Postharvest handling of ethylene with oxidative and absorptive means.

Fruit ripening is an unfolding of a series of genetically-programmed modifications and tend to be highly orchestrated irrevocable phenomenon mediated by ethylene. Phytohormone ethylene also leads to over-ripening, senescence, loss of texture, microbial attack, reduced post-harvest life and other associated problems during storage and transportation of fruits. Its harmful impacts on fresh fruits, vegetables, and ornamentals result in substantial product losses even up to 80%. Curbing of this inevitable menace is therefore need of the hour. Accrual of ethylene in packaging system should fundamentally be ducked to extend the shelf-life and uphold an adequate superiority of perishables in visual and organoleptic terms. The current review discusses about properties, factors affecting and impact of ethylene, intimidation of its impact at gene vis-à-vis activity level using gene-modification/inhibition techniques, chemical/physical in conjunction with other suitable approaches. It also entails the most commercially cultivated approaches worldwide viz. KMnO4-based oxidation together with adsorption-based scrubbing of ethylene in thorough details. Future ethylene removal strategies should focus on systematic evaluation of KMnO4-based scavenging, exploring the mechanism of adsorption, adsorbent(s) behavior in the presence of other gases and their partial pressures, volatiles, temperature, relative humidity, development of hydrophobic adsorbents to turn-up under high RH, regeneration of adsorbent by desorption, improvement in photocatalytic oxidation etc. and further improvements thereof. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-023-05777-1.

Clinical and radiological spectrum of anti-myelin oligodendrocyte glycoprotein (MOG) antibody encephalitis: single-center observational study.

OBJECTIVE: The objective was to describe the clinical presentations, radiologic features, and outcomes of patients with autoimmune encephalitis associated with myelin oligodendrocyte glycoprotein antibody (MOG). BACKGROUND: During the past decade, the spectrum of the myelin oligodendrocyte glycoprotein antibody-associated diseases (MOGAD) has expanded. Recently, patients with MOG antibody encephalitis (MOG-E) who do not fulfill the criteria for ADEM have been reported. In this study, we aimed to describe the spectrum of MOG-E. METHODS: Sixty-four patients with MOGAD were screened for encephalitis-like presentation. We collected the clinical, radiological, laboratory, and outcome data of the patients who presented with encephalitis and compared it with the non-encephalitis group. RESULTS: We identified sixteen patients (nine males and seven females) with MOG-E. The median age of the encephalitis population was significantly lower than the non-encephalitis group (14.5 years (11.75-18) vs. 28 years (19.75-42), p = 0.0004). Twelve out of sixteen patients (75%) had fever at the time of encephalitis. Headache and seizure were present in 9/16 (56.2%) and 7/16 (43.75%) patients, respectively. FLAIR cortical hyperintensity was present in 10/16 (62.5%) patients. Supratentorial deep gray nuclei were involved in 10/16 (62.5%) patients. Three patients had tumefactive demyelination, and one patient had a leukodystrophy-like lesion. Twelve of 16 (75%) patients had a good clinical outcome. Patient with leukodystrophy pattern and other with generalized CNS atrophy showed a chronic progressive course. CONCLUSION: MOG-E can have heterogeneous radiological presentations. FLAIR cortical hyperintensity, tumefactive demyelination, and leukodystrophy-like presentations are novel radiological presentations associated with MOGAD. Though majority of MOG-E have a good clinical outcome, few patients can have chronic progressive disease even on immunosuppressive therapy.

Digestive exophagy: Phagocyte digestion of objects too large for phagocytosis.

Mammalian phagocytes carry out several essential functions, including killing and digesting infectious organisms, clearing denatured proteins, removing dead cells and removing several types of debris from the extracellular space. Many of these functions involve phagocytosis, the engulfment of a target in a specialized endocytic process and then fusion of the new phagosome with lysosomes. Phagocytes such as macrophages can phagocytose targets that are several micrometers in diameter (eg, dead cells), but in some cases they encounter much larger objects. We have studied two such examples in some detail: large deposits of lipoproteins such as those in the wall of blood vessels associated with atherosclerosis, and dead adipocytes, which are dozens of micrometers in diameter. We describe a process, which we call digestive exophagy, in which macrophages create a tight seal in contact with the target, acidify the sealed zone and secrete lysosomal contents into the contact zone. By this process, hydrolysis by lysosomal enzymes occurs in a compartment that is outside the cell. We compare this process to the well characterized digestion of bone by osteoclasts, and we point out key similarities and differences.

Polyubiquitin and ubiquitin-like signals share common recognition sites on proteasomal subunit Rpn1.

Proteasome-mediated substrate degradation is an essential process that relies on the coordinated actions of ubiquitin (Ub), shuttle proteins containing Ub-like (UBL) domains, and the proteasome. Proteinaceous substrates are tagged with polyUb and shuttle proteins, and these signals are then recognized by the proteasome, which subsequently degrades the substrate. To date, three proteasomal receptors have been identified, as well as multiple shuttle proteins and numerous types of polyUb chains that signal for degradation. While the components of this pathway are well-known, our understanding of their interplay is unclear-especially in the context of Rpn1, the largest proteasomal subunit. Here, using nuclear magnetic resonance (NMR) spectroscopy in combination with competition assays, we show that Rpn1 associates with UBL-containing proteins and polyUb chains, while exhibiting a preference for shuttle protein Rad23. Rpn1 appears to contain multiple Ub/UBL-binding sites, theoretically as many as one for each of its hallmark proteasome/cyclosome repeats. Remarkably, we also find that binding sites on Rpn1 can be shared among Ub and UBL species, while proteasomal receptors Rpn1 and Rpn10 can compete with each other for binding of shuttle protein Dsk2. Taken together, our results rule out the possibility of exclusive recognition sites on Rpn1 for individual Ub/UBL signals and further emphasize the complexity of the redundancy-laden proteasomal degradation pathway.

Impact of exercise as a complementary management strategy in people with epilepsy: A randomized controlled trial.

OBJECTIVE: To measure the impact of 12 weeks of physical exercise as complementary management strategy on quality of life (QOL) in people with epilepsy (PWE). METHODS: In a parallel-group, randomized controlled study with blinded outcome assessment, PWE of 18-65 years old, smartphone users were randomized into two groups. The exercise group was advised minimum 150 min per week of moderate-intense aerobic activity, as per current WHO recommendation [1], in addition to standard medical care; the control group received only standard medical care. QOL was assessed using Quality of Life in Epilepsy (QOLIE-31) inventory [2,3]; physical activity, with Global Physical Activity Questionnaire version 2 (GPAQ), and Pedometer Step Counter (a smartphone-based activity tracker application), at baseline and after 12 weeks. Body weight, body mass index, seizure frequency, and stigma scores (Epilepsy Stigma Scale Austin and colleagues) [4] were also noted. RESULTS: One hundred and seventeen PWE were recruited (58 exercise, 59 control). Although there was an improvement in the physical activity correlates after 12 weeks compared to mean values at baseline, the differences were not significant between the groups. The total QOL mean scores at baseline in the exercise and control groups were 64.9 and 63.7 (p = 0.597) and after 12 weeks, 68.4 and 66.9 (p = 0.660), respectively. However, intragroup comparison of energy/fatigue score in the exercise group showed significant change with a p value of 0.009 and intragroup comparison of Overall QOL score in the control group showed a significant change with a p value of 0.003. Similar improvement was seen in stigma scores (p = 0.500) and seizure frequency (p = 0.388) at 12 weeks in exercise and control groups. After 12 weeks, mean values of METS ((metabolic equivalents) were 794.81 and 714.27 (p = 0.159), steps per day were 4018.32 and 3730.0 (p = 0.314), calories spent per day were 173.85 and 159.68 (p = 0.320 and distance walked per day in meters were 2576.52 and 2198.42 (p = 0.072), in the exercise and control groups, respectively. SIGNIFICANCE: Regular physical activity for at least 150 min per week, in the form of moderate-intense aerobic exercises resulted in positive yet non-significant improvement of QOL, seizure frequency, and stigma in PWE.

Late-onset cobalamin C disease: rare but treatable.

Cobalamin C disease is the most common inborn error of cobalamin metabolism, resulting from mutations in methylmalonic aciduria and homocystinuria type C protein (MMACHC) gene. There is associated elevation of homocysteine and methylmalonic acid and decreased synthesis of methionine. It is a multisystem disorder characterised by cognitive impairment, psychiatric manifestations, haematological manifestations and thromboembolic phenomena. Its variable clinical presentation and wide age distribution at presentation necessitates a high index of diagnostic suspicion. The diagnosis is suggested by amino acid chromatography and confirmed by sequencing analysis of the MMACHC gene Parenteral hydroxycobalamin and betaine can bring significant clinical and biochemical improvement and is the recommended long-term therapy.

High-density lipoprotein or cyclodextrin extraction of cholesterol from aggregated LDL reduces foam cell formation.

Low-density lipoprotein (LDL) deposition, aggregation and retention in the endothelial sub-intima are critical initiating events during atherosclerosis. Macrophages digest aggregated LDL (agLDL) through a process called exophagy. High-density lipoprotein (HDL) plays an atheroprotective role, but studies attempting to exploit it therapeutically have been unsuccessful, highlighting gaps in our current understanding of HDL function. Here, we characterized the role of HDL during exophagy of agLDL. We find that atherosclerotic plaque macrophages contact agLDL and form an extracellular digestive compartment similar to that observed in vitro During macrophage catabolism of agLDL in vitro, levels of free cholesterol in the agLDL are increased. HDL can extract free cholesterol directly from this agLDL and inhibit macrophage foam cell formation. Cholesterol-balanced hydroxypropyl-ß-cyclodextrin similarly reduced macrophage cholesterol uptake and foam cell formation. Finally, we show that HDL can directly extract free cholesterol, but not cholesterol esters, from agLDL in the absence of cells. Together, these results suggest that the actions of HDL can directly extract free cholesterol from agLDL during catabolism, and provide a new context in which to view the complex relationship between HDL and atherosclerosis.

TLR4 (Toll-Like Receptor 4)-Dependent Signaling Drives Extracellular Catabolism of LDL (Low-Density Lipoprotein) Aggregates.

OBJECTIVE: Aggregation and modification of LDLs (low-density lipoproteins) promote their retention and accumulation in the arteries. This is a critical initiating factor during atherosclerosis. Macrophage catabolism of agLDL (aggregated LDL) occurs using a specialized extracellular, hydrolytic compartment, the lysosomal synapse. Compartment formation by local actin polymerization and delivery of lysosomal contents by exocytosis promotes acidification of the compartment and degradation of agLDL. Internalization of metabolites, such as cholesterol, promotes foam cell formation, a process that drives atherogenesis. Furthermore, there is accumulating evidence for the involvement of TLR4 (Toll-like receptor 4) and its adaptor protein MyD88 (myeloid differentiation primary response 88) in atherosclerosis. Here, we investigated the role of TLR4 in catabolism of agLDL using the lysosomal synapse and foam cell formation. Approach and Results: Using bone marrow-derived macrophages from knockout mice, we find that TLR4 and MyD88 regulate compartment formation, lysosome exocytosis, acidification of the compartment, and foam cell formation. Using siRNA (small interfering RNA), pharmacological inhibition and knockout bone marrow-derived macrophages, we implicate SYK (spleen tyrosine kinase), PI3K (phosphoinositide 3-kinase), and Akt in agLDL catabolism using the lysosomal synapse. Using bone marrow transplantation of LDL receptor knockout mice with TLR4 knockout bone marrow, we show that deficiency of TLR4 protects macrophages from lipid accumulation during atherosclerosis. Finally, we demonstrate that macrophages in vivo form an extracellular compartment and exocytose lysosome contents similar to that observed in vitro for degradation of agLDL. CONCLUSIONS: We present a mechanism in which interaction of macrophages with agLDL initiates a TLR4 signaling pathway, resulting in formation of the lysosomal synapse, catabolism of agLDL, and lipid accumulation in vitro and in vivo.

Dynamic Actin Reorganization and Vav/Cdc42-Dependent Actin Polymerization Promote Macrophage Aggregated LDL (Low-Density Lipoprotein) Uptake and Catabolism.

Objective- During atherosclerosis, LDLs (low-density lipoproteins) accumulate in the arteries, where they become modified, aggregated, and retained. Such deposits of aggregated LDL (agLDL) can be recognized by macrophages, which attempt to digest and clear them. AgLDL catabolism promotes internalization of cholesterol and foam cell formation, which leads to the progression of atherosclerosis. Therapeutic blockade of this process may delay disease progression. When macrophages interact with agLDL in vitro, they form a novel extracellular, hydrolytic compartment-the lysosomal synapse (LS)-aided by local actin polymerization to digest agLDL. Here, we investigated the specific regulators involved in actin polymerization during the formation of the LS. Approach and Results- We demonstrate in vivo that atherosclerotic plaque macrophages contacting agLDL deposits polymerize actin and form a compartment strikingly similar to those made in vitro. Live cell imaging revealed that macrophage cortical F-actin depolymerization is required for actin polymerization to support the formation of the LS. This depolymerization is cofilin-1 dependent. Using siRNA-mediated silencing, pharmacological inhibition, genetic knockout, and stable overexpression, we elucidate key roles for Cdc42 Rho GTPase and GEF (guanine nucleotide exchange factor) Vav in promoting actin polymerization during the formation of the LS and exclude a role for Rac1. Conclusions- These results highlight critical roles for dynamic macrophage F-actin rearrangement and polymerization via cofilin-1, Vav, and Cdc42 in LS formation, catabolism of agLDL, and foam cell formation. These proteins might represent therapeutic targets to treat atherosclerotic disease.

Morpholine as ubiquitous pharmacophore in medicinal chemistry: Deep insight into the structure-activity relationship (SAR).

Morpholine is a versatile moiety, a privileged pharmacophore and an outstanding heterocyclic motif with wide ranges of pharmacological activities due to different mechanisms of action. The ability of morpholine to enhance the potency of the molecule through molecular interactions with the target protein (kinases) or to modulate the pharmacokinetic properties propelled medicinal chemists and researchers to synthesize morpholine ring by the efficient ways and to incorporate this moiety to develop various lead compounds with diverse therapeutic activities. The present review primarily focused on discussing the most promising synthetic leads containing morpholine ring along with structure-activity relationship (SAR) to reveal the active pharmacophores accountable for anticancer, anti-inflammatory, antiviral, anticonvulsant, antihyperlipidemic, antioxidant, antimicrobial and antileishmanial activity. This review outlines some of the recent effective chemical synthesis for morpholine ring. The review also highlighted the metabolic liability of some clinical drugs containing this nucleus and various researches on modified morpholine to enhance the metabolic stability of drugs as well. Drugs bearing morpholine ring and those under clinical trials are also mentioned with the role of morpholine and their mechanism of action. This review will provide the necessary knowledge base to the medicinal chemists in making strategic structural changes in designing morpholine derivatives.

Medicinal chemistry of indole derivatives: Current to future therapeutic prospectives.

Indole is a versatile pharmacophore, a privileged scaffold and an outstanding heterocyclic compound with wide ranges of pharmacological activities due to different mechanisms of action. It is an superlative moiety in drug discovery with the sole property of resembling different structures of the protein. Plenty of research has been taking place in recent years to synthesize and explore the various therapeutic prospectives of this moiety. This review summarizes some of the recent effective chemical synthesis (2014-2018) for indole ring. This review also emphasized on the structure-activity relationship (SAR) to reveal the active pharmacophores of various indole analogues accountable for anticancer, anticonvulsant, antimicrobial, antitubercular, antimalarial, antiviral, antidiabetic and other miscellaneous activities which have been investigated in the last five years. The precise features with motives and framework of each research topic is introduced for helping the medicinal chemists to understand the perspective of the context in a better way. This review will definitely offer the platform for researchers to strategically design diverse novel indole derivatives having different promising pharmacological activities with reduced toxicity and side effects.

Novel ketoprofen-antioxidants mutual codrugs as safer nonsteroidal anti-inflammatory drugs: Synthesis, kinetic and pharmacological evaluation.

Ketoprofen belongs to one of the most common nonsteroidal anti-inflammatory drugs (NSAIDs) but its clinical usefulness has been restricted due to the high incidence of gastrointestinal complications. The release of reactive oxygen species (ROS) in NSAIDs therapy plays a major role in causing gastric complications. Antioxidants not only prevent gastric ulceration and lipid peroxidation but also preserve glutathione-type peroxidase (GPO) activity. Therefore, the present study investigates the utility of combining anti-inflammatory and antioxidant properties of two different compounds in a single molecule to form a series of 16 ketoprofen-antioxidant mutual codrugs. The free carboxylic group, which is believed to be one of the reasons for gastric toxicity of ketoprofen, was masked temporarily by simple and double esterification with alcoholic/phenolic-OH of natural antioxidants. In simple esterification, ketoprofen is directly linked to natural antioxidants (IIa-h) in the hope to obtain drugs free of gastric side effects. In an attempt to improve the in vivo lability, as well as gastric side effects, the double ester codrugs, that is, ketoprofen-antioxidant through the glycolic acid spacer (-CH2 COO; IIIa-h), have also been designed and synthesized. The synthesized codrugs were characterized by IR, 1 H NMR, 13 C NMR, mass spectroscopy and elemental analysis. The in vitro hydrolysis studies showed the lowest hydrolysis (highest stability) in acidic pH 1.2, whereas moderate hydrolysis was seen at pH 7.4 and significant hydrolysis in 80% human blood plasma, as indicated by their t1/2 . The pharmacological evaluation results indicate that these ketoprofen-antioxidant mutual codrugs showed the retention of anti-inflammatory and analgesic activity with a significant reduction in the ulcer index.

Chronomics of Circulating Plasma Lipid Peroxides and Antioxidant Enzymes in Renal Stone Formers.

The chronome of lipid peroxidation and anti-oxidant defense mechanisms may relate to the efficacy and management of time qualified preventive therapeutic and dietary interventions. One hundred renal stone patients, 20-60 years of age, and 50 clinically healthy volunteers, 21-45 years, were synchronized for 1 week with diurnal activity from 06:00 to 22:00 and nocturnal rest. All subjects took their usual meals three times daily (breakfast around 08:30, lunch around 13:00, and dinner around 20:30) with usual fluid intake. Drugs known to affect free radical system were not taken. Blood samples were collected at 6-h intervals for 24-h under standardized, presumably 24-h synchronized conditions. Determinations included plasma lipid peroxides, in terms of malondialdehyde (MDA) and blood superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and catalase (CAT) activities. A marked circadian variation was demonstrated for each studied variable by population-mean cosinor in renal stone patients and healthy participants (p < 0.001). By comparison to healthy subjects, parameter tests indicate that the stone formers had a higher MESOR of MDA, but a lower MESOR of SOD, GPx, GR and CAT. Furthermore, the patients also differed from the healthy controls in terms of their circadian amplitude and acrophase (tested jointly) of all variables (p < 0.001). Mapping the broader time structure with multifrequency circadian characteristics of oxidants and anti-oxidants is needed for exploring their role as marker in the treatment and management of urolithiasis.

Degradation of aggregated LDL occurs in complex extracellular sub-compartments of the lysosomal synapse.

Monocyte-derived cells use an extracellular, acidic, lytic compartment (a lysosomal synapse) for initial degradation of large objects or species bound to the extracellular matrix. Akin to osteoclast degradation of bone, extracellular catabolism is used by macrophages to degrade aggregates of low density lipoprotein (LDL) similar to those encountered during atherogenesis. However, unlike osteoclast catabolism, the lysosomal synapse is a highly dynamic and intricate structure. In this study, we use high resolution three dimensional imaging to visualize compartments formed by macrophages to catabolize aggregated LDL. We show that these compartments are topologically complex, have a convoluted structure and contain sub-regions that are acidified. These sub-regions are characterized by a close apposition of the macrophage plasma membrane and aggregates of LDL that are still connected to the extracellular space. Compartment formation is dependent on local actin polymerization. However, once formed, compartments are able to maintain a pH gradient when actin is depolymerized. These observations explain how compartments are able to maintain a proton gradient while remaining outside the boundaries of the plasma membrane.

Evaluation of cerebral arterial and venous system in tuberculous meningitis.

BACKGROUND: Central nervous system infection especially pyogenic results in cerebral venous sinus thrombosis. Tuberculous meningitis (TBM) although associated with infarctions but there is no comprehensive study evaluating the role of CVST contributing in infarction. PURPOSE: To evaluate cerebral arterial and venous system using MR angiography (MRA) and MR venography (MRV) in TBM, and correlate with clinical and MRI findings. MATERIALS AND METHODS: Consecutive patients with TBM were evaluated clinically and their consciousness was assessed by using Glasgow Coma scale. Cerebrospinal fluid analysis was done. Patients were subjected to MRI, MRA and MRV studies. The severity of TBM was categorized as grades I to III. Presence of infarction on MRI and its cause as arterial or venous was noted based on MRA and MRV abnormalities. RESULTS: Twenty-six patients were included whose median age was 23 years. Seven (26.9%) patients had stage I, 12 (46.2%) stage II and 7 (26.9%) stage III TBM. MRI revealed infarction in 13 (50%) patients and were in tubercular zone (caudate, lentiform nuclei, anterior limb and genu of internal capsule, and anterior thalamus) in all except one. MRA was abnormal in 11/25 (42.3%) patients; 7 had middle cerebral artery, 2 both posterior cerebral artery and middle cerebral artery, and 2 had narrowing of all intracranial vessels. MRV however did not reveal any evidence of CVST although revealed variation in normal anatomy in 14 (53.8%) patients, commonest being hypoplastic transverse sinus. CONCLUSION: In TBM, infarction occurs in 50% patients, and is of arterial in origin. Cerebral venous system is usually spared in TBM.

Ceramide activation of RhoA/Rho kinase impairs actin polymerization during aggregated LDL catabolism.

Macrophages use an extracellular, hydrolytic compartment formed by local actin polymerization to digest aggregated LDL (agLDL). Catabolism of agLDL promotes foam cell formation and creates an environment rich in LDL catabolites, including cholesterol and ceramide. Increased ceramide levels are present in lesional LDL, but the effect of ceramide on macrophage proatherogenic processes remains unknown. Here, we show that macrophages accumulate ceramide in atherosclerotic lesions. Using macrophages from sphingosine kinase 2 KO (SK2KO) mice to mimic ceramide-rich conditions of atherosclerotic lesions, we show that SK2KO macrophages display impaired actin polymerization and foam cell formation in response to contact with agLDL. C16-ceramide treatment impaired wild-type but not SK2KO macrophage actin polymerization, confirming that this effect is due to increased ceramide levels. We demonstrate that knockdown of RhoA or inhibition of Rho kinase restores agLDL-induced actin polymerization in SK2KO macrophages. Activation of RhoA in macrophages was sufficient to impair actin polymerization and foam cell formation in response to agLDL. Finally, we establish that during catabolism, macrophages take up ceramide from agLDL, and inhibition of ceramide generation modulates actin polymerization. These findings highlight a critical regulatory pathway by which ceramide impairs actin polymerization through increased RhoA/Rho kinase signaling and regulates foam cell formation.

Hydrophobic Patch of Ubiquitin is Important for its Optimal Activation by Ubiquitin Activating Enzyme E1.

Protein ubiquitination plays a role in essentially every process in eukaryotic cells. The attachment of ubiquitin (Ub) or Ub-like (UBL) proteins to target proteins is achieved by parallel but distinct cascades of enzymatic reactions involving three enzymes: E1, E2, and E3. The E1 enzyme functions at the apex of this pathway and plays a critical role in activating the C-terminus of ubiquitin or UBL, which is an essential step that triggers subsequent downstream transfer to their cognate E2s resulting in the fidelity of the Ub/UBL conjugation machinery. Despite the central role of the E1 enzyme in protein modification, a quantitative method to measure Ub/UBL activation by E1 is lacking. Here, we present a mass spectrometry-based assay to accurately measure the activation of Ub/UBL by E1 independent of the E2/E3 enzymes. Our method does not require radiolabeling of any components and therefore can be used in any biochemical laboratory having access to a mass spectrometer. This method allowed us to dissect the concerted process of E1-E2-catalyzed Ub conjugation in order to separately characterize the process of Ub activation and how it is affected by select mutations and other factors. We found that the hydrophobic patch of Ub is important for the optimal activation of Ub by E1. We further show that the blockers of the Ub-proteasome system such as ubistatin and fullerenol inhibit Ub activation by E1. Interestingly, our data indicate that the phosphorylation of Ub at the S65 position augments its activation by the E1 enzyme.

Monocyte-Derived Dendritic Cells Upregulate Extracellular Catabolism of Aggregated Low-Density Lipoprotein on Maturation, Leading to Foam Cell Formation.

OBJECTIVE: Although dendritic cells are known to play a role in atherosclerosis, few studies have examined the contribution of the wide variety of dendritic cell subsets. Accordingly, their roles in atherogenesis remain largely unknown. We investigated the ability of different dendritic cell subsets to become foam cells after contact with aggregated low-density lipoprotein (LDL; the predominant form of LDL found in atherosclerotic plaques). APPROACH AND RESULTS: We demonstrate that both murine and human monocyte-derived dendritic cells use exophagy to degrade aggregated LDL, leading to foam cell formation, whereas monocyte-independent dendritic cells are unable to clear LDL aggregates by this mechanism. Exophagy is a catabolic process in which objects that cannot be internalized by phagocytosis (because of their size or association with extracellular structures) are initially digested in an extracellular acidic lytic compartment. Surprisingly, we found that monocyte-derived dendritic cells upregulate exophagy on maturation. This contrasts various forms of endocytic internalization in dendritic cells, which decrease on maturation. Finally, we show that our in vitro results are consistent with dendritic cell lipid accumulation in plaques of an ApoE(-/-) mouse model of atherosclerosis. CONCLUSIONS: Our results show that monocyte-derived dendritic cells use exophagy to degrade aggregated LDL and become foam cells, whereas monocyte-independent dendritic cells are unable to clear LDL deposits. Furthermore, we find that exophagy is upregulated on dendritic cell maturation. Thus, exophagy-mediated foam cell formation in monocyte-derived dendritic cells could play a significant role in atherogenesis.

Recent advances in novel heterocyclic scaffolds for the treatment of drug-resistant malaria.

Malaria is a major public health problem all over the world, particularly in tropical and subtropical countries due to the development of resistance and most deadly infection is caused by Plasmodium falciparum. There is a direct need for the discovery of new drugs with unique structures and mechanism of action to treat sensitive and drug-resistant strains of various plasmodia for radical cure of this disease. Traditional compounds such as quinine and related derivatives represent a major source for the development of new drugs. This review presents recent modifications of 4-aminoquinoline and 8-aminoquinolone rings as leads to novel active molecules which are under clinical trials. The review also encompasses the other heterocyclic compounds emerged as potential antimalarial agents with promising results such as acridinediones and acridinone analogues, pyridines and quinolones as antimalarials. Miscellaneous heterocyclics such as tetroxane derivatives, indole derivatives, imidazolopiperazine derivatives, biscationic choline-based compounds and polymer-linked combined antimalarial drugs are also discussed. At last brief introduction to heterocyclics in natural products is also reviewed. Most of them have been under clinical trials and found to be promising in the treatment of drug-resistant strains of Plasmodium and others can be explored for the same purpose.