Myricetin: targeting signaling networks in cancer and its implication in chemotherapy.

The gaps between the complex nature of cancer and therapeutics have been narrowed down due to extensive research in molecular oncology. Despite gathering massive insight into the mysteries of tumor heterogeneity and the molecular framework of tumor cells, therapy resistance and adverse side effects of current therapeutic remain the major challenge. This has shifted the attention towards therapeutics with less toxicity and high efficacy. Myricetin a natural flavonoid has been under the spotlight for its anti-cancer, anti-oxidant, and anti-inflammatory properties. The cutting-edge molecular techniques have shed light on the interplay between myricetin and dysregulated signaling cascades in cancer progression, invasion, and metastasis. However, there are limited data available regarding the nano-delivery platforms composed of myricetin in cancer. In this review, we have provided a comprehensive detail of myricetin-mediated regulation of different cellular pathways, its implications in cancer prevention, preclinical and clinical trials, and its current available nano-formulations for the treatment of various cancers.

Pb induced mitochondrial fission of fibroblast cells via ATM activation.

Previous study showed that lead (Pb) could induce ATM-dependent mitophagy. However, whether Pb has any impact on mitochondrial fusion and fission, the upstream events of mitophagy, and how ATM connects to these processes remain unclear. In this study, we found that Pb can disrupt mitochondrial network morphology as indicated by increased percentage of shortened mitochondria and by decreased mitochondrial footprints. Correspondingly, the expression of fission protein Drp1 and its association with mitochondrial marker Hsp60 were significantly increased, while those of fusion proteins Mfn2 and Opa1 and their co-localization with Hsp60 were drastically attenuated. Notably, the expression of p-Drp1 (Ser616) and its translocation to mitochondria were dramatically elevated. Moreover, a small amount of ATM could be detected in the cytoplasm around mitochondria in response to Pb, and the co-localization of p-ATM (Ser1981) with Drp1 and p-Drp1 (Ser616) was obviously increased while its co-localization with Mfn2 and Opa1 was dramatically decreased. Furthermore, siRNA silencing of ATM evidently promoted greater fission in response to Pb stress, indicating that ATM is involved in mitochondrial fragmentation. Our results suggest that cytoplasmic ATM is an important regulator of Pb-induced mitochondrial fission.

High temperature induced masculinization of zebrafish by down-regulation of sox9b and esr1 via DNA methylation.

Elevated temperature could influence the sex differentiation by altering the expression of sex-related genes in fish. However, the underlying mechanisms by which the gene expression is altered remain poorly understood. Here, we aimed to explore the role of DNA methylation in sex differentiation of zebrafish (Danio rerio) in response to elevated temperature. The results showed that high temperature (33°C) exposure of fish from 20 to 30 days post fertilization (dpf), compared to normal temperature (28°C), resulted in male-biased sex ratio and decreased expression of female-related genes including cyp19a1a, sox9b and esr1. Meanwhile, the expressions of DNA methyltransferases dnmt3a1 and dnmt3a2, and the DNA methylation levels in sox9b and esr1 promoter were significantly increased by high temperature, strongly implying that DNA methylation is involved in high temperature-induced masculinization of zebrafish. Co-treatment with 5-aza-2'-deoxycytidine (a DNA methylation inhibitor) attenuated the high temperature-induced masculinizing effect, recovered the expression of esr1 and sox9b, suppressed the transcription of dnmt3a1 and dnmt3a2, and decreased the methylation of esr1 and sox9b promoter, further confirming that DNA methylation plays an important role in high temperature-induced masculinization of zebrafish. Furthermore, the methylation of sox9b promoter decreased the enrichment of transcription factor CREB (cAMP-responsive element binding proteins). Overall, these findings suggest that high temperature induce masculinization of zebrafish by down-regulation of female-related genes via DNA methylation, providing a new insight in understanding the epigenetic mechanism of thermal-mediated sex differentiation in fish.

Genistein as a regulator of signaling pathways and microRNAs in different types of cancers.

Cancers are complex diseases orchestrated by a plethora of extrinsic and intrinsic factors. Research spanning over several decades has provided better understanding of complex molecular interactions responsible for the multifaceted nature of cancer. Recent advances in the field of next generation sequencing and functional genomics have brought us closer towards unravelling the complexities of tumor microenvironment (tumor heterogeneity) and deregulated signaling cascades responsible for proliferation and survival of tumor cells. Phytochemicals have begun to emerge as potent beneficial substances aimed to target deregulated signaling pathways. Isoflavonoid genistein is an essential phytochemical involved in regulation of key biological processes including those in different types of cancer. Emerging preclinical evidence have shown its anti-cancer, anti-inflammatory and anti-oxidant properties. Testing of this substance is in various phases of clinical trials. Comprehensive preclinical and clinical trials data is providing insight on genistein as a modulator of various signaling pathways both at transcription and translation levels. In this review we have explained the mechanistic regulation of several key cellular pathways by genistein. We have also addressed in detail various microRNAs regulated by genistein in different types of cancer. Moreover, application of nano-formulations to increase the efficiency of genistein is also discussed. Understanding the pleiotropic potential of genistein to regulate key cellular pathways and development of efficient drug delivery system will bring us a step towards designing better chemotherapeutics.

The role of endoplasmic reticulum stress in lead (Pb)-induced mitophagy of HEK293 cells.

It is well-documented that lead (Pb) toxicity can affect almost all systems in living organisms. It can induce selective autophagy of mitochondria (mitophagy) by triggering reactive oxygen species production. Emerging evidence has suggested that Pb-induced autophagy can also be activated by the endoplasmic reticulum (ER) stress pathway. However, the interplay between ER stress and mitophagy remains to be elucidated. In this study, human embryonic kidney HEK293 cells were employed to investigate the role of ER stress in Pb-induced mitophagy. The results showed that the cell viability was decreased and cell damage was induced after exposure to Pb (0, 0.5, 1, 2, and 4 mM) for 24 h in a dose-dependent manner. Moreover, the expression of LC3-Ⅱ was significantly increased, and the expression of HSP60 was dramatically decreased after exposure to 1 mM and 2 mM Pb, indicating the induction of mitophagy following Pb exposure. Meanwhile, the expressions of activating transcription factor 6, inositol-requiring protein-1α, CCAAT/enhancer binding protein homologous protein, and glucose-regulated protein 78 were dramatically increased after Pb treatment, signifying the initiation of ER stress. Notably, the mitophagic effect was significantly compromised when ER stress was inhibited by 0.5 mM 4-phenylbutyrate, which was evidenced by lesser decreases in HSP60 expression and level of LC3-Ⅱ, suggesting Pb-induced mitophagy may be activated by the ER stress. Taken together, these findings provide a better understanding of Pb toxicity and suggest that Pb-induced ER stress may play a regulatory role in the upstream of mitophagy.

NIX compensates lost role of parkin in cd-induced mitophagy in HeLa cells through phosphorylation.

Our previous study demonstrated that cadmium (Cd) is an effective inducer of mitophagy, which is mainly mediated by PINK1/Parkin pathway. However, the role of other mitophagy pathways in Cd-induced mitophagy remains elusive. The present study employed HeLa cells, lacking fully functional Parkin, as a cell model to study Parkin-independent mitophagy pathway induced by Cd. Our results showed that BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like (Bnip3L/NIX), an outer mitochondrial membrane mitophagy receptor, could provide an alternate pathway for Cd-induced mitophagy in HeLa cells. Specifically, 10 µM Cd for 12 h induced mitophagy in GM00637 and HeLa cells which was assessed by mitochondrial fusion to lysosomes and decreased expression of mitochondrial markers such as COX-IV and HSP60. Notably, in GM00637 cells, Cd-induced mitophagy was predominantly mediated by PINK1/Parkin pathway as evinced by translocation of Parkin to mitochondria. Interestingly, in HeLa cells, significant increase in NIX expression was occurred and mitophagy was induced under Cd exposure, suggesting NIX compensates lost role of Parkin in Cd-induced mitophagy in HeLa cells. These results were verified by knocking down NIX using siRNA in HeLa cells, which lead to abolished mitophagy process. Moreover, NIX phosphorylation at serine-81 significantly increased in cells treated with Cd implying that phosphorylation of NIX plays an important role in NIX-mediated mitophagy. These findings reveal a novel mechanism of Cd toxicity and suggest a compensatory role of NIX in Cd-induced mitophagy.

Comparison Of Solubility And Water Sorption Of Two Different Soft Lining Material.

BACKGROUND: Soft denture lining materials play a very important role in Removable Prosthodontics because of their ability to provide a cushioning effect for maintaining the health of traumatized, swollen and deformed mucosa through absorption and equal redistribution of stresses over the entire area covered by denture, thus eliminating the distortion of oral mucosa. The objective of this investigation is to quantify and relate the mean solubility and water sorption of acrylic resin based permanent soft liner with a silicone based permanent soft liner. METHODS: Two different permanent soft denture liners, i.e., acrylic and silicone based are selected for this study, 30 samples of each material are prepared in the form of circular disks of the 30 disks, and three subgroups of ten disks each are made for the two materials. Initially the processed disks will be weighed 3 times daily with an analytical balance until a constant weight is achieved. This initial weight of each specimen is denoted by W1. Each subgroup of 10 specimens is immersed in 250 ml of 37 °C distilled water in a sealed polyethylene container. First subgroup is tested after 1 week, second after 4 weeks and third after 6 weeks of immersion. RESULTS: Ever soft has higher solubility (1.67mg/cm2 ±0.26 mg/cm2laboratory-processed) and sorption (0.84 mg/cm2 ±0.35 mg/cm2laboratory-processed) than Molloplast B (0.40 mg/cm2 ±0.08 mg/cm2solubility and 0.27 mg/cm2 ±0.16 mg/cm2 sorption) after 6 weeks of immersion. CONCLUSIONS: It is therefore concluded that Molloplast B may provide better clinical success based on its lower solubility and water sorption.

Temporal variations and spatial distributions of heavy metals in a wastewater-irrigated soil-eggplant system and associated influencing factors.

Heavy metal pollution in farmlands is highly concerned as crops' easy-uptake of heavy metal can ultimately affect consumers. In order to offer suggestions on cultivating safe quality vegetable, specifically eggplant which is widely consumed for its nutritional value and antioxidant activity, a field study was undertaken to investigate the temporal variations and spatial distributions of heavy metals in a wastewater-irrigated soil-eggplant system. In the present study, eggplants were planted in the farmlands of Weichuan village (WC) (relatively unpolluted field), Liangzhuang village (LZ) (moderately polluted field) and Minqin village (MQ) (seriously polluted field) to elucidate their temporal uptake processes of heavy metals described by the sigmoid model. Eggplant tissues from severely polluted farmlands were found with higher heavy metal concentrations and lower yields compared with other two groups. What is more, 25 farmlands along the Dongdagou stream (heavy metals polluted stream) were chosen to analyze the spatial distribution of heavy metals in soils and eggplants. Heavy metal concentrations in eggplants decreased with the decline of heavy metal concentrations in soil from upstream (pollution source) to downstream. Moreover, several methods were employed to assess bioavailability of heavy metals in soils. All the bioavailable heavy metals were found in linear positive correlations with heavy metal concentrations. Meanwhile, linear correlations were found between heavy metals in soils and eggplants. At last, redundancy analysis was used to investigate the effects of soil properties (pH, organic matter and texture of soils) and heavy metals on eggplants' uptake. The results indicated that soil heavy metals had a dominant impact on their accumulations in eggplant fruit, with a variance contribution of 78.0%, while soil properties had a regulatory effect, with a variance contribution of 5.2%.

Label-free proteomic analysis of intestinal mucosa proteins in common carp (Cyprinus carpio) infected with Aeromonas hydrophila.

Outbreaks of infectious diseases in common carp Cyprinus carpio, a major cultured fish in northern regions of China, constantly result in significant economic losses. Until now, information proteomic on immune defence remains limited. In the present study, a profile of intestinal mucosa immune response in Cyprinus carpio was investigated after 0, 12, 36 and 84 h after challenging tissues with Aeromonas hydrophila at a concentration of 1.4 × 108 CFU/mL. Proteomic profiles in different samples were compared using label-free quantitative proteomic approach. Based on MASCOT database search, 1149 proteins were identified in samples after normalisation of proteins. Treated groups 1 (T1) and 2 (T2) were first clustered together and then clustered with control (C group). The distance between C and treated group 3 (T3) represented the maxima according to hierarchical cluster analysis. Therefore, comparative analysis between C and T3 was selected in the following analysis. A total of 115 proteins with differential abundance were detected to show conspicuous expressing variances. A total of 52 up-regulated proteins and 63 down-regulated proteins were detected in T3. Gene ontology analysis showed that identified up-regulated differentially expressed proteins in T3 were mainly localised in the hemoglobin complex, and down-regulated proteins in T3 were mainly localised in the major histocompatibility complex II protein complex. Forty-six proteins of differential abundance (40% of 115) were involved in immune response, with 17 up-regulated and 29 down-regulated proteins detected in T3. This study is the first to report proteome response of carp intestinal mucosa against A. hydrophila infection; information obtained contribute to understanding defence mechanisms of carp intestinal mucosa.

The toxic effects of chlorophenols and associated mechanisms in fish.

Chlorophenols (CPs) are ubiquitous contaminants in the environment primarily released from agricultural and industrial wastewater. These compounds are not readily degraded naturally, and easily accumulate in organs, tissues and cells via food chains, further leading to acute and chronic toxic effects on aquatic organisms. Herein, we review the available literature regarding CP toxicity in fish, with special emphasis on the potential toxic mechanisms. CPs cause oxidative stress via generation of reactive oxygen species, induction of lipid peroxidation and/or oxidative DNA damage along with inhibition of antioxidant systems. CPs affect immune system by altering the number of mature B cells and macrophages, while suppressing phagocytosis and down-regulating the expression of immune factors. CPs also disrupt endocrine function by affecting hormone levels, or inducing abnormal gene expression and interference with hormone receptors. CPs at relatively higher concentrations induce apoptosis via mitochondria-mediated pathway, cell death receptor-mediated pathway, and/or DNA damage-mediated pathway. CPs at relatively lower concentrations promote cell proliferation, and foster cancers-prone environment by increasing the rate of point mutations and oxidative DNA lesions. These toxic effects in fish are induced directly by CPs per se or indirectly by their metabolic products. In addition, recent studies on the alteration of DNA methylation by CPs through high-throughput DNA sequencing analysis provide new insights into our understanding of the epigenetic mechanisms underlying CPs toxicity.

A field study on the dynamic uptake and transfer of heavy metals in Chinese cabbage and radish in weak alkaline soils.

Vegetables and crops can take up heavy metals when grown on polluted lands. The concentrations and dynamic uptake of heavy metals vary at different growth points for different vegetables. In order to assess the safe consumption of vegetables in weak alkaline farmlands, Chinese cabbage and radish were planted on the farmlands of Baiyin (polluted site) and Liujiaxia (relatively unpolluted site). Firstly, the growth processes of two vegetables were recorded. The growth curves of the two vegetables observed a slow growth at the beginning, an exponential growth period, and a plateau towards the end. Maximum concentrations of copper (Cu), zinc (Zn), lead (Pb), and cadmium (Cd) were presented at the slow growth period and showed a downtrend except the radish shoot. The concentrations of heavy metals (Cu, Zn, and Cd) in vegetables of Baiyin were higher than those of Liujiaxia. In the meanwhile, the uptake contents continued to increase during the growth or halted at maximum at a certain stage. The maximum uptake rates were found on the maturity except for the shoot of radish which took place at the exponential growth stages of root. The sigmoid model could simulate the dynamic processes of growth and heavy metals uptake of Chinese cabbage and radish. Conclusively, heavy metals have higher bioaccumulation tendency for roots in Chinese cabbage and for shoots in radish.

Relationship of the inter-condylar width with mandibular inter-canine width.

BACKGROUND: Aesthetic tooth selection and physiological tooth arrangement are the objectives of the complete denture fabrications. The objective of this study was to determine the relationship of the intercondylar width with mandibular inter-canine width. METHODS: This cross-sectional comparative study was conducted in Department of Prosthodontics, Lahore Medical and Dental College, Lahore from January to June 2011. A total of 250 dentate subjects were selected according to the inclusion criteria. Maxillary and mandibular arch impressions were taken. The distance between the cusp tips of mandibular canines was measured by using vernier calliper. The intercondylar width was measured using arbitrary face bow. The width between the two condylar rods was measured with vernier calliper in millimetres. Every width was measured three times by the same operator to ensure the accuracy. Data recorded on the Performa for statistical analysis. RESULT: Pearson correlation coefficients (r) for the inter condylar width and mandibular inter-canine are showing positive correlation and significant (r = 0.24, p = 0.005). CONCLUSIONS: Inter-condylar width provides significant measurements for the selection of anterior teeth in edentulous patients.