Cancer Vaccines in the Immunotherapy Era: Promise and Potential.

Therapeutic vaccines are a promising alternative for active immunotherapy for different types of cancers. Therapeutic cancer vaccines aim to prevent immune system responses that are not targeted at the tumors only, but also boost the anti-tumor immunity and promote regression or eradication of the malignancy without, or with minimal, adverse events. Clinical trial data have pushed the development of cancer vaccines forward, and the US Food and Drug Administration authorized the first therapeutic cancer vaccine. In the present review, we discuss the various types of cancer vaccines and different approaches for the development of therapeutic cancer vaccines, along with the current state of knowledge and future prospects. We also discuss how tumor-induced immune suppression limits the effectiveness of therapeutic vaccinations, and strategies to overcome this barrier to design efficacious, long-lasting anti-tumor immune responses in the generation of vaccines.

Unlocking therapeutic potential: integration of drug repurposing and immunotherapy for various disease targeting.

Drug repurposing, also known as drug repositioning, entails the application of pre-approved or formerly assessed drugs having potentially functional therapeutic amalgams for curing various disorders or disease conditions distinctive from their original remedial indication. It has surfaced as a substitute for the development of drugs for treating cancer, cardiovascular diseases, neurodegenerative disorders, and various infectious diseases like Covid-19. Although the earlier lines of findings in this area were serendipitous, recent advancements are based on patient centered approaches following systematic, translational, drug targeting practices that explore pathophysiological ailment mechanisms. The presence of definite information and numerous records with respect to beneficial properties, harmfulness, and pharmacologic characteristics of repurposed drugs increase the chances of approval in the clinical trial stages. The last few years have showcased the successful emergence of repurposed drug immunotherapy in treating various diseases. In this light, the present review emphasises on incorporation of drug repositioning with Immunotherapy targeted for several disorders.

Efficacy of Bioactive Compounds in the Regulation of Metabolism and Pathophysiology in Cardiovascular Diseases.

PURPOSE OF REVIEW: An imbalance in reactive oxygen species (ROS) homeostasis can wreak damage to metabolic and physiological processes which can eventually lead to an advancement in cardiovascular diseases (CVD). Mitochondrial dysfunction is considered as a key source of ROS. The purpose of the current review is to concisely discuss the role of bioactive compounds in the modulation of cardiovascular metabolism and their potential application in the management of cardiovascular diseases. RECENT FINDINGS: Recently, it has been shown that bioactive compounds exhibit immunomodulatory function by regulating inflammatory pathways and ROS homeostasis. It has also been reported that bioactive compounds regulate mitochondria dynamics, thus modulating the autophagy and energy metabolism in the cells. In the present article, we have discussed the roles of different bioactive compounds in the modulation of different inflammatory drivers. The functional properties of bioactive compounds in mitochondrial dynamics and its impact on cardiac disease protection have been briefly summarized. Furthermore, we have also discussed various aspects of bioactive compounds with respect to metabolism, immune modulation, circadian rhythm, and its impact on CVD's pathophysiology.

A rat model of polymicrobial infection in full-thickness excision wounds.

AIM: A reproducible animal model is required to study the pathophysiology of wound infections and for development of effective therapeutic interventions. The objective of this study was to produce an infected skin wound model utilizing the cecal microbiota in non-immunocompromised rats. MATERIALS AND METHODS: An excision wound was created on the dorsal surface of rats and inoculated with different concentration of cecal slurry (CS). Wound progression was investigated macroscopically by wound scoring and imaging. The rats were sacrificed on day 6 and microbial load, myeloperoxidase activity, histopathology, and scanning electron microscopy (SEM) were performed in wound tissue. RESULTS: Inoculation of CS into excision wounds caused significantly (p < 0.05) delayed wound healing in comparison to non-infected wounds as revealed by slow wound closure (9.1 to 12.83%). A significant (p < 0.05) difference in wound score was observed between the infected and non-infected wounds. A significantly (p < 0.05) high microbial load (~10 9 CFU/gm) was observed in infected wound which was supported by the presence of intensive bacterial colonization with sparse development of amorphous material on wound tissue during SEM analysis. A maximum increase of 1.76-fold in myeloperoxidase activity was observed in the infected wounds in comparison to non-infected wounds. Histopathology revealed increased amount of cellular infiltration, hematoma formation, and presence of bacterial aggregates in deep tissues. CONCLUSION: The study reports a reproducible and relevant clinical model of wound infection where cecal microbiota was used as a source of infection. This model can provide a suitable platform for evaluation of new therapeutic interventions.

Topical application of Jatyadi Ghrita and Jatyadi Taila accelerates wound healing in Sprague-Dawley rats: a study in gamma-radiation-induced skin wound model.

PURPOSE: Radiation-induced skin wounds/dermatitis can occur due to therapeutic, occupational, or accidental exposure to ionizing radiation. This study investigated the therapeutic efficacy of standardized Ayurvedic formulations [Jatyadi ghrita (JG) and Jatyadi taila (JT)] against 60Co-γ-radiation-induced acute skin wounds in rats. MATERIAL AND METHODS: Animal's [Sprague-Dawley rats (200 ± 20 g)] flanked skin was locally exposed to 45 Gy radiation (R45Gy) in Cobalt-60-teletherapy unit (Bhabhatron) to generate radiation wounds. JG and JT were applied topically twice daily on wounds from day 14 onwards after appearance of moist desquamation and wound healing efficacy was observed for a period of 42 days. RESULTS: R45Gy induced significant time dependent changes in rat's skin with erythema on day 7 followed by dry and moist desquamation. JG and JT application significantly (p < .001) reduced skin damage score, wound area (92% and 97% respectively on day 42), and bacterial load, when compared with R45Gy and showed better efficacy than sucralfate and betamethasone (positive controls). Formulations significantly reduced lipid peroxidation and enhanced antioxidant defenses, reduced inflammatory infiltrates and collagen fibers deposition as evident by decreased myeloperoxidase and hydroxyproline levels, and also reduced transforming growth factor-beta 1 (TGF-ß1) expression. Further, histology revealed reduced epidermal hyperplasia and dermal thinning with improved densities of hair follicles. Formulations were found to be nontoxic on 28 days application. CONCLUSIONS: The results demonstrated that JG and JT accelerated wound healing in irradiated skin tissue by faster re-epithelialization; reducing inflammation, collagen fibers deposition, and TGF-ß1 expression, indicated their potential human application in countering radiation wounds.

Analysis of the surface density and reactivity of perfluorophenylazide and the impact on ligand immobilization.

Perfluorophenylazide (PFPA) chemistry is a novel method for tailoring the surface properties of solid surfaces and nanoparticles. It is general and versatile, and has proven to be an efficient way to immobilize graphene, proteins, carbohydrates, and synthetic polymers. The main thrust of this work is to provide a detailed investigation on the chemical composition and surface density of the PFPA tailored surface. Specifically, gold surfaces were treated with PFPA-derivatized (11-mercaptoundecyl)tetra(ethylene glycol) (PFPA-MUTEG) mixed with 2-[2-(2-mercaptoethoxy)ethoxy]ethanol (MDEG) at varying solution mole ratios. Complementary analytical techniques were employed to characterize the resulting films including Fourier transform infrared spectroscopy to detect fingerprints of the PFPA group, x-ray photoelectron spectroscopy and ellipsometry to study the homogeneity and uniformity of the films, and near edge x-ray absorption fine structures to study the electronic and chemical structure of the PFPA groups. Results from these studies show that the films prepared from 90:10 and 80:20 PFPA-MUTEG/MDEG mixed solutions exhibited the highest surface density of PFPA and the most homogeneous coverage on the surface. A functional assay using surface plasmon resonance with carbohydrates covalently immobilized onto the PFPA-modified surfaces showed the highest binding affinity for lectin on the PFPA-MUTEG/MDEG film prepared from a 90:10 solution.

Synthetic polymer nanoparticle-polysaccharide interactions: a systematic study.

The interaction between synthetic polymer nanoparticles (NPs) and biomacromolecules (e.g., proteins, lipids, and polysaccharides) can profoundly influence the NPs fate and function. Polysaccharides (e.g., heparin/heparin sulfate) are a key component of cell surfaces and the extracelluar matrix and play critical roles in many biological processes. We report a systematic investigation of the interaction between synthetic polymer nanoparticles and polysaccharides by ITC, SPR, and an anticoagulant assay to provide guidelines to engineer nanoparticles for biomedical applications. The interaction between acrylamide nanoparticles (~30 nm) and heparin is mainly enthalpy driven with submicromolar affinity. Hydrogen bonding, ionic interactions, and dehydration of polar groups are identified to be key contributions to the affinity. It has been found that high charge density and cross-linking of the NP can contribute to high affinity. The affinity and binding capacity of heparin can be significantly diminished by an increase in salt concentration while only slightly decreased with an increase of temperature. A striking difference in binding thermodynamics has been observed when the main component of a polymer nanoparticle is changed from acrylamide (enthalpy driven) to N-isopropylacryalmide (entropy driven). This change in thermodynamics leads to different responses of these two types of polymer NPs to salt concentration and temperature. Select synthetic polymer nanoparticles have also been shown to inhibit protein-heparin interactions and thus offer the potential for therapeutic applications.

Photogenerated carbohydrate microarrays to study carbohydrate-protein interactions using surface plasmon resonance imaging.

A photochemical strategy to generate carbohydrate microarrays on flat sensor surfaces, and to study the protein-binding effects of these arrays by surface plasmon resonance imaging is described. The approach was validated using a panel of carbohydrate-binding proteins. The coupling agents, thiol-functionalized perfluorophenyl azides, allow the covalent attachment of underivatized carbohydrates to gold surfaces by a fast photochemical reaction. Carbohydrate microarrays composed of 3,6-di-O-(α-D-mannopyranosyl)-D-mannopyranose (Man3), 2-O-α-D-mannopyranosyl-D-mannopyranose (Man2), D-mannose (Man), D-glucose (Glc), and D-galactose (Gal) were constructed, and the binding studies were carried out in real-time using surface plasmon resonance imaging. Results showed that the immobilized carbohydrate ligands retained their binding affinities with lectins, the rank order of which was consistent with that of the free ligands in solution. The detection limit of Man3, Man2, Man, and Glc with the lectin Concanavalin A was measured to be 0.29 nM, 0.18 nM, 0.61 nM, and 3.1 nM, respectively. In addition, soybean agglutinin and Griffonia simplicifolia lectin II were tested on the array, and the results were consistent with the binding selectivity of these lectins with the carbohydrate ligands.

Differential pulse voltammetric determination of methylprednisolone in pharmaceuticals and human biological fluids.

Electrochemical behaviour of methylprednisolone (MP) at the fullerene-C60-modified glassy carbon electrode has been investigated using differential pulse voltammetry. The experimental results suggest that the modified electrode exhibits electrocatalytic effect on the oxidation of MP resulting in a marked enhancement of the peak current response. Under the selected conditions, the oxidation peak current was linearly dependent on the concentration of MP in the range 5.0 nM-1.0 microM with a sensitivity of 0.0107 microA microM(-1). The detection limit was estimated to be 5.6 nM. The electrode showed good sensitivity, selectivity, stability and reproducibility. In addition, the developed method was satisfactorily applied to the determination of MP in pharmaceutical formulations and human serum and urine samples without any necessity for sample treatment or time-consuming extraction steps prior to the analysis. GC-MS method was used to cross-validate the results obtained for the quantitative estimation of MP in biological fluids and the results showed approximately 2% deviation to those obtained using the proposed method.

Determination of methylprednisolone acetate in biological fluids at gold nanoparticles modified ITO electrode.

The electrochemical behavior of a corticosteroid methylprednisolone (MP), used for doping, has been studied at gold nanoparticles modified indium tin oxide (nanoAu/ITO) electrode. The nanoAu/ITO electrode exhibited an effective catalytic response towards its oxidation and lowered its oxidation potential by approximately 127 mV when compared with bare ITO electrode. Oxidation of MP has been carried out in phosphate containing electrolyte in the pH range 2.13-10.00 and a well-defined oxidation peak was noticed. Linear concentration curves are obtained over the concentration range 0.01-1.0 microM with a detection limit of 2.68 x 10(-7)M at nanoAu/ITO electrode. A diffusion coefficient of 2.36 x 10(-6)cm(2)/s is calculated for MP using chronoamperometry. The proposed method is effectively applied to detect the concentration of MP in pharmaceutical formulations and human blood plasma and urine samples. A comparison of MP concentration determined in blood plasma and urine by the proposed method and GC/MS indicated that the results are essentially similar. It is believed that the method will be useful in determining this drug in case of doping.

Simultaneous determination of guanosine and guanosine-5'-triphosphate in biological sample using gold nanoparticles modified indium tin oxide electrode.

A nanogold modified indium tin oxide (ITO) electrode was used for the simultaneous determination of guanosine and GTP at pH 7.2. The electrode exhibited an effective catalytic response towards their oxidation and lowered the oxidation potential of guanosine by approximately 120 mV and GTP by approximately 183 mV. Linear concentration curves were obtained for guanosine with a detection limit of 9.8 x 10(-8) M and 5.5 x 10(-8) M for GTP. The concentration of guanosine and GTP were also estimated in the human blood plasma samples using gold nanoparticles modified ITO electrode with good reproducibility.

Voltammetric determination of anabolic steroid nandrolone at gold nanoparticles modified ITO electrode in biological fluids.

The electrochemical behavior of nandrolone decanoate (ND) at gold nanoparticles modified indium tin oxide (ITO) electrode was investigated. Oxidation of ND has been carried out in phosphate containing supporting electrolyte in the pH range 2.1-9.2 and a well-defined oxidation peak was noticed. The peak potential (E(p)) of the oxidation peak decreases linearly with increasing pH. Linear calibration curve is obtained over the nandrolone decanoate concentration range of 50nM to 1.5muM at pH 7.2 with a detection limit of 1.36x10(-7)M. The proposed method is effectively applied to detect the concentration of ND in human blood serum and urine samples after 24 and 72h of intramuscular injection. The method is rapid and does not require any pre-treatment.

Oxidation chemistry of adenosine-3', 5'-cyclic monophosphate at pyrolytic graphite eletrode.

The voltammetric oxidation of adenosine-3',5'-cyclic monophosphate (3',5'-CAMP) has been studied in the pH range 2.13-10.07 using pyrolytic graphite electrode (PGE). Voltammetric, coulometric, spectral studies, and product characterization indicate that the oxidation of 3',5'-CAMP occurs in an EC reaction involving a 6H+, 6e process at pH 7.24. Electrooxidized products were seperated by semipreparative high performance liquid chromatography (HPLC) and were characterized by mp, 1HNMR, FTIR, and GC-mass as allantoin cyclic ribose monophosphate and 3 dimers as the major products. A detailed interpretation of the redox mechanism of 3',5'-CAMP also has been presented to account for the formation of various products.

Investigations into the electrooxidation of guanosine-5'-triphosphate at the pyrolytic graphite electrode.

The electrochemical oxidation of guanosine-5'-triphosphate has been investigated in phosphate-containing electrolytes in the pH range 1.5-10.9 at a pyrolytic graphite electrode by cyclic sweep voltammetry, spectral studies, bulk electrolysis and related techniques. In this pH range, the oxidation occurred in a single well-defined peak (Ia). The peak potential of oxidation peaks (Ep) was found to be dependent on pH, concentration and sweep rate. The kinetics of the UV-absorbing intermediates was followed spectrophotometrically and the decay of the intermediate occurred in a pseudo-first-order reaction. The first-order rate constants for the disappearance of the UV-absorbing intermediate have also been calculated. The products of the electrode reaction were characterized by HPLC and GC/MS. A tentative mechanism for the formation of the products has also been suggested.