Phytochemicals as inhibitors of tumor necrosis factor alpha and neuroinflammatory responses in neurodegenerative diseases.

Inflammatory processes and proinflammatory cytokines have a key role in the cellular processes of neurodegenerative diseases and are linked to the pathogenesis of functional and mental health disorders. Tumor necrosis factor alpha has been reported to play a major role in the central nervous system in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis and many other neurodegenerative diseases. Therefore, a potent proinflammatory/proapoptotic tumor necrosis factor alpha could be a strong candidate for targeted therapy. Plant derivatives have now become promising candidates as therapeutic agents because of their antioxidant and chemical characteristics, and anti-inflammatory features. Recently, phytochemicals including flavonoids, terpenoids, alkaloids, and lignans have generated interest as tumor necrosis factor alpha inhibitor candidates for a number of diseases involving inflammation within the nervous system. In this review, we discuss how phytochemicals as tumor necrosis factor alpha inhibitors are a therapeutic strategy targeting neurodegeneration.

Update on Statin Treatment in Patients with Neuropsychiatric Disorders.

Statins are widely accepted as first-choice agents for the prevention of lipid-related cardiovascular diseases. These drugs have both anti-inflammatory and anti-oxidant properties, which may also make them effective as potential treatment marked by perturbations in these pathways, such as some neuropsychiatric disorders. In this narrative review, we have investigated the effects of statin therapy in individuals suffering from major depressive disorder (MDD), schizophrenia, anxiety, obsessive-compulsive disorder (OCD), bipolar disorder (BD), delirium, and autism spectrum disorders using a broad online search of electronic databases. We also explored the adverse effects of these drugs to obtain insights into the benefits and risks associated with their use in the treatment of these disorders. Lipophilic statins (including simvastatin) because of better brain penetrance may have greater protective effects against MDD and schizophrenia. The significant positive effects of statins in the treatment of anxiety disorders without any serious adverse side effects were shown in numerous studies. In OCD, BD, and delirium, limitations, and contradictions in the available data make it difficult to draw conclusions on any positive effect of statins. The positive effects of simvastatin in autism disorders have been evaluated in only a small number of clinical trials. Although some studies showed positive effect of statins in some neuropsychiatric disorders, further prospective studies are needed to confirm this and define the most effective doses and treatment durations.

RNA Silencing in the Management of Dyslipidemias.

PURPOSE OF REVIEW: Remarkable reductions in cardiovascular morbidity and mortality have been achieved in recent decades through the widespread use of 'small-molecule' hypolipidaemic drugs such as statins and ezetimibe. An alternative approach is to perturb the production of proteins through ribonucleic acid (RNA) silencing, leading to long-lasting knock-down of specific biological molecules. This review describes the scientific basis of RNA silencing, and critically evaluates the evidence relating to inclisiran, a small interfering RNA against proprotein convertase subtilisin kexin 9 (PCSK9). RECENT FINDINGS: Pooled analysis of three recent ORION trials has demonstrated that twice-yearly administration of inclisiran reduces LDL-C by 50% in a range of patient groups, with only mild adverse effects. Inclisiran provides safe, effective and long-lasting reductions in PCSK9 and LDL-C. The results of the phase-3 ORION-4 outcomes study are eagerly awaited. Further promising RNA silencing technologies have the potential to improve the management of dyslipidaemia.

Effects of statins on brain tumors: a review.

Evidence from preclinical studies suggests that the competitive HMG-CoA reductase (HMGCR) inhibitors universally known as 'statins,' in addition to being powerful drugs that reduce cholesterol and improve cardiovascular risk, also have promising antitumor properties. Statins appear to enhance the treatment outcome of various cancers before and concurrent with other cancer treatment interventions. Glioblastoma multiforme (GBM), a particularly invasive cerebral tumor associated with high mortality, holds a poor median overall survival (OS) of around one year after surgical resection followed by concurrent radiation and chemotherapy. Recently, statins have increasingly appeared as potential adjuvant drugs for the treatment of GBM because of their potential to suppress cell growth, survival, migration, metastasis, inflammation, angiogenesis, and promote apoptosis during both in vitro and in vivo studies. However, the clinical outcomes of statins on the survival of patients with GBM are still controversial. This study aims to review and address some of the documented effects of statin drugs when focusing entirely on cancer treatment, especially GBM, including concurrent statin therapy with chemotherapeutic agents.

Protective Effects of Curcumin in the Reproductive System: Anti-toxic, Semen Cryopreservative, and Contraceptive Actions.

Human daily exposure to various chemical and biological agents is growing due to modern life, and most of these chronic or acute exposures lead to important recognized toxicities. Multiple tissues and body systems could be affected following these exposures and among them is the human reproductive system, which is very vulnerable to toxins. Here we focus mainly on the male reproductive system, and available data show that various exogenous materials could have negative effects on male reproductive parameters. Interestingly, the well-known antioxidant natural product curcumin may have properties which could diminish these toxic effects. Curcumin has also shown some promise in the cryoprotection of sperm samples through its antioxidant potential. Finally, limited data exists on the putative contraceptive activity of curcumin. This narrative review aims to appraise the activity of curcumin within these topics through the available data.

Vernakalant hydrochloride for the treatment of atrial fibrillation: evaluation of its place in clinical practice.

Vernakalant is an intravenous anti-arrhythmic drug available in Europe, Canada and some countries in Asia for the restoration of sinus rhythm in acute onset atrial fibrillation. Currently, it is not available in USA because the US FDA have ongoing concerns about its safety. Vernakalant has a unique pharmacological profile of multi-ion channel activity and atrial-specificity that distinguishes it from other anti-arrhythmic drugs. This is thought to enhance efficacy but there are concerns of adverse events stemming from its diverse pharmacology. This ambiguity has prompted a review of the available clinical evidence on efficacy and safety to help re-evaluate its place in clinical practice.

Neuroprotection by curcumin: A review on brain delivery strategies.

Neurodegenerative diseases are a major global public health concern in the elderly population but therapeutic options are limited. Curcumin is a hydrophobic polyphenol extracted from the dried rhizomes of Curcuma longa L. and shows good potential for the treatment of neurodegenerative diseases and brain tumors. The blood-brain barrier (BBB) is the major obstacle for the delivery of curcumin into the brain, limiting its therapeutic potential. The development of promising approaches to facilitate curcumin transportation across the BBB may resolve some of the problems associated with drug delivery. Studies have shown nano delivery of curcumin can improve a number of outcome measures in neurodegenerative diseases. The present review highlights current and emerging strategies to facilitate curcumin permeation across the BBB for the treatment of various neurodegenerative diseases.

The role of nuclear factors as "Find-Me"/alarmin signals and immunostimulation in defective efferocytosis and related disorders.

Efferocytosis as an apoptotic cell (AC) clearance mechanism facilitates the removal of dangerous and damaged cells, an important process in regulating normal homeostasis. Failure to correctly execute apoptosis and efferocytosis is associated with atherosclerosis, as well as chronic inflammatory and autoimmune disorders such as systemic lupus erythematosus (SLE). Effective and timely efferocytosis involves various molecules that act as "Find-Me" signals or as alarmins to quickly allow identification by phagocytic cells. In recent years, most of these molecules have been investigated, but less attention has been paid to the nuclear molecules associated with efferocytosis of ACs and necrotic cells (NCs). These molecules have several functions including acting as alarmin signals for faster recognition of ACs, facilitating the cleanup of ACs and for maintaining self-tolerance. The same group of molecules is also implicated in several inflammatory and autoimmune diseases. Previous studies have shown that these molecules also serve as targets for pharmacological agents such as necrostatins, recombinant Fcnb, anti-histone, neutralizing antibodies, calbiochem, aminophylline, activated protein C, CD24IgG recombinant fission protein, and recombinant thrombomodulin. Thus, greater understanding of these molecules/pathways will enable developments in the treatment and/or prevention of various disorders, especially autoimmune diseases. Here, we review current knowledge about the mechanisms by which nucleic acids, histones, nucleosomes and monosodium urate microcrystals (MSU) can act as alarmins/"Find-Me" signals, how they might be stimulated in defective efferocytosis and their function and importance as biomarkers for prognosis and treatment of atherosclerosis, inflammatory disorders and autoimmune diseases.

Neuromodulatory effects of anti-diabetes medications: A mechanistic review.

Diabetes mellitus is a potent upstream event in the molecular pathophysiology which gives rise to various diabetes-related complications. There are several classes of anti-diabetic medications that have been developed to normalize blood glucose concentrations through a variety of molecular mechanisms. Beyond glucose-lowering effects, these agents may also provide further therapeutic potential. For instance, there is a high incidence of diabetes-induced neuronal disorders among patients with diabetes, who may also develop neurodegenerative and psychological complications. If anti-diabetic agents can modify the molecular mechanisms involved in the pathophysiology of neuronal comorbidities, this could potentially be translated to reducing the risk of other neurological conditions such as Alzheimer's disease, Parkinson's disease, depression, memory deficits and cognition impairments among patients with diabetes. This review aimed to shed light on some of the potentially beneficial aspects of anti-diabetic agents in lowering the risk or treating neuronal disorders by reviewing the molecular mechanisms by which these agents can potentially modulate neuronal behaviors.

A survey of antibiotic administration practices involving patients with sepsis in UK critical care units.

Background Alternative administration methods are emerging as a key area of research to improve clinical efficacy of antibiotics and address concerns regarding multi-drug resistance. Extended intermittent infusions or continuous infusions of antibiotics exhibiting time-dependent kill characteristics may be favourable in critically ill septic patients, but more evidence is needed to determine best practice. Objective To find out whether any common practice exists for intravenous antibiotic administration in critical care units across UK NHS Trusts, and identify factors influencing the adoption of extended or continuous infusions. Setting UK hospitals. Method UK critical care pharmacists were invited to participate in a survey on behalf of all 240 critical care units via a UK Clinical Pharmacy Association message board. The survey focused on administration practices for 22 antibacterial agents. Main outcome measure Antibiotic administration method. Results Responses were received covering 64 units, a response rate of 26.2%. Common, but not uniform administration methods were apparent for 17/22 antibiotics. Four antibiotics (piperacillin/tazobactam, doripenem, meropenem and vancomycin) were more likely to be administered as continuous or extended-intermittent infusions. Choice of administration method was especially influenced by altered pk/pd properties in sepsis or severe burns patients, or by the presence of organisms requiring high minimal inhibitory concentrations. Conclusion Unlicensed alternative practices of antibiotic administration are widespread but only weak evidence exists of any patient benefit, such as reduced length of stay in critical care, and none showing improvement in mortality. Further research is needed to determine whether extended infusion methods offer clinically meaningful advantages over shorter licenced administration methods in patients in critical care units.

A large-conductance (BK) potassium channel subtype affects both growth and mineralization of human osteoblasts.

The pharmacology of the large-conductance K(+) (BK) channel in human osteoblasts is not well defined, and its role in bone is speculative. Here we assess BK channel properties in MG63 cells and primary human osteoblasts and determine whether pharmacological modulation affects cell function. We used RT-PCR and patch-clamp methods to determine the expression of BK channel subunits and cell number assays in the absence and presence of BK channel modulators. RT-PCR showed the presence of KCNMA1, KCNMB1, KCNMB2, KCNMB3, and KCNMB4 subunits. The BK channel was voltage dependent, with a mean unitary conductance of 228.8 pS (n = 10) in cell-attached patches (140 mM K(+)/140 mM K(+)) and a conductance of 142.5 pS (n = 16) in excised outside-out and 155 pS (n = 6) in inside-out patches in 3 mM K(+)/140 mM K(+). The selectivity ratio (ratio of K(+) to Na(+) permeability) was 15:1. The channel was blocked by tetraethylammonium (TEA, 0.3 mM), iberiotoxin (5-60 nM), tetrandrine (5-30 microM), and paxilline (10 microM) and activated by isopimaric acid (20 microM). BK channel modulators affected MG63 cell numbers: TEA and tetrandrine significantly increased cell numbers at low concentrations (3 mM and 3 microM, respectively) and reduced cell numbers at higher concentrations (>10 mM and >10 microM, respectively). Neither iberiotoxin (20-300 nM) nor slotoxin (300 nM) affected cell numbers. The increase in cell numbers by TEA was blocked by isopimaric acid. TEA (0.1-3.0 mM) significantly increased mineralization in primary osteoblasts. In conclusion, the BK channel has a distinctive pharmacology and is thus a target for therapeutic strategies aimed at modulating osteoblast proliferation and function.