Visfatin/nicotinamide phosphoribosyltransferase (NAMPT) is an adipokine expressed predominately in visceral fat tissues. High circulating levels of visfatin/NAMPT have been implicated in vascular ...remodeling, vascular inflammation, and atherosclerosis, all of which pose increased risks of cardiovascular events. In this context, increased levels of visfatin have been correlated with several upregulated pro‐inflammatory mediators, such as IL‐1, IL‐1Ra, IL‐6, IL‐8, and TNF‐α. Furthermore, visfatin is associated with leukocyte recruitment by endothelial cells and the production of adhesion molecules such as vascular cell adhesion molecule 1, intercellular cell adhesion molecule 1, and E‐selectin, which are well known to mediate the progression of atherosclerosis. Moreover, diverse angiogenic factors have been found to mediate visfatin‐induced angiogenesis. These include matrix metalloproteinases, vascular endothelial growth factor, monocyte chemoattractant protein 1, and fibroblast growth factor 2. This review aims to provide a comprehensive overview of the pro‐inflammatory and angiogenic actions of visfatin, with a focus on the pertinent signaling pathways whose dysregulation contributes to the pathogenesis of atherosclerosis. Most importantly, some hypotheses regarding the integration of the aforementioned factors with the plausible atherogenic effect of visfatin are put forth for consideration in future studies. The pharmacotherapeutic potential of modulating visfatin's roles could be important in the management of cardiovascular disease, which continues to be the leading cause of death worldwide.
This review aims to provide a comprehensive overview of the pro‐inflammatory and angiogenic actions of visfatin, with a focus on the pertinent signaling pathways whose dysregulation contributes to the pathogenesis of atherosclerosis. The pharmacotherapeutic potential of modulating visfatin's roles could be important in the management of cardiovascular disease, which continues to be the leading cause of death worldwide.
C‐peptide, a byproduct of insulin synthesis believed to be biologically inert, is emerging as a multifunctional molecule. C‐peptide serves an anti‐inflammatory and anti‐atherogenic role in type 1 ...diabetes mellitus (T1DM) and early T2DM. C‐peptide protects endothelial cells by activating AMP‐activated protein kinase α, thus suppressing the activity of NAD(P)H oxidase activity and reducing reactive oxygen species (ROS) generation. It also prevents apoptosis by regulating hyperglycemia‐induced p53 upregulation and mitochondrial adaptor p66shc overactivation, as well as reducing caspase‐3 activity and promoting expression of B‐cell lymphoma‐2. Additionally, C‐peptide suppresses platelet‐derived growth factor (PDGF)‐beta receptor and p44/p42 mitogen‐activated protein (MAP) kinase phosphorylation to inhibit vascular smooth muscle cells (VSMC) proliferation. It also diminishes leukocyte adhesion by virtue of its capacity to abolish nuclear factor kappa B (NF‐kB) signaling, a major pro‐inflammatory cascade. Consequently, it is envisaged that supplementation of C‐peptide in T1DM might ameliorate or even prevent end‐organ damage. In marked contrast, C‐peptide increases monocyte recruitment and migration through phosphoinositide 3‐kinase (PI‐3 kinase)‐mediated pathways, induces lipid accumulation via peroxisome proliferator‐activated receptor γ upregulation, and stimulates VSMC proliferation and CD4+ lymphocyte migration through Src‐kinase and PI‐3K dependent pathways. Thus, it promotes atherosclerosis and microvascular damage in late T2DM. Indeed, C‐peptide is now contemplated as a potential biomarker for insulin resistance in T2DM and linked to increased coronary artery disease risk. This shift in the understanding of the pathophysiology of diabetes from being a single hormone deficiency to a dual hormone disorder warrants a careful consideration of the role of C‐peptide as a unique molecule with promising diagnostic, prognostic, and therapeutic applications.
Structural modifications of the antibacterial drug nitrofurantoin were envisioned, employing drug repurposing and biology-oriented drug synthesis, to serve as possible anticancer agents. Eleven ...compounds showed superior safety in non-cancerous human cells. Their antitumor efficacy was assessed on colorectal, breast, cervical, and liver cancer cells. Three compounds induced oxidative DNA damage in cancer cells with subsequent cellular apoptosis. They also upregulated the expression of Bax while downregulated that of Bcl-2 along with activating caspase 3/7. The DNA damage induced by these compounds, demonstrated by pATM nuclear shuttling, was comparable in both MCF7 and MDA-MB-231 (p53 mutant) cell lines. Mechanistic studies confirmed the dependence of these compounds on p53-mediated pathways as they suppressed the p53–MDM2 interaction. Indeed, exposure of radiosensitive prostatic cancer cells to low non-cytotoxic concentrations of compound 1 enhanced the cytotoxic response to radiation indicating a possible synergistic effect. In vivo antitumor activity was verified in an MCF7-xenograft animal model.
Neuroinflammation and cholinergic deficit are key detrimental processes involved in Alzheimer's disease. Hence, in the search for novel and effective treatment strategies, the multi-target-directed ...ligand paradigm was applied to the rational design of two series of new hybrids endowed with anti-inflammatory and anticholinesterase activity via triple targeting properties, namely able to simultaneously hit cholinesterases, cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX) enzymes. Among the synthesized compounds, triazoles 5b and 5d, and thiosemicarbazide hybrid 6e emerged as promising new hits, being able to effectively inhibit human butyrylcholinesterase (hBChE), COX-2 and 15-LOX enzymes with a higher inhibitory potency than the reference inhibitors tacrine (for hBChE inhibition), celecoxib (for COX-2 inhibition) and both NDGA and Zileuton (for 15-LOX inhibition). In addition, compound 6e proved to be a submicromolar mixed-type inhibitor of human acetylcholinesterase (hAChE). The anti-neuroinflammatory activity of the three most promising hybrids was confirmed in a cell-based assay using PC12 neuron cells, showing decreased expression levels of inflammatory cytokines IL-1β and TNF-α. Importantly, despite the structural resemblance to tacrine, they showed ideal safety profiles on hepatic and murine brain cell lines and were safe up to 100 μM when assayed in PC12 cells. All three hybrids were also predicted to have superior BBB permeability than tacrine in the PAMPA assay, and good physicochemical properties, drug-likeness and ligand efficiency indices. Finally, molecular docking studies highlighted key structural elements impacting selectivity and activity toward the selected target enzymes.
To the best of our knowledge, compounds 5b, 5d and 6e are the first balanced, safe and multi-target compounds hitting the disease at the three mentioned hubs.
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•Tetrahydroacridine-triazole and thiosemicarbazide hybrids were synthesized to serve as multi-target directed ligands for Alzheimer’s disease treatment.•Thiosemicarbazide derivative 6e inhibited hAChE, hBChE, COX-2 and 15-LOX enzymes at micromolar concentrations.•Triazoles 5b and 5d selectively inhibited hBChE as well as COX-2 and 15-LOX.•They decreased expression levels of inflammatory cytokines IL-1β and TNF-α in neuron cell-based assay.•These compounds were safe on both hepatic and neuronal cell lines.
Emerging evidence supports an intertwining framework for the involvement of different inflammatory pathways in a common pathological background for a number of disorders. Of importance are pathways ...involving arachidonic acid metabolism by cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX). Both enzyme activities and their products are implicated in a range of pathophysiological processes encompassing metabolic impairment leading to adipose inflammation and the subsequent vascular and neurological disorders, in addition to various pro- and antitumorigenic effects. A further layer of complexity is encountered by the disparate, and often reciprocal, modulatory effect COX-2 and 15-LOX activities and metabolites exert on each other or on other cellular targets, the most prominent of which is peroxisome proliferator-activated receptor gamma (PPARγ). Thus, effective therapeutic intervention with such multifaceted disorders requires the simultaneous modulation of more than one target. Here, we describe the role of COX-2, 15-LOX, and PPARγ in cancer and complications of metabolic disorders, highlight the value of designing multi-target directed ligands (MTDLs) modifying their activity, and summarizing the available literature regarding the rationale and feasibility of design and synthesis of these ligands together with their known biological effects. We speculate on the potential impact of MTDLs in these disorders as well as emphasize the need for structured future effort to translate these early results facilitating the adoption of these, and similar, molecules in clinical research.
Reactive oxygen species (ROS) are natural byproducts of oxygen metabolism in the cell. At physiological levels, they play a vital role in cell signaling. However, high ROS levels cause oxidative ...stress, which is implicated in cardiovascular diseases (CVD) such as atherosclerosis, hypertension, and restenosis after angioplasty. Despite the great amount of research conducted to identify the role of ROS in CVD, the image is still far from being complete. A common event in CVD pathophysiology is the switch of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic phenotype. Interestingly, oxidative stress is a major contributor to this phenotypic switch. In this review, we focus on the effect of ROS on the hallmarks of VSMC phenotypic switch, particularly proliferation and migration. In addition, we speculate on the underlying molecular mechanisms of these cellular events. Along these lines, the impact of ROS on the expression of contractile markers of VSMCs is discussed in depth. We conclude by commenting on the efficiency of antioxidants as CVD therapies.
The metabolic syndrome comprises a family of clinical and laboratory findings, including insulin resistance, hyperglycemia, hypertriglyceridemia, low high‐density lipoprotein cholesterol levels, and ...hypertension, in addition to central obesity. The syndrome confers a high risk of cardiovascular mortality. Indeed, metabolic dysfunction has been shown to cause a direct insult to smooth muscle and endothelial components of the vasculature, which leads to vascular dysfunction and hyperreactivity. This, in turn, causes cerebral vasoconstriction and hypoperfusion, eventually contributing to cognitive deficits. Moreover, the metabolic syndrome disrupts key homeostatic processes in the brain, including apoptosis, autophagy, and neurogenesis. Impairment of such processes in the context of metabolic dysfunction has been implicated in the pathogenesis of neurodegenerative diseases, including Alzheimer, Parkinson, and Huntington diseases.
The aim of this review is to elucidate the role that the metabolic syndrome plays in the pathogenesis of the latter disorders, with a focus on the role of perivascular adipose inflammation in the peripheral‐to‐central transduction of the inflammatory insult. This review delineates common signaling pathways that contribute to these pathologies. Moreover, the role of therapeutic agents aimed at treating the metabolic syndrome, as well as their risk factors that interfere with the aforementioned pathways, are discussed as potential interventions for neurodegenerative diseases.
Cis-diacetonitrilo-bis(bipyridine) ruthenium(II) chloride is a recently introduced cis-platin analogue that has anti-cancer properties with lower side effects. However, the sequence dependence of its ...DNA damaging mechanism is unclear. Here, we present a simple, sensitive, multiplexed mix-and-read assay for ascertaining the molecular mechanism of DNA damage induced by the studied ruthenium complex (Ru-complex). The damage kinetics and sequence specificity for the Ru-complex induced DNA damage are examined by studying the induced damage in various oligonucleotide sequences by EvaGreen-DNA intercalator probe. High-through-put measurements were established using a 96-well microplate platform that allows multiple sequences to be measured simultaneously. The results show that the extent of damage increases with an increasing number of guanines, with considerable amount of damage at GA, GT and GC sites, in particular. Furthermore, the interaction of Ru-complex with DNA was confirmed using thermal analysis and MALDI-TOF-MS. Results indicate that the activated Ru-complex preferentially binds via both mono- and di-adduct formation at G and GG sites, respectively. Moreover, the developed method was successfully applied for the determination of the potency of the studied Ru-complex to induce DNA damage in K-Ras and N-Ras family of genes, one of the most common oncogenic events in cancer.
•Studying the mechanism of DNA damage induced by a novel anticancer drug•The studied drug is a cisplatin analogue•A simple mix-and-read multiplexed assay using EvaGreen biosensor was used•The results were confirmed using MALDI-TOF and thermal analysis•The potential of the studied Ru-complex to induce DNA damage in K-Ras and N-Ras family of genes was studied
Ca 2+ sensitization has been postulated to contribute to the myogenic contraction of resistance arteries evoked by elevation of
transmural pressure. However, the biochemical evidence of ...pressure-induced increases in phosphorylated myosin light chain
phosphatase (MLCP) targeting subunit 1 (MYPT1) and/or 17 kDa protein kinase C (PKC)-potentiated protein phosphatase 1 inhibitor
protein (CPI-17) required to sustain this view is not currently available. Here, we determined whether Ca 2+ sensitization pathways involving Rho kinase (ROK)- and PKC-dependent phosphorylation of MYPT1 and CPI-17, respectively, contribute
to the myogenic response of rat middle cerebral arteries. ROK inhibitors (Y27632, 0.03â10 μmol l â1 ; H1152, 0.001â0.3 μmol l â1 ) and PKC inhibitors (GF109203X, 3 μmol l â1 ; Gö6976; 10 μmol l â1 ) suppressed myogenic vasoconstriction between 40 and 120 mmHg. An improved, highly sensitive 3-step Western blot method was
developed for detection and quantification of MYPT1 and CPI-17 phosphorylation. Increasing pressure from 10 to 60 or 100 mmHg
significantly increased phosphorylation of MYPT1 at threonine-855 (T855) and myosin light chain (LC 20 ). Phosphorylation of MYPT1 at threonine-697 (T697) and CPI-17 were not affected by pressure. Pressure-evoked elevations in
MYPT1-T855 and LC 20 phosphorylation were reduced by H1152, but MYPT1-T697 phosphorylation was unaffected. Inhibition of PKC with GF109203X did
not affect MYPT1 or LC 20 phosphorylation at 100 mmHg. Our findings provide the first direct, biochemical evidence that a Ca 2+ sensitization pathway involving ROK-dependent phosphorylation of MYPT1 at T855 (but not T697) and subsequent augmentation
of LC 20 phosphorylation contributes to myogenic control of arterial diameter in the cerebral vasculature. In contrast, suppression
of the myogenic response by PKC inhibitors cannot be attributed to block of Ca 2+ sensitization mediated by CPI-17 or MYPT1 phosphorylation.
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