Enhanced properties of nickel-silver codoped hydroxyapatite for bone tissue engineering: Synthesis, characterization, and biocompatibility evaluation.

Hydroxyapatite (HAp) is the most well-known bioceramic and widely utilized in bone tissue regeneration. Hydroxyapatite is biocompatible and bioactive however, it lacks osteogenesis, angiogenesis, and antibacterial properties. In the current study, we synthesized and evaluated a novel nickel (Ni) and silver (Ag) codoped hydroxyapatite (HAp) in comparison to undoped HAp and individually doped HAp samples. Extensive physicochemical characterizations like XRD, TEM, FE-SEM/EDS, FTIR, Raman spectroscopy, and TGA were performed, confirming the crystal structure and morphology of the synthesized HAp samples. All HAp samples exhibited elongated spherical-like nanoparticle morphologies with lengths between 34 and 44 nm and widths between 21 and 26 nm. The presence of dopant atoms, Ag and Ni, were observed in the doped/codoped HAp samples by EDS elemental mapping. Biocompatibility assessments using pre-osteoblast cells indicated high cell viability for all the doped and undoped HAp samples. Osteoinduction potential through alkaline phosphatase (ALP) activity measurements and alizarin red S (ARS) staining revealed enhanced calcium deposition in the presence of Ni-Ag codoped HAp compared to other HAp samples and control groups. This highlights the importance of Ni-Ag co-doping in promoting osteogenesis, surpassing the effects of silver doped HAp and nickel doped HAp. The potential of this novel Ni-Ag codoped HAp to induce osteogenesis in pre-osteoblast cells makes it a promising material for various applications in bone tissue engineering.

Polysaccharide-bioceramic composites for bone tissue engineering: A review.

Limitations associated with conventional bone substitutes such as autografts, increasing demand for bone grafts, and growing elderly population worldwide necessitate development of unique materials as bone graft substitutes. Bone tissue engineering (BTE) would ensure therapy advancement, efficiency, and cost-effective treatment modalities of bone defects. One way of engineering bone tissue scaffolds by mimicking natural bone tissue composed of organic and inorganic phases is to utilize polysaccharide-bioceramic hybrid composites. Polysaccharides are abundant in nature, and present in human body. Biominerals, like hydroxyapatite are present in natural bone and some of them possess osteoconductive and osteoinductive properties. Ion doped bioceramics could substitute protein-based biosignal molecules to achieve osteogenesis, vasculogenesis, angiogenesis, and stress shielding. This review is a systemic summary on properties, advantages, and limitations of polysaccharide-bioceramic/ion doped bioceramic composites along with their recent advancements in BTE.

The circadian rhythm: an influential soundtrack in the diabetes story.

Type 2 Diabetes Mellitus (T2DM) has been the main category of metabolic diseases in recent years due to changes in lifestyle and environmental conditions such as diet and physical activity. On the other hand, the circadian rhythm is one of the most significant biological pathways in humans and other mammals, which is affected by light, sleep, and human activity. However, this cycle is controlled via complicated cellular pathways with feedback loops. It is widely known that changes in the circadian rhythm can alter some metabolic pathways of body cells and could affect the treatment process, particularly for metabolic diseases like T2DM. The aim of this study is to explore the importance of the circadian rhythm in the occurrence of T2DM via reviewing the metabolic pathways involved, their relationship with the circadian rhythm from two perspectives, lifestyle and molecular pathways, and their effect on T2DM pathophysiology. These impacts have been demonstrated in a variety of studies and led to the development of approaches such as time-restricted feeding, chronotherapy (time-specific therapies), and circadian molecule stabilizers.

Enhanced Targeted Delivery of Minocycline via Transferrin Conjugated Albumin Nanoparticle Improves Neuroprotection in a Blast Traumatic Brain Injury Model.

Traumatic brain injury (TBI) is a major source of death and disability worldwide as a result of motor vehicle accidents, falls, attacks and bomb explosions. Currently, there are no FDA-approved drugs to treat TBI patients predominantly because of a lack of appropriate methods to deliver drugs to the brain for therapeutic effect. Existing clinical and pre-clinical studies have shown that minocycline's neuroprotective effects either through high plasma protein binding or an increased dosage requirement have resulted in neurotoxicity. In this study, we focus on the formulation, characterization, in vivo biodistribution, behavioral improvements, neuroprotective effect and toxicity of transferrin receptor-targeted (tf) conjugated minocycline loaded albumin nanoparticles in a blast-induced TBI model. A novel tf conjugated minocycline encapsulated albumin nanoparticle was developed, characterized and quantified using a validated HPLC method as well as other various analytical methods. The results of the nanoformulation showed small, narrow hydrodynamic size distributions, with high entrapment, loading efficiencies and sustained release profiles. Furthermore, the nanoparticle administered at minimal doses in a rat model of blast TBI was able to cross the blood-brain barrier, enhanced nanoparticle accumulation in the brain, improved behavioral outcomes, neuroprotection, and reduced toxicity compared to free minocycline. Hence, tf conjugated minocycline loaded nanoparticle elicits a neuroprotective effect and can thus offer a potential therapeutic effect.

Fuzzy Drug Targets: Disordered Proteins in the Drug-Discovery Realm.

Intrinsically disordered proteins (IDPs) and regions (IDRs) form a large part of the eukaryotic proteome. Contrary to the structure-function paradigm, the disordered proteins perform a myriad of functions in vivo. Consequently, they are involved in various disease pathways and are plausible drug targets. Unlike folded proteins, that have a defined structure and well carved out drug-binding pockets that can guide lead molecule selection, the disordered proteins require alternative drug-development methodologies that are based on an acceptable picture of their conformational ensemble. In this review, we discuss various experimental and computational techniques that contribute toward understanding IDP "structure" and describe representative pursuances toward IDP-targeting drug development. We also discuss ideas on developing rational drug design protocols targeting IDPs.

An Insight into the Polymeric Nanoparticles Applications in Diabetes Diagnosis and Treatment.

Diabetes Mellitus (DM) is a type of chronic metabolic disease that has affected millions of people worldwide and is known with a defect in the amount of insulin secretion, insulin functions, or both. This deficiency leads to an increase in the amounts of glucose, which could be accompanied by long-term damages to other organs such as eyes, kidneys, heart, and nervous system. Thus, introducing an appropriate approach for diagnosis and treatment of different types of DM is the aim of several researches. By the emergence of nanotechnology and its application in medicine, new approaches were presented for these purposes. The object of this review article is to introduce different types of polymeric nanoparticles (PNPs), as one of the most important classes of nanoparticles, for diabetic management. To achieve this goal, at first, some of the conventional therapeutic and diagnostic methods of DM will be reviewed. Then, different types of PNPs, in two forms of natural and synthetic polymers with different properties, as a new method for DM treatment and diagnosis will be introduced. In the next section, the transport mechanisms of these types of nano-carriers across the epithelium, via paracellular and transcellular pathways will be explained. Finally, the clinical use of PNPs in the treatment and diagnosis of DM will be summarized. Based on the results of this literature review, PNPs could be considered one of the most promising methods for DM management.

Molecular Insights on the Therapeutic Effect of Selected Flavonoids on Diabetic Neuropathy.

One of the common clinical complications of diabetes is diabetic neuropathy affecting the nervous system. Painful diabetic neuropathy is widespread and highly prevalent. At least 50% of diabetes patients eventually develop diabetic neuropathy. The four main types of diabetic neuropathy are peripheral neuropathy, autonomic neuropathy, proximal neuropathy (diabetic polyradiculopathy), and mononeuropathy (Focal neuropathy). Glucose control remains the common therapy for diabetic neuropathy due to limited knowledge on early biomarkers that are expressed during nerve damage, thereby limiting the cure through pharmacotherapy. Glucose control dramatically reduces the onset of neuropathy in type 1 diabetes but proves to be less effective in type 2 diabetes. Therefore, the focus is on various herbal remedies for prevention and treatment. There is numerous research on the use of anticonvulsants and antidepressants for the management of pain in diabetic neuropathy. Extensive research is being conducted on natural products, including the isolation of pure compounds like flavonoids from plants and their effect on diabetic neuropathy. This review focuses on the use of important flavonoids such as flavanols (e.g., quercetin, rutin, kaempferol, and isorhamnetin), flavanones (e.g., hesperidin, naringenin and class eriodictyol), and flavones (e.g., apigenin, luteolin, tangeretin, chrysin, and diosmin) for the prevention and treatment of diabetic neuropathy. The mechanisms of action of flavonoids against diabetic neuropathy by their antioxidant, anti-inflammation, anti-glycation properties, etc., are also covered in this review article.

Bone tissue engineering: Anionic polysaccharides as promising scaffolds.

Bone repair is a self-healing process. However, critical-sized bone defects need bone augmentation where bone tissue engineering plays vital role. Bone tissue Engineering (BTE) requires unique combinations of scaffolds, cells, and bio-signal molecules. Bone scaffold materials should be biocompatible, bioresorbable and exhibit biomimetic properties. Natural polymers, acquiring cell binding motives, producing nontoxic degradation products and tunable properties are ideal materials. Anionic polysaccharides of natural origin mimic mammalian ECM components and even the group called GAGs (Glycosaminoglycan) are actual components of ECM possessing various functions including cell adhesion, cell signaling, maintenance of homeostasis and inflammation control. Among them, anionic polysaccharides provide stabilization and sustained release of growth factors (GFs), porosity, calcium phosphate nucleation site, viscoelasticity, and water retention. Therefore, anionic polysaccharides are unique biomaterials for BTE. In this review, we have summarized the highlights of bone tissue engineering and recent applications of anionic polysaccharides in BTE.

Role of GLP-1 Analogs in the Management of Diabetes and its Secondary Complication.

The cardiovascular complications of Type 2 Diabetes Mellitus (T2DM) including myocardial infarction, heart failure, peripheral vascular disease and, stroke and retinopathy, nephropathy and neuropathy are microvascular complications. While the newer therapies like glitazones or even Dipeptidyl- peptidase-IV (DPP-IV) inhibitors increase the risk of therapy, the Glucagon Like Peptide-1 Receptor Agonists (GLP-1RAs), were reported as suitable alternates. The GLP-1RAs reduce Major Adverse Cardiovascular Events (MACE), have anti-atherogenic potential, and possess pleiotropic activity. The GLP-1RAs were found to improve neuroprotection, enhance neuronal growth, reduce the incidence of stroke, and improve central insulin resistance. The GLP-1RAs are beneficial in improving the glycemic profile, preventing macroalbuminuria and reducing the decline in eGFR and enhancing renal protection. The renal benefits of add-on therapy of GLP-1RAs with SGLT-2 inhibitors have composite renal outcomes such as suppression of inflammatory pathways, improvement in natriuresis, diuresis, found to be nephroprotective. Improvement in glycemic control with a reduction in body weight and intraglomerular pressure and prevention of tubular injury makes the GLP-1RAs as suitable add-on therapies in improving cardiorenal outcomes. Obesity, an important contributor to insulin resistance and a reduction in weight, is an essential therapeutic option in addressing diabetic-obesity. It also reduces the damage to blood-retinal-barrier, thus beneficial in halting the development of diabetic retinopathy. In diabetic complications, glycemic control, addressing insulin resistance through weight loss, controlling atherosclerosis through anti-inflammatory effects and cardio-renal-neuro protection, makes GLP-1RAs a suitable therapeutic strategy on long-term treatment of T2DM. This review discusses the role of GLP-1RAs in diabetes, the dosage, mono or combination therapy with other antidiabetics in long-term treatment and its effect in uncontrolled diabetes.

Current Trends in the Therapeutic Strategies for Diabetes Management.

Diabetes mellitus is one of the fastest-growing non-communicable diseases. Diabetes mellitus is caused due by the destruction of pancreatic ß-cell or due to insulin resistance and characterized by hyperglycemia. Diabetes imposes a very serious economic crisis as the diabetic drug market is growing very rapidly. Even after very path-breaking scientific discoveries, the availability of better healthcare infrastructure, and a rise in literacy rates, the diabetes burden is continuously spreading in various sections all over the world but more especially in low- and middle-income countries. The recent developments in scientific discoveries have given several new generations of antidiabetic medicines such as sulphonylurea, biguanides, thiazolidinedione, α-glucosidase inhibitors. All these drugs have proved a significant reduction in blood glucose level. There are some new classes of hypoglycaemic drugs that have also been developed and reported, such as GLP-1 analogous, DPP-IV inhibitors, amylin inhibitors, and peroxisome proliferator- activated receptors. There are some active molecules and bioactive substances that have been purified from herbs and plants, which add value to the war against diabetes. These phytoconstituents have overturned drug development and lead identification for drugs against diabetes. The review also focuses on some critical areas of diabetes with more focus on statin-based diabetes management approach and stem cell therapy based next generation antidiabetic therapy.

Nanoemulsions: A Better Approach for Antidiabetic Drug Delivery.

Conventional delivery of antidiabetic drugs faces many problems like poor absorption, low bioavailability, and drug degradation. Nanoemulsion is a unique drug technology, which is very suitable for the delivery of antidiabetic drugs. In recent years, the flaws of delivering anti-hypoglycaemic drugs have been overcome by choosing nanoemulsion drug technology. They are thermodynamically stable and also provide the therapeutic agent for a longer duration. Generally, nanoemulsions are made up of either oil-in-water or water-in-oil and the size of the droplets is from fifty to thousand nanometer. Surfactants are critical substances that are added in the manufacturing of nanoemulsions. Only the surfactants which are approved for human use can be utilized in the manufacturing of nanoemulsions. Generally, the preparation of emulsions includes mixing of the aqueous phase and organic phase and using surfactant with proper agitation. Nanoemulsions are used for antimicrobial drugs, and they are also used in the prophylaxis of cancer. Reduction in the droplet size may cause variation in the elastic and optical behaviour of nanoemulsions.

Synthesis of magnesium phosphate nanoflakes and its PCL composite electrospun nanofiber scaffolds for bone tissue regeneration.

This study describes the preparation of nano-magnesium phosphate (nMP) flakes by one step microwave irradiation method. The synthesized nMP was incorporated with polycaprolactone (PCL), hyperbranched polyglycerol (HPG) and nano-hydroxyapatite (nHA) to fabricate as composite electrospun nanofibrous scaffold for bone tissue engineering applications. The electrospun nanofibers were analyzed by scanning electron microscope, XRD, FTIR, DSC, TGA, and wettability measurement. The nanofibers were smooth, randomly oriented, and surface decorated with nMP. The water contact angle was 32 ± 1° (initial contact angle), which reduces to 0° after 1 min for HPG and nMP containing nanocomposites, while the contact angle of PCL is 104 ± 5°. The nanocomposite scaffolds exhibited higher swelling, biomineralization, and breakages during PBS immersion. The scaffolds were non-cytotoxic to MG63 osteosarcoma cells and hMSCs with higher viability after 72 h. They allowed good adhesion and spreading of these cells when compared to PCL and PCL/nHA electrospun nanofibers. These results indicated that HPG with surface decorated nMP electrospun nanocomposite scaffold can be a promising material for bone tissue engineering applications.

Near infra-red polymeric nanoparticle based optical imaging in Cancer diagnosis.

Cancer disease is a foremost health concern and top basis of death in comparison with many diseases including cardiovascular disorders. During initial diagnosis (usually late diagnosis), a majority of cancer patients suffer from metastatic and advanced cancer stages which resulted in limited therapeutic modalities based interventions and effectiveness. Though considerable advancement has been made in combating the disease, continuous and intense efforts are ongoing for early diagnosis and development of therapies. Generally applied treatment options for cancer are surgery, chemotherapy and radiotherapy, which are restricted by failure to early diagnose, insufficient on-targeted drug delivery, systemic toxicity, and lack of real-time monitoring of therapeutic responses in cancer. Noninvasive imaging or minimally invasive imaging methodology is valuable in clinical diagnostic settings. Specifically, noninvasive optical imaging integrated with polymeric nanomaterial have been extensively investigated in the field of cancer diagnostics and therapy. Currently, optical imaging methods go together with polymer-based fluorescent nanoparticles in accomplishing the molecular level detection of tumor boundaries. NIR probe tagged polymeric nanoparticles have potential to provide an advantage in the early cancer detection, therapeutic monitoring and image guided surgery procedures. This article review the recent progress in state-of-the-art NIRF polymeric nanoparticles used for optical imaging particularly on cancer diagnosis.

Design of antimicrobial polycaprolactam nanocomposite by immobilizing subtilisin conjugated Au/Ag core-shell nanoparticles for biomedical applications.

Preparation of the gold core and silver shell NP (AuAgNP) is challenging because of the facile oxidation of silver. Here such a NP is carefully synthesized and conjugated with subtilisin to arrive at a stable spherical material of 120-130 nm in diameter (AuAgSNP). A biomaterial prepared by immobilizing AuAgSNP on polycaprolactam (PCL) exhibits antibiofilm properties against S. aureus and E. coli, but with lesser potency than the one prepared with bare AuAgNP. Subtilisin degrades the adhesive surface proteins of the bacteria thereby preventing the biofilm formation. Subtilisin conjugated AuAgSNP is not cytotoxic to 3T3 cells at its MIC, in contrast to AuAgNP. The presence of subtilisin promotes the fibroblast proliferation. This study indicates that AuAgSNP has antibacterial/antibiofilm activities as well as biocompatibility unlike NPs which are very cytotoxic to cells. Hence AuAgSNP can be used in medical implants and devices.

Design of a papain immobilized antimicrobial food package with curcumin as a crosslinker.

Contamination of food products by spoilage and pathogenic microorganisms during post process handling is one of the major causes for food spoilage and food borne illnesses. The present green sustainable approach describes the covalent immobilization of papain to LDPE (low density polyethylene), HDPE (high density polyethylene), LLDPE (linear low density polyethylene) and PCL (polycaprolactam) with curcumin as the photocrosslinker. About 50% of curcumin and 82-92% of papain were successfully immobilized on these polymers. After 30 days, the free enzyme retained 87% of its original activity, while the immobilized enzyme retained more than 90% of its activity on these polymers. Papain crosslinked to LLDPE exhibited the best antibiofilm properties against Acinetobacter sp. KC119137.1 and Staphylococcus aureus NCIM 5021 when compared to the other three polymers, because of the highest amount of enzyme immobilized on this surface. Papain acts by damaging the cell membrane. The enzyme is able to reduce the amount of carbohydrate and protein contents in the biofilms formed by these organisms. Meat wrapped with the modified LDPE and stored at 4°C showed 9 log reduction of these organisms at the end of the seventh day when compared to samples wrapped with the bare polymer. This method of crosslinking can be used on polymers with or without functional groups and can be adopted to bind any type of antimicrobial agent.

Functionalized polycaprolactam as an active food package for antibiofilm activity and extended shelf life.

Papain is covalently crosslinked on polycaprolactam and tested as a wrapper for packaging cottage cheese, against E. coli biofilm. The bacterial count on neat polycaprolactam (NP) was 50×10(6)/ml on the 5th day which dramatically increased to 300×10(6) colony forming units (CFU)/ml by the end of 30th day. The corresponding CFU/ml on papain functionalized polycaprolactam (FP) was 10×10(2) on 5th day and 20×10(2) by the end of 30th day. Fourier transform infrared spectroscopic (FTIR) analysis of biofilm on NP showed the presence of polysaccharide, protein, lipid and metabolites which was three times reduced on FP. FT Raman spectroscopy showed the effect of papain on functional groups such as hydroxyl, amino, carbonyl, phosphoryl and aliphatic, leading to the inhibition of the biofilm. Motility, hydrophobicity and zeta potential of E. coli on NP and FP were 10.67 and 5.65 µm/s/V/cm; 88 and 20%; 8.93±2.09 and 2.65±0.52 mV respectively, thereby decreasing the biofilm forming ability of E. coli.

Antibiofilm properties of interfacially active lipase immobilized porous polycaprolactam prepared by LB technique.

Porous biomaterial is the preferred implant due to the interconnectivity of the pores. Chances of infection due to biofilm are also high in these biomaterials because of the presence of pores. Although biofilm in implants contributes to 80% of human infections, there are no commercially available natural therapeutics against it. In the current study, glutaraldehyde cross linked lipase was transferred onto a activated porous polycaprolactam surface using Langmuir-Blodgett deposition technique, and its thermostability, slimicidal, antibacterial, biocompatibility and surface properties were studied. There was a 20% increase in the activity of the covalently crosslinked lipase when compared to its free form. This immobilized surface was thermostable and retained activity and stability until 100°C. There was a 2 and 7 times reduction in carbohydrate and 9 and 5 times reduction in biofilm protein of Staphylococcus aureus and Escherichia coli respectively on lipase immobilized polycaprolactam (LIP) when compared to uncoated polycaprolactam (UP). The number of live bacterial colonies on LIP was four times less than on UP. Lipase acted on the cell wall of the bacteria leading to its death, which was confirmed from AFM, fluorescence microscopic images and amount of lactate dehydrogenase released. LIP allowed proliferation of more than 90% of 3T3 cells indicating that it was biocompatible. The fact that LIP exhibits antimicrobial property at the air-water interface to hydrophobic as well as hydrophilic bacteria along with lack of cytotoxicity makes it an ideal biomaterial for biofilm prevention in implants.

Chalcone coating on cotton cloth - an approach to reduce attachment of live microbes.

Drug resistant bacteria are a major threat to humans, especially those which mediate nosocomial infections. In this paper, three different 4-sulfonylmethyl chalcones are coated onto cotton cloths with acacia as the binder using a padding mangle to make them antibacterial. A 99% reduction in the adhesion of three slime producing organisms, namely Staphylococcus aureus NCIM5021, Escherichia coli NCIM2931 and Pseudomonas aeruginosa NCIM2901, on these surfaces was observed. The coated surfaces are more hydrophobic than the original one. The attachment of the bacteria (CFU ml-1) to the cloth is directly proportional (correlation coefficient, R = 0.58) to the hydrophobicity of the surface of the microorganism. The extent of bacterial attachment on the cloths (CFU ml-1) is not correlated with the minimum inhibitory concentration (MIC) of the chalcones (R = -0.1), but on the other hand it is negatively correlated with the hydrophilicity of the coated cloth (R = -0.52). This indicates that hydrophilic surfaces prevent bacterial attachment and hydrophobic organisms have a greater propensity to attach to hydrophobic surfaces than hydrophilic ones. A simple multi-linear regression model with the surface hydrophobicity of the organism and the hydrophilicity of the cloth is able to predict the extent of bacterial attachment. This study suggests that the coated cloths could find applications in hospital environments.

Novel microarrays for simultaneous serodiagnosis of multiple antiviral antibodies.

We developed an automated diagnostic system for the detection of virus-specific immunoglobulin Gs (IgGs) that was based on a microarray platform. We compared efficacies of our automated system with conventional enzyme immunoassays (EIAs). Viruses were immobilized to microarrays using a radical cross-linking reaction that was induced by photo-irradiation. A new photoreactive polymer containing perfluorophenyl azide (PFPA) and poly(ethylene glycol) methacrylate was prepared and coated on plates. Inactivated measles, rubella, mumps, Varicella-Zoster and recombinant Epstein-Barr viruse antigen were added to coated plates, and irradiated with ultraviolet light to facilitate immobilization. Virus-specific IgGs in healthy human sera were assayed using these prepared microarrays and the results obtained compared with those from conventional EIAs. We observed high correlation (0.79-0.96) in the results between the automated microarray technique and EIAs. The microarray-based assay was more rapid, involved less reagents and sample, and was easier to conduct compared with conventional EIA techniques. The automated microarray system was further improved by introducing reagent storage reservoirs inside the chamber, thereby conserving the use of expensive reagents and antibodies. We considered the microarray format to be suitable for rapid and multiple serological diagnoses of viral diseases that could be developed further for clinical applications.