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Resume Introduction L’etude des produits naturels est l’une des strategies mises en œuvre pour la decouverte de nouvelles drogues utilisables en therapie anticancereuse. En Algerie, le potentiel cytotoxique des plantes aromatiques et medicinales est tres peu explore. Objectifs Dans cette optique, ce travail visait a evaluer les proprietes antioxydante, anti-inflammatoire et anticancereuse de l’huile essentielle (HE) distillee d’une plante a parfum, le geranium rosat (Pelargonium graveolens), ainsi que de ces deux composes majoritaire (citronellol) et caracteristique (linalool). Resultats La composition chimique de l’HE a ete determinee par analyse chromatographique et a revele la presence du citronellol comme compose majoritaire avec un taux de 25,84 %. Un fort pouvoir chelateur des alcools terpeniques (IC50 = 1,58 ± 0,23 mg/mL pour le citronellol) a ete obtenu, avec une difference significative (p Conclusion et perspectives Les resultats de ces travaux montrent que l’essence aromatique du geranium odorant a un potentiel antitumoral sur des lignees cellulaires cancereuses metastasiques. Elle s’est distinguee par ses potentialites antiproliferative, anti-angiogenique, antioxydante et anti-inflammatoire. Ce vaste reservoir vegetal pourrait renfermer de nouvelles molecules, aux structures originales, qui pourraient devenir les chefs de file de nos futurs medicaments anticancereux.

Mohamad EA, Aly AA, Khalaf AA, et al. Drug Des Devel Ther. 2021;15:3151–3162. The Editor and Publisher of Drug Design, Development and Therapy wish to retract the published article. Concerns were raised regarding the integrity of the HPLC chromatograms presented in Figure 1, where the values of the peaks did not appear to correspond with the values shown along the x-axis. The authors did respond to our queries and explained that their laboratory does not have access to an HPLC device and the HPLC experiments were performed by a third-party. They further explained that errors had been made during calculations of the retention times, but they were unable to explain how this occurred. In addition, discrepancies remained in the retention times of the corrected HPLC chromatograms the authors provided, and there was a lack of adequate data associated with these experiments. The Editor determined that the explanation for the calculation errors and availability of original data were both insufficient and had concerns over the reliability of the reported findings. The Editor requested for the article to be retracted and the authors were notified of this. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Ferroptosis is iron-dependent regulated cell death and is a field of research that has been rapidly growing in recent years. Many preclinical studies show therapeutic benefit of ferroptosis modulation in lung cancers. There are advancements using prognostic ferroptosis-related genes to directly predict outcomes in lung cancer. Targeted therapy using RNA and nanoparticle technology have also shown benefits in ferroptosis induction. Currently, there is limited comprehensive evaluation of how ferroptosis can be used in lung cancer therapy. Thus, the aim of this report is to build an overview of all data on ferroptosis modulation in lung cancer.Ferroptotic cell death mechanisms and how ferroptosis is highly distinguished from other forms of cell death, offered insight on the modulations of ferroptosis in killing lung cancer cells in preclinical studies. Search databases included PubMed, Google scholar, and clinicaltrials.gov through the last 10 years.Ferroptosis modulation in lung cancer is a promising therapeutic option, but greater understanding and progression from primarily in vitro studies to animal studies and clinical trials is needed to substantiate its utilization in practice. Future strategies of using ferroptosis modulation adjuvant to first-line therapy may increase its effectiveness and overcome apoptosis-resistance cancers.

We have recently reported on the development of fb-PMT (NP751), a conjugate of the thyroid hormone metabolite tetraiodothyroacetic acid (tetrac) and monodisperse polyethylene glycol 36. It exhibited high affinity for thyrointegrin αvβ3 receptor and potent anti-angiogenic and anticancer activity in vivo. The objective of the current study is to determine the pharmacokinetics (PK) of fb-PMT in experimental animals, such as mice, rats, and monkeys. NP751 was quantified using a propylene diamine-modified tetraiodothyroacetic acid (DAT) as an internal standard. The limit of quantification (LOQ) for fb-PMT was 1.5 ng/μL and the recovery efficiency was 93.9% with the developed method. The peak plasma concentration (Cmax) and the area under the curve (AUC) results at different doses in mice, rats and monkeys suggest that pharmacokinetics of NP751 is dose-dependent within the dose ranges administered. Results indicate that NP751 has comparable PK parameters that provides enough exposure as a molecularly tumor targeted molecule in multiple species and is a promising anticancer therapeutic.

We have previously reported that the αvβ3 inhibitor P-bi-TAT, a bifunctional version of the thyroid hormone metabolite tetraiodothyroacetic acid (tetrac) conjugated to polyethylene glycol (PEG) MW 4000, has excellent efficacy in a glioblastoma multiforme (GBM) mouse model. However, bioanalysis problems due to PEG polydispersity and large-scale synthesis issues led to a search for new molecules, culminating in the discovery of fb-PMT, a conjugate of tetrac and monodisperse PEG36, with a lipophilic 4-fluorobenzyl group at the opposite end of the PEG chain. fb-PMT reduces GBM tumor growth and viability by up to 98%, is suitable for large-scale synthesis, and is amenable to bioanalysis using mass spectrometry-based detection. We also showed that changes in lipophilicity at the opposite end of the PEG chain from the active tetrac component affected the proton NMR chemical shift of the tetrac moiety in D20 and brain levels of the compound after subcutaneous dosing.

The aim of this investigation is to determine the potential protective effect and mechanism of a novel non-anticoagulant heparin-derived product on lead (Pb) mediated endothelial cells (ECs) toxicity. Pb is known to have detrimental effects on human health by affecting the function of all systems of the human body due to its toxicity on ECs. Altered activities of the protective substances secreted by the vascular endothelium such as EC’s tissue factor pathway inhibiter (TFPI), nitric oxide and other protective factors might increase the risk for vascular disorders. Heparin and its sulfated non-anticoagulant low molecular weight heparin (S-NACH) are known to enhance TFPI release from ECs, which is a protective mechanism for the ECs against thrombo-inflammation. We examined 3–100 µM Pb-induced dysfunction on ECs and the potential protective effect of 1–10 µM S-NACH in returning the ECs’ normal function. Methods included an in vitro tube formation assay and an in vivo Matrigel plug angiogenesis model in mice. We found that Pb-induced EC dysfunction by inhibiting EC viability. The cytotoxic effect of 3–100 µM Pb on ECs inhibited angiogenesis in a dose-dependent manner. Pb disrupted ECs’ normal physiological function by hindering the release of its endogenous vascular protective mediators TFPI-1 and TFPI-2. The impairment effect of 3–30 µM Pb on ECs’ release of both TFPIs was effectively reversed to normal levels by S-NACH in a concentration-dependent manner and combatted the harmful Pb effects on physiological angiogenesis. Our data indicate that S-NACH, which is devoid of bleeding side effects, can effectively reverse potentially high-risk Pb-mediated endothelial cytotoxicity by reversing the physiological release of endogenous EC TFPIs.

Sickle cell disease (SCD) is an autosomal recessive genetic disease caused by a single point mutation, resulting in abnormal sickle hemoglobin (HbS). During hypoxia or dehydration, HbS polymerizes to form insoluble aggregates and induces sickling of red blood cells, which increases the adhesiveness of the cells, thereby altering the rheological properties of the blood, and triggers inflammatory responses, leading to hemolysis and vaso-occlusive crises. Unfractionated heparin and low-molecular weight heparins have been suggested as treatments to relieve coagulation complications in SCD. However, they are associated with bleeding complications after repeated dosing. An alternative sulfated non-anticoagulant heparin derivative (S-NACH) was previously reported to have no to low systemic anticoagulant activity and no bleeding side effects, and it interfered with P-selectin-dependent binding of sickle cells to endothelial cells, with concomitant decrease in the levels of adhesion biomarkers in SCD mice. S-NACH has been further engineered and structurally enhanced to bind with and modify HbS to inhibit sickling directly, thus employing a multimodal approach. Here, we show that S-NACH can: (i) directly engage in Schiff-base reactions with HbS to decrease red blood cell sickling under both normoxia and hypoxia in vitro, (ii) prolong the survival of SCD mice under hypoxia, and (iii) regulate the altered steady state levels of pro- and anti-inflammatory cytokines. Thus, our proof-of-concept, in vitro and in vivo preclinical studies demonstrate that the multimodal S-NACH is a highly promising candidate for development into an improved and optimized alternative to low-molecular weight heparins for the treatment of patients with SCD.

Cancer can develop due to abnormal cell proliferation in any body’s cells, so there are over a hundred different types of cancer, each with its distinct behavior and response to treatment. Therefore, many studies have been conducted to slow cancer progression and find effective and safe therapies. Nutraceuticals have great attention for their anticancer potential. Therefore, the current study was conducted to investigate the anticancer effects of curcumin (Cur), thymoquinone (TQ), and 3, 3′-diindolylmethane (DIM) combinations on lung (A549) and liver (HepG2) cancer cell lines’ progression. Results showed that triple (Cur + TQ + DIM) and double (Cur + TQ, Cur + DIM, and TQ + DIM) combinations of Cur, TQ, and DIM significantly increased apoptosis with elevation of caspase-3 protein levels. Also, these combinations exhibited significantly decreased cell proliferation, migration, colony formation activities, phosphatidylinositol 3-kinase (PI3K), and protein kinase B (AKT) protein levels with S phase reduction. Triple and double combinations of Cur, TQ, and DIM hindered tumor weight and angiogenesis of A549 and HepG2 implants in the chorioallantoic membrane model. Interestingly, Cur, TQ, and DIM combinations are considered promising for suppressing cancer progression via inhibiting tumor angiogenesis. Further preclinical and clinical investigations are warranted.

Antioxidants are one of the effective treatment lines in managing type 2 diabetes (typ2diab) and its complications. Nanoformulations could help in ameliorating the oral bioavailability and biocompatibility properties. Ellagic acid (Ella) is a natural antioxidant compound commonly present in fruits. This study examined the effect Ella nanoparticles (Ella NPs) alone and combined with metformin, the standard antidiabetic drug, on controlling blood glucose in typ2diab. Forty-eight adult Sprague-Dawley rats were used in this study. Except for the control group that was fed a regular pellet diet, all animals were fed a high-fat diet (HFD) for 9 weeks. For the last 4 weeks, rats were injected with streptozotocin (35 mg /kg). Then the rats were randomized into 8 groups: control, HFD, diabetic, Ella, Ella + metformin, Ella NPs, and Ella NPs + metformin. Data showed that Ella NPs improved blood glucose levels and the body weights of diabetic rats throughout all the weeks of the experiment whereas effects of the regular Ella were limited to the last two weeks of the treatment. Additionally, data demonstrated that the antidiabetic action of Ella NPs and its effective duration were similar to metformin. Ella NPs led to a lowering effect on lipid profile markers (total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL)), superior to the regular Ella, which reduced only TG and VLDL. Results of the pathological examination showed improved number and activity of beta islets in all treatment groups. The most enhanced islets were in the Ella NPs and metformin group. The different treatments decreased caspase 3 and increased insulin gene expression, and the effect was superior in the Ella NPs and metformin group. The results of this study confirmed that Ella could manage typ2diab by lowering glucose and lipid levels and improving body weight with the superiority of Ella NPs. The mechanisms behind these effects are inhibition of beta-cell apoptosis and stimulation of insulin production.

Pomegranate fruit extract contains many polyphenols and flavonoids of diverse biological importance including anticancer potential. In cancer, the angiogenesis process facilitates solid cancer growth and metastasis. Here, the antiangiogenic effect of pomegranate fruit extract against human pancreatic cancer (Suit-2) and colon (colo205) cell lines in the chick chorioallantoic membrane (CAM) model was studied along with the effect of pomegranate fruit extract on fibroblast growth factor (FGF2). Pomegranate fruit extract significantly reduced the tumor weight and hemoglobin content in CAM models of pancreatic Suit-2 and colon colo205.

The oxidative stress leading to degenerative changes in the brain of Alzheimer’s disease (AD) is evident. Our aim was to evaluate the therapeutic and protective effects of pomegranate extract (PE) and pomegranate extract-loaded nanoparticles (PE nano) in an AlCl 3-induced AD rat model. Nanoparticles were synthesized with a PE load of 0.68% w/w, and 70 male Wistar rats were divided into 7 groups: Group I was the control, Group II received PE., Group III received PE nano for 2 weeks, Group IV received AlCl 3 (50 mg/kg) daily orally for 4 weeks, Group V received PE for 2 weeks, Group VI received PE nano for 2 weeks, and Groups V and VI were started after AlCl 3 administration was stopped. Group VII received PE for 2 weeks and was stopped before AlCl 3 was administered. The Results revealed that the discrimination index in the novel object recognition test was the least in AD rat model but increased in cases protected with PE treated with PE nano. Similar results were shown based on calculating the brain weight/body weight percent. The biomarkers of antioxidant activity (catalase, glutathione and total antioxidant activity) in brain homogenate were significantly increased in groups treated with either PE or PE nano. The thiobarbituric acid reactive substance measured to estimate lipid peroxidation was significantly increased in AD rat model and decreased in groups protected with PE or treated with PE nano. Histopathological studies using hematoxylin and eosin, cresyl violet, and silver stains revealed hyaline degeneration, chromatolysis, and hallmarks of AD; neurofibrillary tangles and the senile plaques in brains of AD rat model. Restoration of the histological architecture, Nissl granules, and minimal appearance of hallmarks of AD characterized brains treated with PE or PE nano. In conclusion, PE was more effective as a protectant than a therapeutic measure in alleviating the antioxidant, lipid peroxidative effects and histopathological hallmarks in AD brains. But, the therapeutic PE-loaded nanoparticles increased the efficacy of active components and produced similar results as the protective PE.

Cancer is a worldwide disease that causes millions of cases of mortality and morbidity. The major problem associated with the cancer is its resistance to conventional therapy and a high relapse rate. The use of chemotherapy to treat cancer began at the start of the twentieth century with attempts to control cancer. In time advance, many cancer chemotherapeutic agents have been developed for cancer treatment with different mechanisms of action including the alkylating agents, antimetabolites, antimicrotubule, topoisomerase inhibitors, and cytotoxic antibiotics, all of which have toxic effects toward normal cells in the body. Here, we reviewed chemotherapeutics' anticancer role potentiation and safety by thymoquinone (TQ) alone or in combination with the most common therapeutic drugs. Our search was done through PubMed, Science Direct, Springer Link, Taylor & Francis Online, Wiley Online Library, Nature publication group, SAGE Journals, and Web of Science databases. We recognized that TQ-chemotherapeutics combination increased chemo-modulation to the anticancer effect of different chemotherapeutics and protected the normal body cells from the toxic injuries that are induced by chemotherapeutics based on its antioxidant power. Moreover, the current study investigates the possible combinatory effect of TQ and chemotherapeutics to control cancer stem cells through molecular docking targeting of wingless/integrated (Wnt) and Hedgehog (Hh). We found that TQ modulates the Wnt and Hh pathways, by binding with tankyrase-2 and smoothened 7TM receptor, respectively, more efficiently than most chemotherapeutics drugs, while methotrexate showed high-binding affinity compared with TQ. Therefore, we encourage researchers to investigate the chemo-modulatory potential and protective effects of TQ in combination with chemotherapeutics for either cancer or cancer stem cell treatment.

Complications with atherosclerosis can often lead to fatal clot formation and blood vessel occlusion - also known as atherothrombosis. A key component to the development of atherosclerosis and atherothrombosis is the endothelium and its ability to regulate the balance between prothrombotic and antithrombotic activities. Endothelial surface glycocalyx has a critical role in maintenance of vascular integrity. The endothelial glycocalyx, nitric oxide, prostacyclins, heparan sulfate, thrombomodulin, and tissue factor pathway inhibitor all prevent thrombosis, while P-selectin, among many other factors, favors thrombosis. However, endothelial dysfunction gives rise to the acceleration of thrombotic development and eventually the requirement of antithrombotic therapy. Most FDA-approved anticoagulant and antiplatelet therapies today carry a side effect profile of major bleed. Within the past five years, several preclinical studies using different endothelial targets and nanotechnology as a drug delivery method have emerged to target the endothelium and to enhance current antithrombosis without increasing bleed risk. While clinical studies are required, this review illustrates the proof-of-concept of nanotechnology in promoting a greater safety and efficacy profile through multiple in vitro and in vivo studies.

Background: Ischemic heart disease is the main cause of death globally. Cardioprotection is the process whereby mechanisms that reduce myocardial damage, and activate protective factors, contribute to the preservation of the heart. Targeting these processes could be a new strategy in the treatment of post-ischemic heart failure (HF). Triiodothyronine (T3) and thyroxine (T4), which have multiple effects on the heart, prevent myocardial damage. Results: This study describes the formulation, and characterization, of chemically modified polymeric nanoparticles incorporating T3, to target the thyroid hormone receptors. Modified T3 was conjugated to polylactide-co-glycolide (PLGA) to facilitate the active targeting of PLGA-T3. Modified T3 and PLGA-T3 was characterized with 1H-NMR. Protective role of synthesized Phosphocreatine (PCr) encapsulated PLGA-T3 nanoparticles (PLGA-T3/PCr NPs) and PLGA-T3 nanoparticles (PLGA-T3 NPs) in hypoxia-mediated cardiac cell insults were investigated. Conclusions: Data demonstrated that PLGA-T3/PCr NPs represent a potentially new therapeutic for the control of tissue damage in cardiac ischemia and resuscitation.

Nuclear factor-κB (NF-κB) is a transcription factor that regulates various genes that mediate various cellular activities, including propagation, differentiation, motility, and survival. Abnormal activation of NF-κB is a common incidence in several cancers. Glioblastoma multiforme (GBM) is the most aggressive brain cancer described by high cellular heterogeneity and almost unavoidable relapse following surgery and resistance to traditional therapy. In GBM, NF-κB is abnormally activated by various stimuli. Its function has been associated with different processes, including regulation of cancer cells with stem-like phenotypes, invasion of cancer cells, and radiotherapy resistance identification of mesenchymal cells. Even though multimodal therapeutic approaches such as surgery, radiation therapy, and chemotherapeutic drugs are used for treating GBM, however; the estimated mortality rate for GBM patients is around 1 year. Therefore, it is necessary to find out new therapeutic approaches for treating GBM. Many studies are focusing on therapeutics having less adverse effects owing to the failure of conventional chemotherapy and targeted agents. Several studies of compounds suggested the involvement of NF-κB signaling pathways in the growth and development of a tumor and GBM cell apoptosis. In this review, we highlight the involvement of NF-κB signaling in the molecular understanding of GBM and natural compounds targeting NF-κB signaling.

Discovery of bioactive molecules that target integrins has implicated their role in tumor angiogenesis, tumor growth, metastasis, and other pathological angiogenesis processes. Integrins are members of a family of cell surface receptors that play a critical role in the angiogenesis process. Tetraiodothyroacetic acid (tetrac), a deaminated derivative of l-thyroxine (T4), is a "thyrointegrin" antagonist that blocks the actions of l-triiodothyronine (T3) and T4 with an interaction site that is located at or near the RGD recognition site identified on integrin αvβ3's binding pocket (thyrointegrin αvβ3 receptors). We have enhanced the biological activity of a tetrac-based inhibitor via significantly improving its αvβ3 receptor binding affinity by introducing a triazole ring on the outer ring of tetrac and covalently conjugating to polymer to increase the product's hydrophilicity via PEGylation. The product, P-bi-TAT, was restricted from nuclear translocation and demonstrated high blood brain barrier permeability and retention in contrast to the non-PEG conjugated derivative. Results of biological activity indicated that this macromolecule new chemical entity P-bi-TAT has greater than 400-fold potent integrin αvβ3 affinity versus the parent compound tetrac and has potent anticancer/anti-angiogenesis efficacy against glioblastoma multiforme (GBM). P-bi-TAT administered subcutaneously once daily for 21 days at 1-10 mg/kg mouse body weight resulted in a dose-dependent suppression of GBM tumor growth and viability as monitored with IVIS imaging (P 95% volume loss and maximal loss of GBM cell viability during the 21 days ON-treatment experiment as well as in the 21 days ON followed by 21 days OFF-treatment experiment (P < 0.001). In conclusion, P-bi-TAT is a promising lead clinical candidate effective in the treatment of human GBM.

Samar A Shahein1,*Ahmed M Aboul-Enein,1 Iman M Higazy,2 Faten Abou-Elella,1 Witold Lojkowski,3 Esam R Ahmed,4 Shaker A Mousa,5 Khaled AbouAitah3,6,*1Biochemistry Department, Faculty of Agriculture, Cairo University, Giza, Egypt; 2Department of Pharmaceutical Technology, Pharmaceutical and Drug Industries Research Division, National Research Centre (NRC), Giza, Egypt; 3Laboratory of Nanostructures, Institute of High Pressure Physics, Polish Academy of Sciences, Warsaw, Poland; 4Confirmatory Diagnostic Unit, Egyptian Organization for Vaccine, Sera and Biological Products (VACSERA), Giza, Egypt; 5The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, New York, NY, USA; 6Medicinal and Aromatic Plants Research Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (NRC), Giza, Egypt*These authors contributed equally to this workBackground and purpose: Glioma is one of the most aggressive primary brain tumors and is incurable. Surgical resection, radiation, and chemotherapies have been the standard treatments for brain tumors, however, they damage healthy tissue. Therefore, there is a need for safe anticancer drug delivery systems. This is particularly true for natural prodrugs such as thymoquinone (TQ), which has a high therapeutic potential for cancers but has poor water solubility and insufficient targeting capacity. We have tailored novel core-shell nanoformulations for TQ delivery against glioma cells using mesoporous silica nanoparticles (MSNs) as a carrier.Methods: The core-shell nanoformulations were prepared with a core of MSNs loaded with TQ (MSNTQ), and the shell consisted of whey protein and gum Arabic (MSNTQ-WA), or chitosan and stearic acid (MSNTQ-CS). Nanoformulations were characterized, studied for release kinetics and evaluated for anticancer activity on brain cancer cells (SW1088 and A172) and cortical neuronal cells-2 (HCN2) as normal cells. Furthermore, they were evaluated for caspase-3, cytochrome c, cell cycle arrest, and apoptosis to understand the possible anticancer mechanism.Results: TQ release was pH-dependent and different for core and core-shell nanoformulations. A high TQ release from MSNTQ was detected at neutral pH 7.4, while a high TQ release from MSNTQ-WA and MSNTQ-CS was obtained at acidic pH 5.5 and 6.8, respectively; thus, TQ release in acidic tumor environment was enhanced. The release kinetics fitted with the Korsmeyer–Peppas kinetic model corresponding to diffusion-controlled release. Comparative in vitro tests with cancer and normal cells indicated a high anticancer efficiency for MSNTQ-WA compared to free TQ, and low cytotoxicity in the case of normal cells. The core-shell nanoformulations significantly improved caspase-3 activation, cytochrome c triggers, cell cycle arrest at G2/M, and apoptosis induction compared to TQ.Conclusion: Use of MSNs loaded with TQ permit improved cancer targeting and opens the door to translating TQ into clinical application. Particularly good results were obtained for MSNTQ-WA.Keywords: brain cancer targeting, drug delivery system, thymoquinone core-shell nanoformulation, mesoporous silica nanoparticles, pH-dependent release kinetics

Integrin αvβ3 receptors are overexpressed in different tumors and their associated neovascularization and hence, represent a potential cancer target. We previously synthesized a high affinity thyrointegrin αvβ3, P4000-bi-TAT (tetrac derivative), with potent anticancer properties. However, the long polydisperse PEG conjugate showed large scaleup and analytical/bioanalytical issues. Hence, in the present study, we synthesized a mono versus bi-triazole tetrac with discrete monodisperse PEG, which provided improvement in scaleup and bioanalysis. In the present study, we compared binding affinity and anticancer activates with a smaller PEG size (P1600-bi-TAT, Compound 2) and the removal of one TAT molecule (P1600-m-TAT, Compound 3) versus P4000-bi-TAT, Compound 1. The results of the selectivity and affinity of TATs showed greater affinity to integrin αvβ3. The xenograft weights and tumor cell viabilities were decreased by &gt, 90% at all doses compared to the control (ON Treatment, *** p &lt, 0.001) in cells treated with Compounds 1, 2, and 3 in U87-Luc-treated mice. The in vivo luminescent signals of U87-luc cells reflect the proliferation and distribution of tumor cells in the animals and the maximum intensity corresponding to the maximum tumor cells that the animals could tolerate. We found that the three thyrointegrin αvβ3 antagonists exhibited optimal therapeutic efficacy against U87 or primary glioblastoma cells. Biological studies showed that decreasing the PEG linker size (1600 vs. 4000) or having mono-TAT or bi-TAT had no significant impact on their αvβ3 binding affinity, anti-angiogenesis, or overall anti-cancer efficacy.

Ebtesam A Mohamad,1 Aya A Aly,2 Aya A Khalaf,2 Mona I Ahmed,2 Reham M Kamel,2 Sherouk M Abdelnaby,2 Yasmine H Abdelzaher,2 Marize G Sedrak,2 Shaker A Mousa3 1Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt; 2Biotechnology/Biomolecular Chemistry Program, Faculty of Science, Cairo University, Giza, Egypt; 3The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USACorrespondence: Shaker A MousaThe Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, 12144, USATel +1-518-694-7397Fax +1-518-694-7567Email shaker.mousa@acphs.eduIntroduction: Skin aging is a normal process that might be accelerated or delayed by altering the balance between antioxidants and free radicals due to increase in the exposure to reactive oxygen species (ROS) into skin cells via UV radiation. Antioxidants can neutralize the harmful effects of ROS, and secondary plant metabolites might help protect against UV radiation.Methods: In this study, punicalagin was extracted from pomegranate, and concentrations of total polyphenolics and flavonoids were determined, and antioxidant activities were measured. Punicalagin was loaded onto niosomes, and its morphology and release were studied. An in vitro study was performed on human fibroblast cell line HFB4 cells with aging induced by H2O2 and UV radiation. Cell cycle arrest was studied, and different genes (MMP3, Col1A1, Timp3, and TERT) involved in the skin aging process were selected to measure punicalagin’s effect.Results: Punicalagin succeeded in reducing the growth arrest of HFB4 cells, activated production of the Col1A1 and Timp3 genes, maintained collagen level, and lowered MMP3. Punicalagin increased human TERT concentration in skin cells.Discussion: Punicalagin is promising as a natural antioxidant to protect human skin from aging.Keywords: skin aging, punicalagin, niosomes, UV radiation, collagen

As a crucial organ, the lung is exposed to various harmful agents that may induce inflammation and oxidative stress, which may cause chronic or acute lung injury. Nigella sativa, also known as black seed, has been widely used to treat various diseases and is one of the most extensively researched medicinal plants. Thymoquinone (TQ) is the main component of black seed volatile oil and has been proven to have antioxidant, anti-inflammatory, and antineoplastic properties. The potential therapeutic properties of TQ against various pulmonary disorders have been studied in both in vitro and in vivo studies. Furthermore, the application of nanotechnology may increase drug solubility, cellular absorption, drug release (sustained or control), and drug delivery to lung tissue target sites. As a result, fabricating TQ as nanoparticles (NPs) is a potential therapeutic approach against a variety of lung diseases. In this current review, we summarize recent findings on the efficacy of TQ and its nanotypes in lung disorders caused by immunocompromised conditions such as cancer, diabetes, gastric ulcers, and other neurodegenerative diseases. It is concluded that TQ nanoparticles with anti-inflammatory, antioxidant, antiasthma, and antitumor activity may be safely applied to treat lung disorders. However, more research is required before TQ nanoparticles can be used as pharmaceutical preparations in human studies.

COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has a disastrous effect on mankind due to the contagious and rapid nature of its spread. Although vaccines for SARS-CoV-2 have been successfully developed, the proven, effective, and specific therapeutic molecules are yet to be identified for the treatment. The repurposing of existing drugs and recognition of new medicines are continuously in progress. Efforts are being made to single out plant-based novel therapeutic compounds. As a result, some of these biomolecules are in their testing phase. During these efforts, the whole-genome sequencing of SARS-CoV-2 has given the direction to explore the omics systems and approaches to overcome this unprecedented health challenge globally. Genome, proteome, and metagenome sequence analyses have helped identify virus nature, thereby assisting in understanding the molecular mechanism, structural understanding, and disease propagation. The multi-omics approaches offer various tools and strategies for identifying potential therapeutic biomolecules for COVID-19 and exploring the plants producing biomolecules that can be used as biopharmaceutical products. This review explores the available multi-omics approaches and their scope to investigate the therapeutic promises of plant-based biomolecules in treating SARS-CoV-2 infection.

Introduction Cancer-associated thrombosis (CAT) accounts for about 20% of all cases of Venous Thromboembolism (VTE). Tissue factor (TF) is documented to be highly expressed on cancer cells and pathological angiogenic endothelial cells. Here, we used a novel oxidized sulfated ultra-LMWH, S-NACH, which is devoid of anti-factor Xa and IIa activities with limited to no systemic anticoagulant effects. This sulfated form has enhanced binding to vascular endothelial cells (EC) and releases and potentiates the action of tissue factor pathway inhibitor (TFPI). S-NACH binds with high affinity to EC, releases and binds to EC TFPI, and promotes vascular antithrombotic effect with limited to no risk of bleeding complications. Materials and methods We investigated the effects of S-NACH on clot kinetics in vitro and in vivo. Also, we investigated the effects of S-NACH on CAT mediated by human acute leukemia cells (K562) and human pancreatic cancer cells (SUIT2). Results S-NACH was associated with ~3-fold increase of TFPI 2 levels within 3 h. Also, S-NACH reversed the hypercoagulability state that is associated with cancer cells in vitro. In vivo, S-NACH at 20 mg/kg subcutaneously (SC) had no effect on bleeding time compared to both tinzaparin and enoxaparin at 5 mg/kg SC. S-NACH did not show any anti-IIa or anti-Xa activities in comparison to tinzaparin and enoxaparin (p Conclusion Data suggest the importance of S-NACH through its EC binding, EC TFPI release and its interaction with TFPI in enhancing its activity in the prevention of cancer and non-cancer associated thrombosis with limited to no bleeding complications.

International audience; At the end of 2019, a novel coronavirus (CoV) was found at the seafood market of Hubei province in Wuhan, China, and this virus was officially named coronavirus diseases 2019 (COVID-19) by World Health Organization (WHO). COVID-19 is mainly characterized by severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) and creates public health concerns as well as significant threats to the economy around the world. Unfortunately, the pathogenesis of COVID-19 is unclear and there is no effective treatment of this newly life-threatening and devastating virus. Therefore, it is crucial to search for alternative methods that alleviate or inhibit the spread of COVID-19. In this review, we try to find out the etiology, epidemiology, symptoms as well as transmissions of this novel virus. We also summarize therapeutic interventions and suggest antiviral treatments, immune-enhancing candidates, general supplements, and CoV specific treatments that control replication and reproduction of SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV).

Alzheimer’s disease (AD) is an irreversible chronic neurodegenerative disorder that occurs when neurons in the brain degenerate and die. Pain frequently arises in older patients with neurodegenerative diseases including AD. However, the presence of pain in older people is usually overlooked with cognitive dysfunctions. Most of the times dementia patients experience moderate to severe pain but the development of severe cognitive dysfunctions tremendously affects their capability to express the presence of pain. Currently, there are no effective treatments against AD that emphasize the necessity for increasing research to develop novel drugs for treating or preventing the disease process. Furthermore, the prospective therapeutic use of cannabinoids in AD has been studied for the past few years. In this regard, targeting the endocannabinoid system has considered as a probable therapeutic strategy to control several associated pathological pathways, such as mitochondrial dysfunction, excitotoxicity, oxidative stress, and neuroinflammation for the management of AD. In this review, we focus on recent studies about the role of cannabinoids for the treatment of pain and related neuropathological changes in AD.

Cisplatin is an anticancer drug commonly used for solid tumors. However, it causes nephrotoxicity. OAT1 and OAT3 are organic anion transporters known to contribute to the uptake of cisplatin into renal tubular cells. The present study was designed to examine the protective role of ellagic acid nanoformulation (ellagic acid nano) on cisplatin-induced nephrotoxicity in rats, and the role of OAT1/OAT3 in this effect. Four groups of male Wistar rats were used (n = 6): (1) control, (2) cisplatin (7.5 mg/kg single dose, intraperitoneal), (3) cisplatin + ellagic acid nano (1 mg/kg), and (4) cisplatin + ellagic acid nano (2 mg/kg). Nephrotoxic rats treated with ellagic acid nano exhibited a significant reduction in elevated serum creatinine, urea, and oxidative stress marker, malondialdehyde (MDA). Additionally, ellagic acid nano restored renal glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Ellagic acid nano improved the histopathological changes induced by cisplatin, such as tubular dilatation, necrosis, and degeneration. Interestingly, OAT1 and OAT3 showed significantly lower expression at both mRNA and protein levels following ellagic acid nano treatment relative to the cisplatin-exposed group. These findings reveal a potential inhibitory role of ellagic acid antioxidant on OAT1 and OAT3 expression and thus explains its nephroprotective effect against cisplatin nephrotoxicity.

One of the major causes of women’s death in the world is breast cancer. Consequently, numerous regimens for the control of this severe disease have been created. The chemotherapeutic agent doxorubicin (DOX) is frequently used to treat breast cancer, but DOX can also cause cardiotoxic effects that lead to heart failure. Therefore, many research studies have been done to find a natural product that effectively potentiates or does not interfere with DOX’s anticancer effect and protects against its cardiotoxicity. We studied the impact of combined nanoformulated Ajwa (Phoenix dactylifera) selected bioactive compounds (BAC) rutin (R) and quercetin (Q) in nude mice breast cancer xenografts on DOX-mediated anticancer efficacy. We also studied if this Ajwa BAC could safeguard against DOX-mediated cardiomyopathies by evaluating plasma cardiac troponin-I (cTn-I) levels and cardiac histopathology. Nanoformulated Ajwa BAC effectively alleviated weight loss induced by DOX in mice and significantly decreased the elevated cTn-I. Furthermore, 5 mg RQ-NPs/kg of nude mice that subcutaneously daily injected for 11 days, attenuated the histopathological alterations induced in cardiac muscles due to DOX without any interference with the anticancer effects of DOX against breast cancer.

Repositioning of dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists is a breakthrough in the field of neural regeneration research increasing glucagon like peptide-1 bioavailability, hence its neuroprotective activities. In this article, the authors suggest not only crossing blood-brain barrier and neurodegenerative disease as off target for dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists, but also for ophthalmic preparations for diabetic retinopathy, which may be the latest breakthrough in the field if prepared and used in an appropriate nano-formulation to target the retinal nerves. The relation of neurodegenerative diseases' different mechanisms to the dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists should be further examined in preclinical and clinical settings. The repositioning of already marketed antidiabetic drugs for neurodegenerative diseases should save the high cost of the time-consuming normal drug development process. Drug repositioning is a hot topic as an alternative to molecular target based drug discovery or therapeutic switching. It is a relatively inexpensive pathway due to availability of previous pharmacological and safety data. The glucagon like peptide-1 produced in brain has been linked to enhanced learning and memory functions as a physiologic regulator in central nervous system by restoring insulin signaling. Intranasal administration of all marketed gliptins (or glucagon like peptide-1 receptor agonists) may show enhanced blood-brain barrier crossing and increased glucagon like peptide-1 levels in the brain after direct crossing of the drug for the olfactory region, targeting the cerebrospinal fluid. Further blood-brain barrier crossing tests may extend dipeptidyl peptidase-4 inhibitors' effects beyond the anti-hyperglycemic control to intranasal spray, intranasal powder, or drops targeting the blood-brain barrier and neurodegenerative diseases with the most suitable formula. Moreover, novel nano-formulation is encouraged either to obtain favorable pharmacokinetic parameters or to achieve promising blood-brain barrier penetration directly through the olfactory region. Many surfactants should be investigated either as a solubilizing agent for hydrophobic drugs or as penetration enhancers. Different formulae based on in vitro and in vivo characterizations, working on sister gliptins (or glucagon like peptide-1 receptor agonists), different routes of administration, pharmacokinetic studies, dose response relationship studies, monitoring of plasma/brain concentration ratio after single and multiple dose, and neurodegenerative disease animal models are required to prove the new method of use (utility) for dipeptidyl peptidase-4 inhibitors as potential neuroprotective agents. Furthermore, investigations of glucagon like peptide-1 receptor agonists' neuroprotective effects on animal models will be considered carefully because they crossed the blood-brain barrier in previous studies, enabling their direct action on the central nervous system. Combination therapy of dipeptidyl peptidase-4 inhibitors or glucagon like peptide-1 receptor agonists with already marketed drugs for neurodegenerative disease should be considered, especially regarding the novel intranasal route of administration.

Background: Aluminum toxicity induces neurodegenerative changes in the brain and results in Alzheimer’s disease (AD). Objective: Here, the aim was to evaluate the antioxidant therapeutic effects of ellagic acid (EA) and EA-loaded nanoparticles (EA-NP) in an aluminum chloride-induced AD rat model. Methods: The nanoparticles’ loading of EA was 0.84/1 w/w. The in vitro release kinetics of EA from EA-NP in fetal bovine serum showed 60% release in the first 1-5 hours, followed by sustained release at 60-70% over 6-24 hours. Six groups were implemented; group 1 served as the control, group 2 received EA, group 3 received EA-NP, group 4 was the AD rat model administered AlCl3 (50 mg/kg) for 4 weeks, groups 5 (AD+EA) and 6 (AD+EA-NP) were treated with EA and EA-NP, respectively, for 2 weeks after AlCl3 was stopped. The neurotoxicity in the rat brain was examined by measuring the brain antioxidant biomarkers catalase, glutathione, and total antioxidant activity and lipid peroxidation (thiobarbituric acid, TBA). Histopathological studies using hematoxylin and eosin, cresyl violet, silver stains, and the novel object recognition test were examined. Results: Data revealed significant increase of antioxidant biomarkers and decreased TBA in the EA-NP group. The pathological hallmarks of AD-vacuolation of the neurons, chromatolysis, neurofibrillary tangles, and the senile plaques in brains of the AD rat model were decreased and restoration of Nissl granules was noted. The calculated discrimination index in the behavioral test increased more in cases treated with EA-NP. Conclusion:: The treatment of AD with EA-NP was more effective than EA in alleviating the oxidative neurotoxic effects on AD rat brains.

Many neuromuscular diseases are genetically inherited or caused by mutations in motor function proteins. Two of the most prevalent neuromuscular diseases are Duchenne Muscular Dystrophy (DMD) and Spinal Muscular Atrophy (SMA), which are often diagnosed during the early years of life, contributing to life-long debilitation and shorter longevity. DMD is caused by mutations in the dystrophin gene resulting in critical muscle wasting, with cardiac or respiratory failure by age 30. Lack of dystrophin protein is the leading cause of degeneration of skeletal and cardiac muscle. Corticosteroids and artificial respirators remain as the gold-standard management of complications and have significantly extended the life span of these patients. Additionally, drug therapies including eteplirsen (EXONDYS 51®), golodirsen (VYONDYS 53™), and viltolarsen (VILTEPSO®) have been approved by the FDA to treat specific types of DMD. SMA is defined by the degeneration of the anterior horn cells in the spinal cord and destruction of motor neuron nuclei in the lower brain-stem caused by SMN1 gene deletion. Loss of SMN1 protein is partly compensated by SMN2 protein synthesis with disease severity being affected by the success of SMN2 gene synthesis. Evidence-based recommendations for SMA are directed towards supportive therapy and providing adequate nutrition and respiratory assistance as needed. Treatment and prevention of complications of muscle weakness are crucial for reducing the phenotype expression of SMA. Furthermore, drug therapies including injectables such as onasemnogene abeparvovec-xioi (ZOLGENSMA®), nusinersen (SPINRAZA®), and an oral-solution, risdiplam (EVRYSDI™), are medications that have been FDA-approved for the treatment of SMA. This review discusses the current and emerging therapeutic options for patients with DMD and SMA.

Pancreatic cancer decreases survival time and quality of life because of drug resistance and peripheral neuropathy during conventional treatment. This study was undertaken to investigate whether alpha v beta 3 integrin receptor antagonist compounds NDAT and XT199 can suppress the development of cisplatin resistance and cisplatin-induced peripheral neuropathy in an orthotopic pancreatic SUIT2-luc cancer cell mouse model. Anticancer effects of these compounds and their combination with cisplatin were assessed in this tumor mouse model with bioluminescent signaling and histopathology, and a cytokine assay was used to examine expression of inflammatory cytokines IL-1 beta, IL-6, IL-10, and TNF-alpha from plasma samples. To determine the neuroprotective effects of the compounds on cisplatin-induced peripheral neuropathy, behavioral hind-limb posture of the mice was evaluated. The combination therapy of NDAT or XT199 with cisplatin elicited greater inhibition of tumor growth and increased tumor necrosis compared to cisplatin alone. NDAT and XT199 in combination with cisplatin significantly decreased expression of pro-inflammatory cytokines IL-1 beta, IL-6, and TNF-alpha and significantly increased expression of anti-inflammatory cytokine IL-10 in comparison to cisplatin alone. Cisplatin-treated groups showed stocking-glove hind-limb posture, whereas NDAT and XT199 with cisplatin-treated groups displayed normal hind-limb posture. Results clearly suggest that NDAT and XT199 treatment with cisplatin that inactivates NF-kappa B may contribute to increased antitumor and anti-inflammatory efficacy as well as alleviate cisplatin-mediated loss of motor function in this pancreatic tumor mouse model. Pharmaceutical Research Institute at Albany College of Pharmacy Health and Sciences

Proprotein convertase subtilisin/kexin type 9 is a protease enzyme secreted by liver that downregulates hepatic low-density lipoprotein receptor (LDLR) by binding and chaperoning LDLR to lysosomes for degradation, causing hypercholesteremia. The development of anti-PCSK9 therapeutics attracted considerable attention for the management of cardiovascular disease risk. However, only subcutaneous injectable PCSK9 monoclonal antibodies have been FDA approved. Oral administration of small-molecule PCSK9 inhibitors has the potential to become a practical therapeutic option if achievable. In the present work, we used nanotechnological approaches to develop the first small oral molecule nano-hepatic targeted anti-PCSK9. Using high-throughput optimization and a series of evaluations, a stable water-dispersible 150-200 nm nano-encapsulated drug (named P-4) conjugated with hepatic targeting moiety was synthesized and characterized (named P-21). Pharmacodynamic (PD), pharmacokinetic (PK) and bioavailability studies were conducted using a high fat diet nutritionally induced hypercholesterolemia mouse model to evaluate the efficacy of P-21 as an anti-PCSK9 LDL-cholesterol lowering hepatic targeted nanodrug. The PD results demonstrate that P-21 in a dose-dependent manner is highly effective in lowering LDL-C by 50-90%. PK results show the maximum plasma concentration (Cmax) of P-4 was observed after 30 min of administration with 31% oral bioavailability and had a sustained longer half-life up to 24 h. In vivo safety studies in rats showed no apparent adverse effects, normal chemical biomarkers and normal histopathological findings in all P-21 treated groups at different escalating doses. Compared to the FDA-approved monoclonal antibodies, P-21 offers a more efficient, and practical treatment protocol for targeting uncontrolled hypercholesterolemia in reducing the risk of cardiovascular diseases. The present study introduced a nano-targeted drug delivery approaches for PCSK9/LDLR antagonist.

Background The efficacy of heparins and low-MW-heparins (LMWH) against human asthma has been known for decades. However, the clinical utility of these compounds has been hampered by their anticoagulant properties. Much effort has been put into harnessing the anti-inflammatory properties of LMWH but none have been used as therapy for asthma. Sulfated-non-anticoagulant heparin (S-NACH) is an ultra-LMWH with no systemic anticoagulant effects. Objective The present study explored the potential of S-NACH in blocking allergic asthma and examined the potential mechanism by which it exerts its effects. Methods Acute and chronic ovalbumin-based mouse models of asthma, splenocytes, and a lung epithelial cell line were used. Mice were challenged with aerosolized ovalbumin and administered S-NACH or saline 30 min after each ovalbumin challenge. Results Sulfated-non-anticoagulant heparin administration in mice promoted a robust reduction in airway eosinophilia, mucus production, and airway hyperresponsiveness even after chronic repeated challenges with ovalbumin. Such effects were linked to suppression of Th2 cytokines IL-4/IL-5/IL-13/GM-CSF and ovalbumin-specific IgE without any effect on IFN-γ. S-NACH also reduced lung fibrosis in mice that were chronically-exposed to ovalbumin. These protective effects of S-NACH may be attributed to modulation of the IL-4/JAK1 signal transduction pathway through an inhibition of STAT6 phosphorylation and a subsequent inhibition of GATA-3 and inducible NO synthase expression. The effect of the drug on STAT6 phosphorylation coincided with a reduction in JAK1 phosphorylation upon IL-4 treatment. The protective effects of S-NACH treatment was associated with reduction of the basal expression of the two isoforms of arginase ARG1 and ARG2 in lung epithelial cells. Conclusions Our study demonstrates that S-NACH constitutes an opportunity to benefit from the well-known anti-asthma properties of heparins/LMWH while bypassing the risk of bleeding. Our results show, for the first time, that such anti-asthma effects may be associated with reduction of the IL-4/JAK1/STAT6 pathway.

Ischemic heart disease is the main cause of death globally. Cardioprotection is the process whereby mechanisms that reduce myocardial damage, and activate protective factors, contribute to the preservation of the heart. Targeting these processes could be a new strategy in the treatment of post-ischemic heart failure (HF). Triiodothyronine (T3) and thyroxine (T4), which have multiple effects on the heart, prevent myocardial damage. This study describes the formulation, and characterization, of chemically modified polymeric nanoparticles incorporating T3, to target the thyroid hormone receptors. Modified T3 was conjugated to polylactide-co-glycolide (PLGA) to facilitate T3 delivery and restrict its nuclear translocation. Modified T3 and PLGA-T3 was characterized with 1H-NMR. The protective role of synthesized phosphocreatine (PCr) encapsulated PLGA-T3 nanoparticles (PLGA-T3/PCr NPs) and PLGA-T3 nanoparticles (PLGA-T3 NPs) in hypoxia-mediated cardiac cell insults was investigated. The results showed that PLGA-T3/PCr NPs represent a potentially new therapeutic agent for the control of tissue damage in cardiac ischemia and resuscitation.

Corchorus olitorius is a common, leafy vegetable locally known as “Saluyot” in the Philippines. Several studies have reported on its various pharmacological properties, such as antioxidant, anti-inflammatory, analgesic, and anticancer properties. However, little is known about its effects on angiogenesis. This study aimed to evaluate the anticancer properties, such as the antiproliferative, anti-angiogenic, and antitumor activities, of the C. olitorius aqueous extract (CO) and its bioactive compounds, chlorogenic acid (CGA) and isoquercetin (IQ), against human melanoma (A-375), gastric cancer (AGS), and pancreatic cancer (SUIT-2), using in vitro and in ovo biological assays. The detection and quantification of CGA and IQ in CO were achieved using LC-MS/MS analysis. The antiproliferative, anti-angiogenic, and antitumor activities of CO, CGA, and IQ against A-375, AGS, and SUIT-2 cancer cell lines were evaluated using MTT and CAM assays. CGA and IQ were confirmed to be present in CO. CO, CGA, and IQ significantly inhibited the proliferation of A-375, AGS, and SUIT-2 cancer cells in a dose-dependent manner after 48 h of treatment. Tumor angiogenesis (hemoglobin levels) of A-375 and AGS tumors was significantly inhibited by CO, CGA, IQ, and a CGA–IQ combination. The growth of implanted A-375 and AGS tumors was significantly reduced by CO, CGA, IQ, and a CGA–IQ combination, as measured in tumor weight. Our investigation provides new evidence to show that CO has promising anticancer effects on various types of human cancer cells. CO and its compounds are potential nutraceutical products that could be used for cancer treatment.

Aim: Nano-diamino-tetrac (NDAT) targets a receptor on integrin alpha v beta 3; alpha v beta 3 is generously expressed by cancer cells and dividing endothelial cells and to a small extent by nonmalignant cells. The tetrac (tetraiodothyroacetic acid) of NDAT is covalently bound to a poly(lactic-co-glycolic acid) nanoparticle that encapsulates anticancer drugs. We report NDAT delivery efficiency of cisplatin to agent-susceptible urinary bladder cancer xenografts. Materials & methods: Cisplatin-loaded NDAT (NDAT-cisplatin) was administered to xenograft-bearing nude mice. Tumor size response and drug content were measured. Results: Intratumoral drug concentration was up to fivefold higher (p < 0.001) in NDAT-cisplatin-exposed lesions than with conventional systemic administration. Tumor volume reduction achieved was NDAT-cisplatin > NDAT without cisplatin > cisplatin alone. Conclusion: NDAT markedly enhances cisplatin delivery to urinary bladder cancer xenografts and increases drug efficacy. NanoPharmaceuticals LLC (NY, USA) NanoPharmaceuticals LLC

Heparin is a highly sulfated, complex polysaccharide and widely used anticoagulant pharmaceutical. In this work, we chemoenzymatically synthesized perdeuteroheparin from biosynthetically enriched heparosan precursor obtained from microbial culture in deuterated medium. Chemical de-N-acetylation, chemical N-sulfation, enzymatic epimerization, and enzymatic sulfation with recombinant heparin biosynthetic enzymes afforded perdeuteroheparin comparable to pharmaceutical heparin. A series of applications for heavy heparin and its heavy biosynthetic intermediates are demonstrated, including generation of stable isotope labeled disaccharide standards, development of a non-radioactive NMR assay for glucuronosyl-C5-epimerase, and background-free quantification of in vivo half-life following administration to rabbits. We anticipate that this approach can be extended to produce other isotope-enriched glycosaminoglycans.

D-galactose (D-gal) administration causes oxidative disorder and is widely utilized in aging animal models. Therefore, we subcutaneously injected D-gal at 200 mg/kg BW dose to assess the potential preventive effect of thymoquinone (TQ) and curcumin (Cur) against the oxidative alterations induced by D-gal. Other than the control, vehicle, and D-gal groups, the TQ and Cur treated groups were orally supplemented at 20 mg/kg BW of each alone or combined. TQ and Cur effectively suppressed the oxidative alterations induced by D-gal in brain and heart tissues. The TQ and Cur combination significantly decreased the elevated necrosis in the brain and heart by D-gal. It significantly reduced brain caspase 3, calbindin, and calcium-binding adapter molecule 1 (IBA1), heart caspase 3, and BCL2. Expression of mRNA of the brain and heart TP53, p21, Bax, and CASP-3 were significantly downregulated in the TQ and Cur combination group along with upregulation of BCL2 in comparison with the D-gal group. Data suggested that the TQ and Cur combination is a promising approach in aging prevention.

l-Thyroxine (T4) is the principal replacement hormone for patients who have hypothyroidism. Some preclinical and clinical evidence supports the possibility that T4 can at least permissively affect certain features of established cancers and cancer-relevant angiogenesis. Thus, in the occasional patient with hypothyroidism and concomitant cancer, it appears reasonable to consider thyroid hormone replacement exclusively with 3,3',5-triiodo-l-thyronine (T3). This use of T3 has been shown to be effective and safe in early experience with medical induction of euthyroid hypothyroxinemia in patients with advanced solid tumors.

Statins and other lipid-lowering drugs have dominated the market for many years for achievement of recommended levels of low-density lipoprotein cholesterol (LDL-C). However, a substantial number of high-risk patients are unable to achieve the LDL-C goal. Proprotein convertase subtilisin/kexin 9 (PCSK9) has recently emerged as a new, promising key therapeutic target for hypercholesterolemia. PCSK9 is a protease involved in chaperoning the low-density lipoprotein receptor to the process of degradation. PCSK9 inhibitors and statins effectively lower LDL-C. The PCSK9 inhibitors decrease the degradation of the LDL receptors, whereas statins mainly interfere with the synthetic machinery of cholesterol by inhibiting the key rate limiting enzyme, the HMG CoA reductase. PCSK9 inhibitors are currently being developed as monoclonal antibodies for their primary use in lowering LDL-C. They may be especially useful for patients with homozygous familial hypercholesterolemia, who at present receive minimal benefit from traditional statin therapy. The monoclonal antibody PCSK9 inhibitors, recently granted FDA approval, show the most promising safety and efficacy profile compared to other, newer LDL-C lowering therapies. This review will primarily focus on the safety and efficacy of monoclonal antibody PCSK9 inhibitors in comparison to statins. The review will also address new, alternative PCSK9 targeting drug classes such as small molecules, gene silencing agents, apolipoprotein B antisense oligonucleotides, and microsomal triglyceride transfer protein inhibitors.

Background Probiotics have gained exponential attention worldwide because they are used as a therapeutic tool for management, prevention and treatment of diseases like cancer. Here, antiproliferation, anti-angiogenesis and antitumor effects of Lactobacillus acidophilus (LA) and Bifidobacterium longum (BL) were examined on gastric (AGS) and bladder (J253) cancer cell lines. Methods Cancer cell viability was monitored with MTT assay. The chick embryo chorioallantoic membrane (CAM) assay was used to screen tumor growth and hemoglobin content of cancer cells alone and with different LA and BL concentrations. Protein expression of COX2 was analyzed with Western blot in cell lines treated with LA, BL, celecoxib at 60 and 100 μM, or their combination. Results Treatment with either probiotic showed increased vacuolated gastric cancer (AGS) cells with significant morphological changes at high concentration (2.5 × 107 cfu/ml) of LA and BL bacteria compared to bladder cancer cells (J253). Similarly, AGS cells responded well to LA and BL and there was decreased cancer cell viability, tumor weight and hemoglobin content (p Conclusions This study is the first to document antiproliferation and anti-angiogenesis of LA and BL against gastric cancer by downregulating COX2 expression. LA and BL might be new, safe agents for targeting COX2 and suppressing growth of some cancers.

Sickle cell disease (SCD) is an autosomal recessive genetic disease caused by the inheritance of a single point mutation, resulting in abnormal sickle hemoglobin (HbS). During hypoxia or dehydration, HbS polymerizes to form insoluble aggregates and induces sickling of red blood cells (RBCs). RBC sickling increases the adhesiveness of RBCs to alter the rheological properties of the blood and trigger inflammatory responses, leading to hemolysis, vasoocclusive crisis, pulmonary complications, plethora, and other pathological sequelae. Glycosaminoglycans, such as low molecular weight heparin (LMWH), have been suggested as treatments to relieve coagulation complications in SCD because of their ability to decrease thrombin generation and sickle cell adhesion. However, they are associated with bleeding complications after repeated dosing. An alternative, sulfated non-anticoagulant LMWH derivative (S-NACH) was previously reported to have none to low systemic anticoagulant activity and no bleeding side effects, and it interfered with P-selectin-dependent binding of sickle cells to endothelial cells, with concomitant decrease in the levels of adhesion biomarkers in SCD mice (1,2). S-NACH has been further engineered to possess an aldehyde moiety, which confers anti-sickling properties primarily due to specific interactions with HbS to increase its affinity for oxygen. Our in vitro sickling assay under hypoxic conditions using S-NACH at 0.5 - 2 mM demonstrated that S-NACH significantly reduced the sickling of SS cells and in a concentration-dependent manner, with comparable to that of 1 mM GBT440 (Figure 1 A-C). A similar concentration dependent effect on increasing HbS affinity for oxygen using oxygen equilibrium study was documented. In an vivo animal model using Townes' SCD animals plasma levels of pro-inflammatory cytokines IL-1β, IL-6, IFN-γ, MCP-1, TNF-α, M-CSF, and VEGF were increased in SCD untreated samples in contrast to a significant decrease (*P< 0.001) in S-NACH-treated animals, at both 2 and 6 h. In addition, S-NACH was able to increase the decreased levels of the endogenous anti-inflammatory IL-10 (Figure 1 D). The above set of novel findings about S-NACH established it to be effective for the management of SCD via the modulation of thromboinflammatory pathways, involved in thromboembolism and end organ damage, beside anti-sickling, anti-selectin and without causing any bleeding risk. Reference 1. Alshaiban A, Muralidharan-Chari V, Nepo A, Mousa SA. Modulation of Sickle Red Blood Cell Adhesion and its Associated Changes in Biomarkers by Sulfated Non-anticoagulant Heparin Derivative. Clin Appl Thromb Hemost. 2016 ;22(3):230-8. 2. Mousa SA: Compositions and method for anti-sickling of red blood cells in sickle cell disease. US Patent 9,822,190, November 2017. Disclosures Mousa: Vascular Vision Pharma Co.: Patents & Royalties.

This study investigated the effects of oral administration of β-glucan 1,3 (pharmaceutical grade 10%) on growth performance and carcass traits in two breeds of weanling rabbits adapted to survive in Egypt, New Zealand White (NZW) and Animal Production Research Institute (APRI) rabbits, with special attention to relative mRNA expression of interleukins and antioxidant enzyme genes, biochemical, and histological alterations. Oral administration of β-glucan with doses 0.25 and 0.5 ml per one-liter of drinking water significantly accelerated body weight gain (BWG) in both rabbits' breeds, reduced total feed consumption (FC), and reduced feed conversion ratio (FCR), especially the 0.5 ml per one-liter dose in both rabbit breeds. There are remarkable differences in all the growth performance traits due to breed effect. The interaction effect between β-glucan and breed significantly improved BWG, FC, and FCR. There were non-significant differences in all carcass traits studied due to oral administration of β-glucan with both doses, except in dressing percentages. The highest of the dressing percentages were observed at doses 0.25 ml per one-liter (51%) and 0.5 ml per one-liter (52%) compared with control (50%). Our findings show significant variations in the final BW, total daily gain, feed consumption, and total feed conversion ratio between NZW and APRI rabbits. Absence of significant differences in the hot carcass weight and dressing percentage between the genetic groups had been reported in this study. Supplementing NZW and APRI rabbits with β-glucan increased blood total protein and globulin. The duodenal villi dimensions, splenic lymphoid diameter, muscular fiber diameter, and muscular glycogen areas were significantly increased by β-glucan administration. Expression of intestinal interleukin-18 (IL-18) in NZW rabbits treated with 0.25 and 0.5 doses of β-glucan was significantly upregulated and enhanced the immune response. β-glucan upregulated the expression of intestinal occludin mRNA particularly at dose 0.5 β-glucan as well as upregulated intestinal superoxide dismutase 1 (SOD1) and glutathione peroxidase 1 (GPx1), which modulates anti-inflammatory and antioxidant properties. In conclusion, oral administration of β-glucan at a dose of 0.25 or 0.5 ml per one-liter drinking water provided beneficial effects in the growth performance and health status of rabbits.

Gastric ulcers are among the most broadly perceived illnesses affecting individuals. Alcohol consumption is the main cause of gastric ulceration. This study assessed the protective effects of Salvadora persica (SP) extract against ethanol-induced gastric ulcer and elucidated the conceivable underlying mechanisms involved. For this purpose, 40 rats were allotted into 4 equal groups (control, ethanol- (EtOH-) treated, and SP-treated “SP200 and SP400” groups). The control and EtOH-treated groups were given phosphate buffer saline (PBS), and both the SP200 and SP400 groups were given SP extract dissolved in PBS at doses of 200 and 400 mg/kg b.w., respectively. All treatments were given orally for 7 constitutive days. On the 8th day, all rats were fasted for 24 h followed by oral gavage of PBS in the control group and chilled absolute ethanol solution (5 ml/kg b.w.) in the EtOH- and SP-treated groups to induce gastric lesions. One hour later, the rats were sacrificed and the stomachs were harvested. Gross and microscopic examinations of the EtOH-treated group showed severe gastric hemorrhagic necrosis, submucosal edema, destruction of epithelial cells, and reduced glycoprotein content at the mucus surface. These pathological lesions were defeated by SP extract treatment. Administration of SP extract modulated the oxidative stress and augmented the antioxidant defenses. The elevated ethanol-expressed tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) genes, as well as bcl-2-like protein 4 (Bax) and inducible nitric oxide synthase (iNOS), were diminished in the SP-treated group. Curiously, SP extract upregulated endothelial nitric oxide synthase (eNOS) and transforming growth factor-β1 (TGF-β1) gene expression comparable to that of the EtOH-treated rats. Aggregately, SP exerted antiulcer activities in ethanol-induced gastric ulcer rat models via modulation of oxidant/antioxidant status, mitigation of proinflammatory cytokines, and apoptosis, as well as remodeling of both NOS isoforms.

Drug repositioning is a revolution breakthrough of drug discovery that presents outstanding privilege with already safer agents by scanning the existing candidates as therapeutic switching or repurposing for marketed drugs. Sitagliptin, vildagliptin, saxagliptin & linagliptin showed antioxidant and neurorestorative effects in previous studies linked to DPP-4 inhibition. Literature showed that gliptins did not cross the blood brain barrier (BBB) while omarigliptin was the first gliptin that crossed it successfully in the present work. LC-MS/MS determination of once-weekly anti-diabetic DPP-4 inhibitors; omarigliptin & trelagliptin in plasma and brain tissue was employed after 2 h of oral administration to rats. The brain/plasma concentration ratio was used to deduce the penetration power through the BBB. Results showed that only omarigliptin crossed the BBB due to its low molecular weight & lipophilic properties suggesting its repositioning as antiparkinsonian agent. The results of BBB crossing will be of interest for researchers interested in Parkinson’s disease. A novel intranasal formulation was developed using sodium lauryl sulphate surfactant to solubilize the lipophilic omarigliptin with penetration enhancing & antimicrobial properties. Intranasal administration showed enhanced brain/plasma ratio by 3.3 folds compared to the oral group accompanied with 2.6 folds increase in brain glucagon-like peptide-1 concentration compared to the control group.

Targeting angiogenesis in the microenvironment of a tumor can enable suppression of tumor angiogenesis and delivery of anticancer drugs into the tumor. Anti-angiogenesis targeted delivery systems utilizing passive targeting such as Enhanced Permeability and Retention (EPR) and specific receptor-mediated targeting (active targeting) should result in tumor-specific targeting. One targeted anti-angiogenesis approach uses peptides conjugated to nanoparticles, which can be loaded with anticancer agents. Anti-angiogenesis agents can suppress tumor angiogenesis and thereby affect tumor growth progression (tumor growth arrest), which may be further reduced with the targetdelivered anticancer agent. This review provides an update of tumor vascular targeting for therapeutic and diagnostic applications, with conventional or long-circulating nanoparticles decorated with peptides that target neovascularization (anti-angiogenesis) in the tumor microenvironment.

This review analyzes current studies of the therapeutic effects of Phoenix dactylifera, or date palm fruit, on the physiologic system. Specifically, we sought to summarize the effects of its application in preventing cell damage, improving cancer therapeutics and reducing damage caused by conventional chemotherapy. Phoenix dactylifera exhibits potent anti-oxidative properties both in vitro and in vivo. This allows the fruit to prevent depletion of intrinsic protection from oxidative cell damage and assist these defense systems in reducing cell damage. Macroscopically, this mechanism may be relevant to the prevention of various adverse drug events common to chemotherapy including hepatotoxicity, nephrotoxicity, gastrotoxicity, and peripheral neuropathy. While such effects have only been studied in small animal systems, research suggests a potential application to more complex mammalian systems and perhaps a solution to some problems of chemotherapy in hepato-compromised and nephro-compromised patients.