Pharmaceuticals, Volume 13, Issue 7 (July 2020) – 21 articles

Glioma is the most frequent and aggressive type of brain neoplasm, being anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM), its most malignant forms. The survival rate in patients with these neoplasms is 15 months after diagnosis, despite a diversity of treatments, including surgery, radiation, chemotherapy, and immunotherapy. The resistance of GBM to various therapies is due to a highly mutated genome; these genetic changes induce a de-regulation of several signaling pathways and result in higher cell proliferation rates, angiogenesis, invasion, and a marked resistance to apoptosis; this latter trait is a hallmark of highly invasive tumor cells, such as glioma cells. Due to a defective apoptosis in gliomas, induced autophagic death can be an alternative to remove tumor cells. Paradoxically, however, autophagy in cancer can promote either a cell death or survival. Modulating the autophagic pathway as a death mechanism for cancer cells has prompted the use of both inhibitors and autophagy inducers. The autophagic process, either as a cancer suppressing or inducing mechanism in high-grade gliomas is discussed in this review, along with therapeutic approaches to inhibit or induce autophagy in pre-clinical and clinical studies, aiming to increase the efficiency of conventional treatments to remove glioma neoplastic cells. Full article

As the world endures the coronavirus disease 2019 (COVID-19) pandemic, the conditions of 35 million vulnerable individuals struggling with substance use disorders (SUDs) worldwide have not received sufficient attention for their special health and medical needs. Many of these individuals are complicated by underlying health conditions, such as cardiovascular and lung diseases and undermined immune systems. During the pandemic, access to the healthcare systems and support groups is greatly diminished. Current research on COVID-19 has not addressed the unique challenges facing individuals with SUDs, including the heightened vulnerability and susceptibility to the disease. In this systematic review, we will discuss the pathogenesis and pathology of COVID-19, and highlight potential risk factors and complications to these individuals. We will also provide insights and considerations for COVID-19 treatment and prevention in patients with SUDs. Full article

Lipoxygenases (LOXs) are a family of enzymes found in plants, mammals, and microorganisms. In animals and plants, the enzyme has the capability for the peroxidation of unsaturated fatty acids. Although LOXs participate in the plant defense system, the enzyme’s metabolites can have numerous negative effects on human health. Therefore, many types of research are searching for compounds that can inhibit LOXs. The best quantitative structure–activity relationship (QSAR) model was obtained using a Genetic Algorithm (GA). Molecular docking was performed with iGEMDOCK. The inhibition of lipoxygenase was in the range of 7.1 to 96.6%, and the inhibition of lipid peroxidation was 7.0–91.0%. Among the synthesized compounds, the strongest inhibitor of soybean LOX-3 (96.6%) was found to be 3-benzoyl-7-(benzyloxy)-2H-chromen-2-one. A lipid peroxidation inhibition of 91.0% was achieved with ethyl 7-methoxy-2-oxo-2H-chromene-3-carboxylate. The docking scores for the soybean LOX-3 and human 5-LOX also indicated that this compound has the best affinity for these LOX enzymes. The best multiple linear QSAR model contains the atom-centered fragment descriptors C-06, RDF035p, and HATS8p. QSAR and molecular docking studies elucidated the structural features important for the enhanced inhibitory activity of the most active compounds, such as the presence of the benzoyl ring at the 3-position of coumarin’s core. Compounds with benzoyl substituents are promising candidates as potent lipoxygenase inhibitors. Full article

Curcumin, a principal bioactive substance of turmeric (Curcuma longa L.), is reported as a strong antioxidant, anti-inflammatory, antibacterial, antifungal, and antiviral agent. However, its antimicrobial properties require further detailed investigations into clinical and multidrug-resistant (MDR) isolates. In this work, we tested curcumin’s efficacy against over 100 strains of pathogens belonging to 19 species. This activity was determined by the broth microdilution method and by calculating the minimum inhibitory concentration (MIC). Our findings confirmed a much greater sensitivity of Gram-positive than Gram-negative bacteria. This study exhibited a significantly larger variation in the curcumin activity than previous works and suggested that numerous clinical strains of widespread pathogens have a poor sensitivity to curcumin. Similarly, the MICs of the MDR types of Staphylococcus aureus, S. haemolyticus, Escherichia coli, and Proteus mirabilis were high (≥2000 µg/mL). However, curcumin was effective against some species and strains: Streptococcus pyogenes (median MIC = 31.25 µg/mL), methicillin-sensitive S. aureus (250 µg/mL), Acinetobacter lwoffii (250 µg/mL), and individual strains of Enterococcus faecalis and Pseudomonas aeruginosa (62.5 µg/mL). The sensitivity of species was not associated with its affiliation to the genus, and it could differ a lot (e.g., S. pyogenes, S. agalactiae and A. lwoffii, A. baumannii). Hence, curcumin can be considered as a promising antibacterial agent, but with a very selective activity. Full article

Naringenin (NAR), a flavonoid mainly found in citrus and grapefruits, has proven anti-cancer activities. However, the poor water solubility and low bioavailability of NAR limits its use as a therapeutic agent. The aim of this study was to develop and optimize stable naringenin nanoemulsions (NAR-NE) using a Box–Behnken experimental design to obtain a formulation with a higher efficiency. Anticancer activity of optimized NAR-NE was evaluated in A549 lung cancer cells using cell viability, flow-cytometric assays, and enzyme-linked immunosorbent assay. The stabilized nanoemulsion, which showed a spherical surface morphology, had a globule size of 85.6 ± 2.1 nm, a polydispersity index of 0.263 ± 0.02, a zeta potential of −9.6 ± 1.2 mV, and a drug content of 97.34 ± 1.3%. The NAR release from the nanoemulsion showed an initial burst release followed by a stable and controlled release for a longer period of 24 h. The nanoemulsion exhibited excellent thermodynamic and physical stability against phase separation and storage. The NAR-NE showed concentration-dependent cytotoxicity in A549 lung cancer cells, which was greater than that of free NAR. The percentage of apoptotic cells and cell cycle arrest at the G2/M and pre-G1 phases induced by NAR-NE were significantly higher than those produced by free NAR (p < 0.05). NAR-NEs were more effective than the NAR solution in reducing Bcl2 expression, while increasing pro-apoptotic Bax and caspase-3 activity. Therefore, stabilized NAR-NE could be a suitable drug delivery system to enhance the effects of NAR in the treatment of lung cancer. Full article

The objective of this study was to investigate the safety of repeated parenteral ketamine for depression. An electronic survey inquiring about the frequency of adverse events was distributed to providers of parenteral ketamine for depression. In addition, the investigators conducted a search of published studies describing six or more repeated parenteral ketamine treatments administered to individuals for depression, and extracted reported adverse events. The survey was sent to 69 providers, of which 36 responded (52% response rate); after eliminating those that were incomplete, 27 were included in the analysis. The providers in the analysis collectively reported treating 6630 patients with parenteral ketamine for depression, one-third of whom received more than 10 treatments. Only 0.7% of patients experienced an adverse effect that required discontinuation of ketamine. Psychological distress during the treatment was the most frequent cause. Other adverse events were extremely rare (such as bladder dysfunction (0.1%), cognitive decline (0.03%) and psychotic symptoms (0.03%)). Among the 20 published reports of repeated parenteral ketamine treatments, rates of significant adverse events resulting in discontinuation were low (1.2%). The rate of adverse effects reported in the survey and the published literature is low, and suggests that long-term treatment of depression with ketamine is reasonably safe. Full article

Metabolic syndromes share common pathologies with Alzheimer’s disease (AD). Adiponectin, an adipocyte-derived protein, regulates energy metabolism via its receptors, AdipoR1 and AdipoR2. To investigate the distribution of adiponectin receptors (AdipoRs) in Alzheimer’s, we examined their expression in the aged 5XFAD mouse model of AD. In age-matched wild-type mice, we observed neuronal expression of both ARs throughout the brain as well as endothelial expression of AdipoR1. The pattern of receptor expression in the aged 5XFAD brain was significantly perturbed. Here, we observed decreased neuronal expression of both ARs and decreased endothelial expression of AdipoR1, but robust expression of AdipoR2 in activated astrocytes. We also observed AdipoR2-expressing astrocytes in the dorsomedial hypothalamic and thalamic mediodorsal nuclei, suggesting the possibility that astrocytes utilise AdipoR2 signalling to fuel their activated state in the AD brain. These findings provide further evidence of a metabolic disturbance and demonstrate a potential shift in energy utilisation in the AD brain, supporting imaging studies performed in AD patients. Full article

Tramadol and tapentadol are fully synthetic and extensively used analgesic opioids, presenting enhanced therapeutic and safety profiles as compared with their peers. However, reports of adverse reactions, intoxications and fatalities have been increasing. Information regarding the molecular, biochemical, and histological alterations underlying their toxicological potential is missing, particularly for tapentadol, owing to its more recent market authorization. Considering the paramount importance of liver and kidney for the metabolism and excretion of both opioids, these organs are especially susceptible to toxicological damage. In the present study, we aimed to characterize the putative hepatic and renal deleterious effects of repeated exposure to therapeutic doses of tramadol and tapentadol, using an in vivo animal model. Male Wistar rats were randomly divided into six experimental groups, composed of six animals each, which received daily single intraperitoneal injections of 10, 25 or 50 mg/kg tramadol or tapentadol (a low, standard analgesic dose, an intermediate dose and the maximum recommended daily dose, respectively). An additional control group was injected with normal saline. Following 14 consecutive days of administration, serum, urine and liver and kidney tissue samples were processed for biochemical, metabolic and histological analysis. Repeated administration of therapeutic doses of both opioids led to: (i) increased lipid and protein oxidation in liver and kidney, as well as to decreased total liver antioxidant capacity; (ii) decreased serum albumin, urea, butyrylcholinesterase and complement C3 and C4 levels, denoting liver synthesis impairment; (iii) elevated serum activity of liver enzymes, such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and γ-glutamyl transpeptidase, as well as lipid profile alterations, also reflecting hepatobiliary commitment; (iv) derangement of iron metabolism, as shown through increases in serum iron, ferritin, haptoglobin and heme oxygenase-1 levels. In turn, elevated serum cystatin C, decreased urine creatinine output and increased urine microalbumin levels were detected upon exposure to tapentadol only, while increased serum amylase and urine N-acetyl-β-D-glucosaminidase activities were observed for both opioids. Collectively, these results are compatible with kidney injury. Changes were also found in the expression levels of liver- and kidney-specific toxicity biomarker genes, upon exposure to tramadol and tapentadol, correlating well with alterations in lipid profile, iron metabolism and glomerular and tubular function. Histopathological analysis evidenced sinusoidal dilatation, microsteatosis, mononuclear cell infiltrates, glomerular and tubular disorganization, and increased Bowman’s spaces. Although some findings are more pronounced upon tapentadol exposure, our study shows that, when compared with acute exposure, prolonged administration of both opioids smooths the differences between their toxicological effects, and that these occur at lower doses within the therapeutic range. Full article

The identification of natural bioactive compounds, able to counteract the abnormal increase of oxidative stress and inflammatory status in chronic degenerative non-communicable diseases is useful for the clinical management of these conditions. We tested an oral food supplement (OFS), chemically characterized and evaluated for in vitro and in vivo activity. Vitamin C, analyzed by High Performance Liquid Chromatography-Diode Array Detector (HPLC-DAD), was 0.19 mg/g in rosehip dry extract and 15.74 mg/capsule in the OFS. The identification of polyphenols was performed by HPLC-DAD; the total antioxidant capacity was assessed by Folin–Ciocalteu test. Total polyphenols were 14.73 mg/g gallic acid equivalents (GAE) for rosehip extract and 1.93 mg/g GAE for OFS. A total of 21 chronic kidney disease (CKD) patients and 10 healthy volunteers were recruited. The evaluation of routine laboratory and inflammatory parameters, erythrocyte glutathione transferase (e-GST), human oxidized serum albumin (HSAox), and assessment of body composition were performed at two different times, at baseline and after 5 weeks of OFS assumption. In the study, we highlighted a significant decrease of traditional inflammatory biomarkers (such as C-reactive protein, erythrocyte sedimentation rate, platelet to lymphocyte ratio) and other laboratory parameters like e-GST, azotaemia, and albuminuria after OFS treatment in CKD patients. Moreover, we demonstrated a lipid profile improvement in CKD patients after OFS supplementation. Full article

This study aimed to investigate the effect of polymers and storage relative humidity on amorphous rebamipide (RB) and its solid dispersion phase transformation using chemometrics based on multiple datasets. The amorphous RB was prepared using particle mixture and grinding methods with hydroxypropyl cellulose, polyvinylpyrrolidone, and sodium dodecyl sulfate. Prepared amorphous RB and solid dispersion samples were stored under a relative humidity of 30% and 75% for four weeks. Infrared spectra of the dispersion samples suggested that the hydrogen bond network was constructed among quinolinone, carbonyl acid, and amide of RB and other polymers. The dataset combining near-infrared (NIR) spectra and powder X-ray diffractograms were applied to principal component analysis (PCA). The relationship between diffractograms and NIR spectra was evaluated using loadings and the PCA score. The multiple spectra analysis is useful for evaluating model amorphous active pharmaceutical ingredients without a standard sample. Full article

Cancer is a strong global burden with increasing numbers of diseases and ongoing anticancer drug resistance. The number of structurally novel anticancer drugs is strongly limited. They cause high costs for the social health systems. Most critical so-called multidrug resistances (MDR) are caused by transmembrane efflux pumps that transport drugs with various structures out of the cancer cells. Multidrug resistance proteins (MRPs) type 1 and 2 are found overexpressed in various kinds of cancer. There is a strong need for inhibitors of those efflux pumps. We developed novel nonsymmetrical 1,4-dihydropyridines as novel inhibitors of cancer relevant MRP types 1 and 2. The structure-dependent activities of the differently substituted derivatives were evaluated in cellular assays of respective cancer cells and are discussed. Promising candidates were identified. One candidate was demonstrated to resensitize a cisplatin resistant cancer cell line and thus to overcome the anticancer drug resistance. Full article

Preterm birth (PTB), defined as parturition prior to 37 weeks of gestation, is the leading cause of morbidity and mortality in the neonatal population. The incidence and severity of complications of prematurity increase with decreasing gestational age and birthweight. The aim of this review study is to select the most current evidence on the role of oxidative stress in the onset of preterm complication prevention strategies and treatment options with pre-clinical and clinical trials. We also provide a literature review of primary and secondary studies on the role of oxidative stress in preterm infants and its eventual treatment in prematurity diseases. We conducted a systematic literature search of the Medline (Pubmed), Scholar, and ClinicalTrials.gov databases, retroactively, over a 7-year period. From an initial 777 articles identified, 25 articles were identified that met the inclusion and exclusion criteria. Of these, there were 11 literature reviews: one prospective cohort study, one experimental study, three case-control studies, three pre-clinical trials, and six clinical trials. Several biomarkers were identified as particularly promising, such as the products of the peroxidation of polyunsaturated fatty acids, those of the oxidation of phenylalanine, and the hydroxyl radicals that can attack the DNA chain. Among the most promising drugs, there are those for the prevention of neurological damage, such as melatonin, retinoid lactoferrin, and vitamin E. The microbiome also has an important role in oxidative stress. In conclusion, the most recent studies show that a strong relationship between oxidative stress and prematurity exists and that, unfortunately, there is still little therapeutic evidence reported in the literature. Full article

Brain metastases represent one of the incurable end stages in breast cancer (BC). Developing effective or preventive treatments is hampered by a lack of knowledge on the molecular mechanisms driving brain metastasis. Transmigration of BC cells through the brain endothelium is a key event in the pathogenesis of brain metastasis. In this study, we identified miR-101-3p as a critical micro-RNA able to reduce transmigration of BC cells through the brain endothelium. Our results revealed that miR-101-3p expression is downregulated in brain metastatic BC cells compared to less invasive variants, and varies inversely compared to the brain metastatic propensity of BC cells. Using a loss-and-gain of function approach, we found that miR-101-3p downregulation increased transmigration of BC cells through the brain endothelium in vitro by inducing COX-2 expression in cancer cells, whereas ectopic restoration of miR-101-3p exerted a metastasis-reducing effect. In regulatory experiments, we found that miR-101-3p mediated its effect by modulating COX-2-MMP1 signaling capable of degrading the inter-endothelial junctions (claudin-5 and VE-cadherin), key components of the brain endothelium. These findings suggest that miR-101-3p plays a critical role in the transmigration of breast cancer cells through the brain endothelium by modulating the COX-2-MMP1 signaling and thus may serve as a therapeutic target that can be exploited to prevent or suppress brain metastasis in human breast cancer. Full article

The world is currently suffering from a pandemic which has claimed the lives of over 230,000 people to date. The responsible virus is called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and causes the coronavirus disease 2019 (COVID-19), which is mainly characterized by fever, cough and shortness of breath. In severe cases, the disease can lead to respiratory distress syndrome and septic shock, which are mostly fatal for the patient. The severity of disease progression was hypothesized to be related to an overshooting immune response and was correlated with age and comorbidities, including cancer. A lot of research has lately been focused on the pathogenesis and acute consequences of COVID-19. However, the possibility of long-term consequences caused by viral infections which has been shown for other viruses are not to be neglected. In this regard, this opinion discusses the interplay of SARS-CoV-2 infection and cancer with special focus on the inflammatory immune response and tissue damage caused by infection. We summarize the available literature on COVID-19 suggesting an increased risk for severe disease progression in cancer patients, and we discuss the possibility that SARS-CoV-2 could contribute to cancer development. We offer lines of thought to provide ideas for urgently needed studies on the potential long-term effects of SARS-CoV-2 infection. Full article

The present study assessed the relationship between obesity induced by lifestyle and systemic oxidative stress and possible modulations by oral metformin treatments in young individuals, by using a translational swine model of obesity and associated cardiometabolic disorders (Iberian pig). The results indicate the existence of an age-related increase in both adiposity and systemic oxidative stress (using hydrogen peroxide as a marker), which is higher in individuals with obesogenic lifestyle and increased weight and obesity. Such effect was not found in individuals treated with metformin. The translation of these results suggests that childhood obesity increases production of reactive oxygen species (ROS), and therefore systemic oxidative stress. Treatment with metformin would improve such oxidative status. Full article

Chikungunya virus (CHIKV) causes an infectious disease characterized by inflammation and pain of the musculoskeletal tissues accompanied by swelling in the joints and cartilage damage. Currently, there are no licensed vaccines or chemotherapeutic agents to prevent or treat CHIKV infections. In this context, our research aimed to explore the potential in vitro anti-CHIKV activity of acrylamide derivatives. In silico methods were applied to 132 Michael’s acceptors toward the six most important biological targets from CHIKV. Subsequently, the ten most promising acrylamides were selected and synthesized. From the cytotoxicity MTT assay, we verified that LQM330, 334, and 336 demonstrate high cell viability at 40 µM. Moreover, these derivatives exhibited anti-CHIKV activities, highlighting the compound LQM334 which exhibited an inhibition value of 81%. Thus, docking simulations were performed to suggest a potential CHIKV-target for LQM334. It was observed that the LQM334 has a high affinity towards the E3-E2-E1 glycoproteins complex. Moreover, LQM334 reduced the percentage of CHIKV-positive cells from 74.07 to 0.88%, 48h post-treatment on intracellular flow cytometry staining. In conclusion, all virtual simulations corroborated with experimental results, and LQM334 could be used as a promising anti-CHIKV scaffold for designing new drugs in the future. Full article

Erythropoietin-producing hepatocellular carcinoma A (EphA) receptors and their ephrin-A ligands are key players of developmental events shaping the mature organism. Their expression is mostly restricted to stem cell niches in adults but is reactivated in pathological conditions including lesions in the heart, lung, or nervous system. They are also often misregulated in tumors. A wide range of molecular tools enabling the manipulation of the ephrin-A:EphA system are available, ranging from small molecules to peptides and genetically-encoded strategies. Their mechanism is either direct, targeting EphA receptors, or indirect through the modification of intracellular downstream pathways. Approaches enabling manipulation of ephrin-A:EphA forward signaling for the dissection of its signaling cascade, the investigation of its physiological roles or the development of therapeutic strategies are summarized here. Full article

Influenza A and B viruses are a global threat to human health and increasing resistance to the existing antiviral drugs necessitates new concepts to expand the therapeutic options. Glycopeptide derivatives have emerged as a promising new class of antiviral agents. To avoid potential antibiotic resistance, these antiviral glycopeptides are preferably devoid of antibiotic activity. We prepared six vancomycin aglycone hexapeptide derivatives with the aim of obtaining compounds having anti-influenza virus but no antibacterial activity. Two of them exerted strong and selective inhibition of influenza A and B virus replication, while antibacterial activity was successfully eliminated by removing the critical N-terminal moiety. In addition, these two molecules offered protection against several other viruses, such as herpes simplex virus, yellow fever virus, Zika virus, and human coronavirus, classifying these glycopeptides as broad antiviral molecules with a favorable therapeutic index. Full article

With the availability of new technologies, the number of subjects undergoing medical and cosmetic interventions is increasing. Many procedures (e.g., ablative fractional laser treatment) resulting in superficial/minor wounds require appropriate aftercare to prevent complications in wound healing and poor cosmetic outcome. We review the published evidence of the usefulness of topical dexpanthenol in postprocedure wound healing and the associated mechanisms of action at the molecular level. A search in the PubMed and Embase databases was performed to query the terms dexpanthenol, panthenol, superficial wound, minor wound, wound healing, skin repair, and postprocedure. Search results were categorized as clinical trials and in vitro studies. In vitro and clinical studies provided evidence that topically applied dexpanthenol promotes superficial and postprocedure wound healing. Latest findings confirmed that dexpanthenol upregulates genes that are critical for the healing process. The gene expression data are of clinical relevance as evidenced by prospective clinical studies indicating that topical dexpanthenol accelerates wound healing with rapid re-epithelialization and restoration of skin barrier function following skin injury. It can therefore be inferred that topical dexpanthenol represents an appropriate and state-of-the-art treatment option for superficial postprocedure wounds, especially when applied early after the superficial skin damage. Full article

Intra-operative photodynamic therapy (IO-PDT) in combination with surgery for the treatment of non-small cell lung cancer and malignant pleural mesothelioma has shown promise in improving overall survival in patients. Here, we developed a PDT platform consisting of a ruthenium-based photosensitizer (TLD1433) activated by an optical surface applicator (OSA) for the management of residual disease. Human lung adenocarcinoma (A549) cell viability was assessed after treatment with TLD1433-mediated PDT illuminated with either 532- or 630-nm light with a micro-lens laser fiber. This TLD1433-mediated PDT induced an EC₅₀ of 1.98 μM (J/cm²) and 4807 μM (J/cm²) for green and red light, respectively. Cells were then treated with 10 µM TLD1433 in a 96-well plate with the OSA using two 2-cm radial diffusers, each transmitted 532 nm light at 50 mW/cm for 278 s. Monte Carlo simulations of the surface light propagation from the OSA computed light fluence (J/cm²) and irradiance (mW/cm²) distribution. In regions where 100% loss in cell viability was measured, the simulations suggest that >20 J/cm² of 532 nm was delivered. Our studies indicate that TLD1433-mediated PDT with the OSA and light simulations have the potential to become a platform for treatment planning for IO-PDT. Full article

Exogenous human follicle-stimulating hormone (hFSH), either derived from extraction and purification from the urine or obtained by recombinant technology in the form of follitropin α, β and δ (rFSH), has been used for decades in the treatment of infertility. The main applications of FSH treatment in the woman have been, and still are, ovulation induction in oligo-anovulatory subjects, and stimulation of the development of a cohort of follicles in patients undergoing controlled ovarian stimulation (COS) for in vitro fertilization (IVF). In the last years, two biosimilars of follitropin alfa, rFSH compounds structurally and functionally similar to the originator, have been approved and marketed for clinical use in Europe. Moreover, some other rFSH biosimilars are currently under investigation. The objective of this article is to review the available evidences comparing the efficacy, safety, and cost-effectiveness of rFSH follitropin alpha originator with its biosimilars, discussing the clinical trials that allowed biosimilars to get registration and marketing authorization. Full article