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Topic Review
Voltage Gated Ion Channels
Safety Pharmacology is one of the most dynamically developing disciplines, whose objective is to assess the potential risks of improperly conducted pharmacotherapy. Evaluation of a potential risks in the use of a given substance is vital for placing a new medicine on the market. The Organisation for Economic Co-operation and Development (OECD) has issued a number of guidelines for drug safety testing [1, 2]. However, the continuous development of medicine demands the extension and refinement of the test panel that a new molecule must undergo before it can be released for use by patients. Toxic effects of compounds on the most important organs are among the most frequent reasons of elimination of substances from further tests. Additionally, safety tests are also performed for medicines already approved for use. Such trials are required, e.g., to register new indications for "old" drugs.  The above mentioned activities require a suitable identifications of the antitargets which are commonly defined as undesirable molecular targets that play an essential role in the proper functioning of cells. Down modulation of an antitarget results in clinically unacceptable side effects, initiation of disease, or deleterious alterations in disease progression. This results in shorter onset time of the disease, increased disease burden, poorer patient outcome, or decreased survival time.
  • 1.3K
  • 27 Jan 2021
Topic Review
Combination Therapies in Alzheimer’s Disease
Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Until now, available therapeutic agents for AD treatment only provide symptomatic treatment. Since AD pathogenesis is multifactorial, use of a multimodal therapeutic intervention addressing several molecular targets of AD-related pathological processes seems to be the most practical approach to modify the course of AD progression. It has been demonstrated through numerous studies, that the clinical efficacy of combination therapy (CT) is higher than that of monotherapy. It is indeed difficult to combine several pharmacophores into a single molecule.  It is essential to carry out long-duration randomized controlled trials to establish whether CT delays disease progression in early AD stages. Other factors also need to be assessed in CT, such as its potential neuroprotective effects, cost-effectiveness, and a more exhaustive estimation of its potential benefits on the patients at the end-stage of AD.
  • 1.3K
  • 28 Oct 2020
Topic Review
Inhibiting Angiogenesis by Anti-Cancer Saponins
Saponins are one of the broadest classes of high-molecular-weight natural compounds, consisting mainly of a non-polar moiety with 27 to 30 carbons and a polar moiety containing sugars attached to the sapogenin structure. Saponins are found in more than 100 plant families as well as found in marine organisms. Saponins have several therapeutic effects, including their administration in the treatment of various cancers. These compounds also reveal noteworthy anti-angiogenesis effects as one of the critical strategies for inhibiting cancer growth and metastasis.
  • 1.3K
  • 24 Mar 2023
Topic Review
Propofol Sedation
Propofol is a commonly used intravenous sedative for ventilator-dependent patients. Its advantage over other sedative agents, such as benzodiazepines, is in its rapid onset and short half-life which allows for daily awakening and spontaneous breathing trials. The use of propofol is recommended by the Brain Trauma Foundation for the treatment of elevated intracranial pressure and sometimes prolonged continuous large doses are required.
  • 1.3K
  • 07 Jul 2021
Topic Review
Chronicles of Nanoerythrosomes
Nanoerythrosomes (NERs) are the carrier erythrocytes (C-ERs) which are recognized as modern day, novel, and smart drug delivery systems associated with increased bioavailability, improved pharmacokinetics, and low toxicity.
  • 1.3K
  • 30 Apr 2021
Topic Review
The Role of Saponins in the Neuropathic Pain
Neuropathic pain is a chronic pain caused by tissue injury or disease involving the somatosensory nervous system, which seriously affects the patient’s body function and quality of life. Saponins are a class of compounds with diverse structures, consisting of sapogenin and glycosyl groups. The common ones of the saccharides that make up saponins are D-glucose, D-galactose, D-xylose, L-arabinose, and L-rhamnose, etc.
  • 1.3K
  • 18 Jul 2022
Topic Review
Strategies for Improving Transdermal Administration
A transdermal delivery system is a painless method of drug administration through intact skin. Transdermal patches favor the controlled release of active ingredients through the skin into systemic circulation.Substances with analgesic effects can be administered on the skin in the form of topical patches made to produce local effects or transdermal patches that ensure the controlled and prolonged release of the active substance.
  • 1.3K
  • 18 Apr 2023
Topic Review
Biomedical Applications of Modified Dextran
Native DEX (Dextran) exhibits low-cell-adhesive properties and in order to obtain hydrogels with controlled cell-scaffold interactions, specific molecules must be incorporated. Many research groups have chemically modified DEX by introducing functional groups into the molecule through cross-linking reactions, therefore improving mechanical strength and drug-loading ability and increasing the number of compound classes that can be obtained. Furthermore, DEX has been shown to have metal chelating activity and antioxidant properties, as well as antitumour activity by regulating apoptosis and autophagy.
  • 1.3K
  • 10 Feb 2023
Topic Review
Matrix Metalloproteinases
Matrix metalloproteinases (MMPs) are zinc-dependent proteases that have been extensively studied in the context of extracellular matrix (ECM) breakdown and remodelling.
  • 1.3K
  • 18 Mar 2021
Topic Review
Polymicrobial-Sepsis
Cecal ligation and puncture (CLP) is an experimental polymicrobial sepsis induced systemic inflammation that leads to acute organ failure. Aim of our study was to evaluate the effects of SP600125, a specific c-Jun NH2-terminal kinase (JNK) inhibitor, to modulate the early and late steps of the inflammatory cascade in a murine model of CLP-induced sepsis. CB57BL/6J mice were subjected to CLP or sham operation. Animals were randomized to receive either SP600125 (15 mg/kg) or its vehicle intraperitoneally 1 hour after surgery and repeat treatment every 24 hours. To evaluate survival, a group of animals was monitored every 24 hours for 120 hours. Two other animals were sacrificed 4 or 18 hours after surgical procedures; lung and liver samples were collected for biomolecular and histopathologic analysis. The expression of p-JNK, p-ERK, TNF-α, HMGB-1, NF-κB, Ras, Rho, Caspase 3, Bcl-2, and Bax was evaluated in lung and liver samples; SP600125 improved survival, reduced CLP induced activation of JNK, NF-κB, TNF-α, and HMGB-1, inhibited proapoptotic pathway, preserved Bcl-2 expression, and reduced histologic damage in both lung and liver of septic mice. SP600125 protects against CLP induced sepsis by blocking JNK signalling; therefore, it can be considered a therapeutic approach in human sepsis.
  • 1.3K
  • 01 Nov 2020
Topic Review
Mithramycin
Mithramycin is an antineoplastic antibiotic. The use of mithramycin has been previously limited by its narrow therapeutic window. Recent advances in semisynthetic methods have led to mithramycin analogs with improved pharmacological profiles. Mithramycin inhibits the activity of the transcription factor Sp1, which is closely linked with ovarian tumorigenesis and platinum-resistance.
  • 1.3K
  • 02 Feb 2021
Topic Review
Neurogliovascular Unit and Cerebral-microvascular Disease
The distinctive anatomical assemble and functionally discrete multicellular cerebrovasculature dynamics confer varying rheological and blood–brain barrier (BBB) permeabilities to preserve the integrity of cerebral white matter and its neural microenvironment. This homeostasis intricately involves the neurogliovascular unit (NGVU) and glymphatic system that manages the flow of cerebrospinal fluid (CSF), interstitial fluids (ISF), metabolic waste, and clearance through the venous circulation. NGVU refers to the integration of neuronal structures, glial cells (including the microglial), and vasculature (i.e., capillaries, arteries, and/or arterioles) governed by the astrocytes.
  • 1.3K
  • 16 Aug 2021
Topic Review
Type 2 Diabetes and P450
 The most frequent form of diabetes is type 2 diabetes mellitus (T2DM) which is often part of a metabolic syndrome (hyperglycaemia, hypertension, hypercholesterolemia, abdominal obesity) that usually requires the use of several medications from different drug classes to bring each of these conditions under control. T2DM is associated with an increase in inflammatory markers such as interleukin-6 (IL-6) and the tumor necrosis factor alpha (TNF-α). Higher levels of IL-6 and TNF-α are associated with a downregulation of several drug metabolizing enzymes, especially the cytochrome P450 (P450) isoforms CYP3As and CYP2C19. A decrease in these P450 isoenzymes may lead to unexpected rise in plasma levels of substrates of these enzymes. It could also give rise to a mismatch between the genotypes determined for these enzymes, the predicted phenotypes based on these genotypes and the phenotypes observed clinically. This phenomenon is described as phenoconversion. Phenoconversion typically results from either a disease (such as T2DM) or concomitant administration of medications inducing or inhibiting (including competitive or non-competitive inhibition) a P450 isoenzyme used by other substrates for their elimination. Phenoconversion could have a significant impact on drug effects and genotypic-focused clinical outcomes.
  • 1.3K
  • 11 Oct 2021
Topic Review
Fenretinide in Cancer and Neurological Disease
Cancer and neurodegeneration share leadership as causes of morbidity and death worldwide. They can be thought as disease mechanisms at opposite ends: while in neurodegeneration, induction of inflammatory genes and suppression of cell-cycle genes are the prominent signals; the opposite happens in cancer. Fenretinide (all-trans-N-(4-hydroxyphenyl) retinamide, 4-HPR) is a synthetic derivative of all-trans-retinoic acid initially proposed in anticancer therapy for its antitumor effects combined with limited toxicity. It is also studied in many other diseases for its ability to influence several biological pathways and provide a broad spectrum of pharmacological effects.
  • 1.3K
  • 18 Jul 2022
Topic Review
PKSIII
A putative Type III Polyketide synthase (PKSIII) encoding gene was identified from a marine yeast, Naganishia uzbekistanensis strain Mo29 (UBOCC-A-208024) (formerly named as Cryptococcus sp.) isolated from deep-sea hydrothermal vents. This gene is part of a distinct phylogenetic branch compared to all known terrestrial fungal sequences. This new gene encodes a C-terminus extension of 74 amino acids compared to other known PKSIII proteins like Neurospora crassa. Full-length and reduced versions of this PKSIII were successfully cloned and overexpressed in a bacterial host, Escherichia coli BL21 (DE3). Both proteins showed the same activity, suggesting that additional amino acid residues at the C-terminus are probably not required for biochemical functions. We demonstrated by LC-ESI-MS/MS that these two recombinant PKSIII proteins could only produce tri- and tetraketide pyrones and alkylresorcinols using only long fatty acid chain from C8 to C16 acyl-CoAs as starter units, in presence of malonyl-CoA. In addition, we showed that some of these molecules exhibit cytotoxic activities against several cancer cell lines.
  • 1.3K
  • 13 Jan 2021
Topic Review
Antioxidant Properties of Second-Generation Antipsychotics
Recent studies suggest a primary role of oxidative stress in an early phase of the pathogenesis of schizophrenia and a strong neurobiological link has been found between dopaminergic system dysfunction, microglia overactivation, and oxidative stress. Different risk factors for schizophrenia increase oxidative stress phenomena raising the risk of developing psychosis. Oxidative stress induced by first-generation antipsychotics such as haloperidol significantly contributes to the development of extrapyramidal side effects. Haloperidol also exerts neurotoxic effects by decreasing antioxidant enzyme levels then worsening pro-oxidant events. Opposite to haloperidol, second-generation antipsychotics (or atypical antipsychotics) such as risperidone, clozapine, and olanzapine exert a strong antioxidant activity in experimental models of schizophrenia by rescuing the antioxidant system, with an increase in superoxide dismutase and glutathione (GSH) serum levels. Second-generation antipsychotics also improve the antioxidant status and reduce lipid peroxidation in schizophrenic patients. Interestingly, second-generation antipsychotics, such as risperidone, paliperidone, and in particular clozapine, reduce oxidative stress induced by microglia overactivation, decreasing the production of microglia-derived free radicals, finally protecting neurons against microglia-induced oxidative stress. Further, long-term clinical studies are needed to better understand the link between oxidative stress and the clinical response to antipsychotic drugs and the therapeutic potential of antioxidants to increase the response to antipsychotics. 
  • 1.3K
  • 03 Feb 2021
Topic Review
Epithelial to Mesenchymal Transition
Pancreatic ductal adenocarcinoma (PDAC) is one of the malignancies with the worst prognosis despite a decade of efforts. The effectiveness of PDAC therapies is challenged by the early and widespread metastasis. Epithelial to mesenchymal transition (EMT) is a major driver of cancer progression and metastasis. 
  • 1.3K
  • 05 Aug 2021
Topic Review
The Genus Cetraria s. str.
The genus Cetraria s. str. (Parmeliaceae family, Cetrarioid clade) consists of 15 species of mostly erect brown or greenish yellow fruticose or subfoliose thallus. These Cetraria species have a cosmopolitan distribution, being primarily located in the Northern Hemisphere, in North America and in the Eurasia area. 
  • 1.3K
  • 24 Aug 2022
Topic Review
α-Synuclein Phosphorylation and Its Kinases
α-Synuclein is a protein with a molecular weight of 14.5 kDa and consists of 140 amino acids encoded by the SNCA gene. Missense mutations and gene duplications in the SNCA gene cause hereditary Parkinson’s disease. Highly phosphorylated and abnormally aggregated α-synuclein is a major component of Lewy bodies found in neuronal cells of patients with sporadic Parkinson’s disease, dementia with Lewy bodies, and glial cytoplasmic inclusion bodies in oligodendrocytes with multiple system atrophy. Aggregated α-synuclein is cytotoxic and plays a central role in the pathogenesis of the above-mentioned synucleinopathies. In a healthy brain, most α-synuclein is unphosphorylated; however, more than 90% of abnormally aggregated α-synuclein in Lewy bodies of patients with Parkinson’s disease is phosphorylated at Ser129, which is presumed to be of pathological significance. Several kinases catalyze Ser129 phosphorylation, but the role of phosphorylation enzymes in disease pathogenesis and their relationship to cellular toxicity from phosphorylation are not fully understood in α-synucleinopathy. G-protein-coupled receptor kinases, casein kinase II, and polo-like kinase possess the ability to phosphorylate α-synuclein protein. On this point, inhibition of these kinases is able to prevent α-synuclein phosphorylation, which indicates the potential therapeutic targets and availability of drug development for α-synucleinopathies. α-Synuclein phosphorylation can clinically be an accompanying event in the brains of patients with Parkinson’s disease rather than the critical factor for α-synuclein aggregation and toxicity. Nevertheless, increasing phosphorylated α-synuclein and the accumulation with disease progression is useful as a therapeutic target and biomarker.
  • 1.3K
  • 08 Jun 2022
Topic Review
Nutritional Interventions for COVID-19
The coronavirus infection (COVID‐19) conveys a serious threat globally to health and economy because of lack of vaccines and specific treatments. A common factor for conditions that predispose for serious progress is a low-grade inflammation, as seen e.g. in metabolic syndrome, diabetes and heart failure to which micronutrient deficiencies may contribute.  The aim of the present article is to explore the usefulness of early micronutrient intervention, with focus on zinc, selenium and vitamin D, to relieve escalation of COVID-19.  Methods: We have conducted an online search for articles published in the period 2010-2020 on zinc, selenium and vitamin D and corona and related virus infections.  Results: There were a few studies providing direct evidence on association between zinc, selenium and vitamin D and COVID-19.  Adequate supply of zinc, selenium, and vitamin D, is essential for resistance to other viral infections, immune function and reduced inflammation. Hence, it is suggested that nutrition intervention securing an adequate status might protect against SARS-CoV2, and  mitigate the course of COVID‐19.  Conclusion: We recommend initiation of adequate supplementation in high risk areas and/or soon after the time of suspected infection with SARS-CoV-2. Subjects in high-risk groups should have high priority as regards this nutritive adjuvant therapy, which should be started prior to administration of specific and supportive medical measures. 
  • 1.3K
  • 24 Aug 2020
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