HPV16-positive cervical cancer lesions contain NFκB–ERα nuclear complexes to repress the TLR9 promoter.

Humans have been using natural products for medicinal use for ages. Natural products of therapeutic importance are compounds derived from plants, animals, or any microorganism. Ginger is also one of the most commonly used condiments and a natural drug in vogue. It is a traditional medicine, having some active ingredients used for the treatment of numerous diseases. During recent research on ginger, various ingredients like zingerone, shogaol, and paradol have been obtained from it. Zingerone (4-(4-hydroxy-3-methoxyphenyl)-2-butanone) is a nontoxic and inexpensive compound with varied pharmacological activities. It is the least pungent component of Zingiber officinale. Zingerone is absent in fresh ginger but cooking or heating transforms gingerol to zingerone. Zingerone closely related to vanillin from vanilla and eugenol from clove. Zingerone has potent anti-inflammatory, antidiabetic, antilipolytic, antidiarrhoeic, antispasmodic, and so forth properties. Besides, it displays the property of enhancing growth and immune stimulation. It behaves as appetite stimulant, anxiolytic, antithrombotic, radiation protective, and antimicrobial. Also, it inhibits the reactive nitrogen species which are important in causing Alzheimer's disease and many other disorders. This review is written to shed light on the various pharmacological properties of zingerone and its role in alleviating numerous human and animal diseases.

⌬Np73␣, a dominant-negative inhibitor of p53 and p73, exhibits antiapoptotic and transforming activity in in vitro models and is often found to be upregulated in human cancers. The mechanisms involved in the regulation of ⌬Np73␣ protein levels in normal and cancer cells are poorly characterized. Here, we show that that IB kinase beta (IKK␤) increases ⌬Np73␣ protein stability independently of its ability to activate NF-B. IKK␤ associates with and phosphorylates ⌬Np73␣ at serine 422 (S422), leading to its accumulation in the nucleus, where it binds and represses several p53-regulated genes. S422A mutation in ⌬Np73␣ abolished IKK␤-mediated stabilization and inhibition of p53-regulated gene expression. Inhibition of IKK␤ activity by chemical inhibitors, overexpression of dominant-negative mutants, or gene silencing by siRNA also resulted in ⌬Np73␣ destabilization, which under these conditions was rapidly translocated into the cytoplasm and degraded by a calpain-mediated mechanism. We also present evidence for the IKK␤ and ⌬Np73␣ cross talk in cancer-derived cell lines and primary cancers. Our data unveil a new mechanism involved in the regulation of the p73 and p53 network.p53 and its family members, p63 and p73, are transcription factors that play an important role in the regulation of the cell cycle, apoptosis, and cancer development (4, 23). All three proteins show similarity in the amino acid sequences of their N-terminal transcription activation (TA), DNA binding, and oligomerization domains. p73 and p53 are also functionally related, since they have the ability to bind a similar set of p53 regulatory elements (REs) (16). Both proteins are functionally regulated by posttranslational modifications, and p73 appears to be subject to more complex regulatory mechanisms than p53 at transcriptional level. The p73 gene is expressed as multiple isoforms that differ in their N and/or C terminus. The generation of different transcripts of p73 involves the use of two distinct promoters (P1 and P2) and/or alternative splicing. The mRNA of the full-length p73 isoform (TAp73) is transcribed by the P1 promoter located upstream of exon 1, while an isoform called ⌬Np73 is generated by using the P2 promoter in intron 3 (P2). Three additional ⌬ isoforms, ⌬NЈp73, ⌬Ex2p73, and ⌬Ex2/3p73, arise from alternative splicing of the transcripts originating from the first exons. All ⌬N isoforms lack the TA domain located at the N terminus (exons 2 and 3). Multiple splicing of exons 10 to 14 generate additional TA and

Colon cancer is a world-wide health problem and one of the most dangerous type of cancer, affecting both men and women. Naringenin (4, 5, 7-trihydroxyflavanone) is one of the major flavone glycoside present in citrus fruits. Naringenin has long been used in Chinese's traditional medicine because of its exceptional pharmacological properties and non-toxic nature. In the present study, we investigated the chemopreventive potential of Naringenin against 1,2-dimethyhydrazine (DMH)-induced precancerous lesions, that is, aberrant crypt foci (ACF) and mucin depleted foci (MDF), and its role in regulating the oxidative stress, inflammation and hyperproliferation, in the colon of Wistar rats. Animals were divided into five groups. In groups 3-5, Naringenin was administered at the dose of 50 mg/kg b. wt. orally while in groups 2-4, DMH was administered subcutaneously in the groin at the dose of 20 mg/kg b. wt. once a week for first 5 weeks and animals were euthanized after 10 weeks. Administration of Naringenin ameliorated the development of DMH-induced lipid peroxidation, ROS formation, precancerous lesions (ACF and MDF) and it also reduced the infiltration of mast cells, suppressed the immunostaining of NF-κB-p65, COX-2, i-NOS PCNA and Ki 67 Naringenin treatment significantly attenuated the level of TNF-α and it also prevented the depletion of the mucous layer. Our findings suggest that Naringenin has strong chemopreventive potential against DMH-induced colon carcinogenesis but further studies are warranted to elucidate the precise mechanism of action of Naringenin.

Nadeem M., Abdullah M., Hussain I., Inayat S., Javid A., Zahoor Y. (2013): Antioxidant potential of Moringa oleifera leaf extract for the stabilisation of butter at refrigeration temperature. Czech J. Food Sci., 31: 332-339.The antioxidant potential of a leaf extract of Moringa oleifera Lam. (Moringaceae) -LEMO was studied for the stabilisation of butter at refrigeration temperature. LEMO was obtained by extracting the ground and dried leaves with 80% ethanol at room temperature for 48 hours. LEMO was added into butter at three different concentrations, i.e. 400 ppm (T 1 ), 600 ppm (T 2 ), and 800 ppm (T 3 ) and compared with a treatment which was not supplemented with LEMO, i.e. control (T 0 ). The addition of LEMO at all three levels did not have any effect on butter composition. Free fatty acids, peroxide value and p-anisidine value (AnV) of T 2 after 90 days of storage were 0.10%, 0.71 meq/kg and 14.85 as compared to the control 0.16%, 1.24 meq/kg and 28.85, respectively. Peroxide value of the control and T 2 in Schaal oven test after 5 days in oven was 8.19 and 2.99 meq/kg, respectively. Induction period and overall acceptability score of the control and T 2 were 6.35 h, 8.91 h and 7.6, 7.2, respectively. The results of this study suggest that LEMO at 600 ppm may be used for reasonable storage stability of butter at refrigeration temperate with acceptable sensory characteristics.

The DOK1 gene is a putative tumour suppressor gene located on the human chromosome 2p13 which is frequently rearranged in leukemia and other human tumours. We previously reported that the DOK1 gene can be mutated and its expression down-regulated in human malignancies. However, the mechanism underlying DOK1 silencing remains largely unknown. We show here that unscheduled silencing of DOK1 expression through aberrant hypermethylation is a frequent event in a variety of human malignancies. DOK1 was found to be silenced in nine head and neck cancer (HNC) cell lines studied and DOK1 CpG hypermethylation correlated with loss of gene expression in these cells. DOK1 expression could be restored via demethylating treatment using 5-aza-2′deoxycytidine. In addition, transduction of cancer cell lines with DOK1 impaired their proliferation, consistent with the critical role of epigenetic silencing of DOK1 in the development and maintenance of malignant cells. We further observed that DOK1 hypermethylation occurs frequently in a variety of primary human neoplasm including solid tumours (93% in HNC, 81% in lung cancer) and hematopoietic malignancy (64% in Burkitt’s lymphoma). Control blood samples and exfoliated mouth epithelial cells from healthy individuals showed a low level of DOK1 methylation, suggesting that DOK1 hypermethylation is a tumour specific event. Finally, an inverse correlation was observed between the level of DOK1 gene methylation and its expression in tumour and adjacent non tumour tissues. Thus, hypermethylation of DOK1 is a potentially critical event in human carcinogenesis, and may be a potential cancer biomarker and an attractive target for epigenetic-based therapy.

Diabetes is considered as the most common metabolic disease affecting millions of people all around the world. Use of natural herbal medicines can be effective in treating diabetes. Zingerone (4-(4-hydroxy-3-methylphenyl) butan-2-one) a polyphenolic alkanone extracted from ginger has a broad spectrum of pharmacological properties and thus can be used as a promising candidate against various ailments. In the current study we aimed at demonstrating the protective effect of zingerone against diabetes mellitus and elucidating its possible mechanism. Five groups of animals (I-V) were made with ten animals each. Group I (control) was given normal saline orally. Group II (diabetic positive control) was given alloxan at the dose rate of 100 mg/kg bwt once. Group III and IV was given alloxan once at the dose rate of 100 mg/kg bwt. and received oral treatment of zingerone at a dose rate of 50 and 100 mg/kg bwt respectively daily for 21 days. Group V was given alloxan at the dose of 100 mg/kg bwt. and was treated with standard drug glibenclamide at the dose rate of 4.5 mg/kg bwt. daily for 21 days. According to our findings we confirmed that zingerone restrained the alloxan induced oxidative stress by increasing the activity of reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) and reducing the peroxidative damage. We also confirmed that zingerone suppressed the level of redox sensitive transcription factor NFκB and downregulated other downstream inflammatory cytokines like interleukins (IL1-β IL-2, IL-6) and tumor necrosis factor alpha (TNF-α). Moreover, the experimental findings suggested that zingerone improved the insulin levels. Taken together our results indicated that zingerone effectively ameliorated the diabetes induced complications which provide a strong theoretical basis for zingerone to be used clinically for treatment of diabetes.

We previously reported that the oncoproteins E6 and E7 from cutaneous human papillomavirus type 38 (HPV38) can immortalize primary human keratinocytes in vitro and sensitize transgenic mice to develop skin cancer in vivo. Immunofluorescence staining revealed that human keratinocytes immortalized by HPV38 E6 and E7 display fewer actin stress fibers than do control primary keratinocyte cells, raising the possibility of a role of the viral oncoproteins in the remodeling of the actin cytoskeleton. In this study, we show that HPV38 E7 induces actin stress fiber disruption and that this phenomenon correlates with its ability to downregulate Rho activity. The downregulation of Rho activity by HPV38 E7 is mediated through the activation of the CK2-MEK-extracellular signal-regulated kinase (ERK) pathway. In addition, HPV38 E7 is able to induce actin fiber disruption by binding directly to eukaryotic elongation factor 1A (eEF1A) and abolishing its effects on actin fiber formation. Finally, we found that the downregulation of Rho activity by HPV38 E7 through the CK2-MEK-ERK pathway facilitates cell growth proliferation. Taken together, our data support the conclusion that HPV38 E7 promotes keratinocyte proliferation in part by negatively regulating actin cytoskeleton fiber formation through the CK2-MEK-ERK-Rho pathway and by binding to eEF1A and inhibiting its effects on actin cytoskeleton remodeling.Human papillomaviruses (HPVs) are double-stranded small DNA viruses, comprising more than 100 members, that are the causative agents of several human diseases, including cancers (25). According to their tropisms, HPVs are subdivided into mucosal and cutaneous types. High-risk mucosal HPV types, such as HPV type 16 (HPV16) and HPV18, are etiological agents of cervical cancer and other anogenital cancers (25). Their ability to induce cellular immortalization and transformation is attributed primarily to the viral oncoproteins E6 and E7 (20,25). While E6 prevents apoptosis by inducing the degradation of the tumor suppressor p53 through the proteasome system, E7 disrupts cell cycle regulation by inactivating pRb (20,25). In addition, HPV16 E6 and E7 alter several other cellular signaling pathways by interacting with a number of cellular proteins, enhancing their carcinogenic properties (20,38,39,41).A large subgroup of cutaneous HPV types belonging to the beta genus of the HPV phylogenetic tree has been proposed to be involved in the development of nonmelanoma skin cancer (NMSC), since they were isolated for the first time from patients suffering from a rare autosomal recessive genetic disorder called epidermodysplasia verruciformis (EV), characterized by susceptibility to beta HPV infection and NMSC development at sun-exposed anatomical regions (7). Subsequent epidemiological studies have also provided lines of evidence for a possible oncogenic role of beta HPV types in non-EV patients, including the healthy population and immunocompromised individuals, e.g., organ transplant recipients (7, 51).Our group has previously reported t...