Papers by Jayakumar Rajadas
Frontiers in Pharmacology, Sep 29, 2022
Purpose: Alternate formulation strategies need to be devised for improving the absorption and bio... more Purpose: Alternate formulation strategies need to be devised for improving the absorption and bioavailability of drug molecules administered through the intravaginal route. Enhancing the coating of vaginal mucosa can aid the achievement of this goal. The aim of the current study is to develop a mucoadhesive formulation having adequate adhesiveness, spreading, and viscosity profiles that can ensure good tissue absorption of adapalene upon intravaginal application. Method: A combination of mucoadhesive agents has been employed, including Carbopol-934, HPMC K-15M, and xanthan gum, in varying ratios to formulate five different gels. Furthermore, a cost-effective UV-spectroscopic analytical method was developed to quantify the amount of adapalene in tested samples, both of in vitro and in vivo origin. The analytical method was validated for different parameters, including specificity, linearity, range, accuracy, precision, and ruggedness. The modified USP-II apparatus was used for dissolution studies, while in vivo pharmacokinetic validation was performed in a murine model. Result: Of all the tested formulations, on the basis of the rheo-mechanical attributes, ACX3 performed better than the rest, including the commercially available intravaginal reference product. ACX3 had an average adhesion time of 12 min and a spread diameter of 37 mm. It showed 35 mm as average distance travelled by the diluted sample for leakage assessment. The analytical method developed for the adapalene muco-adhesive gel was within the range for all the validation parameters. For further evaluating the performance of the formulation, dissolution studies were conducted in simulated vaginal conditions which showed 94.83% of drug release within 5 minutes, while on completion of 30 min, it was measured to be 92.90%. Moreover, approximately 67% of the administered drug was recovered after 5 min of administration as evaluated through tissue recovery procedures in mice.
Biomedicines, 2021
Autologous platelet-rich fibrin (PRF) is derived from the blood and its use in the bone tissue en... more Autologous platelet-rich fibrin (PRF) is derived from the blood and its use in the bone tissue engineering has emerged as an effective strategy for novel drug and growth factor delivery systems. Studies have approved that combined therapy with PRF ensures higher biological outcomes, but patients still undergo additional treatment with antibiotic drugs before, during, and even after the implantation of biomaterials with PRF. These systematically used drugs spread throughout the blood and lead not only to positive effects but may also induce adverse side effects on healthy tissues. Vancomycin hydrochloride (VANKA) is used to treat severe Staphylococcal infections but its absorption in the target tissue after oral administration is low; therefore, in this study, we have developed and analyzed two kinds of VANKA carriers—liposomes and microparticles in 3D PRF matrices. The adjustment, characterization, and analysis of VANKA carriers in 3D PRF scaffolds is carried out in terms of encapsu...
International Journal of Peptide Research and Therapeutics, 2011
Abstract Genetic, biochemical and pathological evidence support that self-assembly of amyloid-bet... more Abstract Genetic, biochemical and pathological evidence support that self-assembly of amyloid-beta (Aβ) peptide into toxic aggregates is implicated as the cause of Alzheimer's disease. An attractive therapeutic strategy for the treatment of AD is to prevent or interfere ...
Neurobiology of Aging, 2009
Microglia clear amyloid beta (A) after immunization. The interaction of A with the microglial c... more Microglia clear amyloid beta (A) after immunization. The interaction of A with the microglial cell surface also results in cytokine expression. Soluble oligomers and protofibrils of A may be more neurotoxic than A fibrils. We investigated the effects of oligomeric, protofibrillar and fibrillar A40 and A42 peptides on uptake and IL-1␣ expression by primary microglia. A peptide assemblies were extensively characterized. Primary microglial cells were exposed to different A40 and A42 assemblies and IL-1␣ expression was quantified. To study uptake, microglial cells were exposed to different assemblies of Cy3-labeled A. We found that A42 and A40 oligomers and fibrils induced IL-1␣ expression, but protofibrils did not. We also observed that all forms of A42 (oligomer, protofibril and fibril) and A40 fibrils were taken up by the microglial cells. These results demonstrate that microglial cells can take up non-fibrillar A and that oligomeric peptide induces an inflammatory response. The uptake of oligomeric and protofibrillar A by microglia merits further investigation as a potential means for removing these neurotoxic species from the brain.
Neurochemical Research, 2011
Substantial evidence suggests that the aggregation of amyloid-b (Ab) peptide into fibrillar struc... more Substantial evidence suggests that the aggregation of amyloid-b (Ab) peptide into fibrillar structures that is rich in b-sheets is implicated as the cause of Alzheimer's disease. Therefore, an attractive therapeutic strategy is to prevent or alter Ab aggregation. Phenolic compounds are natural substances that are composed of one or more aromatic phenolic rings and present in wine, tea, fruits, vegetables and a wide variety of plants. In this work, we investigated the effects of ferulic acid, morin, quercetin and gossypol against Ab aggregation. From the ThT and turbidity assays, it is observed that in addition to the fibril aggregate, another type of aggregate is formed in the presence of morin, quercetin, and gossypol. On the other hand, ferulic acid did not prevent fibril formation, but it did appear to reduce the average length of fibrils compared to Ab alone. To study the protective effects of phenolic compounds on Ab-induced toxicity, we utilized the nematode Caenorhabditis elegans (C. elegans) as an in vivo model organism, human Ab is expressed intracellularly in the body wall muscle. We found that exposure of Caenorhabditis elegans to ferulic acid give more protection against Ab toxicity than morin, quercetin and gossypol.
Biophysical Journal, 2006
Alzheimer's disease is the most common cause of dementia and is widely believed to be due to the ... more Alzheimer's disease is the most common cause of dementia and is widely believed to be due to the accumulation of b-amyloid peptides (Ab) and their interaction with the cell membrane. Abs are hydrophobic peptides derived from the amyloid precursor proteins by proteolytic cleavage. After cleavage, these peptides are involved in a self-assembly-triggered conformational change. They are transformed into structures that bind to the cell membrane, causing cellular degeneration. However, it is not clear how these peptide assemblages disrupt the structural and functional integrity of the membrane. Membrane fluidity is one of the important parameters involved in pathophysiology of disease-affected cells. Probing the Ab aggregate-lipid interactions will help us understand these processes with structural detail. Here we show that a fluid lipid monolayer develop immobile domains upon interaction with Ab aggregates. Atomic force microscopy and transmission electron microscopy data indicate that peptide fibrils are fragmented into smaller nano-assemblages when interacting with the membrane lipids. Our findings could initiate reappraisal of the interactions between lipid assemblages and Ab aggregates involved in Alzheimer's disease.
Alzheimer's & Dementia, 2006
Acta Biomaterialia, 2010
To study the role of cell-ECM interactions, microscale approaches provide the potential to perfor... more To study the role of cell-ECM interactions, microscale approaches provide the potential to perform high throughput assessment of ECM microenvironments on cellular function and phenotype. Using a microscale direct writing (MDW) technique, we characterized the generation of multicomponent ECM microarrays for cellular micropatterning, localization, and stem cell fate determination. ECMs and other biomolecules of various geometries and sizes were printed onto epoxide-modified glass substrates for evaluation of cell attachment by human endothelial cells. The endothelial cells displayed strong preferential attachment to the ECM-patterned regions and aligned their cytoskeleton along the direction of the micropatterns. We next generated ECM microarrays that contained one or more ECM compositions (namely gelatin, collagen IV, and fibronectin) and then cultured murine embryonic stem cell (ESCs) on the microarrays. The ESCs selectively attached to the micropatterned features and expressed markers associated with a pluripotent phenotype, such as E-cadherin and alkaline phosphatase, when maintained in growth media containing leukemia inhibitory factor. In the presence of soluble factors retinoic acid and bone morphogenetic protein-4, the ESCs differentiated towards ectodermal lineage on the ECM microarray with differential ECM effects. The ESCs cultured on gelatin showed significantly higher levels of pan cytokeratin expression, when compared cells cultured on collagen IV or fibronectin, suggesting that gelatin preferentially promotes ectodermal differentiation. In summary, our results demonstrate that MDW is a versatile approach to print ECMs of diverse geometries and compositions onto surfaces, and it is amenable to the generation of multicomponent ECM microarrays for stem cell fate determination.
Medicinal Chemistry Research, Dec 19, 2012
Genetic, biochemical, and pathological evidence supports that aggregation of amyloid-beta (Ab) pe... more Genetic, biochemical, and pathological evidence supports that aggregation of amyloid-beta (Ab) peptide into fibrillar structures rich in beta-sheets is implicated as the cause of Alzheimer's disease. Therefore, an attractive therapeutic strategy is to prevent or alter amyloidbeta aggregation. In this work we examine the effects of the short D-peptides pgklvya, kklvffarrrra, and kklvffa on Ab aggregation in vitro and toxicity in vivo. These peptides are based on the central hydrophobic region of Ab (residues 16-20), which is believed to be crucial in Ab selfassociation. The effect of peptides on Ab aggregation was examined by circular dichroism spectroscopy, Thioflavin T fluorescence, and ANS binding assay. Transgenic Caenorhabditis elegans model was used to evaluate the pharmacological effect of D-peptides on Ab-initiated toxicity. The data suggested that D-peptides are very effective at inhibiting fibrillogenesis of Ab. Among the three peptides tested, only pgklvya and kklvffa improved survival in the transgenic C. elegans. The activity of these peptides correlates with their ability to inhibit Ab oligomerization. These suggest that D-peptides should be considered during future design of peptide-based inhibitors of amyloid deposition and toxicity.
Polyelectrolyte complexes (PEC) of chitosan and ulvan were fabricated to study ALP mediated forma... more Polyelectrolyte complexes (PEC) of chitosan and ulvan were fabricated to study ALP mediated formation of apatitic minerals. Scaffolds of the PEC were subjected to alkaline phosphatase (ALP) and successful mineral formation was studied using SEM, Raman and XRD techniques. Investigation of the morphology via SEM shows globular structures of the deposited minerals, which promoted cell attachment, proliferation and extracellular matrix formation. The PEC and their successful calcium phosphate based mineralization offers a greener route of scaffold fabrication towards developing resorbable materials for tissue engineering. Suggested Reviewers: Håvard J. Haugen Department of Biomaterials, University of Oslo [email protected] Prof. Haugen is related to the field of biomaterials. Antonella Motta Dipartimento di Ingegneria Industriale , University Trento [email protected] Prof. Motta is renowned for working on cell material interaction on carbohydrates. Jayakumar Rajadas Biomate...
mBio, 2020
Immune responses to infectious agents are initiated when a pathogen or its components bind to pat... more Immune responses to infectious agents are initiated when a pathogen or its components bind to pattern recognition receptors (PRRs). PRR binding sets off a cascade of events that activates immune responses. We now show that, in addition to activating immune responses, PRR signaling also initiates an immunosuppressive response, probably to limit inflammation. The importance of the current findings is that blockade of immunomodulatory signaling, which is mediated by the upregulation of the CD47 molecule, can lead to enhanced immune responses to any pathogen that triggers PRR signaling. Since most or all pathogens trigger PRRs, CD47 blockade could be used to speed up and strengthen both innate and adaptive immune responses when medically indicated. Such immunotherapy could be done without a requirement for knowing the HLA type of the individual, the specific antigens of the pathogen, or, in the case of bacterial infections, the antimicrobial resistance profile.
The FEBS Journal, 2020
Mitochondria are key organelles, which maintain energy metabolism and cellular homeostasis. Mitoc... more Mitochondria are key organelles, which maintain energy metabolism and cellular homeostasis. Mitochondria support transcriptional regulation and proteostatic signaling mechanisms through crosstalk between the mitochondria itself, the nucleus, and the cytoplasm. Mitochondrial dysfunction leads to impaired proteostasis, and both are key pathological features of age‐related neurological disorders. For example, Alzheimer’s and Parkinson’s diseases feature mitochondrial‐targeted protein aggregates and impaired mitochondrial function, although the mechanistic causes are poorly understood. Vascular abnormalities and hypometabolism in such neurological diseases are reported several years before key clinical disease symptoms even become apparent. Recent investigations suggest that processing of such aggregates within mitochondria can offer protective functions, specifically by restoring energy (ATP) in starving cells. We hypothesize that the accumulation of protein aggregates in mitochondria ...
Disease Models & Mechanisms, 2019
Combined pulmonary fibrosis and emphysema (CPFE) is a syndrome that predominantly affects male sm... more Combined pulmonary fibrosis and emphysema (CPFE) is a syndrome that predominantly affects male smokers or ex-smokers and it has a mortality rate of 55% and a median survival of 5 years. Pulmonary hypertension (PH) is a frequently fatal complication of CPFE. Despite this dismal prognosis, no curative therapies exist for patients with CPFE outside of lung transplantation and no therapies are recommended to treat PH. This highlights the need to develop novel treatment approaches for CPFE. Studies from our group have demonstrated that both adenosine and its receptor ADORA2B are elevated in chronic lung diseases. Activation of ADORA2B leads to elevated levels of hyaluronan synthases (HAS) and increased hyaluronan, a glycosaminoglycan that contributes to chronic lung injury. We hypothesize that ADORA2B and hyaluronan contribute to CPFE. Using isolated CPFE lung tissue, we characterized expression levels of ADORA2B and HAS. Next, using a unique mouse model of experimental lung injury that ...
Advances in Wound Care, 2019
Microtubules (MTs) are intracellular polymers that provide structure to the cell, serve as railwa... more Microtubules (MTs) are intracellular polymers that provide structure to the cell, serve as railways for intracellular transport, and regulate many cellular activities, including cell migration. The dynamicity and function of the MT cytoskeleton are determined in large part by its regulatory proteins, including the recently discovered MT severing enzyme Fidgetin-like 2 (FL2). Downregulation of FL2 expression with small interfering RNA (siRNA) results in a more than twofold increase in cell migration rate in vitro as well as translates into improved wound-healing outcomes in in vivo mouse models. Here we utilized a commercially available surfactant polymer dressing (SPD) as a vehicle to deliver FL2 siRNA. To this end we incorporated collagen microparticles containing FL2 siRNA into SPD (SPD-FL2-siRNA) for direct application to the injury site. Topical application of SPD-FL2 siRNA to murine models of full-thickness excision wounds and full-thickness burn wounds resulted in significant improvements in the rate and quality of wound healing, as measured clinically and histologically, compared with controls. Wound healing occurred more rapidly and with high fidelity, resulting in properly organized collagen substructure. Taken together, these findings indicate that the incorporation of FL2 siRNA into existing treatment options is a promising avenue to improve wound outcomes.
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Papers by Jayakumar Rajadas