Ocimum sanctum: The Journey from Sacred Herb to Functional Food.

In recent years, the growing demand for herbal-based formulations, including functional foods, has acquired significant attention. This study highlights historical, botanical, ecological, and phytochemical descriptions and different extraction mechanisms of Ocimum sanctum utilized in its processing. Besides this, it explores the utilization of Ocimum sanctum as a functional food ingredient in various food products such as bakery products (biscuits, bread), dairy products (herbal milk, cheese), and beverages (tea, juice, wine) while focusing on their evaluation parameters, preparation techniques, and pharmacological activities. In terms of other pharmacological properties, Ocimum sanctum-infused functional foods exhibited cognitiveenhancing properties, adaptogenic qualities, anti-obesity effects, gastroprotective, antiinflammatory, hypoglycemic, and immuno-modulatory effects. Thus, the diverse properties of Ocimum sanctum offer exciting opportunities for the development of functional foods that can promote specific health issues, so future research should focus on developing and analyzing novel Ocimum sanctum-based functional foods to meet the growing demand of the functional food industry.

Untargeted and temporal analysis of retinal lipidome in bacterial endophthalmitis.

Bacterial endophthalmitis is a blinding infectious disease typically acquired during ocular surgery. We previously reported significant alterations in retinal metabolism during Staphylococcus (S) aureus endophthalmitis. However, the changes in retinal lipid composition during endophthalmitis are unknown. Here, using a mouse model of S. aureus endophthalmitis and an untargeted lipidomic approach, we comprehensively analyzed temporal alterations in total lipids and oxylipin in retina. Our data showed a time-dependent increase in the levels of lipid classes, sphingolipids, glycerolipids, sterols, and non-esterified fatty acids, whereas levels of phospholipids decreased. Among lipid subclasses, phosphatidylcholine decreased over time. The oxylipin analysis revealed increased prostaglandin-E2, hydroxyeicosatetraenoic acids, docosahexaenoic acid, eicosapentaenoic acid, and α-linolenic acid. In-vitro studies using mouse bone marrow-derived macrophages showed increased lipid droplets and lipid-peroxide formation in response to S. aureus infection. Collectively, these findings suggest that S. aureus-infection alters the retinal lipid profile, which may contribute to the pathogenesis of bacterial endophthalmitis.

Black garlic particles as a natural pigment and emulsifier in a Pickering emulsion based low fat innovative mayonnaise: Improved rheology and bioactivity.

Black garlic is rich in brown pigments and Maillard reaction products are known for antioxidant activity and health promoting effects. In the present investigation, we report a facile strategy for fabricating low-fat innovative mayonnaise (IM) using black garlic particles (BGP) as a natural pigment, and a functional ingredient. Whey protein concentrate and high methoxyl pectin at optimized concentrations were utilized for fabricating an IM which served as a control. IM5 and IM10 were ternary composites constituting whey protein, high methoxyl pectin along with BGP (@5 and 10% respectively). The formulation IM10 (BGP @10%) showed high firmness and low spreadability quotient, hence IM5 was taken forward for fabrication for two more variants namely IM-J (using low methoxyl pectin (LMP) from jackfruit peels) and IM-C (LMP from citrus). The effect of BGP and LMP on the functional quality of IM was confirmed through zeta potential, antioxidant activity, textural, rheological, and microscopic evaluation. Fluorescence microscopy confirmed the presence of solid particles over the fat phase of IM, while interaction of pectin and whey proteins was demonstrated through fluorescence emission spectroscopy which clearly displayed stabilization of IM through the formation of Pickering emulsion. Pronounced difference in color and flavor score with BGP established high sensory scores in IM5, IM-J, and IM-C. Rheology supported the stabilizing effects of LMP in IM-J and IM-C in terms of speedy recovery of thixotropy, with recovering storage modulus (G'). Enhanced viscosity of IM-C and IM-J further corroborated the dual effect of LMP and BGP in improving emulsifying and functional quality of IM. Enhanced oxidative stability of IM was established by reduced peroxide and Totox values. Overall our results suggest the promising applications of black garlic as functional ingredient in protein and pectin based Pickering emulsions.

Oral administration of S-nitroso-L-glutathione (GSNO) provides anti-inflammatory and cytoprotective effects during ocular bacterial infections.

Bacterial endophthalmitis is a severe complication of eye surgeries that can lead to vision loss. Current treatment involves intravitreal antibiotic injections that control bacterial growth but not inflammation. To identify newer therapeutic targets to promote inflammation resolution in endophthalmitis, we recently employed an untargeted metabolomics approach. This led to the discovery that the levels of S-nitroso-L-glutathione (GSNO) were significantly reduced in an experimental murine Staphylococcus aureus (SA) endophthalmitis model. In this study, we tested the hypothesis whether GSNO supplementation via different routes (oral, intravitreal) provides protection during bacterial endophthalmitis. Our results show that prophylactic administration of GSNO via intravitreal injections ameliorated SA endophthalmitis. Therapeutically, oral administration of GSNO was found to be most effective in reducing intraocular inflammation and bacterial burden. Moreover, oral GSNO treatment synergized with intravitreal antibiotic injections in reducing the severity of endophthalmitis. Furthermore, in vitro experiments using cultured human retinal Muller glia and retinal pigment epithelial (RPE) cells showed that GSNO treatment reduced SA-induced inflammatory mediators and cell death. Notably, both in-vivo and ex-vivo data showed that GSNO strengthened the outer blood-retinal barrier during endophthalmitis. Collectively, our study demonstrates GSNO as a potential therapeutic agent for the treatment of intraocular infections due to its dual anti-inflammatory and cytoprotective properties.

Butyrate Ameliorates Intraocular Bacterial Infection by Promoting Autophagy and Attenuating the Inflammatory Response.

Despite an important link between the gut and ocular health, the role of the gut-eye axis remains elusive in ocular infections. In this study, we investigated the role of butyrate, a gut microbial metabolite, in the pathobiology of intraocular bacterial (Staphylococcus aureus) infection, endophthalmitis. We found that intravitreal administration of butyrate derivatives, sodium butyrate (NaB), or phenylbutyrate (PBA) reduced intraocular bacterial growth and retinal inflammatory response. The ocular tissue architecture and retinal function were preserved in butyrate-treated eyes. In cultured mouse bone marrow-derived macrophages (BMDMs) and human retinal Müller glia, NaB or PBA treatment reduced S. aureus-induced inflammatory response by inhibiting NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. However, in vivo data showed NLRP3-independent effects of butyrate. The butyrate-treated mouse retina and cells exhibited induced expression of antimicrobial molecules CRAMP (LL37) and S100A7/A8, resulting in increased bacterial phagocytosis and killing. Moreover, butyrate treatment enhanced AMP-activated protein kinase (AMPK)-dependent autophagy and promoted the co-localization of CRAMP in autophagosomes, indicating autophagy-mediated bacterial killing. Furthermore, pharmacological inhibition of autophagy in mice revealed its role in butyrate-mediated protection. Finally, butyrate exhibited synergy with antibiotic in promoting endophthalmitis resolution. Collectively, our study demonstrated the protective mechanisms of butyrate in ameliorating bacterial endophthalmitis. Therefore, butyrate derivatives could be explored as immunomodulatory and anti-bacterial therapeutics to improve visual outcomes in ocular bacterial infections.

Systemic Candida albicans Infection in Mice Causes Endogenous Endophthalmitis via Breaching the Outer Blood-Retinal Barrier.

Candida albicans is the leading cause of endogenous fungal endophthalmitis; however, its pathobiology studies are limited. Moreover, the contribution of host factors in the pathogenesis of Candida endophthalmitis remains unclear. In the present study, we developed a murine model of C. albicans endogenous endophthalmitis and investigated the molecular pathobiology of ocular candidiasis and blood-retinal barrier permeability. Our data show that intravenous injection of C. albicans in immunocompetent C57BL/6 mice led to endogenous endophthalmitis without causing mortality, and C. albicans was detected in the eyes at 3 days postinfection and persisted for up to 10 days. The intraocular presence of C. albicans coincided with a decrease in retinal function and increased expression of inflammatory mediators (tumor necrosis factor alpha [TNF-α], interleukin 1ß [IL-1ß], MIP2, and KC) and antimicrobial peptides (human ß-defensins [hBDs] and LL37) in mouse retinal tissue. C. albicans infection disrupted the blood-retinal barrier (BRB) by decreasing the expression of tight junction (ZO-1) and adherens junction (E-cadherin, N/R-cadherin) proteins. In vitro studies using human retinal pigment epithelial (ARPE-19) cells showed time-dependent activation of eIF2α, extracellular signal-related kinase (ERK), and NF-κB signaling and decreased activity of AMP-activated protein kinase (AMPK) leading to the induction of an inflammatory response upon C. albicans infection. Moreover, C. albicans-infected cells exhibited increased cellular permeability coinciding with a reduction in cellular junction proteins. Overall, our study provides new insight into the molecular pathogenesis of C. albicans endogenous endophthalmitis. Furthermore, the experimental models developed in the study can be used to identify newer therapeutic targets or test the efficacy of drugs to treat and prevent fungal endophthalmitis. IMPORTANCE Patients with candidemia often experience endophthalmitis, a blinding infectious eye disease. However, the pathogenesis of Candida endophthalmitis is not well understood. Here, using in vivo and in vitro experimental models, we describe events leading to the invasion of Candida into the eye. We show that Candida from the systemic circulation disrupts the protective blood-retinal barrier and causes endogenous endophthalmitis. Our study highlights an important role of retinal pigment epithelial cells in evoking innate inflammatory and antimicrobial responses toward C. albicans infection. This study allows a better understanding of the pathobiology of fungal endophthalmitis, which can lead to the discovery of novel therapeutic targets to treat ocular fungal infections.

Transcriptomics and systems biology identify non-antibiotic drugs for the treatment of ocular bacterial infection.

Increasing antibiotic resistance among ocular pathogens often results in treatment failure for blinding infections such as endophthalmitis. Hence, newer therapeutics is needed to combat multidrug-resistant infections. Here, we show a drug repurposing approach using a connectivity map based on temporal transcriptomics of Staphylococcus aureus (SA) infected mouse retina. The analysis predicted three non-antibiotic drugs, Dequalinium chloride (DC), Clofilium tosylate (CT), and Glybenclamide (Glb) which reversed the SA infection signatures. Predicted drugs exhibited anti-inflammatory properties in human retinal cells against sensitive and resistant strains of SA. Intravitreal administration of all drugs reduced intraocular inflammation in SA-infected mouse eyes while DC and CT also reduced bacterial burden. Drug treatment improved visual function coinciding with reduced Caspase-3 mediated retinal cell death. Importantly, all drugs exhibited synergy with vancomycin in improving disease outcomes. Overall, our study identified three non-antibiotic drugs and demonstrated their therapeutic and prophylactic efficacies in ameliorating intraocular bacterial infection.

Psychopathological Aspects in Children with Epilepsy and Its Contributing Factors: A Cross-Sectional Study from India.

Background Children with epilepsy (CWE) are at high risk of psychopathological problems because of neurobiological, social, and treatment factors. Objectives This study was conducted to estimate the prevalence of psychopathological problems in CWE and their contributing factors. Methods This cross-sectional study was done in pediatric neurology clinic and outpatient department of a government medical college in Northern India. Children between the ages of 4 and 14 years with intelligence quotient > 70 were enrolled; for CWE, the criteria were antiepileptic drugs therapy for more than 6 months and for controls it was being free from any chronic illness. Childhood Psychopathology Measurement Schedule (CPMS) was used for assessing psychopathological problems. Results A total of 135 CWE and 70 controls were enrolled, groups were similar in respect of age, gender, socioeconomic status, and family history. CWE group had significantly high mean ± standard deviation CPMS scores (13.68 ± 10.57) as compared with controls (9.75 ± 7.97) ( p < 0.0001). These scores were particularly high in sectors of low intelligence, conduct disorder, psychotic symptoms, and depression. Academic performance was significantly poor in CWE (39%) versus controls (6%) ( p 0.042). Age of onset, duration, type, and etiology of epilepsy had no significant relation with CPMS scores. Polytherapy and treatment with valproate were associated with high CPMS scores ( p 0.005 and 0.045). Conclusion Psychopathological problems are frequently associated with epilepsy in children and antiepileptic drug therapy might contribute to it.

A Targeted Metabolomics Approach to Study Secondary Metabolites and Antioxidant Activity in 'Kinnow Mandarin' during Advanced Fruit Maturity.

In this study, we investigated the impact of harvest maturity stages and contrasting growing climates on secondary metabolites in Kinnow mandarin. Fruit samples were harvested at six harvest maturity stages (M1−M6) from two distinct growing locations falling under subtropical−arid (STA) and subtropical−humid (STH) climates. A high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) technique was employed to identify and quantify secondary metabolites in the fruit juice. A total of 31 polyphenolics and 4 limonoids, with significant differences (p < 0.05) in their concentration, were determined. With advancing maturity, phenolic acids and antioxidant activity were found to increase, whereas flavonoids and limonoids decreased in concentration. There was a transient increase in the concentration of some polyphenolics such as hesperidin, naringin, narirutin, naringenin, neoeriocitrin, rutin, nobiletin and tangeretin, and limonoid aglycones such as limonin and nomilin at mid-maturity stage (M3) which coincided with prevailing low temperature and frost events at growing locations. A higher concentration of limonin and polyphenolics was observed for fruit grown under STH climates in comparison to those grown under STA climates. The data indicate that fruit metabolism during advanced stages of maturation under distinct climatic conditions is fundamental to the flavor, nutrition and processing quality of Kinnow mandarin. This information can help in understanding the optimum maturity stage and preferable climate to source fruits with maximum functional compounds, less bitterness and high consumer acceptability.

Essential Role of NLRP3 Inflammasome in Mediating IL-1ß Production and the Pathobiology of Staphylococcus aureus Endophthalmitis.

Staphylococcal endophthalmitis is one of the leading causes of blindness following ocular surgery and trauma. Dysregulated inflammation during bacterial endophthalmitis causes host-induced inflammatory damage and vision loss if it remains unchecked. Emerging evidence indicates that inflammasome plays a critical role in regulating innate immunity in various infectious and inflammatory diseases. However, the role of the inflammasome in endophthalmitis remains elusive. Here, using a mouse model of Staphylococcus (S) aureus endophthalmitis, we show that NLRP3/ASC/Caspase-1 signaling regulates IL-1ß production in endophthalmitis. We also show that S. aureus and its cell wall components and toxins induce the activation of the NLRP3 inflammasome complex in mouse eyes. Moreover, we found that both infiltrating neutrophils and retinal microglia contribute toward NLRP3 activation and IL-1ß production in S. aureus-infected eyes. Furthermore, our data using NLRP3-/- and IL-1ß-/- mice revealed that NLRP3 and IL-1ß deficiency leads to increased intraocular bacterial burden and retinal tissue damage. Altogether, our study demonstrated an essential role of NLRP3 inflammasome activation in regulating innate immune responses in bacterial endophthalmitis.

Association of MIF gene polymorphisms with pemphigus vulgaris: a case-control study with comprehensive review of the literature.

BACKGROUND: Functional macrophage migration inhibitory factor (MIF) gene polymorphisms are associated with elevated serum levels of MIF and increased susceptibility to various autoimmune diseases. MIF levels in the sera of pemphigus vulgaris (PV) patients are increased; however, no definite association has been demonstrated between PV and MIF gene polymorphisms. The present study was conducted to ascertain any association between MIF-173*G-C and MIF-794*CATT5-8 polymorphisms and PV. METHODS: Seventy-five patients with PV and 252 healthy, unrelated, voluntary controls were enrolled randomly in the study. MIF-173*G-C polymorphism (rs755622) was genotyped using polymerase chain reaction (PCR) followed by restriction fragment length analysis, and MIF-794*CATT5-8 (rs5844572) was genotyped using PCR followed by capillary gel electrophoresis. Subsequently, the allelic, genotype, and haplotype frequencies were determined and compared for both groups. Data were also analyzed with respect to sex, age at onset, type of disease, and duration of disease. RESULTS: No significant association was observed in terms of allelic, genotype, and haplotype frequencies of MIF gene polymorphisms in PV patients. However, a significantly lower prevalence of the C allele (P=0.02) and CATT7 allele (P=0.03) was seen in our patient population compared to healthy controls. Analysis of the effect of various factors such as gender, age at onset, type of disease, and disease duration revealed no significant association with the genetic variants. CONCLUSIONS: MIF-173*G-C and -794*CATT5-8 polymorphisms are not associated with PV.

Bacterial Burden Declines But Neutrophil Infiltration and Ocular Tissue Damage Persist in Experimental Staphylococcus epidermidis Endophthalmitis.

Coagulase-negative staphylococci (CoNS), including Staphylococcus (S) epidermidis, are responsible for ~70% of all post-surgical endophthalmitis, a potentially blinding eye infection. However, the pathobiology of CoNS endophthalmitis is limited to epidemiological and clinical case studies with few experimental studies. Here, we report both in vitro and in vivo models to study the pathobiology of S. epidermidis endophthalmitis in mice. We found that S. epidermidis is rapidly cleared from mouse eyes, and a relatively higher dose (i.e., 107 CFU/eye) was needed to cause endophthalmitis. Our time-course study revealed that bacterial load peaked at 24 h post-infection followed by a gradual decline up to 72 h. A similar time-dependent decrease in levels of inflammatory mediators and Toll-like receptor (TLR) expression was also observed. In contrast, neutrophil infiltration continued to increase up to 72 h coinciding with significant retinal tissue damage and loss of visual function. In vitro, S. epidermidis induced the activation of various inflammatory signaling pathways (i.e., NF-kB, ERK, and P38) and the production of both cytokines and chemokines in mouse BMDMs, human RPE, and retinal Muller glia. Altogether, we show that bacterial burden is reduced in S. epidermidis endophthalmitis, while tissue damage and visual function loss continue. Thus, our study provides new insights into the pathogenesis of CoNS endophthalmitis.

Multidrug-Resistant Pseudomonas aeruginosa Triggers Differential Inflammatory Response in Patients With Endophthalmitis.

Purpose: Infections with multidrug-resistant Pseudomonas aeruginosa (MDR-PA) lead to poor clinical outcomes in endophthalmitis patients, and its interactions with the host immune system remain largely unknown. The current study aimed to determine the association of MDR-PA infection with the cytokine expression profile in patients with endophthalmitis. Methods: Vitreous of 12 patients with culture-proven MDR-PA along with 12 samples from antibiotic-susceptible P. aeruginosa (S-PA) and 20 non-infectious controls were included in the study. Expression patterns of IL-6, IL-10, IL-1α, IL-1ß, IFN-γ, TNF-α, IL-8, and GM-CSF in the vitreous were analyzed by multiplex immunoassay and correlated with the clinical severity. We also assessed the phosphorylation level of different immune pathway molecules. Results: In the MDR-PA group, significantly (P < 0.05) increased expression of IL-6, IL-8, IL-10, IL-1ß, and TNF-α was observed in comparison with the S-PA group. The increased inflammatory mediators in MDR-PA correlated with the disease severity. Additionally, the increased expression of inflammatory mediators was positively correlated to the activation levels of Akt, STAT3, JNK, p70 S6 kinase, and NF-кB (P < 0.05) in the MDR-PA group. Conclusions: The current study shows the differential host immune response and phosphorylation levels of signaling molecules in MDR-PA endophthalmitis, thereby linking antibiotic resistance with distinct immune regulation. Translational Relevance: This study provides evidence for the use of inflammatory mediator levels of IL-6, IL-8, IL-10, IL-1ß, and TNF-α as potential diagnostic biomarkers of MDR endophthalmitis warranting prompt administration of immune modulators to avoid irreversible damage to the retina and vision loss.

Integrative metabolomics and transcriptomics identifies itaconate as an adjunct therapy to treat ocular bacterial infection.

The eye is highly susceptible to inflammation-mediated tissue damage evoked during bacterial infection. However, mechanisms regulating inflammation to protect the eye remain elusive. Here, we used integrated metabolomics and transcriptomics to show that the immunomodulatory metabolite itaconate and immune-responsive gene 1 (Irg1) are induced in bacterial (Staphylococcus aureus)-infected mouse eyes, bone-marrow-derived macrophages (BMDMs), and Müller glia. Itaconate levels are also elevated in the vitreous of patients with bacterial endophthalmitis. Irg1 deficiency in mice led to increased ocular pathology. Conversely, intraocular administration of itaconate protects both Irg1-/- and wild-type mice from bacterial endophthalmitis by reducing inflammation, bacterial burden, and preserving retinal architecture and visual function. Notably, itaconate exerts synergistic effects with antibiotics. The protective, anti-inflammatory effects of itaconate are mediated via activation of NRF2/HO-1 signaling and inhibition of NLRP3 inflammasome. Collectively, our study demonstrates the Irg1/itaconate axis is a regulator of intraocular inflammation and provides evidence for using itaconate, along with antibiotics, to treat bacterial infections.

Aging, But Not Sex and Genetic Diversity, Impacts the Pathobiology of Bacterial Endophthalmitis.

Purpose: Age, sex, and genetics are important biological variables in determining an individual's susceptibility or response to infectious agents; however, their role has not been evaluated in intraocular infections. In this study, we comprehensively examined the impact of these host biological factors in the pathogenesis of experimental bacterial endophthalmitis. Methods: Endophthalmitis was induced by intravitreal injection of bacteria (Staphylococcus aureus) in the eyes of male and female C57BL/6 mice of different ages: group I (young, 6-8 weeks), group II (mid-age, 18-20 weeks), and group III (old, 1 year). Highly heterogeneous outbred J:DO mice were used for genetic diversity analysis. Eyes were subjected to clinical examination, retinal function testing using electroretinography (ERG), histopathological analysis (hematoxylin and eosin staining), and bacterial burden estimation. The levels of inflammatory mediators were measured using qPCR and ELISA, and the infiltration of neutrophils was determined by flow cytometry. Results: Both inbred C57BL/6 and diversity outbred (J:DO) mice were equally susceptible to S. aureus endophthalmitis, as evidenced by a time-dependent increase in clinical scores, bacterial burden, intraocular inflammation, and retinal tissue damage, in addition to decreased retinal function. However, no significant differences were observed in disease severity and innate responses in male versus female mice. Older mice (group III) exhibited higher clinical scores coinciding with increased bacterial proliferation and intraocular inflammation, resulting in enhanced disease severity. Moreover, bone-marrow-derived macrophages from old mice exhibited reduced phagocytic activity but increased inflammatory response toward S. aureus challenge. Conclusions: Age, but not sex, is an important biological variable in bacterial endophthalmitis. Identification of pathways underlying altered innate immunity and impaired bacterial clearance in aging eyes could provide new insights into the pathobiology of intraocular infections in elderly patients.

Signature genes associated with immunological non-responsiveness to anti-retroviral therapy in HIV-1 subtype-c infection.

OBJECTIVE: HIV-infected individuals undergoing therapy may show an immunological-discordant response to therapy, with poor CD4+ T cells recovery, despite viral suppression below the detection limit. The present study was carried out to delineate the underlying molecular mechanisms of immunological non-responsiveness to HIV therapy. DESIGN: We conducted microarray-based whole gene expression profiles of 30 subjects infected with HIV-1 subtype C, in peripheral blood to discern the signature genes associated with immunological non-responsiveness. After a thorough analysis and comparison of gene-expression profiles, microarray data was validated via qRT-PCR approach. RESULTS: Overall, we found 10 genes significantly up-regulated and 60 genes down-regulated (≥2-fold change) in immunological non-responders as compared to responders. Based on these results and pathway analysis of the protein-protein interaction, 20 genes were shortlisted for validation in human infected cases. We found statistically significant differences in expression levels of twelve genes IL-1α, IL-1ß, IL-7R, TNF-α, FoxP3, PDCD5, COX7B, SOCS1, SOCS3, RPL9, RPL23, and LRRN3 respectively among immunological non-responders compared to therapy responders, confirming their an intimate relationship with immunological responsiveness to therapy. CONCLUSIONS: Altogether, microarray and qRT-PCR validation results indicated that the aberrant expression of key genes involved in the regulation of T cell homeostasis, immune activation, inflammatory cytokine production, apoptosis, and immune-regulatory processes are possibly associated with immunological non-responsiveness in HIV-1 C infected individuals on ART.

Natural history and profile of selective cytokines in patients of acute pancreatitis with acute kidney injury.

OBJECTIVES: To study the natural course of patients with acute pancreatitis (AP) with acute kidney injury (AKI) and their cytokine profile. METHODS: Natural course of patients with AP and AKI was studied in 97 individuals. Levels of TNFα, IL-6, IL-10, IL-8 and IL-1ß were measured at presentation and at 72 h in patients who developed AKI. RESULTS: Amongst the entire cohort, 16.4% patients developed AKI (persistent AKI - 11 patients, transient AKI - 5 patients). Mortality rate was 25% amongst patients with AKI. Levels of IL-6 (p = 0.035) and IL-8 (p = 0.002) were found to be significantly higher in the AKI group. On multivariate analysis, IL-8 levels at baseline were found to be an independent predictor of AKI. AKI group had significant rise of TNF-α (P < 0.001), IL-6 (P < 0.001) and IL- 1ß (P < 0.001) on day 3 whereas persistent-AKI group had significant rise of TNF-α (p = 0.031), IL-6 (p = 0.001) and IL-1ß on day 3 and significant decline of IL-10 (p = 0.015). Using a cut-off of 105 pg/ml, IL-8 levels at baseline could predict AKI with a sensitivity of 87.5% and specificity of 59.2%, with area under the curve being 0.744 (p = 0.002). CONCLUSION: AP patients developing AKI have poor prognosis. IL-8 levels can predict AKI in patients with AP.

Multidrug-Resistant Pseudomonas aeruginosa Evokes Differential Inflammatory Responses in Human Microglial and Retinal Pigment Epithelial Cells.

Increasing incidences of multidrug-resistant (MDR) pathogens causing endophthalmitis threaten our ability to treat this condition, and the modulation of inflammatory responses by MDR bacteria is not known. In this study, using human microglia and retinal pigment epithelial (RPE) cells, we compare the inflammatory responses of sensitive (S-PA) and multidrug-resistant (MDR-PA) clinical isolates of Pseudomonas aeruginosa. Infected cells were subjected to qPCR analysis, enzyme-linked immunosorbent assay (ELISA), and immunostaining to assess the expression of inflammatory mediators. Both microglia and RPE cells, challenged with S-PA and MDR-PA, induced a time-dependent expression of inflammatory cytokines. Significant differences were observed in expression levels of Toll-like receptors (TLR) TLR4, TLR5, and TLR9 in microglia cells challenged with MDR-PA vs. S-PA. Similarly, mRNA levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, Interferon (IFN)-γ, and matrix metalloproteinase (MMP)-9 were also higher in MDR-PA-infected cells. At protein levels, upregulation was observed for IL-10 (p = 0.004), IL-8 (p = 0.0006), IL-1ß (p = 0.02), and Granulocyte-macrophage colony-stimulating factor (GM-CSF) (p = 0.0006) in cells infected MDR-PA versus S-PA in both microglia and RPE cells; however, the response was delayed in RPE cells. Heatmap and STRING analysis highlighted the existence of a cross-talk between the inflammatory and cytokine-mediated signaling pathways. Our study highlights a differential inflammatory response evoked by MDR vs. sensitive pathogens in retinal cells during endophthalmitis.

Glycolytic inhibitor 2-deoxyglucose suppresses inflammatory response in innate immune cells and experimental staphylococcal endophthalmitis.

Previously, we have shown that Staphylococcus (S) aureus induces a glycolytic response in retinal residential (microglia) and infiltrated cells (neutrophils and macrophages) during endophthalmitis. In this study, we sought to investigate the physiological role of glycolysis in bacterial endophthalmitis using a glycolytic inhibitor, 2-deoxyglucose (2DG). Our data showed that 2DG treatment attenuated the inflammatory responses of mouse bone marrow-derived macrophages (BMDM) and neutrophils (BMDN) when challenged with either live or heat-killed S. aureus (HKSA). Among the inflammatory mediators, 2DG caused a significant reduction in levels of cytokines (TNF-α, IL-1ß, IL-6) and chemokines (CXCL1 and CXCL2). Western blot analysis of 2DG treated cells showed downregulation of bacterial-induced MEK/ERK pathways. In vivo, intravitreal administration of 2DG both pre- and post-bacterial infection resulted in a significant reduction in intraocular inflammation in C57BL/6 mouse eyes and downregulation of ERK phosphorylation in retinal tissue. Collectively, our study demonstrates that 2DG attenuates inflammatory response in bacterial endophthalmitis and cultured innate immune cells via inhibition of ERK signaling. Thus glycolytic inhibitors in combination with antibiotics could mitigate inflammation-mediated tissue damage in ocular infections.

Echocardiographic Evaluation of Right Ventricular Function and its Role in the Prognosis of Chronic Obstructive Pulmonary Disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with structural and mechanical changes in the pulmonary vascular bed that increase right ventricular (RV) afterload and subsequently right heart failure. OBJECTIVES: The aim of the study was to elucidate RV dysfunction at rest by echocardiography in a cohort of COPD patients and to study its impact on prognosis. METHODS: 84 patients of COPD and 40 matching healthy controls were evaluated at baseline. Evaluation included clinical examination, pulmonary function tests; 6 minutes walk test and echocardiography. Patient with COPD were again evaluated after 6 months. RESULTS: All echocardiographic parameters of RV function were significantly impaired in COPD patients as compared to controls. Clinical deterioration in COPD group was much more in patients with baseline abnormal RV function (89%) and patients with RV systolic pressure ≥35 mmHg (P = 0.018). All the six patients who died had three or more abnormal RV systolic function parameters. CONCLUSIONS: RV myocardial performance index and basal strain showed largest difference between controls and COPD cases. Clinical deterioration was more common in patients with abnormal RV function parameters and pulmonary hypertension.