O-prenylated carbostyrils as a novel class of 15-lipoxygenase inhibitors: Synthesis, characterization, and inhibitory assessment.

Catalyzed peroxidation of unsaturated lipid in animals and plants intimately is linked to the activity of 15-Lipoxygenase enzymes. Lipoxygenases (LOXs) are well known to play an important role in many acute and chronic syndromes such as inflammation, asthma, cancer, and allergy. In this study, a series of mono prenyloxycarbostyrils were synthesized and evaluated as potential inhibitors of soybean 15-Lipoxygenase (SLO) and their inhibitory potencies were compared to mono prenyloxycoumarins which had been reported in the previous works. The synthetic compounds inhibit lipoxygenase enzyme by competitive mechanism like the prenyloxy coumarins. The results showed that position and length of the prenyl moiety play the important role in lipoxygenase inhibitory activity. Among all of the synthetic compounds (coumarin and carbostyril derivatives), 5-farnesyloxycoumarin and 8-farnesyloxycarbostyril demonstrated the best inhibitory activity by IC50  values of 1.1 µM and 0.53 µM, respectively.

A Review of Monoclonal Antibody-Based Treatments in Non-small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is one of the most common types of lung cancer worldwide. It metastasizes rapidly and has a poor prognosis. The first-line treatment for most patients is a combination of chemotherapy and radiation. In many subjects, using targeted treatments alongside chemoradiation has shown a better outcome in terms of progression and quality of life for patients. These targeted treatments include small biological inhibiting molecules and monoclonal antibodies. In this review, we have assessed studies focused upon the treatment of non-small cell lung cancer. Some therapies are approved, such as bevacizumab and atezolizumab, while some are still in clinical trials, such as ficlatuzumab and ipilimumab, and others have been rejected due to inadequate disease control, such as figitumumab.

Design, synthesis, and SAR study of isopropoxy allylbenzene derivatives as 15-lipoxygenase inhibitors.

OBJECTIVES: Allylbenzenes have been recently developed as inhibitors of lipoxygenases. They decrease peroxidation activity via mimicking 1,4-unsaturated bonds of fatty acids by their allyl portion. We designed and synthesized new derivatives of allyl benzenes (6a-f) with isopropoxy and amide substituents at ortho and meta positions towards allyl group, respectively. The inhibitory potency of the synthetized allylbenzenes against soybean 15-lipoxygenase (SLO) and subsequently structure-activity relationships was assessed. MATERIALS AND METHODS: 3-allyl-4-isopropoxybenzenamine (5) as starting material was synthesized by coupling of 4-nitropheol with allyl bromide, performing Claisen rearrangement and finally reduction of the nitro moiety. Final products 6a-f were prepared via amidation of 5 with the desired acyl chloride. RESULTS: Among the compounds, N-(3-allyl-4-isopropoxyphenyl)adamantan carboxamide (6f) potentially showed best inhibition (IC50 = 1.35 µM) while 6a with cyclopropyl carboxamide moiety was the weakest inhibitor and 6e with phenyl carboxamide moiety showed no effect. Energy minimized 3D structures of the compounds were docked into the active site pocket of SLO. For the aliphatic amides, docking results showed compatibility between inhibitory potency and average Ki of the cluster conformers, in which their allyl moiety oriented towards SLO iron core. For the aliphatic analogs, by enlargement of the amide moiety size the inhibitory potency was increased. CONCLUSION: Docking results showed that orientation of the amide and allyl moieties of the inhibitors in the active site pocket is the major factor in inhibitory potency variation. Based on the mentioned orientation, for cycloaliphatic amides, by enlargement of the amide moiety both inhibition potency and calculated binding energy increases.

Pharmacological and Therapeutic Aspects of Plants from the Genus Ferula: A Comprehensive Review.

Inspired by nature, humankind has been able to attain significant achievements in the drug and food industries. Particularly, medicinal plants are a rich source of medicinal, cosmetic, sanitary, and aromatic substances. Genus Ferula from the Apiaceae family is a plant genus that possesses over 170 species, which have been carefully documented with regard to their medicinal properties. Ferula spp. affects many body organs, and their respective functions, in humans, such as the immune system, gastrointestinal tract, genitourinary, endocrine, respiratory, cardiovascular, nervous system, bone (skeleton), and teeth. In spite of the benefits, ferulosis (Ferula toxicity) is an important aspect of Ferula consumption in humans and animals. Hemorrhagic problems and infertility are important signs of ferulosis. In this review, we have described all of the effects of the active ingredients of Ferula spp. and their mechanisms of actions, when known, based on an extensive literature review. Thus, our review opens a window of the benefits of Ferula as a phyto-pharmaceutical and its therapeutic applications in pharmacy, dentistry, and medicine.

Curcumin for the Management of Periodontal Diseases: A Review.

Periodontal disease is one of the most common causes of tooth loss among adults. Research shows that inflammation is one of the crucial components in the initiation and progression of periodontitis. Various herbal medicines have recently been receiving attention for the management of periodontitis owing to their general safety and efficacy. Curcumin, a bioactive polyphenol extracted from Curcuma longa, has been shown to possess antioxidant, antimicrobial, anti-inflammatory and analgesic properties. Several studies have assessed the efficacy of curcumin against periodontal diseases. These studies have shown equivalent or even higher efficacy of curcumin compared to the commonly used medications for the management of periodontitis such as chlorhexidine. Herein, we review the experimental and clinical findings on the anti-periodontitis effects of curcumin and the pharmacological mechanisms underlying these effects.

The beneficial effects of nutraceuticals and natural products on small dense LDL levels, LDL particle number and LDL particle size: a clinical review.

Cardiovascular diseases (CVDs) are globally the major causes of morbidity and mortality. Evidence shows that smaller and denser low-dense lipoprotein (sdLDL) particles are independent atherogenic risk factors for CVD due to their greater susceptibility to oxidation, and permeability in the endothelium of arterial walls. sdLDL levels are an independent risk factor and of more predictive value than total LDL-C for the assessment of coronary artery disease and metabolic syndrome. Functional food ingredients have attracted significant attention for the management of dyslipidemia and subsequently increase cardio-metabolic health. However, to date there is no study that has investigated the effect of these bioactive natural compounds on sdLDL levels. Therefore, the aim of the present review is to summarize the evidence accrued on the effect of special dietary ingredients such as omega-3 polyunsaturated fatty acids, nutraceuticals and herbal medicines on the levels of sdLDL, LDL particle number, and LDL particle size. Based on the results of the existing clinical trials this review suggests that natural products such as medicinal plants, nutraceuticals and omega-3 fatty acids can be used as adjunct or complementary therapeutic agents to reduce sdLDL levels, LDL particle numbers or increase LDL particle size and subsequently may prevent and treat CVD, with the advantage that theses natural agents are generally safe, accessible, and inexpensive.

Curcumin Therapeutic Modulation of the Wnt Signaling Pathway.

Curcumin, isolated from the rhizome of Curcuma longa, is one of the most extensively studied phytochemicals. This natural compound has a variety of pharmacological effects including antioxidant, anti-inflammatory, anti-tumor, cardio-protective, hepato-protective and anti-diabetic. Wnt signaling pathway, one of the potential targets of curcumin through upregulation and/or downregulation, plays a significant role in many diseases, even in embryogenesis and development of various organs and systems. In order to exert an anti-tumor activity in the organism, curcumin seems to inhibit the Wnt pathway. The downstream mediators of Wnt signaling pathway such as c-Myc and cyclin D1 are also modified by curcumin. This review demonstrates how curcumin influences the Wnt signaling pathway and is beneficial for the treatment of neurological disorders (Alzheimer's and Parkinson's diseases), cancers (melanoma, lung cancer, breast cancer, colon cancer, endothelial carcinoma, gastric carcinoma and hepatocellular carcinoma) and other diseases, such as diabetes mellitus or bone disorders.

Peptide decoys: a new technology offering therapeutic opportunities for breast cancer.

Breast cancer is the most common cancer among women. Absence of hormone receptors (estrogen and progesterone) and lack of overexpression of Human Epidermal Growth Factor 2 (HER2) make triple-negative breast cancer (TNBC) an aggressive subtype of breast cancer that is resistant to conventional therapies. Peptide decoys have emerged as a novel therapeutic approach for the treatment of breast cancer. Decoy peptide technology entails the use of soluble proteins or peptides, including binding proteins or inactive cell surface receptors. Peptide decoys bind to certain ligands (e.g., inflammatory cytokines) with high affinity and specificity as receptors but cannot initiate any signaling pathway that is involved in the pathogenesis of breast cancer. In this review, we discuss the use of decoy peptides as a novel therapeutic approach for breast cancer treatment.

The role of TFEB in tumor cell autophagy: Diagnostic and therapeutic opportunities.

Autophagy is a conserved "self-eating" recycling process which removes aggregated or misfolded proteins, or defective organelles, to maintain cellular hemostasis. In the autophagy-lysosome pathway (ALP), clearance of unwanted debris and materials occurs through the generation of the autophagosome, a complex of double-membrane bounded vesicles that form around cytosolic cargos and catabolize their contents by fusion to lysosomes. In tumors, autophagy has dichotomous functions via preventing tumor initiation but promoting tumor progression. The basic helix-loop-helix leucine zipper transcription factor EB (TFEB) activates the promoters of genes encoding for proteins, which participate in this cellular degradative system by regulating lysosomal biogenesis, lysosomal acidification, lysosomal exocytosis and autophagy. In humans, disturbances of ALP are related to various pathological conditions. Recently, TFEB dysregulation was found to have a crucial pathogenic role in different tumors by modulating tumor cell autophagy. Notably, in renal cell carcinomas, different TFEB gene fusions were reported to promote oncogenic features. In this review, we discuss the role of TFEB in human cancers with a special focus on potential diagnostic and therapeutic implications.

An overview of lipoxygenase inhibitors with approach of in vivo studies.

Lipoxygenases (LOXs) are enzymes which found in organisms that catalyze the peroxidation of polyunsaturated fatty acids (Arachidonic acid, Linoleic acid). The key role of the mentioned enzymes and their metabolites in formation of sensitivities, inflammations, many of cancers (prostate, breast, etc), obesity, diabetes and atherosclerosis had been demonstrated. This review aimed to focus on research findings introducing proved LOXs (5/12/15-LOX) inhibitors, which have been involved in in vivo studies, and discuss on their sources, chemical structures and medicinal applications. By this subject selection, we would introduce the possible LOXs inhibitors (5/12/15-LOX) with special physiological and metabolic levels and open a vision in molecular target selection for the readers.

The molecular mechanisms by which vitamin D improve glucose homeostasis: A mechanistic review.

Diabetes mellitus (DM) is a complex metabolic disorder involving multiple deleterious molecular pathways and cellular defects leading to disturbance in the biologic milieu. It is currently a global health concern with growing incidence, especially among younger adults. There is an unmet need to find new therapeutic targets for the management of diabetes. Vitamin D is a promising target in the pathophysiology of DM, especially since vitamin D deficiency is common in patients with diabetes compared to people without diabetes. Evidence suggests that it can play significant roles in improving peripheral insulin sensitivity and glucose metabolism, however, the exact pathophysiological mechanism is not clarified yet. In this current study, we have reviewed the evidence on the effect of vitamin D in improving insulin resistance via distinct molecular pathways.

Enhancing the Therapeutic Efficacy of Bortezomib in Cancer Therapy Using Polymeric Nanostructures.

Bortezomib (VELCADE®) is a boronate peptide and first-in-class proteasome inhibitor serving an important role in degenerating several intracellular proteins. It is a reversible inhibitor of the 26S proteasome, with antitumor activity and antiproliferative properties. This agent principally exerts its antineoplastic effects by inhibiting key players in the nuclear factor κB (NFκB) pathway involved in cell proliferation, apoptosis, and angiogenesis. This medication is used in the management of multiple myeloma. However, more recently, it has been used as a therapeutic option for mantle cell lymphoma. While promising, bortezomib has limited clinical applications due to its adverse effects (e.g., hematotoxicity and peripheral neuropathy) and low effectiveness in solid tumors resulting from its poor penetration into such masses and suboptimal pharmacokinetic parameters. Other limitations to bortezomib include its low chemical stability and bioavailability, which can be overcome by using nanoparticles for its delivery. Nanoparticle delivery systems can facilitate the targeted delivery of chemotherapeutic agents in high doses to the target site, while sparing healthy tissues. Therefore, this drug delivery system has provided a solution to circumvent the limitations faced with the delivery of traditional cancer chemotherapeutic agents. Our aim in this review was to describe polymer-based nanocarriers that can be used for the delivery of bortezomib in cancer chemotherapy.

Designing mucoadhesive discs containing stem bark extract of Ziziphus jujuba based on Iranian traditional documents.

OBJECTIVE S: Mucoadhesive disc is one of the various routes of drug delivery for curing buccal disease. MATERIALS AND METHODS: Every discs containing 70 mg stem bark extract of Ziziphus jujuba were formulated by using Carbopol 934, PVP k30 and gelatin as polymers. Discs were made by granulation and direct compression. Discs were standardized based on the total phenol. Properties such as in vitro and in vivo mucoadhesion, drug release, water uptake, and disintegration were carried out. RESULTS: Discs showed excellent mucoadhesion and released high amount of the active ingredients (47%) immediately and completed after approximately the first hour. They had a good adhesion in buccal cavity. CONCLUSION: This study showed that the kinetics of release of the active substance from the mucoadhesive disc obeyed the zero order kinetic and didn't follow the fick's law. The water uptake and dissolution (DS), increased with the passing of time.