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Volume 6
Issue 4
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Medicines, Volume 6, Issue 4 (December 2019) – 20 articles

Cover Story (view full-size image): TRAIL exhibits cancer-cell‐specific killing effects or promotes cancer cell survival through inducing NF‐kB. In combination treatment with TRAIL, glucosamine increases the flux toward apoptosis versus survival/inflammation. The addition of glucosamine and TRAIL activates both the extrinsic and intrinsic apoptotic pathways while reducing NF‐kB levels which are typically stimulated by TRAIL treatment alone. These confocal microscopy images demonstrate the translocation of BAK to the mitochondrial outer membrane, triggering the intrinsic apoptosis pathway. This combination treatment provides a potential strategy for treating glucosamine‐sensitive cancers by disturbing the TRAIL‐induced apoptosis and survival balance. View this paper.
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7 pages, 1416 KiB  
Letter
Multimodal Laser Stimulation and Traditional Needle Acupuncture in Post-Stroke Patients—A Pilot Cross-Over Study with Results from Near Infrared Spectroscopy
by Gerhard Litscher, Xiaoning Zhang, Zemin Sheng, Xiang-Hong Jing and Lu Wang
Medicines 2019, 6(4), 115; https://doi.org/10.3390/medicines6040115 - 16 Dec 2019
Cited by 9 | Viewed by 4747
Abstract
Background: The objective of this pilot study was to evaluate the cerebral effects of laser stimulation and traditional needle acupuncture in patients after stroke. Methods: Seventeen stroke patients (12 female and five male; mean age ± SD: 66.5 ± 12.9 years) were randomly [...] Read more.
Background: The objective of this pilot study was to evaluate the cerebral effects of laser stimulation and traditional needle acupuncture in patients after stroke. Methods: Seventeen stroke patients (12 female and five male; mean age ± SD: 66.5 ± 12.9 years) were randomly selected in a stroke rehabilitation hospital. Patients’ regional cerebral blood oxygen saturation (rSO2) values were recorded before, during, and after needle acupuncture (scalp, ear and body) as well as before, during, and after corresponding laser stimulation (red laser, four points: 100 mW, 658 nm, 500 µm; yellow laser, one point: 50 mW, 589 nm, 500 µm; infrared laser, three points: 100 mW, 810 nm, 500 µm; green laser, one point: 5 mW, 532 nm, 500 µm) in a cross-over study design. Results: There were no significant changes after needle acupuncture in the phases immediately after needle insertion or during acupuncture stimulation. However, after manual needle acupuncture and after laser stimulation, the majority of the rSO2 values showed increases. The highest value (+3%) was reached after laser stimulation treatment. Heart rate and blood pressure before and after the treatments did not show significant alterations. Conclusions: Changes in local cerebral oxygen saturation could be quantified, although confirmation may only be expected after extensive follow-up studies. Full article
(This article belongs to the Special Issue Innovative Laser Medicine and Traditional Acupuncture Therapy)
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8 pages, 1239 KiB  
Article
Proteomic and Phosphoproteomic Analysis Reveals that Neurokinin-1 Receptor (NK1R) Blockade with Aprepitant in Human Keratinocytes Activates a Distinct Subdomain of EGFR Signaling: Implications for the Anti-Pruritic Activity of NK1R Antagonists
by Shawn G. Kwatra, Emily Boozalis, Amy H. Huang, Cory Nanni, Raveena Khanna, Kyle A. Williams, Yevgeniy R. Semenov, Callie M. Roberts, Robert F. Burns, Madison Krischak and Madan M. Kwatra
Medicines 2019, 6(4), 114; https://doi.org/10.3390/medicines6040114 - 9 Dec 2019
Cited by 2 | Viewed by 3921
Abstract
Background: Epidermal growth factor receptor (EGFR) inhibitors can cause serious cutaneous toxicities, including pruritus and papulopustular acneiform skin eruptions. Increasingly, the neurokinin-1 receptor (NK1R) antagonist aprepitant is being utilized as an anti-pruritic agent in the treatment of EGFR-inhibitor induced pruritus. Aprepitant is [...] Read more.
Background: Epidermal growth factor receptor (EGFR) inhibitors can cause serious cutaneous toxicities, including pruritus and papulopustular acneiform skin eruptions. Increasingly, the neurokinin-1 receptor (NK1R) antagonist aprepitant is being utilized as an anti-pruritic agent in the treatment of EGFR-inhibitor induced pruritus. Aprepitant is believed to reduce itching by blocking NK1R on the surface of dermal mast cells. However, the effects of aprepitant on human keratinocytes remains unexplored. Methods: Herein, we examine the effects of aprepitant on EGFR stimulation in HaCaT cells using a phosphoproteomic approach including reverse phase protein arrays and Ingenuity Pathway Analysis. Changes in EGFR phosphorylation were visualized using Western blotting and the effect of EGF and aprepitant on the growth of HaCaT cells was determined using the WST-1 Cell Proliferation Assay System. Results: We found that aprepitant increased the phosphorylation of EGFR, as well as 10 of the 23 intracellular proteins phosphorylated by EGF. Analysis of phosphoproteomic data using Ingenuity Pathway Analysis software revealed that 5 of the top 10 pathways activated by EGF and aprepitant are shared. Conclusions: We propose that aprepitant produces its antipruritic effects by partially activating EGFR. Activation of EGFR by aprepitant was also seen in primary human keratinocytes. In addition to itch reduction through partial activation of shared EGFR pathways, aprepitant exerts a dose-dependent cytotoxicity to epithelial cells, which may contribute to its antitumor effects. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment of Chronic Pruritus)
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12 pages, 531 KiB  
Article
Phenolic Compounds from the Aerial Parts of Blepharis linariifolia Pers. and Their Free Radical Scavenging and Enzyme Inhibitory Activities
by Amina Ibrahim Dirar, Mikiyo Wada, Takashi Watanabe and Hari Prasad Devkota
Medicines 2019, 6(4), 113; https://doi.org/10.3390/medicines6040113 - 22 Nov 2019
Cited by 11 | Viewed by 4517
Abstract
Background: Blepharis linariifolia Pers. (Family: Acanthaceae) is used in traditional medicines as a general tonic and for the treatment of various health problems in Sudan. The main aim of this study was to isolate and identify the major chemical constituents from the aerial [...] Read more.
Background: Blepharis linariifolia Pers. (Family: Acanthaceae) is used in traditional medicines as a general tonic and for the treatment of various health problems in Sudan. The main aim of this study was to isolate and identify the major chemical constituents from the aerial parts of B. linariifolia and evaluate their bioactivities. Methods: The dried aerial parts of the plant were extracted successively with 100% acetone and 50% acetone, and thereafter the combined extract was subjected to repeated column chromatography to isolate the main components. Free radical scavenging activity was evaluated using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical method, and in vitro enzyme inhibitory activities against α-glucosidase, pancreatic lipase, and mushroom tyrosinase were evaluated. Results: From the detailed chemical analysis, verbascoside (1), vanillic acid (2), apigenin (3), and 6″-O-p-coumaroylprunin (4), were isolated and their structures were identified on the basis of their nuclear magnetic resonance (NMR) spectral data. Among the isolated compounds, verbascoside (1) showed the most potent free radical scavenging activity (IC50 = 22.03 ± 0.04 μM). Apigenin (3) and 6″-O-p-coumaroylprunin (4) showed promising inhibitory activities against all tested enzymes. Apigenin (3) showed the most potent inhibitory activity against α-glucosidase and tyrosinase (IC50 = 34.73 ± 1.78 μM and 23.14 ± 1.83 μM, respectively), whereas 6″-O-p-coumaroylprunin (4) showed potent inhibition for lipase (IC50 = 2.25 ± 0.17 μM). Conclusions: Four phenolic compounds were isolated and identified from B. linariifolia acetone extract, which are reported for the first time from this plant. All compounds showed good DPPH free radical scavenging activities, with verbascoside (1) being the most potent. Apigenin (3) was the most active as α-glucosidase and mushroom tyrosinase inhibitor, while 6″-O-p-coumaroylprunin (4) showed potent inhibitory activity for pancreatic lipase. Full article
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7 pages, 388 KiB  
Perspective
Itch in Chronic Wounds: Pathophysiology, Impact, and Management
by Michela Iannone, Agata Janowska, Valentina Dini, Giulia Tonini, Teresa Oranges and Marco Romanelli
Medicines 2019, 6(4), 112; https://doi.org/10.3390/medicines6040112 - 15 Nov 2019
Cited by 7 | Viewed by 4001
Abstract
Background: The aims of this review are to analyze the current literature regarding the characteristics and pathophysiological mechanisms of itch in chronic wounds, to assess the impact on quality of life and delayed-healing, to focus on the best strategies of prevention and treatment, [...] Read more.
Background: The aims of this review are to analyze the current literature regarding the characteristics and pathophysiological mechanisms of itch in chronic wounds, to assess the impact on quality of life and delayed-healing, to focus on the best strategies of prevention and treatment, to highlight the importance of on-going research in order to fully understand the pathophysiology, and to improve the management of target therapies. Methods: A systematic literature review was performed using MEDLINE, PubMed, Embase, Scopus, ScienceDirect, and the Cochrane Library. We included a total of 11 articles written in English with relevant information on the pathophysiology of itch in chronic wounds and on management strategies. Results: Itch in chronic wounds was found to be correlated with xerosis, larger wound areas, necrotic tissue and amount of exudate, peripheral tissue edema, sclerosis, granulation tissue, contact dermatitis, and bacterial burden, as well as with lower quality of life. Conclusions: Although there are several aspecific pharmacological and non-pharmacological approaches, there appears to be no validated prevention or management strategy for itch in chronic wounds. Further studies are needed to clarify the association and pathophysiology of itch in chronic wounds, to evaluate the safety and efficacy of topical treatments on perilesional skin to reduce itch, to characterize multidimensional sensations of itch in chronic wounds, to identify specific cytokine and chemokine expressions that are correlated to a tailored-based approach, and to develop practical guidelines. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment of Chronic Pruritus)
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8 pages, 839 KiB  
Case Report
Sweet’s Syndrome Following Therapy with Hydroxychloroquine in a Patient Affected with Elderly-Onset Primary Sjogren’s Syndrome
by Ciro Manzo, Nazareno Pollio and Maria Natale
Medicines 2019, 6(4), 111; https://doi.org/10.3390/medicines6040111 - 15 Nov 2019
Cited by 11 | Viewed by 6515
Abstract
Sweet’s syndrome is an uncommon skin disease characterized by painful polymorphic lesions associated with fever and neutrophilia. When biopsied, these lesions reveal a diffuse infiltrate of mature neutrophils in the papillary dermis. Several drugs can induce Sweet’s syndrome (so-called drug-induced Sweet’s syndrome (DISS)) [...] Read more.
Sweet’s syndrome is an uncommon skin disease characterized by painful polymorphic lesions associated with fever and neutrophilia. When biopsied, these lesions reveal a diffuse infiltrate of mature neutrophils in the papillary dermis. Several drugs can induce Sweet’s syndrome (so-called drug-induced Sweet’s syndrome (DISS)) but reports of DISS associated with hydroxychloroquine (HCQ) are exceptionally limited. A 72-year-old Caucasian female patient with elderly-onset primary Sjogren’s syndrome (EOpSS) but low disease activity presented with an abrupt onset of painful nodular and papular erythematous skin lesions after two weeks of therapy with HCQ 400 mg. A histological examination revealed a diffuse infiltrate of mature neutrophils in the papillary dermis, without vasculitis. After therapy with 25 mg/day prednisone and HCQ withdrawal, the cutaneous manifestations disappeared. When prednisone was permanently discontinued, the primary Sjogren’s syndrome (pSS) manifestations worsened and therapy with HCQ 200 mg was reintroduced. In a few days, the same skin lesions reappeared. Withdrawal of HCQ and a new cycle of prednisone resulted in their permanent disappearance. We reported a case of DISS following therapy with HCQ in a female patient affected by EOpSS. According to a literature review, this is the first report of this association. Full article
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8 pages, 257 KiB  
Article
Role of Dysregulated Ion Channels in Sensory Neurons in Chronic Kidney Disease-Associated Pruritus
by Akishi Momose, Micihihiro Yabe, Shigetoshi Chiba, Kenjirou Kumakawa, Yasuo Shiraiwa and Hiroki Mizukami
Medicines 2019, 6(4), 110; https://doi.org/10.3390/medicines6040110 - 13 Nov 2019
Cited by 7 | Viewed by 5344
Abstract
Background: We investigated ion channels at the skin, including peripheral nerve endings, which serve as output machines and molecular integrators of many pruritic inputs mainly received by multiple G protein-coupled receptors (GPCRs). Methods: Based on the level of chronic kidney disease–associated pruritus (CKD-aP), [...] Read more.
Background: We investigated ion channels at the skin, including peripheral nerve endings, which serve as output machines and molecular integrators of many pruritic inputs mainly received by multiple G protein-coupled receptors (GPCRs). Methods: Based on the level of chronic kidney disease–associated pruritus (CKD-aP), subjects were divided into two groups: non-CKD-aP (no or slight pruritus; n = 12) and CKD-aP (mild, moderate, or severe pruritus; n = 11). Skin samples were obtained from the forearm or elbow during operations on arteriovenous fistulas. We measured ion channels expressed at the skin, including peripheral nerve endings by RT-PCR: Nav1.8, Kv1.4, Cav2.2, Cav3.2, BKCa, Anoctamin1, TRPV1, TRPA1, and ASIC. Results: Expression of Cav3.2, BKCa, and anoctamin1 was significantly elevated in patients with CKD-aP. On the other hand, expression of TRPV1 was significantly reduced in these patients. We observed no significant difference in the levels of Cav2.2 or ASIC between subjects with and without CKD-aP. TRPA1, Nav1.8, and Kv1.4 were not expressed. Conclusions: It was concluded that this greater difference in the expression of ion channels in the skin tissue including, specially cutaneous peripheral nerve endings in CKD patients with CKD-aP may increase generator potential related to itching. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment of Chronic Pruritus)
12 pages, 897 KiB  
Article
Acute Kidney Injury in Pediatric Patients on Extracorporeal Membrane Oxygenation: A Systematic Review and Meta-analysis
by Panupong Hansrivijit, Ploypin Lertjitbanjong, Charat Thongprayoon, Wisit Cheungpasitporn, Narothama Reddy Aeddula, Sohail Abdul Salim, Api Chewcharat, Kanramon Watthanasuntorn, Narat Srivali, Michael A. Mao, Patompong Ungprasert, Karn Wijarnpreecha, Wisit Kaewput and Tarun Bathini
Medicines 2019, 6(4), 109; https://doi.org/10.3390/medicines6040109 - 1 Nov 2019
Cited by 19 | Viewed by 4193
Abstract
Background: Acute kidney injury (AKI) is a well-established complication of extra-corporal membrane oxygenation (ECMO) in the adult population. The data in the pediatric and neonatal population is still limited. Moreover, the mortality risk of AKI among pediatric patients requiring ECMO remains unclear. Thus, [...] Read more.
Background: Acute kidney injury (AKI) is a well-established complication of extra-corporal membrane oxygenation (ECMO) in the adult population. The data in the pediatric and neonatal population is still limited. Moreover, the mortality risk of AKI among pediatric patients requiring ECMO remains unclear. Thus, this meta-analysis aims to assess the incidence of AKI, AKI requiring renal replacement therapy and AKI associated mortality in pediatric/neonatal patients requiring ECMO. Methods: A literature search was performed utilizing MEDLINE, EMBASE, and the Cochrane Database from inception through June 2019. We included studies that evaluated the incidence of AKI, severe AKI requiring renal replacement therapy (RRT) and the risk of mortality among pediatric patients on ECMO with AKI. Random-effects meta-analysis was used to calculate the pooled incidence of AKI and the odds ratios (OR) for mortality. Results: 13 studies with 3523 pediatric patients on ECMO were identified. Pooled incidence of AKI and AKI requiring RRT were 61.9% (95% confidence interval (CI): 39.0–80.4%) and 40.9% (95%CI: 31.2–51.4%), respectively. A meta-analysis limited to studies with standard AKI definitions showed a pooled estimated AKI incidence of 69.2% (95%CI: 59.7–77.3%). Compared with patients without AKI, those with AKI and AKI requiring RRT while on ECMO were associated with increased hospital mortality ORs of 1.70 (95% CI, 1.38–2.10) and 3.64 (95% CI: 2.02–6.55), respectively. Conclusions: The estimated incidence of AKI and severe AKI requiring RRT in pediatric patients receiving ECMO are high at 61.9% and 40.9%, respectively. AKI among pediatric patients on ECMO is significantly associated with reduced patient survival. Full article
(This article belongs to the Section Nephrology and Urology)
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15 pages, 1564 KiB  
Article
Acute Kidney Injury in Patients Undergoing Cardiac Transplantation: A Meta-Analysis
by Charat Thongprayoon, Ploypin Lertjitbanjong, Panupong Hansrivijit, Anthony Crisafio, Michael A. Mao, Kanramon Watthanasuntorn, Narothama Reddy Aeddula, Tarun Bathini, Wisit Kaewput and Wisit Cheungpasitporn
Medicines 2019, 6(4), 108; https://doi.org/10.3390/medicines6040108 - 1 Nov 2019
Cited by 34 | Viewed by 4396
Abstract
Background: Acute kidney injury (AKI) is a common complication following solid-organ transplantation. However, the epidemiology of AKI and mortality risk of AKI among patients undergoing cardiac transplantation is not uniformly described. We conducted this study to assess the incidence of AKI and mortality [...] Read more.
Background: Acute kidney injury (AKI) is a common complication following solid-organ transplantation. However, the epidemiology of AKI and mortality risk of AKI among patients undergoing cardiac transplantation is not uniformly described. We conducted this study to assess the incidence of AKI and mortality risk of AKI in adult patients after cardiac transplantation. Methods: A systematic review of EMBASE, MEDLINE, and Cochrane Databases was performed until June 2019 to identify studies evaluating the incidence of AKI (by standard AKI definitions), AKI requiring renal replacement therapy (RRT), and mortality risk of AKI in patients undergoing cardiac transplantation. Pooled AKI incidence and mortality risk from the included studies were consolidated by random-effects model. The protocol for this study is registered with PROSPERO (no. CRD42019134577). Results: 27 cohort studies with 137,201 patients undergoing cardiac transplantation were identified. Pooled estimated incidence of AKI and AKI requiring RRT was 47.1% (95% CI: 37.6–56.7%) and 11.8% (95% CI: 7.2–18.8%), respectively. The pooled ORs of hospital mortality and/or 90-day mortality among patients undergoing cardiac transplantation with AKI and AKI requiring RRT were 3.46 (95% CI, 2.40–4.97) and 13.05 (95% CI, 6.89–24.70), respectively. The pooled ORs of 1-year mortality among patients with AKI and AKI requiring RRT were 2.26 (95% CI, 1.56–3.26) and 3.89 (95% CI, 2.49–6.08), respectively. Conclusion: Among patients undergoing cardiac transplantation, the incidence of AKI and severe AKI requiring RRT are 47.1% and 11.8%, respectively. AKI post cardiac transplantation is associated with reduced short term and 1-year patient survival. Full article
(This article belongs to the Section Nephrology and Urology)
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22 pages, 1394 KiB  
Review
A Unique Formulation of Cardioprotective Bio-Actives: An Overview of Their Safety Profile
by William Salminen, Mayowa Agbaje-Williams and Funmilayo O. Ajayi
Medicines 2019, 6(4), 107; https://doi.org/10.3390/medicines6040107 - 22 Oct 2019
Cited by 3 | Viewed by 4407
Abstract
The burden of cardiovascular disease (CVD) remains high globally and in the United States despite the availability of pharmaceuticals aimed at its prevention and treatment. An invention by Summit Innovation Labs, which is a formula consisting of a unique blend of select polyphenols [...] Read more.
The burden of cardiovascular disease (CVD) remains high globally and in the United States despite the availability of pharmaceuticals aimed at its prevention and treatment. An invention by Summit Innovation Labs, which is a formula consisting of a unique blend of select polyphenols (i.e., curcumin, quercetin, resveratrol), vitamin K2 as menaquinone-7, and magnesium, was recently developed to modulate the impact of the specific drivers of CVD, namely, vascular calcification, oxidative stress, and chronic inflammation. The SIL formulation is a dietary supplement that was designed leveraging the more bioavailable forms of ingredients with poor absorption, such as curcumin and quercetin. Each ingredient within the SIL formulation has been shown to contribute to CVD risk reduction by moderating the effect of CVD triggers, thereby providing a holistic prevention strategy for CVD in the healthy population. This review focuses on recently published clinical data to support the safety profile of these ingredients following oral administration. The preponderance of clinical trial data reviewed support the overall safety of the bioactives when used singly or in combination. The most commonly reported adverse effects were generally mild dose-related gastrointestinal disturbances, which may be alleviated with diet in some cases. In light of these, we conclude that the combination of the ingredients in the SIL formulation is reasonably expected to be safe. Full article
(This article belongs to the Section Cardiology and Vascular Disease)
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18 pages, 672 KiB  
Review
Toxicological Aspects and Determination of the Main Components of Ayahuasca: A Critical Review
by Ana Y. Simão, Joana Gonçalves, Ana Paula Duarte, Mário Barroso, Ana Clara Cristóvão and Eugenia Gallardo
Medicines 2019, 6(4), 106; https://doi.org/10.3390/medicines6040106 - 18 Oct 2019
Cited by 24 | Viewed by 12946
Abstract
Ayahuasca is a psychoactive beverage prepared traditionally from a mixture of the leaves and stems of Psychotria viridis and Banisteriopsis caapi, respectively, being originally consumed by indigenous Amazonian tribes for ritual and medicinal purposes. Over the years, its use has spread to [...] Read more.
Ayahuasca is a psychoactive beverage prepared traditionally from a mixture of the leaves and stems of Psychotria viridis and Banisteriopsis caapi, respectively, being originally consumed by indigenous Amazonian tribes for ritual and medicinal purposes. Over the years, its use has spread to other populations as a means to personal growth and spiritual connection. Also, the recreational use of its isolated compounds has become prominent. The main compounds of this tea-like preparation are N,N-dimethyltryptamine (DMT), β-Carbolines, and harmala alkaloids, such as harmine, tetrahydroharmine, and harmaline. The latter are monoamine-oxidase inhibitors and are responsible for DMT psychoactive and hallucinogenic effects on the central nervous system. Although consumers defend its use, its metabolic effects and those on the central nervous system are not fully understood yet. The majority of studies regarding the effects of this beverage and of its individual compounds are based on in vivo experiments, clinical trials, and even surveys. This paper will not only address the toxicological aspects of the ayahuasca compounds but also perform a comprehensive and critical review on the analytical methods available for their determination in biological and non-biological specimens, with special focus on instrumental developments and sample preparation approaches. Full article
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7 pages, 1525 KiB  
Perspective
Erythrina suberosa: Ethnopharmacology, Phytochemistry and Biological Activities
by Felicia Patti, Yasaman Taheri, Javad Sharifi-Rad, Miquel Martorell, William C. Cho and Raffaele Pezzani
Medicines 2019, 6(4), 105; https://doi.org/10.3390/medicines6040105 - 18 Oct 2019
Cited by 7 | Viewed by 8301
Abstract
Plants are a great and irreplaceable source of medicines, fuel, food, energy and even cosmetics. Since prehistory, humans have learned to use plants for survival, growth and proliferation and still today it relies on natural and cultivated vegetables for food and the source [...] Read more.
Plants are a great and irreplaceable source of medicines, fuel, food, energy and even cosmetics. Since prehistory, humans have learned to use plants for survival, growth and proliferation and still today it relies on natural and cultivated vegetables for food and the source of novel compounds with pharmacological activity. Not only herbs and flowers, but also trees are used. Indeed, Erythrina suberosa Roxb. is a deciduous tree of the family Fabaceae, common in Southeast Asia. In India, E. suberosa is called the “corky coral tree” or simply the “Indian coral tree”, given its peculiar red-orange flowers that can flower throughout the year and its corky irregular bark covered by prickles. It is a plant commonly used as an ornamental tree, but it also holds ethnopharmacological and socioeconomic uses. This article explored phytobiological features of E. suberosa, analysing its taxonomy, examining its traditional and common uses and investigating its bioactive components and pharmacological properties. Full article
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15 pages, 1917 KiB  
Article
Glucosamine Enhances TRAIL-Induced Apoptosis in the Prostate Cancer Cell Line DU145
by Chao Sun, Viktor Chesnokov, Garrett Larson and Keiichi Itakura
Medicines 2019, 6(4), 104; https://doi.org/10.3390/medicines6040104 - 15 Oct 2019
Cited by 3 | Viewed by 4551
Abstract
Background: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively kills tumor cells in cancer patients. However, patients often develop TRAIL resistance; thus, agents that can sensitize cells to TRAIL therapy would be beneficial clinically. Methods: Immunoblotting, flow cytometry, confocal microscopy, qPCR [...] Read more.
Background: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively kills tumor cells in cancer patients. However, patients often develop TRAIL resistance; thus, agents that can sensitize cells to TRAIL therapy would be beneficial clinically. Methods: Immunoblotting, flow cytometry, confocal microscopy, qPCR and caspase 8 activity assays were used to investigate whether glucosamine (GlcN) can sensitize cancer cells to TRAIL thereby enhancing apoptosis and potentially improving clinical response. Results: GlcN sensitized DU145 cells to TRAIL-induced apoptosis but did not increase death receptor 5 (DR5) cell surface expression. Once treated, these cells responded to TRAIL-induced apoptosis through both extrinsic and intrinsic apoptotic pathways as evidenced by the cleavage of both caspases 8 and 9. The combination of GlcN and TRAIL suppressed the expression of key anti-apoptotic factors cFLIP, BCL-XL, MCL-1 and XIAP and translocated BAK to the mitochondrial outer membrane thereby facilitating cytochrome C and SMAC release. In addition to the activation of apoptotic pathways, TRAIL-mediated inflammatory responses were attenuated by GlcN pretreatment reducing nuclear NF-kB levels and the expression of downstream target genes IL-6 and IL-8. Conclusions: GlcN/TRAIL combination could be a promising strategy for treating cancers by overcoming TRAIL resistance and abrogating TRAIL-induced inflammation. Full article
(This article belongs to the Special Issue Application of Glycobiology in the Treatment of Diseases)
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26 pages, 1531 KiB  
Review
Direct-Acting Oral Anticoagulants and Their Reversal Agents—An Update
by Stephanie A. Kustos and Pius S. Fasinu
Medicines 2019, 6(4), 103; https://doi.org/10.3390/medicines6040103 - 15 Oct 2019
Cited by 37 | Viewed by 26864
Abstract
Background: Over the last ten years, a new class of drugs, known as the direct-acting oral anticoagulants (DOACs), have emerged at the forefront of anticoagulation therapy. Like the older generation anticoagulants, DOACs require specific reversal agents in cases of life-threatening bleeding or the [...] Read more.
Background: Over the last ten years, a new class of drugs, known as the direct-acting oral anticoagulants (DOACs), have emerged at the forefront of anticoagulation therapy. Like the older generation anticoagulants, DOACs require specific reversal agents in cases of life-threatening bleeding or the need for high-risk surgery. Methods: Published literature was searched, and information extracted to provide an update on DOACS and their reversal agents. Results: The DOACs include the direct thrombin inhibitor—dabigatran, and the factor Xa inhibitors—rivaroxaban, apixaban, edoxaban, and betrixaban. These DOACs all have a rapid onset of action and each has a predictable therapeutic response requiring no monitoring, unlike the older anticoagulants, such as warfarin. Two reversal agents have been approved within the last five years: idarucizumab for the reversal of dabigatran, and andexanet alfa for the reversal of rivaroxaban and apixaban. Additionally, ciraparantag, a potential “universal” reversal agent, is currently under clinical development. Conclusions: A new generation of anticoagulants, the DOACs, and their reversal agents, are gaining prominence in clinical practice, having demonstrated superior efficacy and safety profiles. They are poised to replace traditional anticoagulants including warfarin. Full article
(This article belongs to the Section Oral Medicine and Dentistry)
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10 pages, 645 KiB  
Communication
Targeting Aberrant Sialylation to Treat Cancer
by Jennifer Munkley and Emma Scott
Medicines 2019, 6(4), 102; https://doi.org/10.3390/medicines6040102 - 13 Oct 2019
Cited by 57 | Viewed by 8975
Abstract
Cell surface carbohydrates (known as glycans) are often aberrantly expressed or found at atypical levels in cancer. Glycans can impact all steps in tumour progression, from malignant transformation to metastasis, and have roles in all the cancer hallmarks. An increased understanding of glycans [...] Read more.
Cell surface carbohydrates (known as glycans) are often aberrantly expressed or found at atypical levels in cancer. Glycans can impact all steps in tumour progression, from malignant transformation to metastasis, and have roles in all the cancer hallmarks. An increased understanding of glycans in the metastatic cascade offers exciting new therapeutic opportunities. Glycan-based targeting strategies are currently being tested in clinical trials and are a rich and untapped frontier for development. As we learn more about cancer glycobiology, new targets will continue to emerge for drug design. One key change in tumour glycosylation is the upregulation of cancer-associated sialylated glycans. Abnormal sialylation is integral to tumour growth, metastasis and immune evasion; therefore, targeting sialic acid moieties in cancer could be of high therapeutic value. Here, we summarise the changes to sialic acid biology in cancer and discuss recent advances and technologies bringing sialic-acid targeting treatments to the forefront of cancer therapeutics. Full article
(This article belongs to the Special Issue Application of Glycobiology in the Treatment of Diseases)
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13 pages, 1151 KiB  
Article
In Vitro Anti-Inflammatory and Immunomodulatory Activities of an Extract from the Roots of Bupleurum rotundifolium
by Juliette Cholet, Caroline Decombat, Marjolaine Vareille-Delarbre, Maël Gainche, Alexandre Berry, François Senejoux, Isabelle Ripoche, Laetitia Delort, Marion Vermerie, Didier Fraisse, Catherine Felgines, Edwige Ranouille, Jean-Yves Berthon, Julien Priam, Etienne Saunier, Albert Tourrette, Yves Troin, Gilles Thebaud, Pierre Chalard and Florence Caldefie-Chezet
Medicines 2019, 6(4), 101; https://doi.org/10.3390/medicines6040101 - 11 Oct 2019
Cited by 13 | Viewed by 4431
Abstract
Background: Some Bupleurum species, such as the Bupleurum chinense DC. or the Bupleurum scorzonerifolium Willd have been extensively studied (especially their roots) for the treatment of inflammation. In contrast, only compounds extracted from the aerial parts of Bupleurum rotundifolium have been studied and [...] Read more.
Background: Some Bupleurum species, such as the Bupleurum chinense DC. or the Bupleurum scorzonerifolium Willd have been extensively studied (especially their roots) for the treatment of inflammation. In contrast, only compounds extracted from the aerial parts of Bupleurum rotundifolium have been studied and showed anti-inflammatory or antiproliferative activities. This study was conducted to investigate the antioxidant, anti-inflammatory, and immunomodulatory effects of Bupleurum rotundifolium roots. Methods: To tackle the various aspects of inflammation, we studied in vitro a methanolic extract from the roots of Bupleurum rotundifolium on peripheral blood mononuclear cells (PBMCs), polymorphonuclear neutrophils (PMNs), and the monocytic cells THP-1. Its antioxidant capacities and iron-chelating activity were assessed. The extract was tested on THP-1 differentiation, reactive oxygen species (ROS) production by leukocytes, neutrophils chemotaxis, cytokines, PGE2 production, and NF-κB activation in PBMCs. Results: The extract showed a decreased ROS production in stimulated cells. It increased PBMC chemokine secretion and up-regulated the differentiation of THP-1 monocytes into macrophage-like cells, indicating a potential interest of the extract in the resolution of acute inflammation. In addition, the analysis of cytokine production suggests that Bupleurum rotundifolium has immunomodulatory properties. Conclusions: Cytokines secretion, especially IL-1β and IL-12p70, provided us with a set of indicators suggesting that the extract might be able to drive the polarization of macrophages and lymphocytes toward a Th2 anti-inflammatory profile in excessive inflammation. Full article
(This article belongs to the Special Issue Biological Potential and Medical Use of Natural Extracts)
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11 pages, 976 KiB  
Article
Efficacy of a Validated Yoga Protocol on Dyslipidemia in Diabetes Patients: NMB-2017 India Trial
by Raghuram Nagarathna, Rahul Tyagi, Gurkeerat Kaur, Vetri Vendan, Ishwara N. Acharya, Akshay Anand, Amit Singh and Hongasandra R. Nagendra
Medicines 2019, 6(4), 100; https://doi.org/10.3390/medicines6040100 - 11 Oct 2019
Cited by 14 | Viewed by 5006
Abstract
Background: Dyslipidemia is considered a risk factor in Type 2 diabetes mellitus (T2DM) resulting in cardio-vascular complications. Yoga practices have shown promising results in alleviating Type 2 Diabetes pathology. Method: In this stratified trial on a Yoga based lifestyle program in cases with [...] Read more.
Background: Dyslipidemia is considered a risk factor in Type 2 diabetes mellitus (T2DM) resulting in cardio-vascular complications. Yoga practices have shown promising results in alleviating Type 2 Diabetes pathology. Method: In this stratified trial on a Yoga based lifestyle program in cases with Type 2 diabetes, in the rural and urban population from all zones of India, a total of 17,012 adults (>20 years) of both genders were screened for lipid profile and sugar levels. Those who satisfied the selection criteria were taught the Diabetes Yoga Protocol (DYP) for three months and the data were analyzed. Results: Among those with Diabetes, 29.1% had elevated total cholesterol (TC > 200 mg/dL) levels that were higher in urban (69%) than rural (31%) Diabetes patients. There was a positive correlation (p = 0.048) between HbA1c and total cholesterol levels. DYP intervention helped in reducing TC from 232.34 ± 31.48 mg/dL to 189.38 ± 40.23 mg/dL with significant pre post difference (p < 0.001). Conversion rate from high TC (>200 mg/dL) to normal TC (<200 mg/dL) was observed in 60.3% of cases with Type 2 Diabetes Mellitus (T2DM); from high LDL (>130 mg/dL) to normal LDL (<130 mg/dL) in 73.7%; from high triglyceride (>200 mg/dL) to normal triglyceride level (<200 mg/dL) in 63%; from low HDL (<45 mg/dL) to normal HDL (>45 mg/dL) in 43.7% of T2DM patients after three months of DYP. Conclusions: A Yoga lifestyle program designed specifically to manage Diabetes helps in reducing the co-morbidity of dyslipidemia in cases of patients with T2DM. Full article
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9 pages, 1919 KiB  
Article
Association between Itch and Cancer in 3836 Pediatric Pruritus Patients at a Tertiary Care Center
by Micah Belzberg, Valerie A. Larson, Raveena Khanna, Kyle A. Williams, Yevgeniy Semenov, Sonja Ständer, Anna L. Grossberg and Shawn G. Kwatra
Medicines 2019, 6(4), 99; https://doi.org/10.3390/medicines6040099 - 5 Oct 2019
Cited by 6 | Viewed by 3729
Abstract
Background: Pruritus is a well-recognized paraneoplastic phenomenon. Previous studies have examined the association of itch with a variety of malignancies in adults. However, no large study has examined this association in a pediatric population. Methods: A retrospective study was conducted of [...] Read more.
Background: Pruritus is a well-recognized paraneoplastic phenomenon. Previous studies have examined the association of itch with a variety of malignancies in adults. However, no large study has examined this association in a pediatric population. Methods: A retrospective study was conducted of patients age 18 or less seen at Johns Hopkins Health System between 2012 and 2019. Results: A pediatric hospital population of 1,042,976 patients was reviewed. Pruritus was observed in 3836 pediatric patients of whom 130 also had cancer. Pediatric patients with pruritus were significantly more likely to have concomitant malignancy compared to pediatric patients without pruritus (OR 12.84; 95% CI 10.73–15.35, p < 0.001). Malignancies most strongly associated with pruritus included neoplasms of the blood (OR 14.38; 95% CI 11.30–18.29, p < 0.001), bone (OR 29.02, 95% CI 18.28–46.06, p < 0.001) and skin (OR 22.76, 95% CI 9.14–56.72, p < 0.001. Conclusions: Pruritus is significantly associated with malignancy in the pediatric hospital population. Clinicians should also be aware of the high burden of itch in pediatric malignancies and the variation in pruritus across malignancies. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment of Chronic Pruritus)
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7 pages, 1188 KiB  
Article
Racial and Gender Differences in the Presentation of Pruritus
by Katherine A. Whang, Raveena Khanna, Jamael Thomas, Crystal Aguh and Shawn G. Kwatra
Medicines 2019, 6(4), 98; https://doi.org/10.3390/medicines6040098 - 27 Sep 2019
Cited by 32 | Viewed by 4393
Abstract
Background: Pruritus is a common disease symptom with a variety of etiologies known to reduce patient quality of life. We aimed to characterize the racial and gender differences in the presentation of pruritus for itch-related patient visits both within a single institution and [...] Read more.
Background: Pruritus is a common disease symptom with a variety of etiologies known to reduce patient quality of life. We aimed to characterize the racial and gender differences in the presentation of pruritus for itch-related patient visits both within a single institution and nationally. Methods: Cross sectional study of patients ≥ 18 years old seen at Johns Hopkins Health System between 1/1/12 and 1/1/18. Results were compared to data from 2005–2011 from the National Ambulatory Medical Care Survey (NAMCS) and the National Health Ambulatory Medical Care Survey (NHAMCS). Results: Our findings indicate that itch patients at JHHS (n = 18,753) were more likely to be black compared to white patients (37% vs. 19%, p < 0.01) when compared to patients without itch—a trend also noted nationally based on data from NAMCS/NHAMCS (26% vs. 21%, p = 0.05). Black itch patients are also more likely to be diagnosed with prurigo nodularis (OR 2.37, p < 0.0001), lichen planus (OR 1.22, p < 0.0001), and atopic dermatitis OR 1.51, p < 0.0001). Female itch patients are more likely to be diagnosed with autoimmune (OR 1.66, p < 0.0001) and psychiatric comorbidities (OR 1.2–1.8, p < 0.0001) than male itch patients. When compared to black itch patients nationally, white itch patients were more likely to visit a dermatologist (29% vs. 18%, p = 0.028). Our data can identify associated conditions and demographic differences but are unable to support a causal relationship. Conclusions: Black and female patients are more likely to present with pruritus, a symptom associated with comorbidities such as prurigo nodularis, lichen planus, atopic dermatitis, and psychiatric conditions. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment of Chronic Pruritus)
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10 pages, 4011 KiB  
Communication
Diagnostic Workup and Evaluation of Patients with Prurigo Nodularis
by Christina D. Kwon, Raveena Khanna, Kyle A. Williams, Madan M. Kwatra and Shawn G. Kwatra
Medicines 2019, 6(4), 97; https://doi.org/10.3390/medicines6040097 - 26 Sep 2019
Cited by 39 | Viewed by 26065
Abstract
Prurigo nodularis (PN) is a chronic inflammatory skin disease characterized oftentimes by symmetrically distributed, severely pruritic nodules. Currently, the pathophysiology of PN remains to be fully elucidated, but emerging evidence suggests that neuroimmune alterations play principal roles in the pathogenesis of PN. There [...] Read more.
Prurigo nodularis (PN) is a chronic inflammatory skin disease characterized oftentimes by symmetrically distributed, severely pruritic nodules. Currently, the pathophysiology of PN remains to be fully elucidated, but emerging evidence suggests that neuroimmune alterations play principal roles in the pathogenesis of PN. There are several associated etiologic factors thought to be associated with PN, including dermatoses, systemic, infectious, psychiatric, and neurologic conditions. We conducted a systematic literature review to evaluate the clinical presentation, diagnosis, and etiologic factors of PN. In this review, we discuss common differential diagnoses of PN and recommend an evidence-based, standardized diagnostic evaluation for those with suspected PN. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment of Chronic Pruritus)
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11 pages, 625 KiB  
Article
Antipyretic, Antinociceptive, and Anti-Inflammatory Activities from Pogostemon benghalensis Leaf Extract in Experimental Wister Rats
by Sushant Aryal, Balkrishna Adhikari, Kasmira Panthi, Pramod Aryal, Shyam Kumar Mallik, Ram Prasad Bhusal, Bahare Salehi, William N. Setzer, Javad Sharifi-Rad and Niranjan Koirala
Medicines 2019, 6(4), 96; https://doi.org/10.3390/medicines6040096 - 20 Sep 2019
Cited by 7 | Viewed by 6648
Abstract
Background: Pogostemon benghalensis leaves have traditionally been utilized for relieving body aches, headaches and fever. Based on its uses, the present study was designed to investigate the antinociceptive, antipyretic and anti-edematogenic activities from P. benghalensis leaves’ methanol extract (PBME) in Wister rats. Methods: [...] Read more.
Background: Pogostemon benghalensis leaves have traditionally been utilized for relieving body aches, headaches and fever. Based on its uses, the present study was designed to investigate the antinociceptive, antipyretic and anti-edematogenic activities from P. benghalensis leaves’ methanol extract (PBME) in Wister rats. Methods: The thermal (hot plate) and chemical (acetic acid-induced writhing and formalin test) models for antinociceptive effects, and the Brewer’s yeast induced hyperthermia test for antipyretic action and rat paw edema by carrageenan for anti-edematogenic activity, were applied for PBME at different dose levels. The acute toxicity of PBME through the oral route was performed to determine the lethal dose. Results: PBME significantly and dose-dependently reduced pyrexia and diminished edema volume, which depicted its antipyretic and anti-edematogenic effects respectively. The inhibition of writhing reflex, increased reaction latency and reduced frequency of licking indicated that PBME has significant dose-dependent antinociceptive activity. P. benghalensis methanol extract at 4000 mg/kg shows no sign of toxicity, which is a considerable, good margin of safety. Conclusions: The study illustrated the antipyretic, antinociceptive and anti-inflammatory potential of P. benghalensis leaf extract with a safety margin, and validated its traditional use to alleviate fever, pain, and inflammation. Full article
(This article belongs to the Special Issue Biological Potential and Medical Use of Natural Extracts)
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