Anupam Guleria

In recent years, rare earth-doped gadolinium oxide (RE:Gd2O3) nanoparticles (NPs) have captured the attention of biomedical researchers as potent contrast agents (CAs) to enhance the diagnostic accuracy of magnetic resonance imaging (MRI), while simultaneously enabling high sensitivity fluorescence imaging (FI). However, there remains a scarcity of studies demonstrating their successful utilization as dual-modal MRI-FI contrast agents. In this study, a series of paramagnetic gadolinium oxide (Gd2O3) NPs doped with varying europium (Eu3+) concentrations (0.5 to 10 M%) were synthesized using a low-temperature polyol-mediated route assisted by hydrogen peroxide (H2O2). The influence of Eu3+ doping concentration on crystallinity, phase, morphology, magnetic properties and MR relaxometric properties was investigated systematically. X-ray diffraction (XRD) analysis confirmed a cubic crystalline phase for both undoped and Eu-doped Gd2O3 nanoparticles. A systematic decrease in particle size was observed for Eu-doped Gd2O3 with an increase in Eu3+concentration, which was further validated by transmission electron microscopy (TEM) imaging and could be attributed to dopant-induced lattice micro-strain. Fluorescence microscopy of human embryonic kidney (HEK) cells incubated with Eu-doped Gd2O3 NPs revealed efficient cellular uptake and characteristic red emission arising from the Eu3+ 5D0 → 7F2 transition, confirming their fluorescence imaging capability. MRI relaxometric measurements revealed a significant increase in longitudinal (r1) relaxivity for Eu-doped Gd2O3 NPs with an increase in Eu3+dopant concentration. The longitudinal relaxivity has been found to be increased significantly from 5.88 s-1mM-1 for undoped Gd2O3 NPs to 9.17 s-1mM-1 for 10 M% Eu-doped Gd2O3 NPs, corresponding to an ~55% improvement in MRI contrast efficiency. Overall, polyethylene glycol-200 (PEG200)-capped Eu-doped Gd2O3 NPs, within the investigated particle-size regime, exhibit strong potential as bimodal contrast agents for MRI and fluorescence imaging.

Methicillin-resistant Staphylococcus aureus (MRSA) infections pose serious treatment challenges, particularly in peritoneal dialysis patients due to their increased susceptibility to infections and antibiotic resistance. Vancomycin, a standard antibiotic treatment for MRSA, is currently being compromised due to the evolution of multidrug-resistant microorganisms. Therefore, there is an urgent need for alternative therapeutic strategies to obstruct the increasing antibiotic resistance and bacterial biofilm formation. The present study explores curcumin, a natural bioactive compound possessing antimicrobial and anti-inflammatory properties, as a potential therapeutic for MRSA. The standard optical density method confirmed the antibacterial activity of curcumin against Staphylococcus aureus (MTCC-3160). Furthermore, we investigated the impact of curcumin on bacterial metabolism. Metabolic analysis of S. aureus culture media over a 20-h period revealed that curcumin exerts bacteriostatic effects by inhibiting specific metabolic pathways, potentially linked to energy and sugar metabolism. Furthermore, the synergistic effect of curcumin combined with vancomycin was assessed against 20 clinical MRSA strains using the broth microdilution method. The results demonstrated that curcumin enhanced the antibacterial activity of vancomycin in 17 strains by reducing its minimum inhibitory concentration (MIC) significantly. The MIC of curcumin and vancomycin has been found to decrease significantly when used in combination, with curcumin’s MIC decreased to as low as 0.5 µg/mL and vancomycin’s MIC to 0.5 µg/mL for all strains. Synergistic effects were seen in 17 out of 20 strains, having fractional inhibitory concentration index values between 0.04 and 0.56. These findings suggest that curcumin–vancomycin combination therapy could offer an effective treatment strategy for MRSA infections which may combat antibiotic resistance and reduce treatment-related toxicity.

Magnetic nanoparticles (MNPs) are promising tools for biomedical applications, particularly in molecular imaging using magnetic resonance imaging (MRI). The unique magnetic properties of MNPs, combined with their similarity in size to biological objects, make them ideal candidates for in situ imaging probes. The present study explores the use of magnetic nanoparticles (MNPs) as contrast agents in magnetic resonance imaging (MRI) for improved diagnostic accuracy. Specifically, the study investigates the MR contrast properties of polyethylene glycol-coated gadolinium oxide nanoparticles (PEG@GONPs) in five different biological fluids. The nanoparticles were synthesized using the polyol route and their size, shape, and morphology were characterized using TEM, SEM, and FT-IR spectroscopy. The magnetic resonance (MR) relaxivity of PEG@GONPs was studied in different biologically relevant media, and results revealed highest relaxivity in plasma as compared to other media. In addition, comparative analysis of proton relaxivity of the synthesized nanoparticles was carried out with a well-known gadolinium-based contrast agent, Omniscan, in various medium. The present findings revealed that PEG@GONPs can serve as an effective contrast agent for MRI imaging in biological fluids such as plasma, which is crucial for preclinical diagnosis of specific diseases and lesions. The high relaxivity observed in plasma could be attributed to the interaction of the nanoparticles with plasma proteins, amplifying their magnetic properties which further improve their ability to produce contrast in MR images.

The magnetic resonance (MR) contrast enhancement capabilities of gadolinium oxide nanoparticles (GONPs) have high dependency on its surface chemistry- as the solution properties such as colloidal stability and hydrodynamic diameter of nanoparticles which are prime regulatory parameter for MR relaxivity, are all governed by grafting density of surface material. However, the purification of synthesized surface coated nanoparticles, without compromising the surface properties, remains a major challenge. Among the various cleaning methods, dialysis is often used to remove the unwanted by-products produced during synthesis. However, the effect of dialysis time may significantly impact the surface properties and hence, the MR contrast properties of such nano-formulations. The aim of the present study is to evaluate the effect of dialysis time on surface chemistry and MR contrast enhancement properties of GONPs by comparing the proton relaxivity data. Ultra-small polyethylene glycol (PEG)-coated GONPs with an average particle diameter of 17 nm were synthesized using polyol method. The impact of dialysis time has been investigated systematically on the size distribution, hydrophilicity, magnetic properties, polymer grafting density and relaxometric properties of the as synthesized GONPs. A significant impact of dialysis time was observed on surface chemistry and hence, on the MR relaxivity of synthesized NPs. We evidenced a dramatic decrease in the proton relaxivities of GONPs with increase in dialysis time, which correlated well with the observed decrease in the grafting density of surface polymer. The results clearly indicate that the proton relaxivity of GONPs of similar size and same coating material depends on the surface coating thickness and hydrophilicity of the coating polymer. Overall, it is essential to optimize the accurate time duration of dialysis treatment as the prolonged dialysis may have negative effect on the relaxation times and hence on MR contrast enhancement properties of GONPs. This study is a strategic pathway to fine-tune the dialysis treatment of as-synthesized surface-capped GONPs for pre-eminent MR contrast imaging.

Bacterial infections in the abdominal area are a primary cause of complications in patients with renal failure who are on peritoneal dialysis (PD). To combat such infections, Zinc Oxide (ZnO) Nanoparticles (NPs) are gaining popularity because of their well-known antibacterial characteristics. However, due to their quick accumulation and generation of bio-conjugates upon interaction with the components of PD Fluid, surface modification is required. In this context, the current study’s aim was to coat the ZnO-NPs with Silk Fibroin (SF) protein and assess their stability in PD fluid. UV-vis spectroscopy, Proton Nuclear Magnetic Resonance (1 H NMR) spectroscopy, Scanning electron microscopy (SEM) and Dynamic Light Scattering (DLS) characterisations, all validated the stability of SF-coated ZnO-NPs in PD fluid. Furthermore, SF-coated ZnO-NPs were tested as an antibacterial agent against Staphylococcus aureus, and our findings demonstrated that SF-coated ZnO-NPs significantly suppressed S. aureus activity.

Previous research suggests that literacy, specifically learning alphabetic letter-to-phoneme mappings, modifies online speech processing and enhances brain responses, as indexed by the BOLD, to speech in auditory areas associated with phonological processing (Dehaene et al., 2010). However, alphabets are not the only orthographic systems in use in the world, and hundreds of millions of individuals speak languages that are not written using alphabets. In order to make claims that literacy per se has broad and general consequences for brain responses to speech, one must seek confirmatory evidence from nonalphabetic literacy. To this end, we conducted a longitudinal fMRI study in India probing the effect of literacy in Devanagari, an abubgida, on functional connectivity and cerebral responses to speech in 91 variously literate Hindi-speaking male and female human participants. Twenty-two completely illiterate participants underwent 6 months of reading and writing training. Devanagari literacy increases functional connectivity between acoustic-phonetic and graphomotor brain areas, but we find no evidence that literacy changes brain responses to speech, either in cross-sectional or longitudinal analyses. These findings shows that a dramatic reconfiguration of the neurofunctional substrates of online speech processing may not be a universal result of learning to read, and suggest that the influence of writing on speech processing should also be investigated. SIGNIFICANCE STATEMENT It is widely claimed that a consequence of being able to read is enhanced auditory processing of speech, reflected by increased cortical responses in areas associated with phonological processing. Here we find no relationship between literacy and the magnitude of brain response to speech stimuli in individuals who speak Hindi, which is written using a nonalphabetic script, Devanagari, an abugida. We propose that the exact nature of the script under examination must be considered before making sweeping claims about the consequences of literacy for the brain. Further, we find evidence that literacy enhances functional connectivity between auditory processing areas and graphomotor areas, suggesting a mechanism whereby learning to write might influence speech perception.

The aim of the work is to explore structure-relaxivity relationship by observing transverse relaxivity enhancement in magnetic resonance imaging (MRI) of differently organized superparamagnetic complex ensembles of zinc ferrite isotropic/anisotropic nanosystems. We observe that superparamagnetic systems show a correlation of MRI-transverse relaxivity, r₂/r₁, with spatial arrangement of nanoparticles, as well as magnetic easy axes and thermal-energy-dependent anisotropy energy landscape. The presence of highly random/partially aligned easy axes with enhanced anisotropy constant leads to modulation in transverse relaxation. As a result, we achieve highest contrast efficiency in compact ensemble of isotropic nanoparticles and hollow core ensemble. Indeed, core-shell ensemble with combined effect of aligned and randomly oriented easy magnetic axes shows a reduction in MRI contrast efficiency. However, we address a hypothesis for transverse contrast efficiency where we depict the correlation among MRI-transverse contrast efficiency with structural complexity of ensembles, differently arranged primary nanoparticles/magnetic easy axes, anisotropy constant, and collective magnetic behavior. In consequence, we simplify the limitation of quantum mechanical outer-sphere diffusion model of magnetic resonance relaxivity by neglecting the contribution of magnetization and introducing an anisotropy constant contribution with complex structure landscape of easy axes.

Reactive arthritis (ReA) is an aseptic synovitis condition that often develops 2–4 weeks after a distant (extra-articular) infection with Chlamydia, Salmonella, Shigella, Campylobacter, and Yersinia species. The metabolic changes in the synovial fluid (SF) may serve as indicative markers to both improve the diagnostic accuracy and understand the underlying inflammatory pathology of ReA. With this aim, the metabolic profiles of SF collected from ReA (n = 58) and non-ReA, i.e., rheumatoid arthritis (RA, n = 21) and osteoarthritis (OA, n = 20) patients, respectively, were measured using NMR spectroscopy and compared using orthogonal partial least-squares discriminant analysis (OPLS-DA). The discriminatory metabolic features were further evaluated for their diagnostic potential using the receiver operating characteristic (ROC) curve analysis. Compared to RA, two (alanine and carnitine), and compared to OA, six (NAG, glutamate, glycerol, isoleucine, alanine, and glucose) metabolic features were identified as diagnostic biomarkers. We further demonstrated the impact of ReA synovitis condition on the serum metabolic profiles through performing a correlation analysis. The Pearson rank coefficient (r) was estimated for 38 metabolites (profiled in both SF and serum samples obtained in pair from ReA patients) and was found significantly positive for 71% of the metabolites (r ranging from 0.17 to 0.87).

Objectives: Differentiating smoldering disease activity from weakness due to fatty replacement of atrophied muscle can often be a challenge in the idiopathic inflammatory myositis (IIM). We aimed to identify the metabolic disturbances associated with IIM and if these changes can aid in the assessment of disease activity.Methods: Metabolic profiles of sera (N = 99) and muscle (N = 21) from patients with IIM (ACR‐EULAR criteria) were compared with healthy control (HC) samples (N = 75 for serum and N = 12 for muscle tissues) employing 800 MHz NMR (Nuclear Magnetic Resonance) spectroscopy. Metabolic disparity between IIM and HC was established based on Partial Least Squares Discriminant Analysis (PLS‐DA) and the discriminatory metabolites were identified based on variable importance in projection (VIP) statistics (P‐value < .05, corrected for false discovery rate (FDR)).Results: Serum metabolomics profiles were distinctive in IIM as compared to HC, with a visible shift to anaerobic metabolism (increased lactate, low glucose), oxidative defect (high Phenylalanine/tyrosine), decreased muscle mass (low serum creatinine), increased muscle catabolism (increased branched‐chain amino acids), and dyslipidemia (higher lipids, higher very low‐density lipoprotein [VLDL]/low‐density lipoprotein [LDL] ratio, lower polyunsaturated fatty acid [PUFA]). The sera of active IIM patients were characterized by anaerobic metabolism (low glucose), loss of muscle mass (low creatinine, amino acids), and oxidative defect (high Phenylalanine/tyrosine). Three metabolites (isopropanol, succinate, and glycine) were distinctive in muscle tissue metabolomics. NMR‐based serum metabolic disparity was lacking between different clinical subsets of IIM.Conclusion: Serum and muscle tissue metabolomics have the potential to distinguish (a) IIM from HC and (b) active IIM from inactive IIM irrespective of disease subtype.

Hepatocellular carcinoma (HCC) is a major cause of concern as it has substantial morbidity associated with it. Previous reports have ascertained the antiproliferative activity of imatinib mesylate (IMS) against diverse types of carcinomas, but limited bioavailability has also been reported. The present study envisaged optimized IMS-loaded lactoferrin (LF)-modified PEGylated liquid crystalline nanoparticles (IMS-LF-LCNPs) for effective therapy of IMS to HCC via asialoglycoprotein receptor (ASGPR) targeting. Results displayed that IMS-LF-LCNPs presented an optimum particle size of 120.40 ± 2.75 nm, a zeta potential of +12.5 ± 0.23 mV, and 73.94 ± 2.69% release. High-resolution transmission electron microscopy and atomic force microscopy were used to confirm the surface architecture of IMS-LF-LCNPs. The results of cytotoxicity and 4,6-diamidino-2-phenylindole revealed that IMS-LF-LCNPs had the highest growth inhibition and significant apoptotic effects. Pharmacokinetics and biodistribution studies showed that IMS-LF-LCNPs have superior pharmacokinetic performance and targeted delivery compared to IMS-LCNPs and plain IMS, which was attributed to the targeting action of LF that targets the ASGPR in hepatic cells. Next, our in vivo experiment established that the HCC environment existed due to suppression of BAX, cyt c, BAD, e-NOS, and caspase (3 and 9) genes, which thus owed upstream expression of Bcl-xl, iNOS, and Bcl-2 genes. The excellent therapeutic potential of IMS-LF-LCNPs began the significant stimulation of caspase-mediated apoptotic signals accountable for its anti-HCC prospect. ¹H nuclear magnetic resonance (serum) metabolomics revealed that IMS-LF-LCNPs are capable of regulating the disturbed levels of metabolites linked to HCC triggered through N-nitrosodiethylamine. Therefore, IMS-LF-LCNPs are a potentially effective formulation against HCC.