Trace metals and pesticides in water-sediment and associated pollution load indicators of Netravathi-Gurupur estuary, India: Implications on coastal pollution.

Various environmental indicators were used to evaluate the water and sediment quality of the Netravathi-Gurupur estuary, India, for trace metals and pesticide pollution. The descended order of studied metal concentrations (µg/L) in the water was Fe (592.71) > Mn (98.35) > Zn (54.69) > Cu (6.64) > Cd (3.24) > Pb (2.38) > Cr (0.82) and in sediment (mg/kg) was Fe (11,396.53) > Mn (100.61) > Cr (75.41) > Zn (20.04) > Cu (12.77) > Pb (3.46) > Cd (0.02). However, pesticide residues were not detected in this estuarine environment. The various metal indexes categorised the water as uncontaminated, whereas contamination factor, enrichment factor, geo-accumulation index, degree of contamination and pollution load index indicated low to moderate sediment contamination. Multivariate statistics showed that the dominance of natural sources of trace metals with little anthropogenic impact. Improvement in water/sediment quality during the study period might be due to COVID-19 imposed lockdown.

Assessment of water quality of Netravathi-Gurupur estuary, India through chemometric approach for fisheries sustainability.

The present study aimed to assess the water quality dynamics (physicochemical properties, nutrient and chlorophyll-a) in the Netravathi-Gurupur estuary, India across the space and seasons and to simplify the complex water quality dataset through a chemometric approach. The results indicated that pH, EC, temperature, alkalinity, salinity, TDS, hardness, chloride and intense mixing of suspended solids, driven by the semidiurnal tides, are the major factors affecting water quality. Spatial heterogeneity and monsoon have profound impact on nutrient distribution revealing the following values (mg l-1): phosphate-P (0.015-0.105), nitrate-N (0.016-0.094), nitrite-N (0.001-0.012), and silicate (1.83-14.50). The estuary was evaluated for suitability for brackish water fisheries. The results indicated fair water quality during pre- and post-monsoon but marginal quality in monsoon, primarily due to dilution associated with reduced salinity. The outcome of this study can be suitably utilized for the sustainable development of estuaries and their feasibility for brackish water fisheries.

Geochemical distribution and forms of phosphorus in the surface sediment of Netravathi-Gurupur estuary, southwestern coast of India.

Estuaries are the most productive transition ecosystem and phosphorus (P) plays an important role in these ecosystems. Therefore, in the present study, sequential extraction method was used to determine the abundance of five sediment P fractions (calcium (Ca-P), Iron (FeP), aluminum (AlP), exchangeable (Ex-P) and organic (OrgP) bound P) in Netravathi-Gurupur estuary, India. Total phosphorus (TP) content varied from 435-810 mg/kg (non-monsoon) and 258-699 mg/kg (monsoon). Inorganic P was dominant part. Different P fractions followed similar order (Fe-P > Ca-P > Al-P > Org-P > Ex-P) with respect to seasons. FeP was dominant fraction, indicating probable anthropogenic stress. Sediment may act as source of P as bioavailable P constituted 40-69.2 % of TP. Molar ratio of OC to Org-P in sediment indicated terrestrial sources of organic matter. However, the estimated phosphorus pollution index were lower than one except a few cases indicating less ecological risk with respect to sedimentary TP load.

Neuroimaging Markers for Determining Former American Football Players at Risk for Alzheimer's Disease.

NFL players, by virtue of their exposure to traumatic brain injury (TBI), are at higher risk of developing dementia and Alzheimer's disease (AD) than the general population. Early recognition and intervention before the onset of clinical symptoms could potentially avert/delay the long-term consequences of these diseases. Given that AD is thought to have a long pre-clinical incubation period, the aim of the current research was to determine whether former NFL players show evidence of incipient dementia in their structural imaging before diagnosis of AD. To identify neuroimaging markers of AD, against which former NFL players would be compared, we conducted a whole-brain volumetric analysis using a cohort of AD patients (ADNI clinical database) to produce a set of brain regions demonstrating sensitivity to early AD pathology (i.e., the "AD fingerprint"). A group of 46 former NFL players' brain magnetic resonance images were then interrogated using the AD fingerprint, that is, the former NFL subjects were compared volumetrically to AD patients using a T1-weighted magnetization-prepared rapid gradient echo sequence. The FreeSurfer image analysis suite (version 6.0) was used to obtain volumetric and cortical thickness data. The Automated Neuropsychological Assessment Metric-Version 4 was used to assess current cognitive functioning. A total of 55 brain regions demonstrated significant atrophy or ex vacuo dilatation bilaterally in AD patients versus controls. Of the 46 former NFL players, 41% demonstrated a greater than expected number of atrophied/dilated AD regions compared with age-matched controls, presumably reflecting AD pathology.

The Prevalence of Ocular Manifestations in the Various Types of Common Skin Disorders at Tertiary Hospital in Ahmedabad, India.

Aim The article aims to study the prevalence and ocular manifestations of the various types of common skin disorders at a tertiary hospital in Ahmedabad, India.  Materials and methods Five hundred patients were studied in the ophthalmology department from September 2017 to September 2019. Results Out of the 500 patients that were included in our study, 312 were males, and 188 were females. In our study, lid involvement was seen most commonly in patients with herpes zoster ophthalmicus (HZO). Plexiform neurofibroma was seen in eight (14.5%) patients with neurofibromatosis (NF). Cicatricial ectropion was found in half of the patients with ichthyosis. Lagophthalmos was present in 10 (20.4%) patients with leprosy. Conjunctivitis was seen commonly in HZO patients. Papillary conjunctivitis was seen in half of the atopic dermatitis cases. Steven Johnson's syndrome (SJS) was associated with pseudomembranous conjunctivitis. Conjunctival xerosis was seen only in patients with Sjogren's syndrome. The cornea was most commonly involved in patients of HZO. Decreased corneal sensation was seen in leprosy and HZO. Lisch nodules were seen in NF cases. Anterior uveitis was found in seven (6.3%) patients with HZO. Glaucoma was seen most commonly in patients with Sturge Weber syndrome (SWS), followed by leprosy. Facial nerve palsy was seen in patients with leprosy. Episcleritis was seen in patients with leprosy and SWS. Conclusion We conclude that ocular involvement in skin disease is a common feature and could be a major component of the development of various systemic skin disorders.

Malabar sole (Cynoglossus macrostomus) skin as promising source of type I acid and pepsin solubilized collagens with potential bioactivity.

Fish skin is one of the major non-edible by-products formed during fish processing. This investigation focused on the sustainable valorization of Malabar sole (MS) skin for collagen, which can be utilized as potential alternative of mammalian collagen. Acid and pepsin solubilized collagen (ASC and PSC) were successfully isolated from MS skin with a yield (%, dry weight basis) of 49.5 ± 0.6 and 67.6 ± 0.5, respectively. The isolated collagens were characterized by SDS-PAGE, UV-absorption, DSC, SEM, FTIR spectroscopy, etc., analysis. Both collagens were characterized as type I by SDS-PAGE and the well preserved triple helical structure by FTIR and UV absorption analysis. Denaturation temperature (°C) of the MS skin collagens confirmed by DSC analysis was 33.67 (ASC) and 33.38 (PSC). Both collagens showed high solubility in acidic pH and low NaCl level, and also exhibited a comparatively high degree of fibril-forming capacity. Antioxidant potential of the isolated collagens was confirmed by DPPH (31.4-34.6% at 1.5 mg) and peroxyl (64.6-68.3% at 0.3 mg) radical scavenging assays and observed a dose dependent manner activity. Overall, the results suggested the possibility of using the MS skin as a potential substitute source of realistic type I collagen and also help to reduce issues of fish processing discards. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at (10.1007/s13197-021-04996-8).

Phosphorus fractions in the sediment of a tropical reservoir, India: Implications for pollution source identification and eutrophication.

Eutrophication level in lakes and reservoirs depends on both internal and external phosphorus (P) load. Characterization of sediment P fractionation and identifying the P pollution sources are important for assessing the bio-availability of P and the dominant P source, for effectively controlling the water pollution. For determining the availability and sources of sediment P and eutrophication status, spatio-temporal variation in different P fractionation of sediment of hyper-eutrophic Krishnagiri reservoir, Tamil Nadu, India, was investigated. Sediment average total P (TP) content ranged from 4.62 to 5.64 g/kg. Main phosphorus form was the inorganic P (IP), and it makes up to 73.4-87.7% of TP. Among the different P fraction, viz. calcium bound (Ca-P), iron bound (Fe-P), aluminium bound (Al-P), exchangeable (Ex-P) and Organic-P (Org-P), Ca-P was the dominating fraction in both IP and TP. Trend of IP fraction was as follows: Ca-P > Fe-P > Al-P > Ex-P in pre-monsoon season, Fe-P > Ca-P > Al-P > Ex-P in monsoon and Ca-P > Al-P > Fe-P > Ex-P in post-monsoon. Overall the trend was as follows Ca-P > Fe-P > Al-P > Org-P > Ex-P. Bio-available-P (BAP) fractions ranged from 35.2 to 64.0% of TP, indicating its comparative higher value. Pearson's correlation matrix revealed that there was strong correlation among the different P fractions. Factor analysis indicates that different fractions of P were the dominating factor than the other sediment parameters. The observed variation in sediment P fractionation indicate the differences in source and characterization of P which is very helpful for implementation of effective management practices in controlling pollution that arises due to phosphorus in this hyper-eutrophic reservoir.

Ethnomedicine based evaluation of osteoprotective properties of Tinospora cordifolia on in vitro and in vivo model systems.

Indian ethnomedicine acclaims the use of Tinospora cordifolia (TC) in the treatment of bone fractures and vat rakta (gout). The objective of the study is to investigate the effects of alcoholic extract of Tinospora cordifolia on bone remodeling (involving osteoblastic and osteoclastic actions) in vitro and protect against ovariectomy-induced bone loss in vivo. Human osteoblast-like cells MG-63 and primary osteoblast cells isolated from rat femur were used as osteoblast models and RAW macrophage cell line 264.7 induced to take up osteoclastic lineage using RANK ligand were used as osteoclast models in the current study. Sirius red staining, quantification of osteocalcin, cytopathological analysis by Hematoxylin/eosin staining and semiquantitative reverse transcription PCR (RT-PCR) was carried out to ascertain the effects of T. cordifolia extract on osteoblast cells. MTT assay was perfomed to understand the influence of T. cordifolia extract on osteoclast cells. Adult female Sprague-Dawley rats were used as in vivo models to study the effect of T. cordifolia on ovariectomy induced bone loss. Radiological (DEXA analysis), Biochemical (markers of bone formation and resorption), histopathological (Hematoxylin/eosin staining) and histomorphometric analysis of the bone was carried out. Treatment with T. cordifolia extract resulted in enhanced collagen deposition, increased levels of osteocalcin, increased expression of osteogenic genes all indicative of favourable osteoblastogenesis. Treatment with T. cordifolia extract did not exert any significant influence on the proliferation of osteoclasts. Pretreatment with T. cordifolia extract at a dose of 50mg/kg body wt/day orally for 21days followed by treatment for 12 weeks post ovariectomy was able to prevent ovariectomy-induced bone loss in vivo. Results of the study support the use of T. cordifolia in Indian ethnomedicine for the treatment of bone diseases and fractures.

Phase transition kinetics and surface binding states of methylammonium lead iodide perovskite.

We have presented a detailed analysis of the phase transition kinetics and binding energy states of solution processed methylammonium lead iodide (MAPbI3) thin films prepared at ambient conditions and annealed at different elevated temperatures. It is the processing temperature and environmental conditions that predominantly control the crystal structure and surface morphology of MAPbI3 thin films. The structural transformation from tetragonal to cubic occurs at 60 °C with a 30 minute annealing time while the 10 minute annealed films posses a tetragonal crystal structure. The transformed phase is greatly intact even at the higher annealing temperature of 150 °C and after a time of 2 hours. The charge transfer interaction between the Pb 4f and I 3d oxidation states is quantified using XPS.

Anti-skin ageing activity of napthoquinones from Arnebia nobilis Reichb.f.

The present isolation and identification of napthoquinones from roots of Arnebia nobilis Reichb.f. can lead to the discovery of new anti-skin ageing ingredient in colour cosmetics. Four compounds have been isolated and purified by rigorous column chromatography. The compounds are identified as ß, ß-dimethylacryl alkannin (AN-I), acetoxyisovaleryl alkannin (AAN-II), acetyl alkannin (AN-III) and alkannin (AN-IV) by interpretation of spectroscopic data. This study is the first to report the isolation of Acetoxyisovaleryl alkannin (AAN-II) from A. nobilis. The IC50 values of the compounds, determined in human skin cells (human dermal fibroblasts and human keratinocytes) and mouse embryonic fibroblasts (NIH3T3) varied significantly among the four alkannins. Among the four compounds, ß-acetoxyisovaleryl alkannin (AAN-II) significantly inhibited hydrogen peroxide (H2O2)-induced red blood corpuscle haemolysis and cellular senescence in human dermal fibroblasts. Collagen-I, elastin and involucrin syntheses in human dermal fibroblasts or keratinocytes were up regulated by AAN-II. These results support the potential utility of alkannins as novel anti-ageing ingredients.

Improving care coordination between nephrology and primary care: a quality improvement initiative using the renal physicians association toolkit.

BACKGROUND: Individuals at risk for chronic kidney disease (CKD), including those with diabetes mellitus and hypertension, are prevalent in primary care physician (PCP) practices. A major systemic barrier to mitigating risk of progression to kidney failure and to optimal care is failure of communication and coordination among PCPs and nephrologists. STUDY DESIGN: Quality improvement. Longitudinal practice-level study of tool-based intervention in nephrology practices and their referring PCP practices. SETTING & PARTICIPANTS: 9 PCP and 5 nephrology practices in Philadelphia and Chicago. QUALITY IMPROVEMENT PLAN: Tools from Renal Physicians Association toolkit were modified and provided for use by PCPs and nephrologists to improve identification of CKD, communication, and comanagement. OUTCOMES: CKD identification, referral to nephrologists, communication among PCPs and nephrologists, comanagement processes. MEASUREMENTS: Pre- and postimplementation interviews, questionnaires, site visits, and monthly teleconferences were used to ascertain practice patterns, perceptions, and tool use. Interview transcripts were reviewed for themes using qualitative analysis based on grounded theory. Chart audits assessed CKD identification and referral (PCPs). RESULTS: PCPs improved processes for CKD identification, referral to nephrologists, communication, and execution of comanagement plans. Documentation of glomerular filtration rate was increased significantly (P=0.01). Nephrologists improved referral and comanagement processes. PCP postintervention interviews documented increased awareness of risk factors, the need to track high-risk patients, and the importance of early referral. Final nephrologist interviews revealed heightened attention to communication and comanagement with PCPs and increased levels of satisfaction among all parties. LIMITATIONS: Nephrology practices volunteered to participate and recruit their referring PCP practices. Audit tools were developed for quality improvement assessment, but were not designed to provide statistically significant estimates. CONCLUSIONS: The use of specifically tailored tools led to enhanced awareness and identification of CKD among PCPs, increased communication between practices, and improvement in comanagement and cooperation between PCPs and nephrologists.

Fluorocarbon adsorption in hierarchical porous frameworks.

Metal-organic frameworks comprise an important class of solid-state materials and have potential for many emerging applications such as energy storage, separation, catalysis and bio-medical. Here we report the adsorption behaviour of a series of fluorocarbon derivatives on a set of microporous and hierarchical mesoporous frameworks. The microporous frameworks show a saturation uptake capacity for dichlorodifluoromethane of >4 mmol g(-1) at a very low relative saturation pressure (P/Po) of 0.02. In contrast, the mesoporous framework shows an exceptionally high uptake capacity reaching >14 mmol g(-1) at P/Po of 0.4. Adsorption affinity in terms of mass loading and isosteric heats of adsorption is found to generally correlate with the polarizability and boiling point of the refrigerant, with dichlorodifluoromethane > chlorodifluoromethane > chlorotrifluoromethane > tetrafluoromethane > methane. These results suggest the possibility of exploiting these sorbents for separation of azeotropic mixtures of fluorocarbons and use in eco-friendly fluorocarbon-based adsorption cooling.

The serum levels of malondialdehyde, vitamin e and erythrocyte catalase activity in psoriasis patients.

BACKGROUND: Psoriasis is a common skin disease which is characterized by increased epidermal proliferation and dermal inflammation affecting 0.1-3% of general population. Most of the psoriasis patients are young or middle aged adults, although no age exempted. The oxidative stress develops due to imbalance in oxidants and antioxidants, which was proposed to have role in psoriasis. AIMS AND OBJECTIVES: The presented research work was planned to evaluate oxidative stress by measuring serum malondialdehyde (MDA) as oxidant and serum vitamin E, erythrocyte catalase (CAT) activity as antioxidants in psoriasis patients. MATERIALS AND METHODS: Total 90 clinically diagnosed psoriasis patients of age group of 20 to 60 years and without any drug therapy for preceding two months and 90 matched healthy controls were included in the presented study. The severity of psoriasis was determined by PASI score. The fasting blood sample collected and accessed for serum MDA, serum vitamin E and erythrocyte catalase activity. RESULTS: The study results were compiled and statistical analysis was done using students t-test. Our results showed significantly increased levels of serum MDA (p<0.001) and significantly decreased serum vitamin E (p<0.001) as well as erythrocyte catalase activity (p<0.001) in psoriasis patients as compared to controls. CONCLUSION: The presented study concluded the oxidative stress in psoriasis, indicated by increased serum MDA and decreased Vitamin E, erythrocyte catalase activity. Our study also supports the possibility of involvement of oxidative stress in pathogenesis of psoriasis.

Discovery and evaluation of a non-Zn chelating, selective matrix metalloproteinase 13 (MMP-13) inhibitor for potential intra-articular treatment of osteoarthritis.

Osteoarthritis (OA) is a nonsystemic disease for which no oral or parenteral disease-modifying osteoarthritic drug (DMOAD) is currently available. Matrix metalloproteinase 13 (MMP-13) has attracted attention as a target with disease-modifying potential because of its major role in tissue destruction associated with OA. Being localized to one or a few joints, OA is amenable to intra-articular (IA) therapy, which has distinct advantages over oral therapies in terms of increasing therapeutic index, by maximizing drug delivery to cartilage and minimizing systemic exposure. Here we report on the synthesis and biological evaluation of a non-zinc binding MMP-13 selective inhibitor, 4-methyl-1-(S)-({5-[(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)carbamoyl]pyrazolo[1,5-a]pyrimidine-7-carbonyl}amino)indan-5-carboxylic acid (1), that is uniquely suited as a potential IA-DMOAD: it has long durability in the joint, penetrates cartilage effectively, exhibits nearly no detectable systemic exposure, and has remarkable efficacy.

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models.

OBJECTIVE: Matrix metalloproteinases (MMPs) have long been considered excellent targets for osteoarthritis (OA) treatment. However, clinical utility of broad-spectrum MMP inhibitors developed for this purpose has been restricted by dose-limiting musculoskeletal side effects observed in humans. This study was undertaken to identify a new class of potent and selective MMP-13 inhibitors that would provide histologic and clinical efficacy without musculoskeletal toxicity. METHODS: Selectivity assays were developed using catalytic domains of human MMPs. Freshly isolated bovine articular cartilage or human OA cartilage was used in in vitro cartilage degradation assays. The rat model of monoiodoacetate (MIA)-induced OA was implemented for assessing the effects of MMP-13 inhibitors on cartilage degradation and joint pain. The surgical medial meniscus tear model in rats was used to evaluate the chondroprotective ability of MMP-13 inhibitors in a chronic disease model of OA. The rat model of musculoskeletal side effects (MSS) was used to assess whether selective MMP-13 inhibitors have the joint toxicity associated with broad-spectrum MMP inhibitors. RESULTS: A number of non-hydroxamic acid-containing compounds that showed a high degree of potency for MMP-13 and selectivity against other MMPs were designed and synthesized. Steady-state kinetics experiments and Lineweaver-Burk plot analysis of rate versus substrate concentration with one such compound, ALS 1-0635, indicated linear, noncompetitive inhibition, and Dixon plot analysis from competition studies with a zinc chelator (acetoxyhydroxamic acid) and ALS 1-0635 demonstrated nonexclusive binding. ALS 1-0635 inhibited bovine articular cartilage degradation in a dose-dependent manner (48.7% and 87.1% at 500 nM and 5,000 nM, respectively) and was effective in inhibiting interleukin-1alpha- and oncostatin M-induced C1,C2 release in human OA cartilage cultures. ALS 1-0635 modulated cartilage damage in the rat MIA model (mean +/- SEM damage score 1.3 +/- 0.3, versus 2.2 +/- 0.4 in vehicle-treated animals). Most significantly, when treated twice daily with oral ALS 1-0635, rats with surgically induced medial meniscus tear exhibited histologic evidence of chondroprotection and reduced cartilage degeneration, without observable musculoskeletal toxicity. CONCLUSION: The compounds investigated in this study represent a novel class of MMP-13 inhibitors. They are mechanistically distinct from previously reported broad-spectrum MMP inhibitors and do not exhibit the problems previously associated with these inhibitors, including selectivity, poor pharmacokinetics, and MSS liability. MMP-13 inhibitors exert chondroprotective effects and can potentially modulate joint pain, and are, therefore, uniquely suited as potential disease-modifying osteoarthritis drugs.

Steroid resistant nephrotic syndrome is sustained remission attainable.

A prospective study was undertaken to find out the benefit of immunosuppressive therapy(IV methyl prednisolone followed by oral prednisolone therapy for one year along with six doses of pulse monthly IV cyclophosphamide) in children with steroid resistant nephrotic syndrome. Thirty-four children with steroid resistant nephrotic syndrome were treated with above regime. The remission of the disease was determined at the end of first, second and third year. The above protocol could induce and maintain remission in 81.8% of children with minimal change nephrotic syndrome, 66.7% of children with diffuse mesangial proliferation and in only 16.7% of children with focal segmental glomerulosclerosis at the end of three years of the study. The therapy of IV methyl prednisolone followed by oral prednisolone for one year with 6 monthly pulse IV cyclophosphamide, is beneficial in children with steroid resistant minimal change disease and diffuse mesangial proliferative glomerulonephritis. The therapy is not effective in focal segmental glomerulosclerosis.

Biological properties of curcumin-cellular and molecular mechanisms of action.

Curcuminoids, a group of phenolic compounds isolated from the roots of Curcuma longa (Zingiberaceae), exhibit a variety of beneficial effects on health and on events that help in preventing certain diseases. A vast majority of these studies were carried out with curcumin (diferuloyl methane), which is a major curcuminoid. The most detailed studies using curcumin include anti-inflammatory, antioxidant, anticarcinogenic, antiviral, and antiinfectious activities. In addition, the wound healing and detoxifying properties of curcumin have also received considerable attention. As a result of extensive research on the therapeutic properties of curcumin, some understanding on the cellular, molecular, and biochemical mechanism of action of curcumin is emerging. These findings are summarized in this review.

Antifertility effect of ethanolic extract of Amalakyadi churna in male albino mice.

AIM: To evaluate the antifertility activity of the ethanolic extract of Amalakyadi churna by oral administration in male albino mice. METHODS: The ethanol extract of Amalakyadi churna at the dose of 250 mg/kg and 400 mg/kg body weight was administered orally for 30 days to adult male mice. On day 31, the mice were sacrificed and the testis and accessory reproductive organs were removed and weighed. The organs were processed for biochemical estimation and histological work. RESULTS: Treatment with Amalakyadi churna resulted in decrease in the weights of testis and accessory reproductive organs. The diameters of testis, seminiferous tubules and Leydig cell nucleus were decreased. The spermatogenic elements, like spermatogonia, spermatocytes and spermatids in the testis were reduced significantly as well as the sperm count in cauda epididymis. There was a significant reduction in the protein, glycogen, DNA and RNA contents and the activity of acid phosphatase in the testis of extract treated mice compared with the control. The cholesterol content and the alkaline phophatase activity were increased significantly in treated mice. CONCLUSION: Amalakyadi churna extract arrests spermatogenesis in male mice without noticeable side effects.

Plasmodium falciparum glycosylphosphatidylinositol-induced TNF-alpha secretion by macrophages is mediated without membrane insertion or endocytosis.

The glycosylphosphatidylinositols (GPIs) of Plasmodium falciparum are believed to contribute to the pathogenesis of malaria by inducing the secretion of proinflammatory cytokines by macrophages. Previous studies have shown that P. falciparum GPIs elicit toxic immune responses by protein tyrosine kinase (PTK)- and protein kinase C (PKC)-mediated cell signaling pathways, which are activated by the carbohydrate and acyl moieties of the intact GPIs, respectively. In this study, we show that induction of TNF-alpha by P. falciparum GPIs in macrophages is mediated by the recognition of the distal fourth mannose residue. This event is critical but not sufficient for the productive cell signaling; interaction by the acylglycerol moiety of GPIs is also required. These novel interactions are coupled to previously demonstrated PTK and PKC pathways, since the specific inhibitors of these kinases effectively blocked the GPI-induced TNF-alpha production. Surprisingly, sn-2 lyso-GPIs were also able to elicit TNF-alpha secretion. Contrary to the prevailing notion, GPIs are neither inserted to the plasma membranes nor endocytosized. Thus, this study defines the GPI structural requirements and reveals a novel mechanism for the outside-in activation of cell signaling by P. falciparum GPIs in inducing proinflammatory responses.

Glycosylphosphatidylinositol anchors of Plasmodium falciparum: molecular characterization and naturally elicited antibody response that may provide immunity to malaria pathogenesis.

Induction of proinflammatory cytokine responses by glycosylphosphatidylinositols (GPIs) of intraerythrocytic Plasmodium falciparum is believed to contribute to malaria pathogenesis. In this study, we purified the GPIs of P. falciparum to homogeneity and determined their structures by biochemical degradations and mass spectrometry. The parasite GPIs differ from those of the host in that they contain palmitic (major) and myristic (minor) acids at C-2 of inositol, predominantly C18:0 and C18:1 at sn-1 and sn-2, respectively, and do not contain additional phosphoethanolamine substitution in their core glycan structures. The purified parasite GPIs can induce tumor necrosis factor alpha release from macrophages. We also report a new finding that adults who have resistance to clinical malaria contain high levels of persistent anti-GPI antibodies, whereas susceptible children lack or have low levels of short-lived antibody response. Individuals who were not exposed to the malaria parasite completely lack anti-GPI antibodies. Absence of a persistent anti-GPI antibody response correlated with malaria-specific anemia and fever, suggesting that anti-GPI antibodies provide protection against clinical malaria. The antibodies are mainly directed against the acylated phosphoinositol portion of GPIs. These results are likely to be valuable in studies aimed at the evaluation of chemically defined structures for toxicity versus immunogenicity with implications for the development of GPI-based therapies or vaccines.