Sphingosine-1-phosphate (S1P) is a potent sphingolipid metabolite that regulates a wide range of biological functions such as cell proliferation, cell apoptosis and angiogenesis. Its cellular level ...is elevated in breast cancer, which, in turn, would promote cancer cell proliferation, survival, growth and metastasis. However, the cellular concentration of S1P is normally in the low nanomolar range, and our previous studies showed that S1P selectively induced apoptosis of breast cancer cells at high concentrations (high nanomolar to low micromolar). Thus, local administration of high-concentration S1P alone or in combination of chemotherapy agents could be used to treat breast cancer. The breast mainly consists of mammary gland and connective tissue stroma (adipose), which are dynamically interacting each other. Thus, in the current study, we evaluated how normal adipocyte-conditioned cell culture media (AD-CM) and cancer-associated adipocyte-conditioned cell culture media (CAA-CM) would affect high-concentration S1P treatment of triple-negative breast cancer (TNBC) cells. Both AD-CM and CAA-CM may suppress the anti-proliferative effect and reduce nuclear alteration/apoptosis caused by high-concentration S1P. This implicates that adipose tissue is likely to be detrimental to local high-concentration S1P treatment of TNBC. Because the interstitial concentration of S1P is about 10 times higher than its cellular level, we undertook a secretome analysis to understand how S1P would affect the secreted protein profile of differentiated SGBS adipocytes. At 100 nM S1P treatment, we identified 36 upregulated and 21 downregulated secretome genes. Most of these genes are involved in multiple biological processes. Further studies are warranted to identify the most important secretome targets of S1P in adipocytes and illustrate the mechanism on how these target proteins affect S1P treatment of TNBC.
Colorectal cancer (CRC) is a leading cause of death from cancer in Canada. Early detection of CRC remains crucial in managing disease prognosis and improving patient survival. It can also facilitate ...prevention, screening, and treatment before the disease progresses to a chronic stage. In this study, we developed a strategy for identifying colon cancer biomarkers from both gene expression and gene pair correlation. Using the RNA-Seq dataset TCGA-COAD, a panel of 71 genes, including the 20 most upregulated genes, 20 most downregulated genes and 31 genes involved in the most significantly altered gene pairs, were selected as potential biomarkers for colon cancer. This signature set of genes could be used for early diagnosis. Furthermore, this strategy could be applied to other types of cancer.
Due to over-prescription of antibiotics, antimicrobial resistance has emerged to be a critical concern globally. Many countries have tightened the control of antibiotic usage, which, in turn, ...promotes the search for alternatives to antibiotics. Quite a few phytochemicals have been investigated. Benzyl isothiocyanate (BITC) is an important secondary metabolite in cruciferous species and exhibited potent antimicrobial activity under in vitro conditions. In this research, we undertook a comparative mouse model study of BITC with gentamycin sulfate (positive antibiotic control) and ceftiofur hydrochloride (negative antibiotic control) against Pseudomonas aeruginosa infection. Our results showed that BITC exhibited comparable or better antimicrobial activity and lower infiltration of mouse immune cells upon comparing to gentamycin sulfate. Furthermore, BITC did not impose any toxicity to the air pouch skin tissues. In summary, our current study suggests that BITC could be an alternative to antibiotics and deserves further in vivo and clinical trial studies.
Bovine respiratory disease (BRD) is the most common infectious disease in dairy and beef cattle. It is associated with significant morbidity and mortality and causes a huge economic loss each year. ...In western Canada, a one-time injection of tulathromycin is commonly used as a metaphylactic procedure to reduce BRD incidence and eliminate potential BRD outbreak. With increased global concern on antimicrobial usage in dairy and beef products and bacterial resistance to antimicrobials, it is important to develop a novel strategy to eliminate the usage or decrease the dosage of antimicrobials. In this study, we showed that gallic acid was active against both
and
, two key BRD associated-pathogens, with the minimum inhibitory concentration (MIC) measured at 250 and 500 μg/mL, respectively. Co-administration of tulathromycin and gallic acid exhibited a strong additive or weak synergistic effect toward both
and
. Tulathromycin, gallic acid and their combination were also effective against the mixed culture of
and
. Furthermore, we showed that pre-exposure to tulathromycin generated bacterial resistance to the antimicrobial in
but not in
.
Sleep plays an important role in maintaining neuronal circuitry, signalling and helps maintain overall health and wellbeing. Sleep deprivation (SD) disturbs the circadian physiology and exerts a ...negative impact on brain and behavioural functions. SD impairs the cellular clearance of misfolded neurotoxin proteins like α-synuclein, amyloid-β, and tau which are involved in major neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease. In addition, SD is also shown to affect the glymphatic system, a glial-dependent metabolic waste clearance pathway, causing accumulation of misfolded faulty proteins in synaptic compartments resulting in cognitive decline. Also, SD affects the immunological and redox system resulting in neuroinflammation and oxidative stress. Hence, it is important to understand the molecular and biochemical alterations that are the causative factors leading to these pathophysiological effects on the neuronal system. This review is an attempt in this direction. It provides up-to-date information on the alterations in the key processes, pathways, and proteins that are negatively affected by SD and become reasons for neurological disorders over a prolonged period of time, if left unattended.
Parkinson's disease (PD) is an irreversible and incurable multigenic neurodegenerative disorder. It involves progressive loss of mid brain dopaminergic neurons in the substantia nigra pars compacta ...(SN). We compared brain gene expression profiles with those from the peripheral blood cells of a separate sample of PD patients to identify disease-associated genes. Here, we demonstrate the use of gene expression profiling of brain and blood for detecting valid targets and identifying early PD biomarkers. Implementing this systematic approach, we discovered putative PD risk genes in brain, delineated biological processes and molecular functions that may be particularly disrupted in PD and also identified several putative PD biomarkers in blood. 20 of the differentially expressed genes in SN were also found to be differentially expressed in the blood. Further application of this methodology to other brain regions and neurological disorders should facilitate the discovery of highly reliable and reproducible candidate risk genes and biomarkers for PD. The identification of valid peripheral biomarkers for PD may ultimately facilitate early identification, intervention, and prevention efforts as well.
Sphingosine-1-phosphate (S1P) is a highly potent sphingolipid metabolite, which controls numerous physiological and pathological process via its extracellular and intracellular functions. The breast ...is mainly composed of epithelial cells (mammary gland) and adipocytes (stroma). Adipocytes play an important role in regulating the normal functions of the breast. Compared to the vast amount studies on breast epithelial cells, the functions of S1P in breast adipocytes are much less known. Thus, in the current study, we used human preadipocyte cell lines SGBS and mouse preadipocyte cell line 3T3-L1 as in vitro models to evaluate the effects of S1P on cell viability, differentiation, and gene expression in adipocytes. Our results showed that S1P increased cell viability in SGBS and 3T3-L1 preadipocytes but moderately reduced cell viability in differentiated SGBS and 3T3-L1 adipocytes. S1P was also shown to inhibit adipogenic differentiation of SGBS and 3T3-L1 at concentration higher than 1000 nM. Transcriptome analyses showed that S1P was more influential on gene expression in differentiated adipocytes. Furthermore, our network analysis in mature adipocytes showed that the upregulated DEGs (differentially expressed genes) were related to regulation of lipolysis, PPAR (peroxisome proliferator-activated receptor) signaling, alcoholism, and toll-like receptor signaling, whereas the downregulated DEGs were overrepresented in cytokine-cytokine receptor interaction, focal adhesion, starch and sucrose metabolism, and nuclear receptors pathways. Together previous studies on the functions of S1P in breast epithelial cells, the current study implicated that S1P may play a critical role in modulating the bidirectional regulation of adipocyte-extracellular matrix-epithelial cell axis and maintaining the normal physiological functions of the breast.
Abstract Pioglitazone is a widely used anti-diabetic drug that induces cytotoxicity in cancer cells; however, its clinical use is questioned due to its associated liver toxicity caused by increased ...oxidative stress. We therefore employed nitroxide-radical containing nanoparticle, termed redox nanoparticle (RNPN ) which is an effective scavenger of reactive oxygen species (ROS) as a drug carrier. RNPN encapsulation increased pioglitazone solubility, thus increasing cellular uptake of encapsulated pioglitazone which reduced the dose required to induce toxicity in prostate cancer cell lines. Investigation of in vitro molecular mechanism of pioglitazone revealed that both apoptosis and cell cycle arrest were involved in tumor cell death. In addition, intravenously administered pioglitazone-loaded RNPN produced significant tumor volume reduction in vivo due to enhanced permeation and retention effect. Most importantly, oxidative damage caused by pioglitazone in the liver was significantly suppressed by pioglitazone-loaded RNPN due to the presence of nitroxide radicals. It is interesting to note that oral administration of encapsulated pioglitazone, and co-administration of RNPN and pioglitazone, i.e., no encapsulation of pioglitazone in RNPN also significantly contributed to suppression of the liver injury. Therefore, use of RNPN either as an adjuvant or as a carrier for drugs with severe side effects is a promising chemotherapeutic strategy.
Trimethylamine lyases are expressed in a wide range of intestinal microbiota which metabolize dietary nutrients like choline, betaine, and L-carnitine to form trimethylamine (TMA). Trimethylamine ...N-oxide (TMAO) is an oxidative product of trimethylamine (TMA) catalyzed by the action of flavin monooxygenases (FMO) in the liver. Higher levels of TMAO in the plasma and cerebrospinal fluid (CSF) have been shown to contribute to the development of risk factors and actively promote the pathogenesis of metabolic, cardiovascular, and cerebrovascular diseases. The investigations on the harmful effects of TMAO in the development and progression of neurodegenerative and sleep disorders are summarized in this manuscript. Clinical investigations on the role of TMAO in predicting risk factors and prognostic factors in patients with neurological disorders are also summarized. It is observed that the mechanisms underlying TMAO-mediated pathogenesis include activation of inflammatory signaling pathways such as nuclear factor kappa B (NF-κβ), NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, and MAPK/JNK in the periphery and brain. Data suggests that TMAO levels increase with age-related cognitive dysfunction and also induce mitochondrial dysfunction, oxidative stress, neuronal senescence, and synaptic damage in the brain. Further research into the relationships between dietary food consumption and gut microbiota-dependent TMAO levels could provide novel therapeutic options for neurological illnesses.
Solanum nigrum
Linn is a medicinal herb widely used in traditional Chinese medicine to treat ailments such as fever, inflammation and cancer. Although quite a few compounds have been isolated and ...characterized, its anticancer mechanism remains elusive. Thus, in this study, we used network pharmacology and molecular docking strategies to identify the major active ingredients in
S. nigrum
and reveal its putative mechanism against human breast cancer. Six compounds, quercetin, cholesterol, 3-epi-beta-sitosterol, diosgenin, medioresinol and solanocapsine, were identified to be the major active ingredients. Target identification and analysis showed that they regulate 80 breast cancer-related targets. Furthermore, network analysis showed that the six active ingredients regulate multiple pathways including ErbB signaling pathway and estrogen signaling pathway and genes
AKT1
(AKT serine/threonine kinase 1),
ESR1
(estrogen receptor 1),
EGFR
(epidermal growth factor receptor),
SRC
(proto-oncogene tyrosine-protein kinase Src),
AR
(androgen receptor) and
MMP9
(matrix metalloproteinase 9) are crucial genes involved in the regulations. Molecular docking implied that quercetin could form good binding with AKT1, EGFR, SRC and MMP9. Our current study suggests that the anticancer function of
S. nigrum
is likely via synergistic/additive effects of multiple active ingredients’ regulations of different signaling pathways. Further studies are warranted to establish the standard for
S. nuigrum
to be used as a CAM (complementary and alternative medicine) in breast cancer treatment and dissect its potential interactions with chemotherapy drugs.
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