Exploring novel Apalutamide analogues as potential therapeutics for prostate cancer: design, molecular docking investigations and molecular dynamics simulation.

Introduction: Prostate cancer (PC) ranks as the second most frequent type of cancer in men and is the fourth largest cause of mortality worldwide. Androgenic hormones such as testosterone and dihydrotestosterone are crucial for the development and progression of the prostate gland. Androgenic hormones bind to androgen receptors (AR) and trigger the synthesis of many genes that stimulate the growth of prostate cells, initiating PC growth. Apalutamide (APL) is a non-steroidal antiandrogen drug used to treat PC; however, it also causes a variety of toxicities and resistance during the treatment. Methods: The purpose of this study was to computationally identify new and safer analogues of APL, focusing on improved pharmacokinetic properties and reduced toxicity. Drug likeness (DL) and drug score (DS) were also calculated. Docking studies on the designed analogues were conducted to predict their binding affinities and compare their orientations with the ligands in the original crystal structure. Molecular dynamics (MD) simulation of docked ligands was done using Schrödinger suite. Results: We generated a total of 1,415 analogues for different groups of APL using the bioisosteric approach. We selected 80 bioisosteres based on pharmacokinetic profiles, DL and DS score predictions, and found that the designed APL bioisosteres were optimal to good compared to APL. Analogues APL19, APL35, APL43, APL76, and APL80, formed hydrogen bonds with protein (PDB ID: 5T8E) which is similar hydrogen bonding to the standard (APL). The MD simulation result confirmed that APL43 and APL80 complexes were stable during the 100 nS run. Discussion: The results suggest that the APL analogues, particularly APL43 and APL80, are predicted to be potential antiandrogen drugs for the treatment of prostate cancer.

Biochar application for greenhouse gas mitigation, contaminants immobilization and soil fertility enhancement: A state-of-the-art review.

Rising global temperature, pollution load, and energy crises are serious problems, recently facing the world. Scientists around the world are ambitious to find eco-friendly and cost-effective routes for resolving these problems. Biochar has emerged as an agent for environmental remediation and has proven to be the effective sorbent to inorganic and organic pollutants in water and soil. Endowed with unique attributes such as porous structure, larger specific surface area (SSA), abundant surface functional groups, better cation exchange capacity (CEC), strong adsorption capacity, high environmental stability, embedded minerals, and micronutrients, biochar is presented as a promising material for environmental management, reduction in greenhouse gases (GHGs) emissions, soil management, and soil fertility enhancement. Therefore, the current review covers the influence of key factors (pyrolysis temperature, retention time, gas flow rate, and reactor design) on the production yield and property of biochar. Furthermore, this review emphasizes the diverse application of biochar such as waste management, construction material, adsorptive removal of petroleum and oil from aqueous media, immobilization of contaminants, carbon sequestration, and their role in climate change mitigation, soil conditioner, along with opportunities and challenges. Finally, this review discusses the evaluation of biochar standardization by different international agencies and their economic perspective.

Design and In-silico study of bioimaging fluorescence Graphene quantum dot-Bovine serum albumin complex synthesized by diimide-activated amidation.

Graphene quantum dot possesses advantageous characteristics like tunable fluorescence, nanometer size, low cytotoxicity, high biocompatibility enabling them as an ideal material for fluorescence bio-imaging. It exhibits a unique characteristic of DNA cleavage activity enhancer, gene/drug carrier, and anticancer targeting applications. In this article, we discussed the preparation of graphene quantum dot through the bottom-up method. Carbodiimide-activated amidation reactions were used for the functionalization of graphene quantum dot with Bovine Serum Albumin. Fluorescence spectroscopy data showed that the graphene quantum dot has size-dependent fluorescence emission. TEM and AFM studies showed that the size of graphene quantum dot was around 20 nm with narrow size distribution. Carbodiimide-activated amidation conjugation was successful in binding the protein onto graphene quantum dot and these conjugates were characterized by DLS, FTIR, fluorescence spectroscopy, and agarose gel electrophoresis. We also studied the structural-based in-silico molecular dynamic simulation by AutoDock, PyRx, and Discovery Studio Visualizer. Based on the virtual screening analysis and higher negative energy incorporation, it is observed that graphene quantum dot conjugated with bovine serum albumin quickly and formed is highly stable complex, which makes them a potential candidate for future applications in the field of bio-imaging, bio-sensing, gene/drug delivery, and tumor theragnostic.

Biclonal gammopathay in a case of severe COVID-19.

COVID-19 is a disease caused by a coronavirus named as SARS-CoV-2. It has become pandemic due to its contagious nature. Majority of the patients are asymptomatic or having mild flu like symptoms. Few need hospitalisation due to severe acute respiratory infection (SARI). Co-morbidity like diabetes, hypertension, renal failure etc. are associated with severe COVID-19 that often causes death. There have been only two published case reports of monoclonal gammopathy of unknown significance (MGUS) in patients with COVID-19 disease. Cytokine storm is often observed in severe COVID-19 and various cytokines including IL-6 that activates plasma cells are increased in blood in this condition. Here we present a case of severe COVID-19 patient with bioclonal gammopathy. He was known diabetic and hypertensive on treatment. He developed SARI, cytokines storm and septicaemia, treated with antibiotics, enoxaparin, hydroxychloroquine, insulin, anti-hypertensives, put on ventilator, subsequently developed septicaemia, multi-organ failure and died. Two M-bands on serum capillary electrophoresis with presence IgG-κ on both the M-bands indicates a biclonal gammopathy of unknown significance in this patient. We conclude that like MGUS, early stage biclonal gammopathy, although rare, gets manifested with M-bands on plasma protein electrophoresis. It is probably due to high level of IL-6 associated with cytokine storm in severe COVID-19 that stimulate early stage dyscratic plasma cells. Such biclonal gammopathy might be a risk factor for severe COVID-19 and associated mortality.

Kupffer Cells Regulate Natural Killer Cells Via the NK group 2, Member D (NKG2D)/Retinoic Acid Early Inducible-1 (RAE-1) Interaction and Cytokines in a Primary Biliary Cholangitis Mouse Model.

BACKGROUND Kupffer cells and natural killer (NK) cells has been identified as contributing factors in the pathogenesis of hepatitis, but the detailed mechanism of these cell types in the pathogenesis of primary biliary cholangitis (PBC) is poorly understood. MATERIAL AND METHODS In this study, polyinosinic: polycytidylic acid (poly I: C), 2-octynoic acid-bovine serum albumin (2OA-BSA) and Freund's adjuvant (FA) were injected to establish a murine PBC model, from which NK cells and Kupffer cells were extracted and isolated. The cells were then co-cultivated in a designed culture system, and then NK group 2, member D (NKG2D), retinoic acid early inducible-1 (RAE-1), F4/80, and cytokine expression levels were detected. RESULTS The results showed close crosstalk between Kupffer cells and NK cells. PBC mice showed increased surface RAE-1 protein expression and Kupffer cell cytokine secretion, which subsequently activated NK cell-mediated target cell killing via NKG2D/RAE-1 recognition, and increased inflammation. NK cell-derived interferon-γ (IFN-γ) and Kupffer cell-derived tumor necrosis factor alpha (TNF-alpha) were found to synergistically regulate inflammation. Moreover, interleukin (IL)-12 and IL-10 improved the crosstalk between NK cells and Kupffer cells. CONCLUSIONS Our findings in mice are the first to suggest the involvement of the NKG2D/RAE-1 interaction and cytokines in the synergistic effects of NK and Kupffer cells in PBC.

Palbociclib: A breakthrough in breast carcinoma in women.

Breast cancer (BC) is the most common cancer and leading cause of death in women worldwide. Cellular proliferation, growth, and division are tightly controlled by the cell-cycle regulatory machinery. An important pathway is cyclin-dependent kinases (CDKs) which regulate cell cycle and thus control transcriptional processes. In human cancer, multiple CDK family members are commonly deregulated. The cyclin D-CDK4/6-retinoblastoma (RB) protein-INK4 axis is particularly affected in many solid tumors which leads to cancer cell proliferation. This has led to long-standing interest in targeting CDK4/6 as an anticancer strategy. Different investigational agents that have been tested which inhibit multiple cell cycle and transcriptional CDKs but have carried excessive toxicity thus failed to stand the rational of human use. Amongst several selective and potent inhibitors of CDK4/6, palbociclib is the first to be accessed suitable for human use having explicit selectivity toward CDK4/6. Its mechanism is to arrest cells in G1 phase by blocking RB phosphorylation at CDK4/6-specfic sites without affecting the growth of cells which are RB-deficient. Studies conducted in patients of BC having cells with advanced RB-expression demonstrated acceptable side effects but dose-limiting toxicities primarily neutropenia and thrombocytopenia, with prolonged stable disease in patients.

Naloxegol: First oral peripherally acting mu opioid receptor antagonists for opioid-induced constipation.

Opioid-induced constipation (OIC) is one of the most troublesome and the most common effects of opioid use leading to deterioration in quality of life of the patients and also has potentially deleterious repercussions on adherence and compliance to opioid therapy. With the current guidelines advocating liberal use of opioids by physicians even for non-cancer chronic pain, the situation is further complicated as these individuals are not undergoing palliative care and hence there cannot be any justification to subject these patients to the severe constipation brought on by opioid therapy which is no less debilitating than the chronic pain. The aim in these patients is to prevent the opioid-induced constipation but at the same time allow the analgesic activity of opioids. Many drugs have been used with limited success but the most specific among them were the peripherally acting mu opioid receptor antagonists (PAMORA). Methylnaltrexone and alvimopan were the early drugs in this group but were not approved for oral use in OIC. However naloxegol, the latest PAMORA has been very recently approved as the first oral drug for OIC. This article gives an overview of OIC, its current management and more specifically the development and approval of naloxegol, including pharmacokinetics, details of various clinical trials, adverse effects and its current status for the management of OIC.

Tuberculous osteomyelitis of the maxilla: A rarest of rare case report.

Tuberculosis is a chronic granulomatous systemic infectious disease caused by Mycobacterium tuberculosis. The oral lesions found in tuberculosis are relatively rare and may present as ulcers, erythematous patches, indurated lesions, nodules or as bony jaw lesions. Oral tubercular lesions sometimes present a confusing clinical presentation and can be overlooked. Hence, we document a case of tuberculous osteomyelitis of the maxilla in a 19-year-old female patient, who was initially treated for multiple periodontal dental abscesses, which later proved to be tubercular osteomyelitis of the maxilla. Although it is a rare occurrence, the differential diagnosis of tuberculous osteomyelitis must always be considered when it fails to respond to routine therapy.

Recent advances on surface engineering of magnetic iron oxide nanoparticles and their biomedical applications.

Magnetic nanoparticles with appropriate surface coatings are increasingly being used clinically for various biomedical applications, such as magnetic resonance imaging, hyperthermia, drug delivery, tissue repair, cell and tissue targeting and transfection. This is because of the nontoxicity and biocompatibility demand that mainly iron oxide-based materials are predominantly used, despite some attempts to develop 'more magnetic nanomaterials' based on cobalt, nickel, gadolinium and other compounds. For all these applications, the material used for surface coating of the magnetic particles must not only be nontoxic and biocompatible but also allow a targetable delivery with particle localization in a specific area. Magnetic nanoparticles can bind to drugs and an external magnetic field can be applied to trap them in the target site. By attaching the targeting molecules, such as proteins or antibodies, at particles surfaces, the latter may be directed to any cell, tissue or tumor in the body. In this review, different polymers/molecules that can be used for nanoparticle coating to stabilize the suspensions of magnetic nanoparticles under in vitro and in vivo situations are discussed. Some selected proteins/targeting ligands that could be used for derivatizing magnetic nanoparticles are also explored. We have reviewed the various biomedical applications with some of the most recent uses of magnetic nanoparticles for early detection of cancer, diabetes and atherosclerosis.

Bilateral adrenal abscess in a neonate.

A 23-day-old male baby with a history of perinatal hypoxia presented with refusal of feeds and abdominal distension. The child had a right-sided cystic upper abdominal mass and features of neonatal septicemia. Abdominal ultrasound (US) and contrast-enhanced CT scan showed bilateral adrenal abscesses. Laparotomy with drainage of the abscesses successfully treated the condition. The literature on the subject is reviewed.

Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications.

Superparamagnetic iron oxide nanoparticles (SPION) with appropriate surface chemistry have been widely used experimentally for numerous in vivo applications such as magnetic resonance imaging contrast enhancement, tissue repair, immunoassay, detoxification of biological fluids, hyperthermia, drug delivery and in cell separation, etc. All these biomedical and bioengineering applications require that these nanoparticles have high magnetization values and size smaller than 100 nm with overall narrow particle size distribution, so that the particles have uniform physical and chemical properties. In addition, these applications need special surface coating of the magnetic particles, which has to be not only non-toxic and biocompatible but also allow a targetable delivery with particle localization in a specific area. To this end, most work in this field has been done in improving the biocompatibility of the materials, but only a few scientific investigations and developments have been carried out in improving the quality of magnetic particles, their size distribution, their shape and surface in addition to characterizing them to get a protocol for the quality control of these particles. Nature of surface coatings and their subsequent geometric arrangement on the nanoparticles determine not only the overall size of the colloid but also play a significant role in biokinetics and biodistribution of nanoparticles in the body. The types of specific coating, or derivatization, for these nanoparticles depend on the end application and should be chosen by keeping a particular application in mind, whether it be aimed at inflammation response or anti-cancer agents. Magnetic nanoparticles can bind to drugs, proteins, enzymes, antibodies, or nucleotides and can be directed to an organ, tissue, or tumour using an external magnetic field or can be heated in alternating magnetic fields for use in hyperthermia. This review discusses the synthetic chemistry, fluid stabilization and surface modification of superparamagnetic iron oxide nanoparticles, as well as their use for above biomedical applications.

Lactoferrin and ceruloplasmin derivatized superparamagnetic iron oxide nanoparticles for targeting cell surface receptors.

Tissue and cell-specific drug targeting can be achieved by employing nanoparticle coatings or carrier-drug conjugates that contain a ligand recognized by a receptor on the target cell. Superparamagnetic iron oxide nanoparticles have been used for many years in various biomedical applications. In this study, superparamagnetic nanoparticles with specific shape and size have been prepared and coupled to various proteins. These particles are characterized in vitro and their influence on human dermal fibroblasts is assessed in terms of cell adhesion, viability, morphology and cytoskeleton organization using various techniques to observe cell-nanoparticle interaction, including light, fluorescence, scanning and transmission electron microscopy. The results showed that each nanoparticle type with different surface characteristics caused a distinctly different cell response. The underivatized magnetic particles were internalized by the fibroblasts probably due to endocytosis, which resulted in disruption of the cell membrane and disorganized cell cytoskeleton. In contradiction, lactoferrin or ceruloplasmin coated nanoparticles attached to the cell membrane, most likely to the cell expressed receptors and were not endocytosed. One major problem with uncoated magnetic nanoparticles has been the endocytosis of particles leading to irreversible entry. These experiments provide a route to prevent this problem, suggesting that cell response can be directed via specifically engineered particle surfaces.