Lipid droplets provide metabolic flexibility for cancer progression.

A hallmark of cancer cells is their remarkable ability to efficiently adapt to favorable and hostile environments. Due to a unique metabolic flexibility, tumor cells can grow even in the absence of extracellular nutrients or in stressful scenarios. To achieve this, cancer cells need large amounts of lipids to build membranes, synthesize lipid-derived molecules, and generate metabolic energy in the absence of other nutrients. Tumor cells potentiate strategies to obtain lipids from other cells, metabolic pathways to synthesize new lipids, and mechanisms for efficient storage, mobilization, and utilization of these lipids. Lipid droplets (LDs) are the organelles that collect and supply lipids in eukaryotes and it is increasingly recognized that the accumulation of LDs is a new hallmark of cancer cells. Furthermore, an active role of LD proteins in processes underlying tumorigenesis has been proposed. Here, by focusing on three major classes of LD-resident proteins (perilipins, lipases, and acyl-CoA synthetases), we provide an overview of the contribution of LDs to cancer progression and discuss the role of LD proteins during the proliferation, invasion, metastasis, apoptosis, and stemness of cancer cells.

Defensive-lipid droplets: Cellular organelles designed for antimicrobial immunity.

Microbes have developed many strategies to subvert host organisms, which, in turn, evolved several innate immune responses. As major lipid storage organelles of eukaryotes, lipid droplets (LDs) are an attractive source of nutrients for invaders. Intracellular viruses, bacteria, and protozoan parasites induce and physically interact with LDs, and the current view is that they "hijack" LDs to draw on substrates for host colonization. This dogma has been challenged by the recent demonstration that LDs are endowed with a protein-mediated antibiotic activity, which is upregulated in response to danger signals and sepsis. Dependence on host nutrients could be a generic "Achilles' heel" of intracellular pathogens and LDs a suitable chokepoint harnessed by innate immunity to organize a front-line defense. Here, we will provide a brief overview of the state of the conflict and discuss potential mechanisms driving the formation of the 'defensive-LDs' functioning as hubs of innate immunity.

The Multi-Kinase Inhibitor EC-70124 Is a Promising Candidate for the Treatment of FLT3-ITD-Positive Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Patients with AML harboring a constitutively active internal tandem duplication mutation (ITDMUT) in the FMS-like kinase tyrosine kinase (FLT3) receptor generally have a poor prognosis. Several tyrosine kinase/FLT3 inhibitors have been developed and tested clinically, but very few (midostaurin and gilteritinib) have thus far been FDA/EMA-approved for patients with newly diagnosed or relapse/refractory FLT3-ITDMUT AML. Disappointingly, clinical responses are commonly partial or not durable, highlighting the need for new molecules targeting FLT3-ITDMUT AML. Here, we tested EC-70124, a hybrid indolocarbazole analog from the same chemical space as midostaurin with a potent and selective inhibitory effect on FLT3. In vitro, EC-70124 exerted a robust and specific antileukemia activity against FLT3-ITDMUT AML primary cells and cell lines with respect to cytotoxicity, CFU capacity, apoptosis and cell cycle while sparing healthy hematopoietic (stem/progenitor) cells. We also analyzed its efficacy in vivo as monotherapy using two different xenograft models: an aggressive and systemic model based on MOLM-13 cells and a patient-derived xenograft model. Orally disposable EC-70124 exerted a potent inhibitory effect on the growth of FLT3-ITDMUT AML cells, delaying disease progression and debulking the leukemia. Collectively, our findings show that EC-70124 is a promising and safe agent for the treatment of AML with FLT3-ITDMUT.

An evaluation of an array of viruses and fungi in adult Lebanese patients presenting with various dental infections: A cross-sectional study.

INTRODUCTION: The role of bacteria in the pathogenesis of periodontitis, pericoronitis, and periapical infections has been well-established. However, the variation in the severity and prognosis of these lesions could suggest a potential role of other microorganisms, such as viruses and fungi. This study aims to evaluate the presence of adenovirus, human papillomavirus-16, Epstein-Barr virus, Candida, and non-Candida fungi in these infections. METHODOLOGY: A cross-sectional study including 120 healthy adult patients presenting with dental infections requiring dental extractions were conducted to assess the prevalence and the relative quantity of viruses and fungi in saliva, infected, and healthy tissues using quantitative polymerase chain reaction tests. Samples were collected, and a categorical scale was used for the prevalence and a continuous scale for the relative quantification. Statistical analyses were performed using Chi-square for the prevalence and Wilcoxon rank test for the relative quantification. RESULTS: Except for the Epstein-Barr virus and Candida, the presence of viruses and fungi was significantly associated with dental infections. Adenovirus showed an association with pericoronitis, while human papilloma virus-16 exhibited an association with periapical infections. Non-Candida fungi, on the other hand, showed a positive association with all infected tissues and saliva as compared to healthy control lesions except for periapical infections. CONCLUSIONS: According to this study, viruses and fungi were found to be prevalent in dental infections. However, their associations with those infections vary depending on the types of viruses or fungi involved and the category of dental infections.

Characterizing the presence of neutrophil extracellular traps in neutrophilic dermatoses.

Neutrophil extracellular traps (NETs) are implicated in the pathogenesis of multiple inflammatory dermatoses. However, characterization of NETs in neutrophilic dermatoses was performed on very limited number of patients; this limitation precluded definitive conclusions. In this case series of 57 patients, we compared the amounts of neutrophils producing NETs in cutaneous lesions of different entities of neutrophilic dermatoses (17 with pyoderma gangrenosum, 37 with Sweet's syndrome and three with subcorneal pustular dermatosis). NETs were identified by double immunofluorescence on formalin-fixed paraffin-embedded skin biopsies using antibodies against elastase and citrullinated histone 3. Percentages of neutrophils showing NETs were high across all three entities (62.9% in PG, 48.5% in SS and 37.8% in subcorneal pustular dermatosis). The differences in mean percentages were significant between entities, with PG showing significantly superior percentage of NETs compared with SS. In our series, 15.8% of neutrophilic dermatoses were associated with malignancies, 10.5% with autoimmune diseases and 73.7% were idiopathic. Percentages of NETs were not statistically different between aetiologies. These findings suggest that NETs are abundantly produced in the various entities and different aetiologies of neutrophilic dermatoses. In comparison with SS, the superior percentage of NETs in PG is clinically mirrored in its greater ulceronecrotic nature.

Investigating the presence of neutrophil extracellular traps in septal and lobular cutaneous panniculitides.

BACKGROUND: Panniculitides are a heterogeneous group of inflammatory dermatoses involving the subcutaneous fatty tissue. Histologically, they are classified into septal and lobular panniculitis, according to the predominant localization of the inflammatory infiltrate. Neutrophils are frequently found in panniculitis, mainly at the early stages. Here, we investigated whether neutrophils contribute to various types of cutaneous panniculitis by releasing neutrophil extracellular traps (NETs). MATERIALS AND METHODS: Formalin-fixed paraffin-embedded skin biopsies from 25 patients with panniculitis were included in the study. Our cohort was divided into n = 10 erythema nodosum (septal panniculitis) and n = 15 lobular panniculitis, including n = 7 lupus panniculitis, n = 1 pancreatic panniculitis, n = 1 Weber-Christian disease, n = 1 deep fungal infection, n = 2 lipodermatosclerosis, and three cases did not have an identified etiology. The presence of neutrophils and NETs was assessed by double immunofluorescence using antibodies against elastase, a neutrophilic marker, and citrullinated histone 3, a marker of NETs. RESULTS: The mean percentages (±SEM) of elastase-positive neutrophils showing NETs were 44% ± 3% in erythema nodosum and 43% ± 7% in lobular panniculitis. The difference was not statistically significant and reflects the implication of NETs not only in severe scarring lobular panniculitis but also in benign non-scarring self-remitting reactive inflammation such as erythema nodosum. In tissues, NETs were located in the interlobular septa in erythema nodosum and in the inflamed fat lobules in lobular panniculitis. CONCLUSIONS: NETs are massively present in septal and lobular subtypes of panniculitides, suggesting their involvement in tissue damage.

Medicinal Plants Towards Modeling Skin Cancer.

Skin cancer remains a major cause of mortality worldwide. It can be divided into melanoma and non-melanoma cancer, which comprise mainly squamous cell carcinoma and basal cell carcinoma. Although conventional therapies have ameliorated the management of skin cancer, the search for chemopreventive compounds is still the most effective and safer strategy to treat cancer. Nowadays, chemoprevention is recognized as a novel approach to prevent or inhibit carcinogenesis steps with the use of natural products. Crude extracts of plants and isolated phytocompounds are considered chemopreventive agents since they harbor anti-inflammatory, antioxidant and anti-oncogenic properties against many types of diseases and cancers. In this review, we will discuss the therapeutic effect and preventive potential of selected medicinal plants used as crude extracts or as phytocompounds against melanoma and non-melanoma cutaneous cancers.

Comparative characterization of sun exposed and sun protected skin-derived mesenchymal-like stem cells in variegate porphyria and healthy individuals.

BACKGROUND AND PURPOSE: We hypothesized that upon sun exposure, a sub-population of primary skin-derived mesenchymal-like cells is deleteriously affected and thus contribute to the chronic inflammatory state in autosomal recessive variegate porphyria patients. The aim of this study was to isolate and characterize the mesenchymal-like stem cells from different areas of the skin in a porphyria patient (sun exposed, SE, and sun protected, SP) and to compare them with cells from a healthy individual. METHODS: The proliferation rate and the migration ability of SE and SP cells were evaluated in the presence of an antioxidant compound, N-acetylcysteine. A co-culture of SE-damaged cells with the conditioned medium from the enriched mesenchymal cell-like SP population was performed in order to regenerate the dermal injured tissue after sun exposure in patients. RESULTS: Results showed that the percentage of CD105+ cells varies between 3.9% in SP and 5% in SE of the healthy individual and between 3.6% and 1.4% in SP and SE in the porphyria patient, respectively. The osteogenic differentiation potential was lower in the porphyria patient when compared to the control. Furthermore, the expression of stem cell markers was more pronounced in SE than in SP cells of both control and porphyria. The use of N-acetyl cysteine did not show any beneficial effects on porphyria SE cells. Treatment with SP-conditioned medium slightly increased the expression of stem cell markers in SE of porphyria patient. CONCLUSION: In conclusion, the pool of mesenchymal stem-like SE cells is affected in variegate porphyria patient along with modification of their self-renewal and differentiation properties.

SuPAR, a potential inflammatory mediator in psoriasis pathogenesis.

Psoriasis is an inflammatory skin disorder that is strongly associated with the metabolic syndrome. The sole reliance on clinical examination to guide prognostication and treatment is insufficient at best; accurate diagnostic and prognostic psoriatic molecular biomarkers are needed. Soluble urokinase plasminogen activator receptor (suPAR) has been implicated in inflammation. The aim of this study is to determine whether suPAR plays a role in the pathogenesis of psoriasis and whether an association exists between suPAR levels, disease severity, and other variables like insulin, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). This study also compares the pattern of uPAR staining in healthy vs psoriatic skin: 39 psoriatic and 30 control subjects were included. Two biopsies (affected and unaffected skin) and one biopsy were taken from psoriasis patients and healthy controls, respectively, with uPAR staining of all skin biopsies. Blood samples from all subjects were obtained to determine suPAR, ESR, CRP, and fasting insulin levels. uPAR staining was prominent in unaffected skin from psoriasis patients and healthy individuals vs weak/absent uPAR staining in psoriatic skin. CRP, ESR and suPAR levels were not significantly elevated in the mild psoriasis group compared to healthy controls. The loss of epidermal uPAR is suggestive of its tentative role in the pathogenesis of psoriasis. Patients with mild-moderate psoriasis possibly lack the powerful association attributed to metabolic syndrome in psoriatic patients. Further studies on larger cohorts are needed to ascertain the validity of the mentioned conclusions.

A novel TRAF3IP2 variant causing familial scarring alopecia with mixed features of discoid lupus erythematosus and folliculitis decalvans.

Discoid lupus erythematosus (DLE) is an autoimmune disorder with a poorly defined etiology. Despite epidemiologic gender and ethnic biases, a clear genetic basis for DLE remains elusive. In this study, we used exome and RNA sequencing technologies to characterize a consanguineous Lebanese family with four affected individuals who presented with classical scalp DLE and generalized folliculitis. Our results unraveled a novel biallelic variant c.1313C > A leading to a missense substitution p.(Thr438Asn) in TRAF3IP2(NM_147200.3). Expression studies in cultured cells revealed mis-localization of the mutated protein. Functional characterization of the mutated protein showed significant reduction in the physical interaction with the interleukin 17-A receptor (IL17RA), while interaction with TRAF6 was unaffected. By conducting a differential genome-wide transcriptomics analysis between affected and non-affected individuals, we showed that the hair follicle differentiation pathway is drastically suppressed, whereas cytokine and inflammation responses are significantly upregulated. Furthermore, our results were highly concordant with molecular signatures in patients with DLE from a public dataset. In conclusion, this is the first report on a new putative role for TRAF3IP2 in the etiology of DLE. The identified molecular features associated with this gene could pave the way for better DLE-targeted treatment.

Comparative effect of sodium butyrate and sodium propionate on proliferation, cell cycle and apoptosis in human breast cancer cells MCF-7.

INTRODUCTION: Short-chain fatty acids (SCFAs) are ubiquitous lipids produced as a result of bacterial fermentation of dietary fiber. While their role in colorectal cancer is well known, the effect of SCFAs in breast cancer is poorly defined. OBJECTIVE: To understand the various effects of SCFAs on breast carcinogenesis, we investigated the effect of sodium butyrate (NaB) and sodium propionate (NaP) in MCF-7 cell line. MATERIALS AND METHODS: Cells were incubated with different concentrations of NaB or NaP for 24, 48, 72 or 96 h. Cell proliferation was assayed using MTT kit. Cell cycle was performed using propidium iodide staining then analyzed with a flow cytometer. Apoptosis was assessed by Hoechst technique and cell-cycle sub-G1 phase. RESULTS: NaB and NaP inhibited MCF-7 cell proliferation in a dose-dependent manner with respective IC50 of 1.26 mM and 4.5 mM, thus indicating that NaB is more potent than NaP. Low and medium levels of both SCFAs induced morphology changes which are characteristic of a differentiated phenotype. Flow cytometry analysis revealed a blockage in G1 growth phase. Interestingly, removing NaB or NaP from culture media after few days of treatment showed a reversible effect on cell morphology and proliferation where cells reentered the cycle after 24 h of drug wash-out. Finally, treatment with medium levels of these molecules induced low MCF-7 apoptosis, while higher doses led to massive apoptosis. CONCLUSION: Our results show that SCFAs may be considered as an interesting inhibitor for breast cancer progression.

Giant Inflatable Colon Model Enhances Lebanese Community Knowledge and Intention for Colorectal Cancer Screening.

PURPOSE: To assess the knowledge and intention for colorectal cancer (CRC) screening within the Lebanese community before and after a guided tour through an inflatable colon model. METHODS: The Cancer Prevention and Control Program, Naef K. Basile Cancer Institute at the American University of Beirut Medical Center in collaboration with AMALOUNA educational nongovernmental organization launched awareness campaigns during which a walk-through inflatable colon was displayed. Pre- and post-surveys related to the age of screening, risk factors, symptoms, and CRC prevention were collected anonymously before and after touring the inflatable colon to assess the effectiveness of this educational tool. RESULTS: Compiled data collected from 782 participants revealed that older age and higher education were predictors of favorable CRC screening knowledge and behaviors before entering the inflatable colon. Interestingly, touring the inflatable colon model significantly improved participants' awareness and knowledge about CRC. Most importantly, it increased their willingness for screening and social engagement and comfort discussing and promoting CRC screening. CONCLUSION: Overall, these results indicate that the interactive colon is an effective educational tool that can make a positive impact by improving the community CRC awareness and interest in CRC screening. They also highlight the importance of such educational efforts conducted in the community to create more awareness about CRC and emphasize the importance of its prevention.

Ferula hermonis: A Review of Current Use and Pharmacological Studies of its Sesquiterpene Ester Ferutinin.

Ferula hermonis Boiss, is an endemic plant of Lebanon, locally known as "shilsh Elzallouh". It has been extensively used in the traditional medicine as an aphrodisiac and for the treatment of sexual impotence. Crude extracts and isolated compounds of ferula hermonis contain phytoestrogenic substances having a wide spectrum of in vitro and in vivo pharmacological properties including anti-osteoporosis, anti-inflammatory, anti-microbial and anti-fungal, anti-cancer and as sexual activity enhancer. The aim of this mini-review is to highlight the traditional and novel applications of this plant's extracts and its major sesquiterpene ester, ferutinin. The phytochemical constituents and the pharmacological uses of ferula hermonis crude extract and ferutinin specifically will be discussed.

Neutrophil Extracellular Traps are Present in Immune-complex-mediated Cutaneous Small Vessel Vasculitis and Correlate with the Production of Reactive Oxygen Species and the Severity of Vessel Damage.

Formation of neutrophil extracellular traps has been implicated in autoimmunity. However, the presence and clinical relevance of neutrophil extracellular traps in immune-complex-mediated cutaneous small and medium vessel vasculitides has not been investigated. This study retrospectively analysed 72 patients with histology-proven hypersensitivity vasculitis (n = 21), IgA vasculitis (n = 22), urticarial vasculitis (n = 22), erythema elevatum diutinum (n = 3) and polyarteritis nodosa (n = 4). Neutrophil extracellular traps were detected in hypersensitivity vasculitis, IgA vasculitis, urticarial vasculitis and erythema elevatum diutinum, but not in polyarteritis nodosa lesions. Neutrophil extracellular traps were found around inflamed vessels, and their formation was highest early after the onset of vasculitis and decreased progressively thereafter. Neutrophil extracellular traps were strongly correlated with the histological severity of vasculitis and the production of reactive oxygen species. Both hypersensitivity vasculitis and IgA vasculitis showed significantly more neutrophil extracellular traps than did urticarial vasculitis, independent of the histological severity and duration of vasculitis. These results provide evidence on the implication of neutrophil extracellular traps in the early phases of immune-complex-mediated small vessel vasculitis.

Pannexin1 Is Associated with Enhanced Epithelial-To-Mesenchymal Transition in Human Patient Breast Cancer Tissues and in Breast Cancer Cell Lines.

Loss of connexin-mediated cell-cell communication is a hallmark of breast cancer progression. Pannexin1 (PANX1), a glycoprotein that shares structural and functional features with connexins and engages in cell communication with its environment, is highly expressed in breast cancer metastatic foci; however, PANX1 contribution to metastatic progression is still obscure. Here we report elevated expression of PANX1 in different breast cancer (BRCA) subtypes using RNA-seq data from The Cancer Genome Atlas (TCGA). The elevated PANX1 expression correlated with poorer outcomes in TCGA BRCA patients. In addition, gene set enrichment analysis (GSEA) revealed that epithelial-to-mesenchymal transition (EMT) pathway genes correlated positively with PANX1 expression. Pharmacological inhibition of PANX1, in MDA-MB-231 and MCF-7 breast cancer cells, or genetic ablation of PANX1, in MDA-MB-231 cells, reverted the EMT phenotype, as evidenced by decreased expression of EMT markers. In addition, PANX1 inhibition or genetic ablation decreased the invasiveness of MDA-MB-231 cells. Our results suggest PANX1 overexpression in breast cancer is associated with a shift towards an EMT phenotype, in silico and in vitro, attributing to it a tumor-promoting effect, with poorer clinical outcomes in breast cancer patients. This association offers a novel target for breast cancer therapy.

Loss of ferrochelatase is protective against colon cancer cells: ferrochelatase a possible regulator of the long noncoding RNA H19.

BACKGROUND: Ferrochelatase (FECH) is the last enzyme of the heme biosynthesis pathway. Deficiency in FECH was associated with many diseases, including protoporphyria. Correlation studies showed that variations of FECH expression was detected in human carcinomas and more specifically in colon cancer. Nevertheless, the potential role of FECH in colon cancer carcinogenesis in vitro was not depicted yet. METHODS: A small interfering RNA (siRNA) was used to knockdown FECH in human Caco-2 colon cancer cells. The effect of FECH down-regulation on the cellular proliferation, the migration and the expression of target genes was assessed in cancer cells and compared to human normal fibroblasts. RESULTS: Following FECH down-regulation, our results demonstrated that the proliferation of Caco-2 cells was not affected. Furthermore, the migration of cancer and normal cells was affected, only when an additional stress factor (H2O2) was applied to the medium. The expression of twist, snail, hypoxia induced factor (HIF-1α) and vascular endothelial growth factor (VEGF) was reduced in Caco-2 cells. Conversely, VEGF and HIF-1α expression were upregulated by up to 2 folds in control fibroblasts. Interestingly, the pro-carcinogenic long noncoding RNA (LncRNA) H19 was 70% down-regulated in Caco-2 cells upon FECH down regulation whereas no effect was observed in normal fibroblasts. CONCLUSIONS: In conclusion, we showed that loss of FECH is protective against colon cancer tumorigenesis in vitro and this effect could possibly be mediated through inhibition of H19.

Investigating the presence of neutrophil extracellular traps in cutaneous lesions of different subtypes of lupus erythematosus.

Neutrophil extracellular traps (NETs) are implicated in the pathogenesis of systemic lupus erythematosus (SLE). However, little is known about the implication of NETs in cutaneous lupus. In this case series of 30 patients, we compared the amounts of neutrophils producing NETs in cutaneous lesions of different subtypes of lupus (5 with discoid lupus or DLE, 5 with subacute cutaneous lupus or SCLE, 11 with acute cutaneous SLE, 7 with lupus panniculitis and 2 with chilblains). Immunofluorescence was performed on formalin-fixed paraffin-embedded skin biopsies using antibodies against neutrophilic granules (elastase, myeloperoxidase, PR-3 proteins and citrullinated histone 3). Dihydroethidium staining was performed to detect reactive oxygen species (ROS), known inducers of NETs. NETs were detected in the different subtypes of cutaneous lupus as well as in cutaneous lesions of SLE. The amounts of neutrophils producing NETs were significantly higher in lupus panniculitis (49%), acute cutaneous SLE (41%) and DLE (32%), in comparison with SCLE (5%) and chilblains (0%). This suggests that NETs might be associated with more tissue damage and scarring. ROS were observed in the different cutaneous subtypes of lupus independent of NETs.

Neutrophils contribute to vasculitis by increased release of neutrophil extracellular traps in Behçet's disease.

BACKGROUND AND OBJECTIVES: Behçet's disease (BD) is a multi-system inflammatory disorder that can cause vasculitis. Here we questioned whether Neutrophils in BD cause vasculitis via releasing Neutrophil Extracellular Traps (NETs), a process called NETosis. METHODS: Circulating neutrophils were isolated from a cohort of Middle Eastern BD patients with an active disease and healthy volunteers. The percentage of NETs release was monitored in neutrophils stimulated or not with BD serum, and treated or not with Colchicine, Dexamethasone, Cl-amidine or N-Acetyl Cysteine (NAC). The mRNA expression levels of PAD4 (a key enzyme in NETosis) was also assessed. The effect of NETs on the proliferation and cell death of endothelial cells was investigated using an in vitro co-culture model. The presence of NETs in skin tissues of BD patients was examined using immunolabeling of NETs associated proteins. RESULTS: Circulating Neutrophils from BD patients were more prone to release NETs in vitro and expressed higher levels of PAD4 compared to healthy volunteers. Spontaneous NETs formation in BD neutrophils was inhibited by Colchicine and Dexamethasone, two drugs used to treat BD. NETs formation was also inhibited by Cl-amidine, a specific PAD4 inhibitor, and by NAC, a ROS inhibitor. Interestingly, serum from BD patients stimulated circulating neutrophils from healthy volunteers to release more NETs and increased their mRNA PAD4 expression. Moreover, endothelial cells cultured in the presence of NETs from BD patients showed a decrease in proliferation and an increase in apoptosis and cell death. Finally, NETosis was predominantly identified around affected blood vessels in biopsies of vasculitis from BD patients. CONCLUSION: Our results provide evidence on the implication of NETosis in the pathophysiology of BD especially in inducing vasculitis.

SLC35B4, an Inhibitor of Gluconeogenesis, Responds to Glucose Stimulation and Downregulates Hsp60 among Other Proteins in HepG2 Liver Cell Lines.

SLC35B4, solute receptor for UDP-N-acetylglucosamine and UDP-xylose, is associated with diabetes and predisposing conditions. This study investigated the localization of SLC35B4 and compared the differential expression between a knockdown of SLC35B4 and controls in HepG2. Responsiveness to glucose, expression, and localization were assayed using Western blot and immunostaining. Localization was confirmed using a proximity ligation assay. Two-dimensional (2D) gel electrophoresis and MALDI-TOF were used to identify differentially expressed proteins and pathway analysis was performed. SLC35B4 was increased by 60% upon glucose stimulation and localized in Golgi apparatus and endoplasmic reticulum. Presence of SLC35B4 in the Golgi apparatus suggests its involvement in the biosynthesis of glycoconjugate proteins. Four proteins were markedly under-expressed (Hsp60, HspA8, TUBA1A, and ENO1) and linked to the pathogenesis of diabetes or post-translationally modified by O-GlcNAc. Glucose levels activate SLC35B4 expression. This triggers a downstream effect via Hsp60 and other proteins. We hypothesize that the downstream effect on the proteins is mediated via altering the glycosylation pattern inside liver cells. The downstream cascade ultimately alters the ability of cultured liver cells to inhibit endogenous glucose production, and this could play a role in the association of the above-listed genes with the pathogenesis of diabetes.

A ferutinin analogue with enhanced potency and selectivity against ER-positive breast cancer cells in vitro.

Estrogen is considered a risk factor for breast cancer since it promotes breast-cell proliferation. The jaesckeanadiol-3-p-hydroxyphenylpropanoate, a hemi-synthetic analogue of the natural phytoestrogen ferutinin (jaesckeanadiol-p-hydroxybenzoate), is designed to be devoid of estrogenic activity. This analogue induces a cytotoxic effect 30 times higher than that of ferutinin towards MCF-7 breast cancer cell line. We compared these two compounds with respect to their effect on proliferation, cell cycle distribution and cancer stem-like cells in the MCF-7 cell line. Treatment with ferutinin (30 µM) and its analogue (1 µM) produced significant accumulation of cells at the pre G0/G1 cell cycle phase and triggered apoptosis. Importantly, this compound retains its anti-proliferative activity against breast cancer stem/progenitor cells that are naturally insensitive to ferutinin at the same dose. These results position ferutinin analogue as an effective compound inhibiting the proliferation of estrogen-dependent breast cancer cells and consistently targeting their stem-like cells.