Raloxifene encapsulated spanlastic nanogel for the prevention of bone fracture risk via transdermal administration: Pharmacokinetic and efficacy study in animal model.

This research work is to evaluate spanlastic-loaded raloxifene (RLX) nanogel administration via the transdermal route to avoid its hepatic metabolism and to enhance the bioavailability for better management of osteoporosis. RLX-loaded spanlastic nanogel was prepared and characterized for its viscosity, pH, spreadability, and texture profile. The formulation was applied on the skin surface of the animal for pharmacokinetic evaluation, and later, the efficacy of the formulation was assessed in ovariectomized female Wistar rats. The nanogel was obtained with a viscosity (2552.66 ± 30.61 cP), pH (7.1 ± 0.1), and spreadability (7.1 ± 0.2 cm). The texture properties, cohesiveness, and adhesiveness of the nanogel showed its suitability for transdermal application. Nanogel showed no sign of edema and erythema in the skin irritation test which revealed its safety for transdermal application. The t1/2 obtained for RLX-spanlastic nanogel (37.02 ± 0.59 h) was much higher than that obtained for RLX-oral suspension (14.43 h). The relative bioavailability was found to be 215.96% for RLX-spanlastic nanogel, and the drug and formulation did not show any toxicity in any of the vital organs, as well as no hematological changes occurring in blood samples. In microarchitectural measurement, RLX-spanlastic nanogel exhibited no unambiguous deviations along with improved bone mineral density compared to the RLX suspension treated group. Transdermal administration of RLX-spanlastic nanogel showed significant improvement of drug bioavailability (approx. twice to oral administration) without any toxic effect in the treated rats. Hence, spanlastic nanogel could be a better approach to deliver RLX via transdermal route for the management of osteoporosis.

Enhancing Osteoporosis Treatment through Targeted Nanoparticle Delivery of Risedronate: In Vivo Evaluation and Bioavailability Enhancement.

Risedronate-loaded mPEG-coated hydroxyapatite, thiolated chitosan-based (coated) and non-coated nanoparticles were tested for their potential effects in the treatment of osteoporosis. The prepared nanoparticles were evaluated for their bone-targeting potential by inducing osteoporosis in female Wistar rats via oral administration of Dexona (dexamethasone sodium phosphate). In vivo pharmacokinetic and pharmacodynamic studies were performed on osteoporotic rat models treated with different formulations. The osteoporotic model treated with the prepared nanoparticles indicated a significant effect on bone. The relative bioavailability was enhanced for RIS-HA-TCS-mPEG nanoparticles given orally compared to RIS-HA-TCS, marketed, and API suspension. Biochemical investigations also showed a significant change in biomarker levels, ultimately leading to bone formation/resorption. Micro-CT analysis of bone samples also demonstrated that the RIS-HA-TCS-mPEG-treated group showed the best results compared to other treatment groups. Moreover, the histology of bone treated with RIS-HA-TCS-mPEG showed a marked restoration of the architecture of trabecular bone along with a well-connected bone matrix and narrow inter-trabecular spaces compared to the toxic group. A stability analysis was also carried out according to ICH guidelines (Q1AR2), and it was found that RIS-HA-TCS-mPEG was more stable than RIS-HA-TCS at 25 °C. Thus, the results of present study indicated that mPEG-RIS-HA-TCS has excellent potential for sustained delivery of RIS for the treatment and prevention of osteoporosis, and for minimizing the adverse effects of RIS typically induced via oral administration.

Tackling the emerging Artemisinin-resistant malaria parasite by modulation of defensive oxido-reductive mechanism via nitrofurantoin repurposing.

Oxidative stress-mediated cell death has remained the prime parasiticidal mechanism of front line antimalarial, artemisinin (ART). The emergence of resistant Plasmodium parasites characterized by oxidative stress management due to impaired activation of ART and enhanced reactive oxygen species (ROS) detoxification has decreased its clinical efficacy. This gap can be filled by development of alternative chemotherapeutic agents to combat resistance defense mechanism. Interestingly, repositioning of clinically approved drugs presents an emerging approach for expediting antimalarial drug development and circumventing resistance. Herein, we evaluated the antimalarial potential of nitrofurantoin (NTF), a clinically used antibacterial drug, against intra-erythrocytic stages of ART-sensitive (Pf3D7) and resistant (PfKelch13R539T) strains of P. falciparum, alone and in combination with ART. NTF exhibited growth inhibitory effect at submicro-molar concentration by arresting parasite growth at trophozoite stage. It also inhibited the survival of resistant parasites as revealed by ring survival assay. Concomitantly, in vitro combination assay revealed synergistic association of NTF with ART. NTF was found to enhance the reactive oxygen and nitrogen species, and induced mitochondrial membrane depolarization in parasite. Furthermore, we found that exposure of parasites to NTF disrupted redox balance by impeding Glutathione Reductase activity, which manifests in enhanced oxidative stress, inducing parasite death. In vivo administration of NTF, alone and in combination with ART, in P. berghei ANKA-infected mice blocked parasite multiplication and enhanced mean survival time. Overall, our results indicate NTF as a promising repurposable drug with therapeutic potential against ART-sensitive as well as resistant parasites.

Cannabis Sativa in Phytotherapy: Reappraisal of Therapeutic Potential and Regulatory Aspects.

Cannabis sativa is widely used as a folk medicine in many parts of the globe and has been reported to be a treasure trove of phytoconstituents, including cannabinoids, terpenoids, and flavonoids. Accumulating evidence from various pre-clinical and clinical studies revealed the therapeutic potential of these constituents in various pathological conditions, including chronic pain, inflammation, neurological disorders, and cancer. However, the psychoactive effect and addiction potential associated with cannabis use limited its clinical application. In the past two decades, extensive research on cannabis has led to a resurgence of interest in the clinical application of its constituents, particularly cannabinoids. This review summarizes the therapeutic effect and molecular mechanism of various phytoconstituents of cannabis. Furthermore, recently developed nanoformulations of cannabis constituents have also been reviewed. Since cannabis is often associated with illicit use, regulatory aspects are of vital importance and this review therefore also documented the regulatory aspects of cannabis use along with clinical data and commercial products of cannabis.

Antimalarial and Plasmodium falciparum serpentine receptor 12 targeting effect of FDA approved purinergic receptor antagonist.

Intraerythrocytic stages of Plasmodium falciparum responsible for all clinical manifestations of malaria are regulated by array of signalling cascades that represent attractive targets for antimalarial therapy. G-protein coupled receptors (GPCRs) are druggable targets in the treatment of various pathological conditions, however, there is limited understanding about the role of GPCRs in malaria pathogenesis. In Plasmodium, serpentine receptors (PfSR1, PfSR10, PfSR12 and PfSR25) with GPCR-like membrane topology have been reported with the finite knowledge about their potential as antimalarial targets. We analyzed the localization of these receptors in malaria parasite by immunofluorescence assays. All four receptors were expressed in blood stages with PfSR12 expressing more in late intraerythrocytic stages. Further, we evaluated the druggability of PfSR12 using FDA-approved P2Y purinergic receptor antagonist, Prasugrel and its active metabolite R138727, which is proposed to be specific towards PfSR12. Interestingly, biophysical analysis indicated strong binding between PfSR12 and R138727 as compared to the prodrug Prasugrel. This binding interaction was further confirmed by thermal shift assay. Treatment of parasite with Prasugrel and R138727 resulted in growth inhibition of P. falciparum indicating an important role of purinergic signalling and PfSR12 in parasite survival. Next, progression studies indicated the inhibitory effect of Prasugrel begins in late erythrocyte stages corroborating with PfSR12 expression at these stages. Furthermore, Prasugrel also blocked in vivo growth of malaria parasite in a mouse experimental model. This study indicates the presence of P2Y type of purinergic signalling in growth and development of malaria parasite and suggests PfSR12, putative purinergic receptor druggability through Prasugrel.Communicated by Ramaswamy H. Sarma.

WITHDRAWN: Cannabis Sativa In Phytotherapy : Reappraisal Of Therapeutic Potential And Regulatory Aspects

The article has been withdrawn at the request of the editor of the journal Current Pharmaceutical Biotechnology.Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused.The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policies-main.php. BENTHAM SCIENCE DISCLAIMER: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

'Erythritol', a safe natural sweetener exhibits multi-stage anti-malarial activity by permeating into Plasmodium falciparum through aquaglyceroporin channel.

The increased resistance of human malaria parasite Plasmodium falciparum (Pf) to currently used drugs necessities the development of novel anti-malarials. Here, we examine the potential of erythritol, a sugar substitute for therapeutic intervention. Erythritol is a permeant of Plasmodium falciparum aquaglyceroporin (PfAQP) which is a multifunctional channel responsible for maintaining hydro-homeostasis. We show that erythritol effectively inhibited growth and progression of asexual blood stage malaria parasite, and effect invasion and egress processes. It also inhibited the liver stage (sporozoites) and transmission stage parasite (gametocytes) development. Interestingly, erythritol inhibited in vivo growth of malaria parasite in mouse experimental model. It was more effective in inhibiting parasite growth both in vivo and in vitro when tested together with a known anti-malarial 'artesunate'. Additionally, erythritol showed cytokine-modulating effect which suggests its direct effect on the host immune system. Ammonia detection assay demonstrated that erythritol uptake effects the amount of ammonia release across the parasite. Our functional complementation assays suggest that PfAQP expression in yeast mutant restores its growth in hyperosmotic conditions but showed reduced growth in the presence of erythritol. Osmotic lysis assay suggests that erythritol creates osmotic stress for killing the parasite. Overall, our data bestow erythritol as a promising lead compound with an attractive antimalarial profile and could possibly be combined with known drugs without losing its efficacy. We propose the use of erythritol based sweet candies for protection against malaria specially in children living in the endemic area.

Targeting hypercoagulation to alleviate Alzheimer's disease progression in metabolic syndrome.

INTRODUCTION: Metabolic Syndrome (MetS) constitutes an important risk factor for Alzheimer's disease (AD); however, the mechanism linking these two disorders has not been completely elucidated. Hence, hypercoagulation may account for the missing hallmark connecting MetS and AD. The present review proposes how hemostatic imbalance triggered in MetS advances in the context of AD. MetS causes interruption of insulin signaling and inflammation, inciting insulin resistance in the brain. Subsequently, neuroinflammation and brain endothelial dysfunction are prompted that further intensify the exorbitant infiltration of circulating lipids and platelet aggregation, thereby causing hypercoagulable state, impairing fibrinolysis and eventually inducing prothrombic state in the brain leading to neurodegeneration. OBJECTIVE: This study aims to understand the role of hypercoagulation in triggering the progression of neurodegeneration in MetS. It also offers a few interventions to prevent the progression of AD in MetS targeting hypercoagulation. METHODS: Literature studies based on MetS related neurodegeneration, the impact of coagulation on aggravating obesity and AD via the mechanisms of BBB disruption, neuroinflammation, and hypofibrinolysis. CONCLUSION: The present paper proposes the hypothesis that hypercoagulation might amplify MetS associated insulin resistance, neuroinflammation, BBB disruption, and amyloid beta accumulation which eventually leads to AD.

Role of triggering receptor expressed on myeloid cells 2 (TREM2) in neurodegenerative dementias.

Neurodegeneration is a debilitating condition that causes nerve cell degeneration or death. Neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), and Lewy body dementia (LBD) are posing a larger population burden of dementia worldwide. Neurodegenerative dementia is one of the main challenges in public health with its main characteristics being permanent loss of memory, impairment in cognition, and impaired daily functions. The published literature about genetic studies of these disorders suggests genetic underpinning in the pathogenesis of neurodegenerative dementia. In the process of underlining the pathogenesis of NDD, growing evidence has related genetic variations in the triggering receptor expressed on myeloid cells 2 (TREM2). This review paper aims to provide a detailed information regarding the association of TREM2 and NDDs leading to dementia. A central consideration is AD that accounts for almost 50%-70% of all late-life dementias alone or in combination with other neurological disorders. Other prevalent neurodegenerative conditions that lead to dementia are also discussed. Such studies are important as they can give a comprehensive knowledge of TREM2's role in various NDDs, in order to maximize the potential for developing new therapeutic approaches.

Deciphering the Role of Aberrant Protein Post-Translational Modification in the Pathology of Neurodegeneration.

Neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS) and Huntington's Disease (HD), are characterized by progressive neuronal dysfunction and death. Recent studies have established detrimental modifications in the structure and function of brain proteins, which stimulate their aggregation, misfolding and deposition in and around the neurons an important hallmark of neurodegenerative diseases. Post-Translational Modification (PTM) of proteins, including phosphorylation, acetylation, glycosylation, palmitoylation, SUMOylation, and ubiquitination, are important regulators of protein characteristics, including stability, intracellular distribution, activity, interactions, aggregation and clearance. Despite clear evidence that altered protein modifications emerging from impromptu chemical modifications to side chains of amino acid are associated with neurodegeneration, the underlying mechanisms that promote aberrant PTM remain poorly understood. Therefore, elucidating PTM of specific disease-associated proteins can prove to be a significant step in evaluating the functional alteration of proteins and their association with neurodegeneration. This review describes how aberrant PTM of various proteins is linked with the neurodegenerative disease pathogenesis, as well as molecular strategies targeting these modifications for treating such diseases, which are yet incurable.

Lipid-nanopotentiated combinatorial delivery of tamoxifen and sulforaphane: ex vivo, in vivo and toxicity studies.

Aim: This study aims to load tamoxifen (TAM) and sulforaphane (SFN) into nanostructured lipid carriers (NLCs) to enhance their oral delivery. Materials & methods: TAM-SFN-NLCs were prepared using Precirol® ATO5 and Transcutol® HP, characterized and evaluated in vitro and ex vivo to assess the drug release profile and intestinal permeability, respectively. In vivo pharmacokinetic and acute toxicity assessment was performed in Wistar rats. Results: Optimized TAM-SFN-NLCs exhibited a particle size of 121.9 ± 6.42 nm and zeta potential of -21.2 ± 2.91 mV. The NLCs enhanced intestinal permeability of TAM and SFN and augmented oral bioavailability of TAM and SFN 5.2-fold and 4.8-fold, respectively. SFN significantly reduced TAM-associated toxicity in vivo. Conclusion: This coencapsulation of a chemotherapeutic agent with a herbal bioactive in NLCs could pave a novel treatment approach against cancer.

PEGylated Nanoliposomes Potentiated Oral Combination Therapy for Effective Cancer Treatment.

The conventional treatment regimen for cancer with a single chemotherapeutic agent is far behind the clinical expectations due to the complexity of cancer biology and is also associated with poor Quality of Life (QOL) due to off-site toxicity and multidrug resistance. In recent years, nanopotentiated combination therapy has shown significant improvement in cancer treatment via a synergistic approach. However, being synthetic in nature, nanocarriers have been associated with the activation of the Complement (C) activation system resulting in serious hypersensitivity reactions known as CActivation Related Pseudoallergy (CARPA) effect once given via intravenous injection. On the other hand, nanopotentiated oral drug delivery offers several advantages for the effective and safe delivery of the drug to the target site. This hypothesis aims to put forward wherein Exemestane (chemotherapeutic agent) and lycopene (herbal bioactive) co-laden into PEGylated liposomes and delivered to the breast cancer via the oral route. PEGylation of the liposomes would prevent both molecules from the harsh microenvironment of the Gastrointestinal Tract (GIT) and would eventually promote their intestinal absorption via the lymphatic pathway to the systemic circulation. Lycopene being a potent antioxidant and anti-cancer herbal bioactive would promote the therapeutic efficacy of the Exemestane via a synergistic approach. This nanopotentiated oral combination therapy would pave the path for the safe and effective treatment of cancer.

Insights into Nanotherapeutic Strategies as an Impending Approach to Liver Cancer Treatment.

Liver cancer, being the utmost prevalent fatal malignancy worldwide, is ranked as the fifth leading cause of deaths associated with cancer. Patients with liver cancer are diagnosed often at an advanced stage, contributing to poor prognosis. Of all forms of liver cancer, hepatocellular carcinoma (HCC) contributes to 90% of cases, with chemotherapy being the treatment of choice. However, unfavorable toxicity of chemotherapy drugs and the vulnerability of nucleic acid-based drugs to degradation, have limited their application in clinical settings. So, in order to improvise their therapeutic efficacy in HCC treatment, various nanocarrier drug delivery systems have been explored. Furthermore, nanoparticle based imaging provides valuable means of accurately diagnosing HCC. Thus, in recent years, the advent of nanomedicine has shown great potential and progress in dramatically altering the approach to the diagnosis as well as treatment of liver cancer. Nanoparticles (NPs) are being explored as potential drug carriers for small molecules, miRNAs, and therapeutic genes used for liver cancer treatment. This review emphasizes on the current developments and applications of nanomedicine based therapeutic and diagnostic approaches in HCC.

Denouement of Chemicals on Amyotrophic Lateral Sclerosis: Is Green Chemistry the Answer.

Medicinal Chemistry has played a critical role in evolving new products, resources and processes which inexorably correspond to our high standards of living. Unfortunately, this has also caused deterioration of human health and threats to the global environment, even deaths when highly exposed to certain chemicals, whether due to improper use, mishandling or disposal. There are chemicals, which apart from being carcinogens, endocrine disruptors or neurotoxins, are also responsible for climate change and ozone depletion. Certain chemicals are known to cause neurotoxicity and are having tendencies to damage the central and peripheral nervous system or brain by damaging neurons or cells which are responsible for transmitting and processing of signals. This has raised serious concerns for the use and handling of such chemicals and has given growth to a relatively new emerging field known as Green Chemistry that strives to achieve sustainability at the molecular level and has an ability to harness chemicals to meet environmental and economic goals. It has been reported in the literature that apart from family history in the aetiology of Amyotrophic lateral Sclerosis (ALS), also termed as "Lou Gehrig's disease", a neurological disorder, environmental factors, heavy metals, particularly selenium, lead, mercury, cadmium, formaldehyde, pesticides and certain herbicides are known to cause ALS. ALS, a progressive neurodegenerative disease affects the motor cortex, brain stem and spinal cord, causing muscular weakness, spasticity, and hyperreflexia. In this article we are aiming to discuss and summarize the various corroborations and findings supporting the undesirable role of chemical substance/herbicides/pesticides in ALS aetiology and its mitigation by adopting green chemistry.

Decoding Novel Mechanisms and Emerging Therapeutic Strategies in Breast Cancer Resistance.

Breast cancer (BC), an intricate and highly heterogeneous disorder, has presently afflicted 2.09 million females globally. Chemoresistance remains a paramount challenge in the treatment of BC. Owing to its assorted nature, the chemoresistant mechanisms of BC still need intensive research. Accumulating evidence suggests that abnormalities related to the biogenesis of cancer stem cells (CSCs) and microRNAs (miRNAs) are associated with BC progression and chemoresistance. The presently available interventions are inadequate to target chemoresistance, therefore more efficient alternatives are urgently needed to improvise existing therapeutic regimens. A myriad of strategies is being explored, such as immunotherapy, gene therapy, and combination treatment to surmount chemoresistance. Additionally, nanoparticles as chemotherapeutic carriers put forward the options to encapsulate numerous drugs, alone as well as in combination for cancer theranostics. This review summarizes the chemoresistance mechanisms of miRNAs and CSCs as well as the most recently documented therapeutic approaches for the treatment of chemoresistance in BC. By unraveling the underpinning mechanism of BC chemoresistance, researchers could possibly develop more efficient treatment strategies towards BC.