Are we too reluctant about irrational nutraceutical combinations?

Background: The objective of the study was to study the rationality of Vitamins and minerals combinations available in India and to provide comprehensive data of irrational combinations having excess and sub sufficient quantity of vitamin and minerals than recommended by National Guidelines of India.Methods: This observational study and analysis was done between June and August 2016. Data was collected from current index of medical specialties and drug India. Rationality assessment was done using National list approved drug combinations by Central drug standard control organization (CDSCO) and essentially was cross checked using World Health Organization essential drug list 2015. Adequacy was analysed using Dietary reference intake (DRI) for Indians by Nutrional council of India draft guidance.Results: In our analysis, we have found 1184 irrational nutraceutical preparations available in India market. Out of 461(38.9%) are based on fat soluble vitamins, 190 (16.4%) based on B-complex vitamins based and 5339 (45.1%) related to essential minerals. Among 461 fat soluble vitamins, 104 contain excessive level, 334 contain substandard levels. Similarly 128 and 62 Vitamin B-Complex based preparations are having excess and less quantity than recommended levels respectively and almost all the mineral combinations except four are not prepared following guidelines. None of these combinations were included in National essential list of medicines.Conclusions: Multivitamins are generally considered safe; these are irrationally prescribed and taken as self-medication by public. Many of the ill effects are often unnoticed and under reported. Government of India should regulate the manufacture and sale these nutraceuticals to promote rational use of drugs and to promote wellbeing and safety of Indian population which is primary objective of ‘Health for all’

Performance Indicators of Indian Railways at Glance

Indian Railways is aware of the need to be up-to-datewith modern technological developments and best globalpractices to cash on the growing opportunity in freight and passenger business and provide the desired level of service to its passengers and customers. In this research paper, an attempt is made to evaluate the overall performance of Indian railways over the last ten years &to study the comparative position of train accidents and measures to improve safety by Indian Railways. The outcome of the study will explain in detail about the efficiency of Indian railways. Indian railways has always shown keen interest in taking advantage of technology to provide safety for the passengers

Human C1q Induces Apoptosis in an Ovarian Cancer Cell Line via Tumor Necrosis Factor

Copyright: © 2016 Kaur, Sultan, Murugaiah, Pathan, Alhamlan, Karteris and Kishore. Human C1q is the first recognition subcomponent of the complement classical pathway that plays a vital role in the clearance of immune complexes, pathogens and apoptotic cells. C1q also has a homeostatic role involving immune and non-immune cells; these functions not necessarily involve complement activation. Recently, C1q has been shown to be expressed locally in the microenvironment of a range of human malignant tumours, where it can promote cancer cell adhesion, migration and proliferation, without involving complement activation. C1q has been shown to be present in the ascitic fluid formed during ovarian cancers. In this study, we have examined the effects of human C1q and its globular domain on an ovarian cancer cell line, SKOV3. We show that C1q and the recombinant globular modules induce apoptosis in SKOV3 cells in a dose-and time-dependent manner. C1q expression was not detectable in the SKOV3 cells. Exogenous treatment with C1q and globular heads at the concentration of 10μg/ml induced apoptosis in approximately 55% cells, as revealed by immunofluorescence microscopy and FACS. The qPCR and caspase analysis suggested that C1q and globular head modules activated TNF-α and upregulation of Fas. The genes of mTOR, RICTOR and RAPTOR survival pathways, which are often over-expressed in majority of the cancers, were significantly downregulated within few hours of the treatment of C1q and globular head modules. In conclusion, C1q, via its globular domain, induced apoptosis in an ovarian cancer cell line, SKOV3 via TNF-α induced apoptosis pathway involving upregulation of Bax and Fas. This study highlights a potentially protective role of C1q in certain cancers

Potential influences of complement factor H in autoimmune inflammatory and thrombotic disorders

Complement system homeostasis is important for host self-protection and anti-microbial immune surveillance, and recent research indicates roles in tissue development and remodelling. Complement also appears to have several points of interaction with the blood coagulation system. Deficiency and altered function due to gene mutations and polymorphisms in complement effectors and regulators, including Factor H, has been associated with familial and sporadic autoimmune inflammatory - thrombotic disorders, in which autoantibodies play a part. These include systemic lupus erythematosus, rheumatoid arthritis, atypical haemolytic uremic syndrome, anti-phospholipid syndrome and age-related macular degeneration. Such diseases are generally complex – multigenic and heterogeneous in their symptoms and predisposition/susceptibility. They usually need to be triggered by vascular trauma, drugs or infection and non-complement genetic factors also play a part. Underlying events seem to include decline in peripheral regulatory T cells, dendritic cell, and B cell tolerance, associated with alterations in lymphoid organ microenvironment. Factor H is an abundant protein, synthesised in many cell types, and its reported binding to many different ligands, even if not of high affinity, may influence a large number of molecular interactions, outwith the accepted role of Factor H within the complement system. Factor H is involved in mesenchymal stem cell mediated tolerance and also contributes to self tolerance by augmenting iC3b production and opsonisation of apoptotic cells for their silent dendritic cell engulfment via complement receptor CR3, which mediates anti-inflammatory tolerogenic effects in the apoptotic cell context. There may be co-operation with other phagocytic receptors, such as complement C1q receptors, and the Tim glycoprotein family, which specifically bind phosphatidylserine expressed on the apoptotic cell surface. Factor H is able to discriminate between self and nonself surfaces for self-protection and anti-microbe defence. Factor H, particularly as an abundant platelet protein, may also modulate blood coagulation, having an anti-thrombotic role. Here we review a number of interaction pathways in coagulation and in immunity, together with associated diseases, and indicate where Factor H may be expected to exert an influence, based on reports of the diversity of ligands for Factor H

Formulation, inflammation, and RNA sensing impact the immunogenicity of self-amplifying RNA vaccines

To be effective, RNA vaccines require both in situ translation and the induction of an immune response to recruit cells to the site of immunization. These factors can pull in opposite directions with the inflammation reducing expression of the vaccine antigen. We investigated how formulation affects the acute systemic cytokine response to a self-amplifying RNA (saRNA) vaccine. We compared a cationic polymer (pABOL), a lipid emulsion (nanostructured lipid carrier, NLC), and three lipid nanoparticles (LNP). After immunization, we measured serum cytokines and compared the response to induced antibodies against influenza virus. Formulations that induced a greater cytokine response induced a greater antibody response, with a significant correlation between IP-10, MCP-1, KC, and antigen-specific antibody titers. We then investigated how innate immune sensing and signaling impacted the adaptive immune response to vaccination with LNP-formulated saRNA. Mice that lacked MAVS and are unable to signal through RIG-I-like receptors had an altered cytokine response to saRNA vaccination and had significantly greater antibody responses than wild-type mice. This indicates that the inflammation induced by formulated saRNA vaccines is not solely deleterious in the induction of antibody responses and that targeting specific aspects of RNA vaccine sensing might improve the quality of the response

Carbon nanotube-coated recombinant human surfactant protein D reduces cell viability in an ovarian cancer cell line, SKOV3, and modulates mTOR pathway and pro-inflammatory cytokine response

Copyright © 2022 The Authors. Nanoparticles such as carbon nanotubes (CNTs) have various clinical and diagnostic applications as utilised for imaging and drug delivery. Therapeutic proteins/peptides can be loaded on CNT coronas to specifically hit immune cells in overdrive or uncontrolled malignant cells. Previously, it was reported that a recombinant version of human surfactant protein D (rfhSP-D) containing trimeric C-type lectin domains induced apoptosis in several tumour cells/cell lines, including SKOV3, which is an ovarian tumour cell line. Solid-phase rfhSP-D coated on a microtiter plate is considerably more potent in inducing apoptosis in breast tumour cells. We have immobilised highly purified, endotoxin-free rfhSP-D on CNTs and assessed its antiproliferative effect on SKOV3 cells. Biotinylated rfhSP-D-CNTs were phagocytosed by SKOV3 cells, followed by apoptosis in a time-dependent manner. Gene expression analysis revealed compromised mTOR complex as a mechanism of apoptosis. When rfhSP-D-CNTs were added to a culture system of SKOV3 cells, it produced a highly proinflammatory immune response that is likely anti-tumorigenic. Thus, rfhSP-D-CNT seems a worthwhile nanocarrier for testing in vivo using an animal model of orthotopic ovarian cancer.This research was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University, Riyadh, KSA, through the Research Funding Program (Grant No# FRP-1440-27)

Full-length human Surfactant Protein A inhibits Influenza A Virus infection of A549 lung epithelial cells: a recombinant form containing neck and lectin domains promotes infectivity

Hydrophilic lung surfactant proteins have emerged as key immunomodulators aimed at recognition and clearance of pulmonary pathogens. Surfactant protein A (SP-A) is a surfactant-associated innate immune pattern recognition molecule, which is known to interact with a variety of pathogens, and display anti-microbial effects. SP-A, being carbohydrate pattern recognition molecule, has been suggested to have a wide range of innate immune functions against pathogens. In addition, SP-A can work against respiratory pathogens, including influenza A virus (IAV). Some pandemic pH1N1 strains resist neutralization by SP-A due to differences in the N-glycosylation of viral hemagglutinin (HA). Here, we provide evidence, for the first time, that a recombinant form of human SP-A (rfhSP-A) composed of α-helical neck and carbohydrate recognition domains can actually promote the IAV replication, as observed by an upregulation of M1 expression in lung epithelial cell line, A549, when challenged with pH1N1 and H3N2 IAV subtypes. rfhSP-A (10 μg/ml) bound neuraminidase (NA) (˜60 kDa), matrix protein 1 (M1) (˜25 kDa) and M2 (˜17 kDa) in a calcium dependent manner, as revealed by far western blotting, and direct binding ELISA. However, human full length native SP-A downregulated mRNA expression levels of M1 in A549 cells challenged with IAV subtypes. Furthermore, qPCR analysis showed that transcriptional levels of TNF-α, IL-12, IL-6, IFN-α and RANTES were enhanced following rfhSP-A treatment by both IAV subtypes at 6 h post-IAV infection of A549 lung epithelial cells. In the case of full length SP-A treatment, mRNA expression levels of TNF-α, and IL-6 were downregulated during the mid-to-late stage of IAV infection of A549 cells. Multiplex cytokine/chemokine array revealed enhanced levels of both IL-6 and TNF-α due to rfhSP-A treatment in the case of both IAV subtypes tested, while no significant effect was seen in the case of IL-12. Enhancement of IAV infection of pH1N1 and H3N2 subtypes by truncated rfhSP-A, concomitant with infection inhibition by full-length SP-A, appears to suggest that a complete SP-A molecule is required for protection against IAV. This is in contrast to a recombinant form of trimeric lectin domains of human SP-D (rfhSP-D) that acts as an entry inhibitor of IAV.KACST (14-MED258-20

Complement-independent Modulation of Influenza A virus infection by Factor H

Copyright © 2020 Murugaiah, Varghese, Saleh, Tsolaki, Alrokayan, Khan, Collison, Sim, Nal, Al-Mohanna and Kishore. The complement system is an ancient innate immune defence mechanism that can recognise molecular patterns on the invading pathogens. Factor H, as an inhibitor of the alternative pathway, down-regulates complement activation on the host cell surface. Locally synthesised factor H at the site of infection/injury, including lungs, can act as a pattern recognition molecule without involving complement activation. Here, we report that factor H, a sialic acid binder, interacts with influenza A virus (IAV) and modulates IAV replication, as observed by an upregulation of matrix protein 1 (M1) expression in H3N2-infected A549 cells, while downregulating M1 in H1N1 subtype-infected cells. Far-western blot revealed that factor H binds hemagglutinin (HA, ~70kDa), neuraminidase (NA, ~60kDa), and M1 (~25kDa). IAV-induced transcriptional levels of IFN-α, TNF-α, IL-12, IL-6, IFN-α, while RANTES were reduced following factor H treatment for the H1N1 subtype at 6 h post-infection. However, for the H3N2 subtype, mRNA levels of these pro-inflammatory cytokines were enhanced. Recombinant form of vaccinia virus complement control protein (VCP), which like factor H, contains CCP modules and has complement-regulatory activity, mirrored the results obtained with factor H. Both factor H (25%) and VCP (45%) were found to reduce luciferase reporter activity in MDCK cells transduced with H1N1 pseudotyped lentiviral particles. Factor H (50%) and VCP (30%) enhanced the luciferase reporter activity for H3N2, suggesting an entry inhibitory role of factor H and VCP against H1N1, but not H3N2. Thus, factor H can modulate IAV infection and inflammatory response independent of its complement-related functions.King Saud University, Riyadh, International Scientific Partnership Programme (ISPP) ISPP-145

Hyaluronic Acid Present in the Tumor Microenvironment Can Negate the Pro-apototic Effect of a Recombinant Fragment of Human Surfactant Protein D on Breast Cancer Cells

Copyright © 2020 Murugaiah, Agostinis, Varghese, Belmonte, Vieni, Alaql, Alrokayan, Khan, Kaur, Roberts, Madan, Bulla and Kishore. Human surfactant protein D (SP-D) belongs to the family of collectins that is composed of a characteristic amino-terminal collagenous region and a carboxy-terminal C-type lectin domain. Being present at the mucosal surfaces, SP-D acts as is a potent innate immune molecule and offers protection against non-self and altered self-such as pathogens, allergens, and tumour. Here, we examined the effect of a recombinant fragment of human SP-D (rfhSP-D) on a range of breast cancer lines. Breast cancer has four molecular subtypes characterised by varied expression of oestrogen (ER), progesterone (PR) and EGF receptors (HER2). The cell viability of HER2 over-expressing (SKBR3) and triple-positive (BT474) breast cancer cell lines (but not of triple-negative cell line (BT20), was reduced following rfhSP-D treatment at 24h. Upregulation of p21/p27 cell cycle inhibitors and p53 phosphorylation (Ser15) in rfhSP-D-treated BT474 and SKBR3 cell lines signified G2/M cell cycle arrest. Cleaved caspase 9 and 3 were detected in rfhSP-D- treated BT474 and SKBR3 cells, suggesting an involvement of intrinsic apoptosis pathway. However, rfhSP-D-induced apoptosis was nullified in the presence of hyaluronic acid whose increased level in breast tumor microenvironment is associated with malignant tumor progression and invasion. rfhSP-D bound to solid-phase HA and promoted tumor cell proliferation. rfhSP-D-treated SKBR3 cells in the presence of hyaluronic acid showed decreased transcriptional levels of p53 when compared to SKBR3 cells treated with rfhSP-D only. Thus, hyaluronic acid appears to negate the anti-tumorigenic properties of rfhSP-D against HER2-over-expressing and triple-positive breast cancer cells.King Saud University, Riyadh, International Scientific Partnership Program (ISPP) ISPP-145; Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy, RC20/16 and 5MILLE15D

Are we too reluctant about irrational nutraceutical combinations?

Background: The objective of the study was to study the rationality of Vitamins and minerals combinations available in India and to provide comprehensive data of irrational combinations having excess and sub sufficient quantity of vitamin and minerals than recommended by National Guidelines of India.Methods: This observational study and analysis was done between June and August 2016. Data was collected from current index of medical specialties and drug India. Rationality assessment was done using National list approved drug combinations by Central drug standard control organization (CDSCO) and essentially was cross checked using World Health Organization essential drug list 2015. Adequacy was analysed using Dietary reference intake (DRI) for Indians by Nutrional council of India draft guidance.Results: In our analysis, we have found 1184 irrational nutraceutical preparations available in India market. Out of 461(38.9%) are based on fat soluble vitamins, 190 (16.4%) based on B-complex vitamins based and 5339 (45.1%) related to essential minerals. Among 461 fat soluble vitamins, 104 contain excessive level, 334 contain substandard levels. Similarly 128 and 62 Vitamin B-Complex based preparations are having excess and less quantity than recommended levels respectively and almost all the mineral combinations except four are not prepared following guidelines. None of these combinations were included in National essential list of medicines.Conclusions: Multivitamins are generally considered safe; these are irrationally prescribed and taken as self-medication by public. Many of the ill effects are often unnoticed and under reported. Government of India should regulate the manufacture and sale these nutraceuticals to promote rational use of drugs and to promote wellbeing and safety of Indian population which is primary objective of ‘Health for all’