblot analysis, enzyme-linked immunosorbent assay and electrophoretic mobility shift assay, we found that PFE treatment to NHEK resulted in a dose- and time-dependent inhibition of UV-B-mediated nuclear translocation and phosphorylation of NF-kappaB/p65 at Ser(536). Taken together, our data shows that PFE protects against the adverse effects of UV-B radiation by inhibiting UV-B-induced modulations of NF-kappaB and MAPK pathways and provides a molecular basis for the photochemopreventive effects of PFE.

Cells, Cultured↗
PubMedDate not supplied

Photochemopreventive effect of pomegranate fruit extract on UVA-mediated activation of cellular pathways in normal human epidermal keratinocytes.

UVA is the major portion (90-99%) of solar radiation reaching the surface of the earth and has been described to lead to formation of benign and malignant tumors. UVA-mediated cellular damage occurs primarily through the release of reactive oxygen species and is responsible for immunosuppression, photodermatoses, photoaging and photocarcinogenesis. Pomegranate fruit extract (PFE) possesses strong antioxidant and anti-inflammatory properties. Our recent studies have shown that PFE treatment of normal human epidermal keratinocytes (NHEK) inhibits UVB-mediated activation of MAPK and NF-kappaB pathways. Signal transducers and activators of transcription 3 (STAT3), Protein Kinase B/AKT and Map Kinases (MAPKs), which are activated by a variety of factors, modulate cell proliferation, apoptosis and other biological activities. The goal of this study was to determine whether PFE affords protection against UVA-mediated activation of STAT3, AKT and extracellular signal-regulated kinase (ERK1/2). Immunoblot analysis demonstrated that 4 J/cm2 of UVA exposure to NHEK led to an increase in phosphorylation of STAT3 at Tyr705, AKT at Ser473 and ERK1/2. Pretreatment of NHEK with PFE (60-100 microg/mL) for 24 h before exposure to UVA resulted in a dose-dependent inhibition of UVA-mediated phosphorylation of STAT3 at Tyr705, AKT at Ser473 and ERK1/2. mTOR, structurally related to PI3K, is involved in the regulation of p70S6K, which in turn phosphorylates the S6 protein of the 40S ribosomal subunit. We found that UVA radiation of NHEK resulted in the phosphorylation of mTOR at Thr2448 and p70S6K at Thr421/Ser424. PFE pretreatment resulted in a dose-dependent inhibition in the phosphorylation of mTOR at Thr2448 and p70S6K at Thr421/Ser424. Our data further demonstrate that PFE pretreatment of NHEK resulted in significant inhibition of UVA exposure-mediated increases in Ki-67 and PCNA. PFE pretreatment of NHEK was found to increase the cell-cycle arrest induced by UVA in the G1 phase of the cell cycle and the expression of Bax and Bad (proapoptotic proteins), with downregulation of Bcl-X(L) expression (antiapoptotic protein). Our data suggest that PFE is an effective agent for ameliorating UVA-mediated damages by modulating cellular pathways and merits further evaluation as a photochemopreventive agent.

Anti-Inflammatory Agents, Non-Steroidal↗