Current Drug Targets - Volume 21, Issue 16, 2020

Background: Bone is a dynamic tissue that continuously undergoes the modeling and remodeling process to maintain its strength and firmness. Bone remodeling is determined by the functioning of osteoblast and osteoclast cells. The imbalance between the functioning of osteoclast and osteoblast cells leads to osteoporosis. Osteoporosis is divided into primary and secondary osteoporosis. Generally, osteoporosis is diagnosed by measuring bone mineral density (BMD) and various osteoblast and osteoclast cell markers. Methods: Relevant literature reports have been studied and data has been collected using various search engines like google scholar, scihub, sciencedirect, pubmed, etc. A thorough understanding of the mechanism of bone targeting strategies has been discussed and related literature has been studied and compiled. Results: Bone remodeling process has been described in detail including various approaches for targeting bone. Several bone targeting moieties have been stated in detail along with their mechanisms. Targeting of osteoclasts and osteoblasts using various nanocarriers has been discussed in separate sections. The toxicity issues or Biosafety related to the use of nanomaterials have been covered. Conclusion: The treatment of osteoporosis targets the inhibition of bone resorption and the use of agents that promote bone mineralization to slow disease progression. Current osteoporosis therapy involves the use of targeting moieties such as bisphosphonates and tetracyclines for targeting various drugs. Nanotechnology has been used for targeting various drug molecules such as RANKLinhibitors, parathyroid hormone analogues, estrogen agonists and antagonists, Wnt signaling enhancer and calcitonin specifically to bone tissue (osteoclast and osteoblasts). So, a multicomponent treatment strategy targeting both the bone cells will be more effective rather than targeting only osteoclasts and it will be a potential area of research in bone targeting used to treat osteoporosis. The first section of the review article covers various aspects of bone targeting. Another section comprises details of various targeting moieties such as bisphosphonates, tetracyclines; and various nanocarriers developed to target osteoclast and osteoblast cells and summarized data on in vivo models has been used for assessment of bone targeting, drawbacks of current strategies and future perspectives.

Beh's disease (BD) is presumably an autoinflammatory disease of unknown etiology for which several animal models have been described over the years. Agents and methods used for the development of these models have ranged from the herpes simplex type one virus (hsv-1) pathogen to the use of transgenic mice. Other models have also been used to investigate a possible autoimmune component. Each model possesses its own unique set of benefits and shortcomings, with no one model fully being able to recapitulate the disease phenotype. Here, we review the proposed models and provide commentary on their effectiveness and usefulness in studying the disease.

Background: Immune checkpoint inhibitors targeting the programmed death receptor ligand 1 (PD-L1)/programmed death receptor 1 (PD-1) pathway represent a drastic change in the treatment landscape of RCC resulting in a dynamic and evolving scenario. There is an urgent need for predictive biomarkers of response to provide a personalized therapeutic strategy for individual patients. Objective: In this review, we focused on trials that investigated the administration of a PD-1 and PDL1 inhibitor alone or in combination with another agent and compared the different assays applied in each trial to evaluate the role of PD-L1 as a prognostic and predictive biomarker. Conclusion: So far, the use of PD-L1 expression alone is not sufficient to predict treatment response and present many limitations: the lack of consensus between different methodologies on biomarker assessment, the heterogeneity of PD-L1 between primary tumors and metastatic sites, different criteria of response to therapy (RECIST vs. irRECIST), the complex interplay with inflammatory components, previous treatments, administration of antibiotic therapy. Combinations of different biomarkers and biological features, such as gene expression associated with angiogenesis, immune response and myeloid inflammation are promising biological variables that need to be validated in the context of prospective clinical trials.

Female genital tract infections have a high incidence among different age groups and represent an important impact on public health. Among them, vaginitis refers to inflammation of the vulva and/or vagina due to the presence of pathogens that cause trichomoniasis, bacterial vaginosis, and vulvovaginal candidiasis. Several discomforts are associated with these infections, as well as pregnancy complications and the facilitation of HIV transmission and acquisition. The increasing resistance of microorganisms to drugs used in therapy is remarkable, since women report the recurrence of these infections and associated comorbidities. Different resistant mechanisms already described for the drugs used in the therapy against Trichomonas vaginalis, Candida spp., and Gardnerella vaginalis, as well as aspects related to pathogenesis and treatment, are discussed in this review. This study aims to contribute to drug design, avoiding therapy ineffectiveness due to drug resistance. Effective alternative therapies to treat vaginitis will reduce the recurrence of infections and, consequently, the high costs generated in the health system, improving women’s well-being.

Homeostasis of bone is closely regulated by the balanced activities between the bone resorbing activity of osteoclast cells and bone-forming ability of osteoblast cells. Multinucleated osteoclasts degrade bone matrix and involve in the dynamic bone remodelling in coordination with osteoblasts. Disruption of this regulatory balance between these cells or any imbalance in bone remodelling caused by a higher rate of resorption over construction of bone results in a decrease of bone matrix including bone mineral density (BMD). These osteoclast-dominant effects result in a higher risk of bone crack and joint demolition in several bone-related diseases, including osteoporosis and rheumatoid arthritis (RA). Tridax procumbens is a very interesting perennial plant and its secondary metabolites called here T. procumbens flavonoids (TPFs) are well128;known phytochemical agents owing to various therapeutic practices such as anti-inflammatory, anti-anaemic and anti-diabetic actions. This review designed to focus the systematic convention concerning the medicinal property and mechanism of actions of TPFs for the management of bone-related diseases. Based on the current literature, the review offers evidence-based information of TPFs for basic researchers and clinicians for the prevention and treatment of bone related diseases, including osteoporosis. It also emphasizes the medical significance for more research to comprehend the cellular signalling pathways of TPFs for the regulation of bone remodelling and discusses the possible promising ethnobotanical resource that can convey the preclinical and clinical clues to develop the next generation therapeutic agents for the treatment of bonerelated disorders.

The emergence of coronavirus disease 2019 (COVID-19) is caused by the 2019 novel coronavirus (2019-nCoV). The 2019-nCoV first broke out in Wuhan and subsequently spread worldwide owing to its extreme transmission efficiency. The fact that the COVID-19 cases and mortalities are reported globally and the WHO has declared this outbreak as the pandemic, the international health authorities have focused on rapid diagnosis and isolation of patients as well as search for therapies able to counter the disease severity. Due to the lack of known specific, effective and proven therapies as well as the situation of public-health emergency, drug repurposing appears to be the best armour to find a therapeutic solution against 2019-nCoV infection. Repurposing anti-malarial drugs and chloroquine (CQ)/ hydroxychloroquine (HCQ) have shown efficacy to inhibit most coronaviruses, including SARS-CoV-1 coronavirus. These CQ analogues have shown potential efficacy to inhibit 2019-nCoV in vitro that leads to focus several future clinical trials. This review discusses the possible effective roles and mechanisms of CQ analogues for interfering with the 2019-nCoV replication cycle and infection.

Biodegradable nanoparticles (NPs) are the novel carriers for the administration of drug molecules. Biodegradable nanoparticles have become popular recently because of their special features such as targeted delivery of drugs, improved bioavailability, and better therapeutic effectiveness to administer the drug at a constant rate. Polymeric NPs are very small-sized polymeric colloidal elements in which a drug of interest may be encapsulated or incorporated in their polymeric network or conjugated or adsorbed on the layer. Various polymers are employed in the manufacturing of nanoparticles, some of the frequently employed polymers are agents, chitosan, cellulose, gelatin, gliadin, polylactic acid, polylactic-co-glycolic acid, and pullulan. Nanoparticles have been progressively explored for the delivery of targeted ARVs to cells of HIV-infected and have performed the prolonged kinetic release. Drug embedded in this system can give better effectiveness, diminished resistance of drugs, reduction in systemic toxicity and symptoms, and also enhanced patient compliance. The present review highlights the frequently employed manufacturing methods for biodegradable nanoparticles, various polymers used, and its application in anti-retroviral therapy. Also, common evaluation parameters to check the purity of nanoparticles, ongoing and recently concluded clinical trials and patents filled by the various researchers, and the future implication of biodegradable NPs in an innovative drug delivery system are described. The biodegradable NPs are promising systems for the administration of a broad variety of drugs including anti-retroviral drugs, and hence biodegradable nanoparticles can be employed in the future for the treatment of several diseases and disorders.

The global incidence of cancer is on the increase and researchers are prospecting for specific and non-selective therapies derived from the immune system. The killer activating receptors of NK cells are known to be involved in immunosurveillance against tumor and virally-infected cells. These receptors belong to two main categories, namely the immunoglobulin like and C-lectin like families. Though they have different signal pathways, all the killer activating receptors have similar effector functions which include direct cytotoxicity and the release of inflammatory cytokines such as IFN-gamma and TNF-alpha. To transduce signals that exceed the activation threshold for cytotoxicity, most of these receptors require synergistic effort. This review profiles 21 receptors: 13 immunoglobulin-like, 5 lectin-like, and 3 others. It critically explores their structural uniqueness, role in disease, respective transduction signal pathways and their status as current and prospective targets for cancer immunotherapy. While the native ligands of most of these receptors are known, much work is required to prospect for specific antibodies, peptides and multi-target small molecules with high binding affinities.