How Does Literacy Affect Speech Processing? Not by Enhancing Cortical Responses to Speech, But by Promoting Connectivity of Acoustic-Phonetic and Graphomotor Cortices.

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.

Clinical metabolomics by NMR revealed serum metabolic signatures for differentiating sarcoidosis from tuberculosis.

BACKGROUND: Pulmonary sarcoidosis (SAR) and tuberculosis (TB) are two granulomatous lung-diseases and often pose a diagnostic challenge to a treating physicians. OBJECTIVE: The present study aims to explore the diagnostic potential of NMR based serum metabolomics approach to differentiate SAR from TB. MATERIALS AND METHOD: The blood samples were obtained from three study groups: SAR (N = 35), TB (N = 28) and healthy normal subjects (NC, N = 56) and their serum metabolic profiles were measured using 1D 1H CPMG (Carr-Purcell-Meiboom-Gill) NMR spectra recorded at 800 MHz NMR spectrometer. The quantitative metabolic profiles were compared employing a combination of univariate and multivariate statistical analysis methods and evaluated for their diagnostic potential using receiver operating characteristic (ROC) curve analysis. RESULTS: Compared to SAR, the sera of TB patients were characterized by (a) elevated levels of lactate, acetate, 3-hydroxybutyrate (3HB), glutamate and succinate (b) decreased levels of glucose, citrate, pyruvate, glutamine, and several lipid and membrane metabolites (such as very-low/low density lipoproteins (VLDL/LDL), polyunsaturated fatty acids, etc.). CONCLUSION: The metabolic disturbances not only found to be well in concordance with various previous reports, these further demonstrated very high sensitivity and specificity to distinguish SAR from TB patients suggesting serum metabolomics analysis can serve as surrogate method in the diagnosis and clinical management of SAR.

Structure-Correlated Magnetic Resonance Transverse Relaxivity Enhancement in Superparamagnetic Ensembles with Complex Anisotropy Landscape.

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.

NMR-Based Metabolomics Revealed the Underlying Inflammatory Pathology in Reactive Arthritis Synovial Joints.

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).

Fabrication of Imatinib Mesylate-Loaded Lactoferrin-Modified PEGylated Liquid Crystalline Nanoparticles for Mitochondrial-Dependent Apoptosis in Hepatocellular Carcinoma.

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.

NMR-based clinical metabolomics revealed distinctive serum metabolic profiles in patients with spondyloarthritis.

Spondyloarthritis (SpA) is a common rheumatic disorder of the young, marred by delay in diagnosis, and paucity of biomarkers of disease activity. The present study aimed to explore the potential of serum metabolic profiling of patients with SpA to identify biomarker for the diagnosis and assessment of disease activity. The serum metabolic profiles of 81 patients with SpA were compared with that of 86 healthy controls (HCs) using nuclear magnetic resonance (NMR)-based metabolomics approach. Seventeen patients were followed up after 3 months of standard treatment, and paired sera were analyzed for effects of therapy. Comparisons were done using the multivariate partial least squares discriminant analysis (PLS-DA), and the discriminatory metabolic entities were identified based on variable importance in projection (VIP) statistics and further evaluated for statistical significance (p value < 0.05). We found that the serum metabolic profiles differed significantly in SpA as compared with HCs. Compared with HC, the SpA patients were characterized by increased serum levels of amino acids, acetate, choline, N-acetyl glycoproteins, Nα-acetyl lysine, creatine/creatinine, and so forth and decreased levels of low-/very low-density lipoproteins and polyunsaturated lipids. PLS-DA analysis also revealed metabolic differences between axial and peripheral SpA patients. Further metabolite profiles were found to differ with disease activity and treatment in responding patients. The results presented in this study demonstrate the potential of serum metabolic profiling of axial SpA as a useful tool for diagnosis, prediction of peripheral disease, assessment of disease activity, and treatment response.

Metabolomics analysis revealed significantly higher synovial Phe/Tyr ratio in reactive arthritis and undifferentiated spondyloarthropathy.

OBJECTIVE: To compare the synovial phenylalanine/tyrosine (Phe/Tyr) ratio between ReA/uSpA and RA and OA by NMR spectroscopy. METHODS: Paired SF and serum of 30 patients with ReA/uSpA were collected and analysed using a 1D 1H Carr Purcell Meiboom Gill NMR spectra recorded on 800 MHz NMR spectrometer equipped with a TCI Cryoprobe (at 300 K). Phe and Tyr were quantified. SF from 25 patients with RA fulfilling ACR classification criteria and 21 patients with OA were taken as inflammatory and non-inflammatory controls. RESULTS: The synovial Phe/Tyr ratio was significantly higher in ReA/uSpA compared with RA and OA. Synovial Phe/Tyr ratios were comparable in RA and OA patients. Compared with serum, the Phe/Tyr was significantly higher in the SF in ReA/uSpA. The Phe/Tyr ratio was also found to be positively correlated between serum and SF samples, with a regression coefficient (r2) of 0.287. CONCLUSIONS: This NMR-based metabolomics study demonstrates that the synovial Phe/Tyr ratio is specifically elevated in ReA/uSpA.

Nuclear magnetic resonance-based targeted profiling of urinary acetate and citrate following cyclophosphamide therapy in patients with lupus nephritis.

OBJECTIVE: Metabolomics, the study of global alterations in small metabolites, is a useful tool to look for novel biomarkers. Recently, we reported a reprogramming of the serum metabolomic profile by nuclear magnetic resonance (NMR) spectroscopy following treatment in lupus nephritis (LN). This study aimed to compare the urine excretory levels of citrate and acetate in patients with biopsy-proven LN before and six months after cyclophosphamide induction therapy and to evaluate their correlation with the Systemic Lupus Erythematosus Disease Activity Index 2K (SLEDAI 2K) and renal SLEDAI. METHODS: Urine obtained from LN patients (N = 18, 16 female) at diagnosis and six months following induction therapy with cyclophosphamide and healthy controls (HC; N = 18, median age = 35 years, all female) were stored at -80°C. Metabolomic profiling was done using high resolution 800 MHz 1D 1H NMR spectroscopy. The urinary ratio of metabolites was calculated as (metabolite×1000)/creatinine. Disease activity was measured using the SLEDAI. Metabolomic profiles were compared between groups and correlated with clinical parameters. RESULTS: Compared to HC, LN patients had significantly lower median urinary citrate/creatinine levels (LN = 18.26, range 12.80-27.62; HC = 107.7, range 65.39-138.4; p < 0.0001) which significantly increased after six months of cyclophosphamide treatment (51.05, range 11.51-170.2; p = 0.03). LN patients also differed from HC by having a higher mean urinary acetate/creatinine ratio (LN = 17.44, range 11.6-32.7; HC = 9.61, range 7.97-13.71; p = 0.054) with a non-significant fall in values after six months of treatment. The Area under curve for differentiating LN from HC for urinary citrate was 0.9136, and urinary acetate was 0.6883. The urinary acetate levels correlated with SLEDAI (r = 0.337, p = 0.048). Urinary citrate levels correlated positively with C3 (r = 0.362, p = 0.03) and negatively with urine protein/creatinine (r = -0.346, p = 0.039). CONCLUSIONS: Urinary citrate, which reflects dampened aerobic glycolysis and oxidative phosphorylation, improved significantly and is a potential non-invasive biomarker for diagnosis and monitoring treatment response in LN.

NMR-Based Serum Metabolomics Revealed Distinctive Metabolic Patterns in Reactive Arthritis Compared with Rheumatoid Arthritis.

Reactive arthritis (ReA) is a member of seronegative spondyloarthropathy (SSA), which involves an acute/subacute onset of asymmetrical lower limb joint inflammation weeks after a genitourinary/gastrointestinal infection. The diagnosis is clinical because it is difficult to culture the microbes from synovial fluid. Arthritis patients with a similar clinical picture but lapsed history of an immediate preceding infection that do not fulfill the diagnostic criteria of other members of SSA, such as ankylosing spondylitis, psoriatic arthritis, and arthritis associated with inflammatory bowel disease, are labeled as peripheral undifferentiated spondyloarthropathy (uSpA). Both ReA and uSpA patients show a strong association with class I major histocompatibility complex allele, HLA-B27, and a clear association with an infectious trigger; however, the disease mechanism is far from clear. Because the clinical picture is largely dominated by rheumatoid-arthritis (RA)-like features including elevated levels of inflammatory markers (such as ESR, CRP, etc.), these overlapping symptoms often confound the clinical diagnosis and represent a clinical dilemma, making treatment choice more generalized. Therefore, there is a compelling need to identify biomarkers that can support the diagnosis of ReA/uSpA. In the present study, we performed NMR-based serum metabolomics analysis and demonstrated that ReA/uSpA patients are clearly distinguishable from controls and further that these patients can also be distinguished from the RA patients based on the metabolic profiles, with high sensitivity and specificity. The discriminatory metabolites were further subjected to area under receiver operating characteristic curve analysis, which led to the identification of four metabolic entities (i.e., valine, leucine, arginine/lysine, and phenylalanine) that could differentiate ReA/uSpA from RA.

Metabolite assignment of ultrafiltered synovial fluid extracted from knee joints of reactive arthritis patients using high resolution NMR spectroscopy.

Currently, there are no reliable biomarkers available that can aid early differential diagnosis of reactive arthritis (ReA) from other inflammatory joint diseases. Metabolic profiling of synovial fluid (SF)-obtained from joints affected in ReA-holds great promise in this regard and will further aid monitoring treatment and improving our understanding about disease mechanism. As a first step in this direction, we report here the metabolite specific assignment of 1 H and 13 C resonances detected in the NMR spectra of SF samples extracted from human patients with established ReA. The metabolite characterization has been carried out on both normal and ultrafiltered (deproteinized) SF samples of eight ReA patients (n = 8) using high-resolution (800 MHz) 1 H and 1 H─13 C NMR spectroscopy methods such as one-dimensional 1 H CPMG and two-dimensional J-resolved1 H NMR and homonuclear 1 H─1 H TOCSY and heteronuclear1 H─13 C HSQC correlation spectra. Compared with normal SF samples, several distinctive 1 H NMR signals were identified and assigned to metabolites in the 1 H NMR spectra of ultrafiltered SF samples. Overall, we assigned 53 metabolites in normal filtered SF and 64 metabolites in filtered pooled SF sample compared with nonfiltered SF samples for which only 48 metabolites (including lipid/membrane metabolites as well) have been identified. The established NMR characterization of SF metabolites will serve to guide future metabolomics studies aiming to identify/evaluate the SF-based metabolic biomarkers of diagnostic/prognostic potential or seeking biochemical insights into disease mechanisms in a clinical perspective.

NMR-Based Serum Metabolomics of Patients with Takayasu Arteritis: Relationship with Disease Activity.

Takayasu arteritis (TA) is a large vessel vasculitis of unknown pathogenesis. Assessment of disease activity is a challenge, and there is an unmet need for relevant biomarker(s). In our previous study, NMR based serum metabolomics had revealed distinctive metabolic signatures in TA patients compared with age/sex matched healthy controls and systemic lupus erythematosus (SLE). In this study we investigate whether the metabolites correlate with disease activity. Patients with TA fulfilling American College of Rheumatology (ACR) criteria were enrolled, and disease activity was assessed using Indian Takayasu Clinical Activity Score using acute phase reactant-erythrocyte sedimentation rate [ITAS-A (ESR)]. Sera were analyzed using 800 MHz NMR spectrometer to identify metabolites [based on partial least squares discriminant analysis (PLS-DA) VIP (variable importance in projection) score > 1.0 and permutation test, p-value <0.01]. 45 active and 53 inactive TA patients with median age 27 [(IQR) 22-35 years] and 27 [(IQR) 23-37 years], female to male ratio 3.5:1 and 4.9:1, and median duration of illness 5 [(IQR) 2-9 years] and 3 [(IQR) 1-6 years], respectively, were enrolled. The key metabolites with highest discriminatory potential in active TA (ITAS-A ≥ 4) were glutamate and N-acetyl glycoprotein (NAG), both elevated, with area under the curve 0.775 and 0.769 ( p-value <0.001). On follow up assessment, metabolic spectra started to differ with change in disease activity. This large cohort of patients revealed metabolic profiles discriminating between clinically active and inactive TA patients. It suggests glutamate and NAG have strong potential as biomarkers for disease activity in TA and may serve as a guide to therapy. We are now working to further validate these results in longitudinal studies.

NMR-Based Serum Metabolomics Reveals Reprogramming of Lipid Dysregulation Following Cyclophosphamide-Based Induction Therapy in Lupus Nephritis.

Lupus nephritis (LN) is a major cause of morbidity and mortality in lupus. Renal biopsy is the gold standard for classification of nephritis, but because of its impracticality, new approaches for improving patient prognostication and monitoring treatment efficacy are needed. We aimed to evaluate the potential of metabolic profiling in identifying biomarkers to distinguish disease and monitor treatment efficacy in patients with LN. Serum samples from patients with LN ( n = 18) were profiled on NMR-based metabolomics platforms at diagnosis and after 6 months of treatment. LN patients had a different metabolomic fingerprint as compared with healthy controls, with increased lipoproteins and lipids and reduced acetate and amino acids. Using multivariate statistical analysis, we found that the metabolic changes observed in naïve LN patients at diagnosis displayed a variation in the opposite direction upon responding to treatment. Increased levels of lipid metabolites including low- and very-low-density lipoproteins (LDL/VLDL) in LN patients significantly decreased after 6 months of treatment, whereas the serum levels of acetate increased. These levels correlated significantly with SLE Disease Activity Index (SLEDAI 2K), renal SLEDAI, and serum C3 and C4 levels. The result presented in this pilot longitudinal study revealed the reprogramming of metabolome in LN patients on immunosuppressive therapy using NMR-based metabolomics, and thus this approach may be used to monitor the response to treatment.

NMR-based urinary profiling of lactulose/mannitol ratio used to assess the altered intestinal permeability in acute on chronic liver failure (ACLF) patients.

The article presents a simplified NMR-based protocol for urinary profiling of lactulose/mannitol ratio (LMR) and demonstrates here its utility to assess increased intestinal permeability (IP) in patients with acute on chronic liver failure (ACLF). ACLF is a serious clinical complication associated with chronic liver disease (cirrhosis). The major risk factor in its development is increased IP ('leaky gut'), which has been linked to disease progression and to infectious complications. However, IP has seldom been investigated in patients with ACLF, even though patients frequently report gastrointestinal disorders and associated complications. To this end, we first optimized the NMR-based targeted profiling of urinary metabolites (i.e. actulose, mannitol, and creatinine) and subsequently used this resulted protocol (a) first to evaluate the altered IP in ACLF patients and then (b) to explore its utility for monitoring the treatment response in these patients. The normal profiles were obtained for 7 age and sex matched healthy volunteers. The results revealed that the urinary LMR excretion was significantly higher in ACLF patients compared to normal controls (median ~0.7, range (0.12-2.84), vs median ~0.11, range (0.02-0.28), p < 0.001) suggesting that the ACLF patients' exhibit altered IP. However, the LMR excretion in six clinically improved follow-up ACLF patients was comparable to normal controls indicating restored IP after the treatment. The protocol-as demonstrated here with ACLF-is equally applicable for evaluating IP or mucosal barrier function in other intestinal disorders with reasonable sensitivity and specificity, highlighting its general utility. Copyright © 2016 John Wiley & Sons, Ltd.

NMR-Based Serum Metabolomics Discriminates Takayasu Arteritis from Healthy Individuals: A Proof-of-Principle Study.

Takayasu arteritis (TA) is a debilitating, systemic disease that involves the aorta and large arteries in a chronic inflammatory process that leads to vessel stenosis. Initially, the disease remains clinically silent (or remains undetected) until the patients present with vascular occlusion. Therefore, new methods for appropriate and timely diagnosis of TA cases are needed to start proper therapy on time and also to monitor the patient's response to the given treatment. In this context, NMR-based serum metabolomic profiling has been explored in this proof-of-principle study for the first time to determine characteristic metabolites that could be potentially helpful for diagnosis and prognosis of TA. Serum metabolic profiling of TA patients (n = 29) and healthy controls (n = 30) was performed using 1D (1)H NMR spectroscopy, and possible biomarker metabolites were identified. Using projection to least-squares discriminant analysis, we could distinguish TA patients from healthy controls. Compared to healthy controls, TA patients had (a) increased serum levels of choline metabolites, LDL cholesterol, N-acetyl glycoproteins (NAGs), and glucose and (b) decreased serum levels of lactate, lipids, HDL cholesterol, and glucogenic amino acids. The results of this study are preliminary and need to be confirmed in a prospective study.

Neuro-cognitive aspects of "OM" sound/syllable perception: A functional neuroimaging study.

The sound "OM" is believed to bring mental peace and calm. The cortical activation associated with listening to sound "OM" in contrast to similar non-meaningful sound (TOM) and listening to a meaningful Hindi word (AAM) has been investigated using functional magnetic resonance imaging (MRI). The behaviour interleaved gradient technique was employed in order to avoid interference of scanner noise. The results reveal that listening to "OM" sound in contrast to the meaningful Hindi word condition activates areas of bilateral cerebellum, left middle frontal gyrus (dorsolateral middle frontal/BA 9), right precuneus (BA 5) and right supramarginal gyrus (SMG). Listening to "OM" sound in contrast to "non-meaningful" sound condition leads to cortical activation in bilateral middle frontal (BA9), right middle temporal (BA37), right angular gyrus (BA 40), right SMG and right superior middle frontal gyrus (BA 8). The conjunction analysis reveals that the common neural regions activated in listening to "OM" sound during both conditions are middle frontal (left dorsolateral middle frontal cortex) and right SMG. The results correspond to the fact that listening to "OM" sound recruits neural systems implicated in emotional empathy.

Metabolite characterisation in peritoneal dialysis effluent using high-resolution (1) H and (1) H-(13) C NMR spectroscopy.

Metabolite analysis of peritoneal dialysis (PD) effluent may provide information regarding onset and progression of complications associated with prolonged PD therapy. In this context, the nuclear magnetic resonance detectable small metabolites of PD effluent samples were characterised using high-resolution (1) H and (1) H-(13) C NMR spectroscopy. The various spectra were recorded (at 800 MHz proton frequency) on PD effluent samples obtained after 4-h (intraperitoneal) dwell time from patients with end-stage renal failure and continuing normally on PD therapy. In spite of devastating spectral feature of PD effluent due to the presence of intense resonances from glucose and lactate, we were able to identify 53 small endogenous metabolites (including many complex coupled spin systems) and more than 90% of the total CH cross peaks of (1) H-(13) C heteronuclear single-quantum correlation spectrum specific to various metabolites of PD effluent. We foresee that the characteristic fingerprints of various metabolites of control PD effluent samples will be used to identify and distinguish metabolic differences from PD-related complications.

Assessment of hyaluronic acid-modified imatinib mesylate cubosomes through CD44 targeted drug delivery in NDEA-induced hepatic carcinoma.

This study aimed at the development of hyaluronic acid-functionalised imatinib mesylate cubosomes (HA-IM-CBs) that might be useful in CD44 targeting against hepatic cancer. The HA-IM-CBs had a 130.7 ±â€¯2.92 nm particle size, -31.40 ±â€¯2.76 mV zeta potential, and 76.14 ±â€¯2.69% release. The architecture of HA-IM-CBs was confirmed using HR-TEM and AFM. When compared to plain IM and IM-CBs, in vitro experiments revealed that HA-IM-CBs outperformed by significantly reducing cell viability. DAPI staining and ROS corroborated the apoptotic effects. Biodistribution and Pharmacokinetics studies showedthat HA-IM-CBs exhibit a higher drug concentration in tumour tissue and better pharmacokinetic activity. This is the first study to show that HA-IM-CBs had CD44 targeting activity against HCC. CD44 regulates apoptosis via Bcl-2 family proteins and caspases, which interact with HA. Higher levels of e-NOS, BAD, BAX, and Cyt C and lower expressions of Bcl-xl, i-NOS, and Bcl-2 demonstrated the anti-HCC potential of HA-IM-CBs in qrt-PCR investigations. The remarkable therapeutic potential of HA-IM-CBs began with substantial stimulation of CD44 regulated caspase-mediated mitochondrial apoptotic pathway, accountable for their anti-HCC activity. The perturbed metabolites are restored to acceptable levels as indicated by metabolomic studies (1H NMR). Interestingly, the antineoplastic effect of HA-IM-CBs was proven to be potentially valuable against HCC.

Biotinylated Mn3O4 nanocuboids for targeted delivery of gemcitabine hydrochloride to breast cancer and MRI applications.

Multifunctional nanocarriers have been found as potential candidate for the targeted drug delivery and imaging applications. Herein, we have developed a biocompatible and pH-responsive manganese oxide nanocuboid system, surface modified with poly (ethylene glycol) bis(amine) and functionalized with biotin (Biotin-PEG-MNCs), for an efficient and targeted delivery of an anticancer drug (gemcitabine, GEM) to the human breast cancer cells. GEM-loaded Biotin-PEG@MNCs showed high drug loading efficiency, controlled release of GEM and excellent storage stability in the physiological buffers and different temperature conditions. GEM-loaded Biotin-PEG@MNCs showed dose- and time-dependent decrease in the viability of human breast cancer cells. Further, it exhibited significantly higher cell growth inhibition than pure GEM which suggested that Biotin-PEG@MNCs has efficiently delivered the GEM into cancerous cells. The role of biotin in the uptake was proved by the competitive binding-based cellular uptake study. A significant decrease in the amount of manganese was observed in biotin pre-treated cancer cells as compared to biotin untreated cancer cells. In MRI studies, Biotin-PEG-MNCs showed both longitudinal and transverse relaxivity about 0.091 and 7.66 mM-1 s-1 at 3.0 T MRI scanner, respectively. Overall, the developed Biotin-PEG-MNCs presents a significant potential in formulation development for cancer treatment via targeted drug delivery and enhanced MRI contrast imaging properties.

Targeted NMR-based serum metabolic profiling of serine, glycine and methionine in acute-on-chronic liver failure patients: Possible insights into mitochondrial dysfunction.

Background: A recent study based on blood metabolomics analysis revealed inflammation-associated mitochondrial dysfunction as a potential mechanism underlying acute-on-chronic liver failure (ACLF) in cirrhotic patients. Serine, glycine, and methionine serve to maintain a healthy immune system and adequately sustain mitochondrial functionality in hepatocytes for regulating redox homeostasis through the production of antioxidant glutathione (GSH). Based on this, we hypothesized that the circulatory levels of serine, glycine and methionine will be altered in ACLF patients due to acute worsening of hepatic function and may provide novel insights into the mitochondrial dysfunction as well. Methods: The circulatory concentrations of serine, glycine, and methionine were estimated in the sera of 40 ACLF patients and 49 normal controls (NC) subject using 1D 1H-CPMG NMR spectra recorded at 800 MHz NMR spectrometer. The resulting metabolite concentrations were compared using unpaired Student t-test and p-value < 0.05 was considered as the criterion of statistical significance. The diagnostic potential and statistical correlations were established using receiver-operating-characteristic (ROC) curve analysis and Pearson-r method, respectively. Results: Circulating levels of serine and glycine were significantly decreased in ACLF patients (Ser = 23.06 ± 1.67 µM and Gly = 83.11±7.52 µM) compared to NC subjects (Ser = 55.61 ± 2.28 µM and Gly = 156.9±7.16 µM) with p-value < 0.0001, whereas those of methionine were significantly increased in ACLF (22.60 ± 2.49 µM) compared to NC subjects (=14.63 ± 0.85 µM) with p-value < 0.0015. Further, the ROC analysis yielded satisfactory sensitivity and specificity for serine, glycine, and methionine-to-glycine ratio (MGR) with area under ROC (AUROC) curve values equal to: 0.95 [95%CI = 0.91-0.99] for Ser; 0.87 [95%CI = 0.79-0.95] for Gly; and 0.90 [95%CI = 0.83-0.97] for MGR. Conclusion: Compared to NC subjects, the sera of ACLF patients were characterized by hypermethioninemia and aberrantly decreased levels of serine and glycine suggesting mitochondrial dysfunction as the possible mechanism for disturbed redox homeostasis and therefore depressed immune system in ACLF.

NMR-based serum and muscle metabolomics for diagnosis and activity assessment in idiopathic inflammatory myopathies.

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.