Poly-γ-glutamic acid nanoparticles as adjuvant and antigen carrier system for cancer vaccination.

Vaccination is an innovative strategy for cancer treatment by leveraging various components of the patients' immunity to boost an anti-tumor immune response. Rationally designed nanoparticles are well suited to maximize cancer vaccination by the inclusion of immune stimulatory adjuvants. Also, nanoparticles might control the pharmacokinetics and destination of the immune potentiating compounds. Poly-γ-glutamic acid (γ-PGA) based nanoparticles (NPs), which have a natural origin, can be easily taken up by dendritic cells (DCs), which leads to the secretion of cytokines which ameliorates the stimulation capacity of T cells. The intrinsic adjuvant properties and antigen carrier properties of γ-PGA NPs have been the focus of recent investigations as they can modulate the tumor microenvironment, can contribute to systemic anti-tumor immunity and subsequently inhibit tumor growth. This review provides a comprehensive overview on the potential of γ-PGA NPs as antigen carriers and/or adjuvants for anti-cancer vaccination.

Acrylamide; a neurotoxin in popcorns: a systematic review and meta-analysis.

Acrylamide is a known neurotoxic compound for humans. Foods that have high concentrations of acrylamide need to be identified. One of the food products containing acrylamide is popcorn. Popcorn is an important source of snacks for children, especially students. The presented study is a systematic review and meta-analysis of the level of acrylamide in popcorn. The search was done in different databases with the keywords; acrylamide, popcorn, popped corn. 27 articles were found by searching various databases. After initial screening and full text evaluation, 8 articles were selected for systematic review and 6 articles for meta-analysis. The amount of acrylamide in this product was in the range of 1,017.7-106 µg/kg. Microwaved corn contains lower amounts of acrylamide than other methods of preparation. The type of popcorn also had an effect on the amount of acrylamide with Meta-regression. It was found that sweet popcorn contains higher amounts of acrylamide. The overall value of acrylamide concentration in popcorns was calculated to be 459.6 ± 220.3 µg/kg. This amount is high and requires measures to reduce the amount of acrylamide.

A novel dual-targeting delivery system for specific delivery of CRISPR/Cas9 using hyaluronic acid, chitosan and AS1411.

A facile method was designed that can specifically deliver CRISPR/Cas9 into target cells nuclei and reduce the off-target effects. A multifunctional delivery vector for FOXM1 knockout was composed by integration of cell targeting polymer (hyaluronic acid) and cell and nuclear targeting group (AS1411 aptamer) on the surface of nanoparticles formed by genome editing plasmid and chitosan (CS) as the core (Apt-HA-CS-CRISPR/Cas9). The data of cytotoxicity experiment and western blot confirmed this issue. The results of flow cytometry analysis and fluorescence imaging demonstrated that Apt-HA-CS-CRISPR/Cas9 was significantly internalized into target cells (MCF-7, SK-MES-1, HeLa) but not into nontarget cells (HEK293). Furthermore, the in vivo studies displayed that the Apt-HA-CS-CRISPR/Cas9 was strongly rendered tumor inhibitory effect and delivered efficiently CRISPR/Cas9 into the tumor with no detectable distribution in other organs compared with naked plasmid. This approach provides an avenue for specific in vivo gene editing therapeutics with the lowest side effect.

Quercetin and its role in modulating endoplasmic reticulum stress: A review.

The endoplasmic reticulum (ER) is the place where proteins and lipids are biosynthesized and where transmembrane proteins are folded. Both pathological and physiological situations may disturb the function of the ER, resulting in ER stress. Under stress conditions, the cells initiate a defensive procedure known as the unfolded protein response (UPR). Cases of severe stress lead to autophagy and/or the induction of cell apoptosis. Many studies implicate ER stress as a major factor contributing to many diseases. Therefore, the modulation of ER stress pathways has become an attractive therapeutic target. Quercetin is a plant-derived metabolite belonging to the flavonoids class which presents a range of beneficial effects including anti-inflammatory, cardioprotective, anti-oxidant, anti-obesity, anti-carcinogenic, anti-atherosclerotic, anti-diabetic, anti-hypercholesterolemic, and anti-apoptotic activities. Quercetin also has anti-cancer activity, and can be used as an adjuvant to decrease resistance to cancer chemotherapy. Furthermore, the effect of quercetin can be increased with the help of nanotechnology. This review discusses the role of quercetin in the modulation of ER stress (and related diseases) and provides novel evidence for the beneficial use of quercetin in therapy.

The possible role of Sirtuins and microRNAs in hepatocellular carcinoma therapy.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Sirtuins are NAD+-dependent histone deacetylases that regulate many cellular processes such as proliferation, apoptosis, and metabolism. SIRT (silent information regulator)-1, 5, 6 and 7, members of the mammalian Sirtuin family of proteins (SIRT1-SIRT7), are involved in carcinogenesis, prognosis, metastasis, and chemical resistant of HCC. These proteins act through the deacetylation of tumor suppressor or oncogenic factors. MicroRNAs (miRNAs) are a group of small non-coding RNAs that down regulate gene expression by targeting the 3'-untranslated region of miRNAs. MiRNAs can function as tumor suppressors or as oncogenes and are involved in progression, differentiation, apoptosis and drug resistance of tumor cells. The focus of this review is to delineate the relationship between some microRNAs and their target, Sirtuins, and to present an overview of their function in HCC as currently understood.

Tropisetron ameliorates cyclophosphamide-induced hemorrhagic cystitis in rats.

Hemorrhagic cystitis is one of the most important complications of cyclophosphamide, a drug widely used in cancer chemotherapy and bone marrow transplantation. 5-HT3 antagonists are anti-emetic agents and have been shown to have notable anti-inflammatory and antioxidant properties. This study was designed to investigate the possible protective effects of tropisetron against cyclophosphamide-induced hemorrhagic cystitis in rats. Hemorrhagic cystitis was induced in female rats by cyclophosphamide (270 mg/kg). Tropisetron (2.5, 5 and 7.5 mg/kg), granisetron (2.5 and 5 mg/kg), and ondansetron (5 mg/kg) were injected 15 min before, 4 and 8 h after cyclophosphamide. To evaluate the role of alpha7 nicotinic acetylcholine receptor (α7nAChR), its antagonist, methyllycaconitine (5 mg/kg) was administered 30 min before tropisetron. After 24 h, animals were killed under anesthesia. Macroscopic and histological changes were evaluated. Malondialdehyde (MDA), glutathione (GSH) and Evans blue were measured spectrophotometrically. Furthermore, the protein levels of p38 mitogen-activated protein kinases (P38 MAPK), p-P38, signal transducer and activator of transcription 3 (STAT3), p-STAT3 and Poly (ADP-ribose) polymerase (PARP) were determined using Western blot. Cyclophosphamide administration significantly induced histopathological damages and increased MDA, p-p38/p38, p-STAT3/STAT3, and PARP levels compared with the saline group. Tropisetron treatment diminished histopathological injuries as well as MDA level, and STAT3 activity compared to cyclophosphamide treated rats. Co-administration of methyllycaconitine with tropisetron, partially or completely reversed the protective effects of tropisetron. Our results showed that prophylactic administration of tropisetron markedly ameliorated the cyclophosphamide-induced bladder hemorrhage and inflammation in rats. These effects of tropisetron were α7nAChR dependent.

Natural products as safeguards against monosodium glutamate-induced toxicity.

Monosodium glutamate is a sodium salt of a nonessential amino acid, L-glutamic acid, which is widely used in food industry. Glutamate plays an important role in principal brain functions including formation and stabilization of synapses, memory, cognition, learning, as well as cellular metabolism. However, ingestion of foodstuffs rich in monosodium glutamate can result in the outbreak of several health disorders such as neurotoxicity, hepatotoxicity, obesity and diabetes. The usage of medicinal plants and their natural products as a therapy against MSG used in food industry has been suggested to be protective. Calendula officinalis, Curcuma longa, Green Tea, Ginkgo biloba and vitamins are some of the main natural products with protective effect against mentioned monosodium glutamate toxicity through different mechanisms. This review provides a summary on the toxicity of monosodium glutamate and the protective effects of natural products against monosodium glutamate -induced toxicity.

Oxytocinergic system mediates the proconvulsant effects of sildenafil: The role of calcineurin.

Sildenafil is a phosphodiesterase type 5 inhibitor used to treat male erectile dysfunction and pulmonary hypertension. A potential side effect of sildenafil is a noticeable decrease in seizure threshold. Oxytocin (OXT) secretion and the subsequent cAMP-responsive element-binding (CREB) phosphorylation are involved in proconvulsant effects of sildenafil in experimental models. The aim of the present study was to investigate the potential role of OXT receptors and their downstream calcineurin (CN)/inducible nitric oxide synthase (iNOS) pathways in proconvulsant effects of sildenafil. The pentylenetetrazole (PTZ)-induced seizure was used as a standard convulsion model in this study. Cortical CN activity, hippocampal nitrite levels, and proinflammatory cytokine content were measured. Our results indicated that following PTZ administration, sildenafil significantly increased CN activity at 40 mg/kg, respectively, in the control group. The combination of sildenafil and OXT receptor antagonist, atosiban (10 µg/kg, i.c.v) 30 min before sildenafil administration significantly reduced the CN activity. Also, the subeffective dose of CN inhibitor cyclosporine (5 mg/kg) 30 min before the administration of effective dose of sildenafil (40 mg/kg) reversed proconvulsant actions of sildenafil. This effect was iNOS-dependent because pretreatment of a low dose of aminoguanidine (20 mg/kg) 15 min before the administration of a low dose of cyclosporine (1 mg/kg) reversed the proconvulsant action of sildenafil (40 mg/kg). Finally, sildenafil induced the elevation of tumor necrosis factor alpha (TNF-α) and the nitrite level was blocked by the administration of cyclosporine in PTZ-treated mice. Collectively, our data provide insights into the role of OXT receptor/CN/iNOS pathway in the proconvulsant aspect of sildenafil.

Curcumin and its analogues protect from endoplasmic reticulum stress: Mechanisms and pathways.

The endoplasmic reticulum (ER), a cellular organelle with multiple functions, plays an important role in several biological processes including protein folding, secretion, lipid biosynthesis, calcium homeostasis, and cellular stress. Accumulation of misfolded or unfolded proteins in the ER makes cells undergo a stress response known as the unfolded protein response (UPR). UPR is initially protective. However, prolonged and severe ER stress can lead to autophagy and/or the induction of apoptosis in stressed cell. Many studies have demonstrated that ER stress and the UPR are involved in different diseases such as neurodegenerative diseases, cancer, osteoporosis, diabetes, and inflammatory diseases. Curcumin, a natural polyphenol, has well documented evidence supporting its numerous biological properties including antioxidant, anti-inflammatory, immune-modulatory, anti-microbial, anti-ischemic, anti-angiogenesis, neuroprotective, hepatoprotective, nephroprotective, anti-atherogenic and anti-diabetic activities. In this review, the role of ER stress in several pathological condition and the potential protective effects of curcumin are discussed.

5-HT3 Receptor Antagonists in Neurologic and Neuropsychiatric Disorders: The Iceberg Still Lies beneath the Surface.

5-HT3 receptor antagonists, first introduced to the market in the mid-1980s, are proven efficient agents to counteract chemotherapy-induced emesis. Nonetheless, recent investigations have shed light on unappreciated dimensions of this class of compounds in conditions with an immunoinflammatory component as well as in neurologic and psychiatric disorders. The promising findings from multiple studies have unveiled several beneficial effects of these compounds in multiple sclerosis, stroke, Alzheimer disease, and Parkinson disease. Reports continue to uncover important roles for 5-HT3 receptors in the physiopathology of neuropsychiatric disorders, including depression, anxiety, drug abuse, and schizophrenia. This review addresses the potential of 5-HT3 receptor antagonists in neurology- and neuropsychiatry-related disorders. The broad therapeutic window and high compliance observed with these agents position them as suitable prototypes for the development of novel pharmacotherapeutics with higher efficacy and fewer adverse effects.

Immunoregulatory and anti-inflammatory properties of Crocus sativus (Saffron) and its main active constituents: A review.

The medicinal uses of saffron, the dried stigmas of Crocus sativus L., have very long history in food coloring agent, and flavoring agent as well as traditional medicine for the treatment of several diseases. Crocus sativus is rich in carotenoids that affect immunity. This review summarizes the putative immunoregulatory effects of saffron and its active its derivatives including crocin, crocetin and safranal. In modern studies, its active constituents including protective effects, anti-inflammatory activities and molecular mechanisms of saffron on thimmune system have been demonstrated. Furthermore, the beneficial effects of saffron on inhibition of serum levels nuclear transcription factor κB (NF-κB) p65 unit, tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ) and some interleukin (IL) such as IL-1ß, IL-6, IL-12, IL-17A were reported. Furthermore, saffron has been known as the antagonist of NF-κB and the agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ). In addition, saffron down-regulates the key pro-inflammatory enzymes such as myeloperoxidase (MPO), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), phospholipase A2, and prostanoids. This review summarizes the protective roles of C. sativus and its constituents against the pathogenesis of immune diseases and understanding a better management of these problems. Taken together, the main bioactive constituents of saffron may have health-promoting with important benefits in immune-related disorders. Finally, our study indicates that these bioactive constituents can affect both cellular and humoral immunity functions.

Mechanisms behind the atherothrombotic effects of acrolein, a review.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. The majority of cardiovascular complications are secondary to atherosclerosis. Extensive evidence has showed that environmental pollutants such as cigarette smoke and automobile exhaust increase the risk of developing atherosclerosis. Acrolein, a highly reactive unsaturated aldehyde, is found as a contaminant in air, food and water. Investigations during the last decades have shown that acrolein via various mechanisms such as oxidative stress, enhancement of inflammatory processes and the activation of matrix metalloproteases can initiate and accelerate atherosclerotic lesions formation. Furthermore, exposure to acrolein has been suggested to induce or exacerbate systemic dyslipidemia, an important risk factor for the development of atherosclerosis. Finally, there are reports which indicate acrolein can increase platelet activation and stimulation of the coagulation cascade which subsequently leads to thrombosis. Even a modest reduction of pollutants such as acrolein can have substantial effects on population health. Public health efforts to reduce acrolein exposures from known sources may lower the prevalence of vascular disease. This review focuses on the potential pathways and mechanisms behind the acrolein-induced atherothrombotic effects.

Antidotes for aluminum phosphide poisoning - An update.

Aluminum phosphide (AlP), an inexpensive solid fumigant, is frequently used for grain conservation despite its alleged high toxicity. Increased utilization of AlP for agricultural and non-agricultural purposes during the last four decades has resulted in increment of AlP-attributed poisoning numbers. Moreover, due to its limitless accessibility in developing countries, AlP has been increasingly used for suicide. Moisture-exposed AlP undergoes a chemical reaction producing phosphine gas, which in turn inhibits cytochrome oxidase and impedes cellular oxygen consumption. Lethality remains elevated reaching rates of >50% and no effective antidote is available. Nevertheless, experimental and clinical studies suggested that magnesium sulfate, melatonin, N-acetylcysteine, glutathione, sodium selenite, vitamin C and E, triiodothyronine, liothyronine, vasopressin, milrinone, Laurus nobilis L., 6-aminonicotinamide, boric acid, acetyl-L-carnitine and coconut oil, may serve as antidotes by reducing the deleterious oxidative properties of AlP. This article reviews the afore-mentioned chemicals suggested to specifically treat AlP poisoning and discusses their protective mechanisms and main outcomes.

Crosstalk in cancer resistance and metastasis.

The main obstacles that lead to clinical failure in cancer treatment are the development of resistant to chemotherapy and a rise in invasive characteristics in cancer tumor cells due to prolonged chemotherapeutic processes. Recent studies have revealed some evidence about the existence of a direct relationship between development of drug resistance and triggering of invasive capability in tumor cells. Therefore, devising and application of chemotherapeutic procedures that are not prone to the development of chemotherapy resistance are necessary. Here, we focus on CD147, CD44, ANAX2, P-gp, MMPs, and UCH-L1 proteins involved in the crosstalk between metastasis and cancer treatment. We think that further structural and functional analysis of these proteins may direct scientists towards designing highly effective chemotherapy procedures.

Computer-aided Drug Design and Drug Pharmacokinetic Prediction: A Mini-review.

Prediction of pharmacokinetics and drug targeting is a challenge in drug design. There are different types of software that can help to predict the pharmacokinetic profile of a drug. Quantitative structure-activity relationship (QSAR) modeling is used for drug design with less cost. Drug-excipient interactions are predicted by docking tools. Computerized drug target prediction and docking programs offer additional options to predict potential effects and adverse reactions of a given candidate as well as the best orientation of the compound on the receptor active site. Information on the absorption, distribution, metabolism and excretion of the drug in the body can enhance prediction of drug release and distribution in the blood and central nervous system (CNS). Computer- aided drug design and delivery can help to save the time and cost in the process of rational drug development.

Ellagic Acid: A Logical Lead for Drug Development?

BACKGROUND: Naturally occurring polyphenols are the subject of increasing attention due to their potent antioxidant activity and their marked effects on the prevention of various oxidative stress-associated diseases such as cancer. Ellagic acid (EA) is an herbal polyphenol that is structurally a condensed dimer of gallic acid. METHODS: This review aims to provide a comprehensive and updated overview on the biological activities of EA and potential therapeutic applications. RESULTS: EA is found in fruits and nuts, either in the combined form with hexahydroxydiphenic acid or in the bound form (ellagitannins). EA exhibits many biological properties such as antioxidant, anti-diabetic, anticancer and apoptosis-inducing activities. These biological and pharmacological properties are relevant to the treatment of several human diseases. CONCLUSION: Owing to its multiple mechanisms of action, EA represents a potential therapeutic agent against human diseases particularly cancer.

Protective effects of tropisetron on cerulein-induced acute pancreatitis in mice.

Acute pancreatitis (AP) causes morbidity and mortality. The aim of the present study was to investigate the protective effect of tropisetron against AP induced by cerulein. Cerulein (50µg/kg, 5 doses) was used to induce AP in mice. Six hours after final cerulein injection, animals were decapitated. Hepatic/pancreatic enzymes in the serum, pancreatic content of malondialdehyde (MDA), pro-inflammatory cytokines and myeloperoxidase (MPO) activity were measured. Tropisetron significantly attenuated pancreatic injury markers and decreased the amount of elevated serum amylase, lipase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), MPO activities and pro-inflammatory cytokines levels caused by AP in mice. Tropisetron didn't affect the pancreatic levels of MDA. Our results suggest that tropisetron could attenuate cerulein-induced AP by combating inflammatory signaling. Further clinical studies are needed to confirm its efficacy in patients with AP.