Current Molecular Pharmacology - Volume 11, Issue 4, 2018

Objective: Sepsis, a serious and life threatening complication arising from infection caused by lipopolysaccharide, is a complex inflammatory syndrome, and one of the main causes of death in intensive care units (ICU). It is characterized as an over-response of pro-coagulant agents promotes coagulopathy and thrombus formation, resulting in disseminated intravascular coagulation (DIC). Furthermore, it can cause multiple organ dysfunction and hypotension (septic shock) resulting in death. Thrombocytopenia, which is a hallmark of sepsis, is strongly correlated as a negative marker of the infection. Additionally, platelets contribute with the oxidative stress in septic patients in order to exterminate the microbial pathogen. This review summarises the important role of platelets in the pathology of sepsis, and highlights potential treatment targets to improve the outcome of sceptic patients. Methods: The search was performed in PubMed, books and retrieved journal articles for a period of three months. The figures were developed through Servier Medical Arts software. Conclusion: The exact treatment of sepsis is still the subject of considerable debate. Although here we presented several therapies that have shown promise for improving the outcome of patients, researching platelet function in sepsis has provided us targets to develop new medical approaches focusing specially on thrombocytopenia and DIC.

Background: The brain is a vital part of the central nervous system (CNS), characterized by the presence of soft tissue in its internal structure which protects itself. Research on design of drugs for CNS disorders is in progress and up to date information is required for further investigation. Objective: The present paper is written with the objective to compile all the available data and information on CNS disorders and CNS acting drugs. CNS acting drugs are important to consider because some drugs get ineffective owing to incapability to efficiently deliver and sustain them within the brain for effective treatment. CNS Disorders: The current trend to design therapeutic drugs for CNS disorders focuses on neurotransmitters release and their reuptake, including Parkinson's, Alzheimer's, and other CNS disorders. The disorders associated with CNS are characterized by the progressive loss of gray matter and/or white matter structures. Drugs: CNS stimulants are the class of drugs, producing response to alleviate a particular medical condition. CNS stimulants improve the brain function in patients with schizophrenia and related diseases. CNS stimulants are a class of therapeutic drugs used to treat CNS disorder including the conditions like lack of adrenergic stimulation, symptoms of narcolepsy and neonatal apnea, etc. Apart from drugs, a number of smart tools including Multi-Target Designed Ligands (MTDL) and “predictor” models are contemporarily used to design therapeutic agents for CNS disorders. Mechanism: The majority of CNS stimulants causes stimulation of the traditional "fight or flight" syndrome which is concerned with activation of sympathetic nervous system. These neurotransmitters associated receptors are concerned in drug abuse and addiction withdrawal related phenomenon. Conclusion: The present review embarks on detail up-to-date information on CNS stimulant drugs, their mechanism of action, in vivo models for biological evaluations with major emphasis on tools in design of therapeutic drugs for CNS disorders.

Background and Objective: Sphingolipid metabolites, including ceramide, sphingosine, and their phosphorylates (ceramide-1-phosphonate [C1P] and sphingosine-1-phosphate [S1P]), regulate diverse cellular processes including apoptosis, the cell cycle, and cellular differentiation. Recent studies have shown that these sphingolipid metabolites are generated in response to ototoxic agents and play important roles in determining the fate of cochlear hair cells in ototoxic injury. Methods: This review summarizes the current knowledge on the roles of sphingolipid mediators in cochlear ototoxicity. Results: During ototoxicity, ceramide is mainly generated via sphingomyelinase in the cochlea through a ceramide/sphingomyelin cycle from sphingomyelin. The generated ceramide is converted to other sphingolipid mediators. Ceramide and sphingosine accelerate cochlear hair cell death induced by ototoxic agents, while, C1P and S1P, on the other hand, protect cochlear hair cells. Hair cell protection of S1P is mediated by S1P receptor subtype 2 (S1PR2). Conclusion: Sphingolipid mediators play important roles in cochlear hair cell survival or death in ototoxic injury.

Background: Nowadays, ionizing radiations are used for various medical and terroristic aims. These purposes involve exposure to ionizing radiations. Hence, people are at risk for acute or late effects. Annually, millions of cancer patients undergo radiotherapy during their course of treatment. Also, some radiological or nuclear events in recent years pose a threat to people, hence the need for radiation mitigation strategies. Amifostine, the first FDA approved radioprotector, has shown some toxicities that limit its usage and efficiency. Due to these side effects, scientists have researched for other agents with less toxicity for better radioprotection and possible mitigation of the lethal effects of ionizing radiations after an accidental exposure. Flavonoids have shown promising results for radioprotection and can be administered in higher doses with less toxicity. Studies for mitigation of ionizing radiation-induced toxicities have concentrated on natural antioxidants. Detoxification of free radicals, management of inflammatory responses and attenuation of apoptosis signaling pathways in radiosensitive organs are the main mechanisms for radiation protection and mitigation with flavonoids and natural antioxidants. However, several studies have proposed that a combination in the form of some antioxidants may alleviate radiation toxicities more effectively in comparison to a single form of antioxidants. Conclusion: In this review, we focus on recent findings about natural radioprotectors and mitigators which are clinically applicable for radiotherapy patients, as well as injured people in possible radiation accidents.

Background and Objective: Ezrin links the cortical cytoskeleton to the plasma membrane and plays a role in regulating changes in cell shape. Recently, NSC668394 has been shown to inhibit a key step for its activity, i.e. phosphorylation at threonine 567. In neutrophils, another key regulatory step is the Ca2+-mediated cleavage of ezrin by calpain. Methods: In this paper, we use NSC668394 as a pharmacological inhibitor to investigate the interplay between these two steps in regulating changes in neutrophil shape. Results: NSC668394 reduced the amount of peripherally located ezrin in neutrophils, and increased Ca2+-dependent ezrin cleavage. Neutrophils with NSC668394-inhibited ezrin phosphorylation remained both phagocytic and chemotactically competent. However, phagocytosis was slightly impaired and chemotaxis could not be maintained over longer periods. The characteristic chemotactic morphology which neutrophils adopt was also aberrant. Although phosphorylation of ezrin plays a minor role in limiting the rapid changes in cell shape in neutrophils, inhibition of ezrin phosphorylation by NSC668394 prevented multiple and prolonged shape changes during extended chemotaxis. Conclusion: The susceptibility of prolonged chemotaxis to inhibition by NSC668394 may point to a useful target for anti-inflammatory therapy. Inhibition of neutrophil chemotaxis towards chronically inflamed sites without compromising their ability to undergo phagocytosis is a much sought after the effect of anti-neutrophil therapy.

Objective: To explore the mechanism by which lobaplatin, as monotherapy and in combination with paclitaxel, inhibits the proliferation of human gastric cancer SGC-7901 cells. Methods: After treatment, the MTT assay was used to assess cell viability; cell cycle distribution was evaluated flow-cytometrically. Western blot was used to quantitate cyclin D1, E1, B1, and Cdk2/4 protein levels. Results: Lobaplatin and paclitaxel inhibited SGC-7901 cell growth in a concentration and timedependent manner, with IC25 values at 48h of 1.97±0.17μg/ml and 1.98±0.19 ng/ml, respectively. Interestingly, both drugs synergistically inhibited SGC-7901 cells (combination index [CI]<0.95). Lobaplatin did not affect cyclin D1 and CDK4 protein expression, while cyclin E1 and CDK2 levels were significantly increased, with cyclin B1 amounts markedly decreased (p<0.05). More S phase cells were observed after lobaplatin treatment compared with controls (60.03±1.25 vs. 18.69±0.96%; p<0.05). After treatment with paclitaxel, cyclin D1 and CDK4 protein levels were similar to control values; meanwhile, cylinE1 and CDK2 protein amounts were reduced, with increased cyclin B1 levels, compared with control values (p<0.05). More G2/M cells were obtained after treatment with paclitaxel compared with control values (74.54±0.92 vs. 18.62±0.44% (p<0.05). Lobaplatin and paclitaxel combination did not affect cyclin D1 and CDK4 protein levels (p>0.05); meanwhile, cyclin E1 and CDK2 levels were increased, with reduced cyclin B1 amounts, compared with control values (p<0.05). Notably, more S (43.23±0.81 vs. 22.32±0.86%) and G2/M (31.22±0.96 vs. 25.81±2.08%) phase cells were obtained after combined treatment compared with control values. Conclusion: Lobaplatin and paclitaxel synergistically inhibit SGC-7901 cells.

Purpose: Radiation causes damage to irradiated tissues and also tissues that do not receive direct irradiation through a phenomenon called bystander effects. Melatonin as a potent antioxidant and anti-inflammatory agent is known for protection of normal tissues against ionizing irradiation. In addition, some studies have suggested that Melatonin may have some anti-cancer properties. Although the complete mechanisms remain unknown, it can act via immunomodulatory effects. The aim of this study was to evaluate the effect of pretreatment with melatonin on oxidative damage caused by direct irradiation and bystander effects on the lung and heart tissue after xenograft mice colon cancer irradiation in Balb/c mice. Materials and Methods: Forty nine (49) Balb/c mice were evenly divided into 7 groups including control, irradiation of 5 Gy directly to tumor, melatonin treatment (20 mg/kg) and irradiation (5 Gy single fraction) directly to tumor, irradiation of 5 Gy directly to chest area, melatonin treatment (20 mg/kg) and radiation directly to chest, only melatonin treatment and whole-body scatter group (which gave radiation dose equal to the amount of radiation that the lung had received from the localized pelvic irradiation) to evaluate the effect of melatonin on the MDA level as well as SOD and GPx activity after 24 and 72 h of irradiation of 5 Gy single fraction directly to the tumor tissue and chest area, in the tumor tissue, the lung tissue, and the heart tissue. Results: The results revealed that exposure to irradiation resulted in an increase in MDA level and suppressed SOD and GPx activity in the targeted and non-targeted lung and heart tissues, and the tumor tissue. Melatonin decreased MDA level in the lung and heart tissues. Also, melatonin improved SOD and GPx activity in non-targeted tissues, while it was able to reduce these two enzymes and decreased MDA level in the tumor tissue. Conclusion: Melatonin exhibited its ability to ameliorate oxidative stress in both targeted and nontargeted tissues. Administration of melatonin boosted SOD and GPx activity in the normal tissues, but not in the tumor cells. Through stimulation and suppression of the antioxidant system, Melatonin may cause sensitization of the tumor cells while protecting the normal tissues.

Background: Besides the first-line medication for the treatment of type 2 diabetes, the growth inhibitory activity of metformin alone or in combination with conventional chemotherapeutics has been addressed on a panel of cell lines. In this study, we investigated the cytotoxicity and apoptosis of the metformin alone and in combination with dacarbazine in Raji and Ramos lymphoma cell lines. Methods: Cell viability and apoptosis measured using resazurin assay, flow cytometry of PI stained cells and western blot analysis. Results: Metformin showed synergistic cytotoxic effects in combination with dacarbazine, reduced cell viability, and increased apoptosis in Raji and Ramos lymphoma cells in comparison with the use of each drug alone. The activation of MAPK and SAPK/JNK (P-SAPK/JNK) were shown in both cells. Conclusion: Overall, the result verified the synergistic effect of the metformin-dacarbazine combination, which has the value in reducing the chemotherapeutic agent dose, adverse effect and the burden of treatment for the community and patients.