Mitochondrial dysfunction in NPC1-deficiency is not rescued by drugs targeting the glucosylceramidase GBA2 and the cholesterol-binding proteins TSPO and StARD1.

Niemann-Pick type C disease (NPCD) is a rare neurodegenerative disorder most commonly caused by mutations in the lysosomal protein Niemann-Pick C1 (NPC1), which is implicated in cholesterol export. Mitochondrial insufficiency forms a significant feature of the pathology of this disease, yet studies attempting to address this are rare. The working hypothesis is that mitochondria become overloaded with cholesterol which renders them dysfunctional. We examined two potential protein targets-translocator protein (TSPO) and steroidogenic acute regulatory protein D1 (StARD1)-which are implicated in cholesterol transport to mitochondria, in addition to glucocerbrosidase 2 (GBA2), the target of miglustat, which is currently the only approved treatment for NPCD. However, inhibiting these proteins did not correct the mitochondrial defect in NPC1-deficient cells.

Methyldecanoate isolated from marine algae Turbinaria ornata enhances immunomodulation in LPS-induced inflammatory reactions in RAW 264.7 macrophages via iNOS/NFκB pathway.

This study identifies the anti-inflammatory, antioxidant, and immunomodulatory potential of a fatty acid methyl ester segregated from the brown algae Turbinaria ornata and identified by nuclear magnetic resonance and mass spectrometry as methyl 6,12-dimethyltridecanoate (ET). Antioxidant and anti-inflammatory effects of ET were studied on lipopolysaccharide (LPS)-induced inflammatory reaction in RAW 264.7 macrophages. Moreover, in silico docking studies of isolated ET with inflammatory markers TNFα, NFκB, and COX-2 showed potent binding scores suggesting anti-inflammatory potential. ET significantly reduced LPO and increased LPS-induced SOD, catalase, and GSH levels. Molecular docking results were further confirmed by checking mRNA levels of selected cytokines (IL6 and IL10), followed by protein expression of iNOS and NFκB in LPS-induced macrophages. ET significantly upregulated the expression of IL10 and downregulated the expression of IL6, iNOS, and NFκB, confirming the inhibition of LPS-induced inflammation via the iNOS/NFκB pathway.

Gene expression based profiling of pleomorphic xanthoastrocytoma highlights two prognostic subgroups.

BACKGROUND: Pleomorphic xanthoastrocytomas (PXAs) are rare, accounting for less than 1% of astrocytomas, and commonly occur in young patients. The majority are WHO grade II. A fraction of tumors that present or recur with malignant change are classified as anaplastic (APXA, grade III). Limited data are available on their molecular characteristics. METHODOLOGY: Genome-wide expression profiling of 14 PXA and 6 APXAs was performed by microarray. Among differentially expressed genes (DEGs), Cyclin-Dependent Kinase 14 (CDK14) and Mitochondrial Fission Process 1 (MTFP1) were validated by qRT PCR. RESULT: Unsupervised hierarchical clustering revealed two distinct molecular clusters (Cluster 1: 10 PXA, 3 APXA and Cluster 2: 4 PXA, 3 APXA) with grade II and III tumors distributed in both highlighting molecular heterogeneity within the same grade. There was an insignificant difference in age, sex, immunohistochemical profile, frequency of BRAF mutation, or CDKN2A deletion among the two clusters. Significantly, worse progression-free survival was observed in cluster 2 (P=0.003). mRNA profiling-based prediction of recurrence was superior to and independent of histological grade, BRAF mutation, or CDKN2A deletion status. A total of 10 upregulated and 418 downregulated genes were identified between the PXA clusters. qRT-PCR validation of CDK14 (upregulated in cluster 2) and MTFP1 (upregulated in cluster 1) showed strong concordance with expression array data. CONCLUSION: This is the first comprehensive study highlighting distinct molecular subgroups of PXA. The differentially expressed genes between two clusters may potentially be used for developing histology independent classification schemes, prognostication and may serve as prospective therapeutic targets for PXA patients.

Immunomodulatory activity of brown algae Turbinaria ornata derived sulfated polysaccharide on LPS induced systemic inflammation.

BACKGROUND: Inflammation and oxidative stress are common pathologies in a wide range of chronic diseases. Polysaccharides are known to exhibit antioxidant and anti-inflammatory potential and are suggested to possess immunomodulatory potential. PURPOSE: Herein, the immunomodulatory activity of a sulfated polysaccharide (PS) separated from a brown marine algae Turbinaria ornata is studied in LPS instigated systemic inflammation in experimental rats. STUDY DESIGN AND METHODS: Male SD rats are pretreated with different doses of PS (2.5, 5, 10 mg/kg bw) for a week followed by inducing systemic inflammation using LPS (10 mg/kg i.p.). Blood withdrawn after 8 h of LPS injection is subjected to hematological analysis (WBC, HCT, and PLT). After 24 h of LPS induction, cardiac tissue was isolated and subjected to biochemical, molecular, and histopathological analysis. Effect of PS pre-treatment (2.5, 5, 10 mg/kg bw) was checked by assessing serum parameters (AST, CK-MB, and γGT), antioxidant markers (LPO, GSH, SOD, Grx) and inflammatory markers (IL1ß, IL6, IL10, NFκB), followed by analyzing the iNOS, PI3k and Akt to identify the probable mode of action. RESULTS: Elevated levels of AST, CK-MB, and γGT in serum were significantly reduced on PS pretreatment. LPS significantly raised the LPO and Grx levels in heart tissue whereas, PS pre-treatment significantly reduced LPO and Grx levels. GSH and SOD levels were reduced upon LPS induction and were brought to near normal by HD of PS. PS also reduced the mRNA levels of IL6, Trx, and increased IL10 levels in the heart tissue substantiating its anti-inflammatory and antioxidant potency. Further, IL1ß, NFκB, iNOS, and pPI3k/pAkt expressions were significantly modulated by PS in the cardiac tissue substantiating the immunomodulatory effect. A trend of improvement in the inflammatory pathology was also observed in the heart tissue compared to LPS control, as confirmed by histopathology analysis. CONCLUSION: Altogether, this study concludes the immunomodulatory potential of PS from the marine macroalgae Turbinaria ornata significantly and prevents LPS induced systemic inflammation in the cardiac tissue presumably influenced by the glucopyranose and fucopyranose subunits in the polysaccharide.

Macrotyloma uniflorum a plant food alleviates the metabolic syndrome through modulation of adipokines and PPARs.

A sedentary lifestyle combined with the intake of high-calorie diet has been the paramount cause of metabolic syndrome (MS) which is now a serious concern of public health worldwide as it involves the coexistence of hypertension, hyperlipidemia, glucose intolerance, and obesity. Hence, identifying a suitable strategy to overcome the worldwide menace of MS is imperative. Macrotyloma uniflorum a lesser known legume is highly nutritious and notable for its ethano-medicinal potential. Herein, the influence of M. uniflorum in high-fat dietinduced metabolic changes in a rodent model of metabolic syndrome was evaluated. Serum levels of glucose, total cholesterol, triglycerides, VLDL-c, and bodyweight were decreased, whereas HDL-c was increased in M. uniflorum-treated MS rats. The protein expression (AMPK-α, PPAR-α, and PPAR-γ) and gene expression (leptin, adiponectin, resistin, UCP2, NF-κB, and IL-6) results are impressive to highlight that M. uniflorum modulates the pathological conditions of MS and proves to be cardioprotective. Furthermore, the histopathological analysis confirmed the pathological changes and substantiates the influence of M. uniflorum to overcome MS. The HPLC and GC (MS) profiling reveals the presence of an array of polyphenols such as rutin (694.61 µg/g), catechin (500.12 µg/g), epicatechin (158.10 µg/g), gallic acid (17.98 µg/g), ferulic acid (10.911 µg/g), daidzein (6.51 µg/g), and PUFA, respectively, which probably exhibits the therapeutic effect on MS and associated complications by modulating lipid metabolism and adipogenesis. PRACTICAL APPLICATIONS: Metabolic disorders like CVD and diabetes are leading cause of mortality and morbidity worldwide. With emerging issues on adverse effects of modern drugs, the emphasis on "Food is Medicine and Medicine as Food" has taken dramatic dimensions in the healthcare sector. Therefore, nutraceuticals are in great demand in the developed world off late. Legumes, are potent elements in a balanced diet next to cereals. Exploring the medicinal properties of legumes could bring a revolution in public health and nutraceutical industries. This study scientifically validated the phytochemicals in M. uniflorum for its functional potential in the management of Metabolic Syndrome (MS). This study would help the nutraceutical industries to develop functional foods using M. uniflorum seeds to make porridges and soups or nutraceutical supplements with the bioflavonoids isolated from M. uniflorum for the management of metabolic disorders by mitigating hyperlipidemia, oxidative stress, and inflammation.

Sulfated polysaccharide from Turbinaria ornata suppress lipopolysaccharide-induced inflammatory response in RAW 264.7 macrophages.

BACKGROUND: Marine macroalgae known for its polysaccharides exhibit potent biomedical properties and its potential as an anti-inflammatory agent has increased in the recent past as inflammation is a major pathology noted in many chronic diseases. PURPOSE: The present study investigates the anti-inflammatory potential of a sulfated polysaccharide (PS) isolated from the marine algae Turbinaria ornata collected from the Indian waters on LPS induced inflammation in RAW 264.7 macrophages. STUDY DESIGN AND METHODS: PS isolated from the macroalgae was characterized using ESI(MS) and was screened for its antioxidant and anti-inflammatory potential in RAW 264.7 cells by assessing markers of oxidative stress, and inflammation. RESULTS: LPS significantly increased the levels of LPO and LDH in RAW 264.7 cells which were significantly reduced in PS pre-treatment groups. Pretreatment significantly increased the antioxidants GSH and SOD and significantly reduced mRNA levels of IL6 and TNFα in vitro confirming its anti-inflammatory potential. NFκB and iNOS were significantly modulated by PS confirming the probable mode of action. CONCLUSION: Altogether, it can be concluded that PS isolated from Turbinaria ornata collected from the Southeast Coast of India exhibits antioxidant and anti-inflammatory potential probably mediated by the sulfated polysaccharide containing glucopyranose and fucopyranose moieties.

Correction to: Neophytadiene from Turbinaria ornata Suppresses LPS-Induced Inflammatory Response in RAW 264.7 Macrophages and Sprague Dawley Rats.

The publisher made a mistake in the published version of this article.

Neophytadiene from Turbinaria ornata Suppresses LPS-Induced Inflammatory Response in RAW 264.7 Macrophages and Sprague Dawley Rats.

This study investigates the mode of action of Neophytadiene (MT), a molecule isolated from a marine algae Turbinaria ornata in LPS-induced inflammation in both in vitro and in vivo conditions. Neophytadiene (25, 50, 100 µM/mL) was treated to LPS-stimulated RAW 264.7 macrophages cells to identify its anti-inflammatory potential by measuring the level of tumour necrosis factor (TNF-α) by enzyme-linked immunosorbent assay (ELISA) and nitric oxide (NO) using Griess reagent. The mRNA levels of inflammatory cytokines, interleukin (IL-6 and IL-10), and the protein expression of nuclear factor-κB (NF-κB) and inducible nitric oxide synthase (iNOS) were quantified by Western blot analysis. Subsequently, Neophytadiene (12, 25, 50 mg/kg b.wt/p.o) was pre-treated for 7 days to the experimental animals followed by LPS (10 mg/kg) injection interaperitonially. After LPS induction, blood was collected and the haematological parameters were analysed followed by isolation of heart tissue for biochemical molecular and histopathological analysis Neophytadiene significantly inhibited the NO production and inflammatory cytokines TNF-α, IL-6 and IL-10 both in in vitro and in vivo conditions. Further, the expression of TNF-α, IL1ß, NF-κB, iNOS, PI3k/Akt and MAPK in the heart tissue was modulated by Neophytadiene significantly confirming the anti-inflammatory potential. Thus, the effect of Neophytadiene on LPS-induced cardiac injury can be attributed to its anti-inflammatory antioxidant and cardioprotective properties.

Inhibition of Cyclooxygenase Enzyme by Bioflavonoids in Horsegram Seeds Alleviates Pain and Inflammation.

BACKGROUND: Inflammation and pain, mainly induced by the prostaglandins synthesized by the cyclooxygenase enzymes, may cause distress. To overcome this unpleasant stress in a safer manner, numerous natural molecules are proven for modulating the COX enzymes. Epicatechin and daidzein are two bioactive natural compounds present in horsegram, a legume known for its medicinal properties. OBJECTIVE: The present study aims at evaluating the potential of horsegram, and some of its bioactive molecules, to be used as an anti-inflammatory and analgesic agent mediated by the inhibition of COX enzymes, which can be recommended as a substitute for chemically synthesized NSAIDs. METHODS: The present work involved the quantification of epicatechin and daidzein present in horsegram seeds. The COX enzyme inhibitory nature of epicatechin and daidzein was tested using in silico docking analysis with Autodock software and was further confirmed by in vitro COX inhibitory biochemical assays. Furthermore, the anti-inflammatory and analgesic activities of the horsegram seeds were evaluated in animal experiments. RESULTS: Horsegram seeds contain 158.1 microgram/g and 6.51 microgram/g of epicatechin and daidzein respectively. The docking studies reveal that both the bioactive molecules exhibit better binding efficiency with COX-2 protein as compared to COX-1. Hence, in vitro COX-2 inhibitory assay was performed for epicatechin, daidzein and compared with known analgesic agent diclofenac which revealed a pronounced dose dependent inhibitory activity. Furthermore, the analgesic and anti-inflammatory activity of horsegram in experimental animals exhibited a dose dependent effect which might be due to the presence of the bioactive compounds such as epicatechin and daidzein. CONCLUSION: The results suggest that epicatechin and daidzein present in horsegram are potent cyclooxygenase inhibitors and thus would be helpful in the management of inflammation and pain.

Cytosolic glucosylceramide regulates endolysosomal function in Niemann-Pick type C disease.

Niemann-Pick type C disease (NPCD) is a neurodegenerative disease associated with increases in cellular cholesterol and glycolipids and most commonly caused by defective NPC1, a late endosomal protein. Using ratiometric probes we find that NPCD cells show increased endolysosomal pH. In addition U18666A, an inhibitor of NPC1, was found to increase endolysosomal pH, and the number, size and heterogeneity of endolysosomal vesicles. NPCD fibroblasts and cells treated with U18666A also show disrupted targeting of fluorescent lipid BODIPY-LacCer to high pH vesicles. Inhibiting non-lysosomal glucocerebrosidase (GBA2) reversed increases in endolysosomal pH and restored disrupted BODIPY-LacCer trafficking in NPCD fibroblasts. GBA2 KO cells also show decreased endolysosomal pH. NPCD fibroblasts also show increased expression of a key subunit of the lysosomal proton pump vATPase on GBA2 inhibition. The results are consistent with a model where both endolysosomal pH and Golgi targeting of BODIPY-LacCer are dependent on adequate levels of cytosolic-facing GlcCer, which are reduced in NPC disease.

Anti-arthritic potential of marine macroalgae Turbinaria ornata in Complete Freund's Adjuvant induced rats.

T. ornata a macroalgae rich in bioactive molecules possess various biological activities. Herein, the aim of the study is to evaluate the aqueous extract and the sulphated polysaccharide isolated from T. ornata for its anti-arthritic potential in Complete Freund's Adjuvant (CFA) induced arthritis in rats. Anti-arthritic potential of aqueous T. ornata (ATO) and T. ornata sulphated polysaccharide (TSP) was evidenced by the significant reduction in paw volume and arthritic score. Inflammatory and antioxidant markers were found to be restored in the drug treated groups which was found to be in line with dexamethasone a standard anti-inflammatory drug. The histopathological and radiological examination adds on the support to the above findings confirming the anti-arthritic potential of ATO and TSP. It is interesting to note that the sulphated polysaccharide inhibits inflammation and bone damage at very low dose itself. Hence, TSP could be considered as a better candidate in the management of chronic inflammatory diseases like rheumatoid arthritis.

Attenuation of inflammation by marine algae Turbinaria ornata in cotton pellet induced granuloma mediated by fucoidan like sulphated polysaccharide.

Turbinaria ornata, a commonly found marine brown algae along the Gulf of Mannar, Southeast coast of India was evaluated for its anti-inflammatory potential and the bioactive compound present in it was characterized. Cotton pellet induced granuloma model in rats was used to assess the anti-inflammatory potential of the aqueous extract of Turbinaria ornata (ATO) (30, 100 and 300mg/kg, p.o) which was compared with dexamethasone (0.1mg/kg, p.o) a standard anti-inflammatory agent. Granuloma weight, haematological parameters and plasma markers (LDH, GPT, and CRP) were estimated. Further, the levels of oxidative stress markers (SOD, GPx, GSH, LPO, and Nitrite) and inflammatory markers (Cathepsin D and MPO) in the hepatic tissue were measured. ATO decreased the granuloma weight dose dependently. ATO significantly reversed the levels of biochemical and inflammatory markers in comparison to the vehicle treated rats. The active constituent, fucoidan (sulphated polysaccharide) from the aqueous extract was fractionated and characterized using GCMS. The sulphated polysaccharide (TSP) from ATO confirms the presence of sulphates and sugars. The present findings suggest ATO to be a potent inhibitor of both proliferative and exudative phases of inflammation possibly mediated by the sulphated polysaccharides which might inhibit the action of COX-2 enzyme analogous to dexamethasone.

Epithelioid Hemangioendothelioma of Tibia and Talus: A Case Report.

Epithelioid hemangioendothelioma (EHE) of the bone is extremely uncommon and consists of less than 1% of primary bone tumors. It is characterized by epithelioid endothelial cells and has variable biological behavior. EHE is more likely to occur between 20 and 30 years of age. Approximately half of EHE present with multifocal disease. Since the behavior of these tumors is intermediate, it is important to not misdiagnose EHE as an angiosarcoma. Here we describe the case of a 43-year-old male who presented with pain and swelling of the leg and ankle to Dr. Ram Manohar Lohia Hospital, India. Radiography and computed tomography of the ankle and leg were performed and suggested an expansile lytic lesion involving the distal tibia and talus bone. The lesion was excised and ankle arthrodesis performed. Histological evaluation of the lesion demonstrated the presence of EHE of the tibia and talus.

Cystic retroperitoneal renal hilar ancient schwannoma: Report of a rare case with atypical presentation masquerading as simple cyst.

Schwannoma is a benign soft tissue tumor of neural origin arising from the Schwann cells of the neural sheath. It has rarely been reported in renal or perirenal region. The preoperative diagnosis has mostly been confused with renal cell carcinoma in this location in most previous reports. We report a case that presented with a large "simple cystic" mass at the renal hilum. The preoperative differential diagnosis included hilar renal cortical cyst, renal sinus cyst, ureteropelvic junction obstruction (UPJO), or even a hydatid cyst. The final diagnosis was clinched only on histopathological examination.

Dormant primary cutaneous actinomycosis: Acute exacerbation after 16 years.

Actinomycosis of head and neck are secondary to a nidus in the oral cavity and the aero-digestive tract. Primary actinomycosis without such predisposition is mostly due to trauma. We are presenting a case of this rare variant involving the forehead. The patient had a swelling over the forehead after a windscreen injury, which was asymptomatic for 17 years. However, 1 year ago, there was a repeat blunt trauma on the same site, but there was no breach of skin. Following this, the swelling became tender and started increasing in size. There was no response to a course of antibiotic and the patient had no concomitant history of any systemic illness. The swelling was excised and the biopsy revealed actinomycosis. This presentation of primary actinomycosis after such a long dormancy has never been reported before. This is yet another unusual presentation of actinomycosis, which is notoriously misdiagnosed owing to its rarity and numerous differential diagnoses.

Occurrence of plant sensitivity among patients of photodermatoses: a control-matched study of 156 cases from New Delhi.

BACKGROUND: Photodermatitis is an abnormal response to ultraviolet radiation (UVR). The photoallergic contact dermatitis caused by plant allergens is a serious cause of morbidity in India. Airborne contact dermatitis is the classical presentation of plant-induced dermatosis, which may become difficult to differentiate from chronic actinic dermatitis in chronic cases. The rapid growth of parthenium weed in India and its ill effects on the population make it important to detect all cases of parthenium sensitivity, which in some cases might simulate photodermatitis. AIMS: This study aims to detect the occurrence of plant sensitivity and photosensitivity in idiopathic-acquired photodermatoses, airborne contact dermatitis and general population taken as controls. METHODS: One hundred and fifty six consecutive patients suffering from polymorphic light eruption (PMLE), chronic actinic dermatitis (CAD) and airborne contact dermatitis (ABCD) were enrolled in the study over a period of three years (June 2004 to May 2007). An equal number of age and sex matched healthy subjects were enrolled in the study as controls. All the patients were subjected to detailed history taking, clinical examination and histopathological examination for diagnosis. Patch and photopatch testing were perfomed in all the patients and healthy controls for detection of allergic and photoallergic reactions to parthenium, xanthium and chrysanthemum plant antigens and control antigens. RESULTS: Out of 156 patients enrolled in the study, 78 (50%) had CAD, 67 (42.9%) had PMLE and 11 (7.05%) had ABCD. The occurrence of parthenium/xanthium allergy and photoallergy, either to parthenium or both was most commonly found in ABCD (72.7%), followed by CAD (32%). In PMLE 4.5% cases showed photoallergy. Only 1.9% in the control group showed sensitivity to parthenium and xanthium. CONCLUSION: This study indicates that parthenium (and possibly xanthium) may act as important environmental factors in the initiation and perpetuation of not only ABCD but of CAD as well. Photoexacerbation to UVA at positive parthenium/xanthium sensitivity sites in ABCD and CAD indicates that ABCD with photosensitivity to compositae can lead to CAD.

Borderline tuberculoid leprosy with upgrading Type 1 reaction in a HIV seropositive patient, after antiretroviral therapy: an immune reconstitution inflammatory syndrome.

A case of borderline tuberculoid (BT) leprosy with upgrading Type 1 reaction, in a HIV seropositive patient, 7 weeks after starting highly active antiretroviral therapy, as an immune reconstitution inflammatory syndrome (IRIS), is reported.

Non-familial multiple keratoacanthomas in a 70 year-old long-term non-progressor HIV-seropositive man.

We describe here multiple keratoacanthomas in an Human Immunodeficiency Virus (HIV)-seropositive 70 year-old man. The patient had multiple epithelial tumors of the skin showing rapid growth, histopathological features of a keratoacanthoma and a conspicuous tendency toward spontaneous remission. A diagnosis of nonfamilial multiple keratoacanthoma was established. The patient had a CD4 count of 633 cells/microL. The HIV disease in our patient was of a nonprogressive nature with CCR5-positive T cells.