@article {6583, title = {Photostimulated Extended Nitric Oxide (NO) Release from Water-Soluble Block Copolymer to Enhance Antibacterial Activity.}, journal = {Biomacromolecules}, volume = {25}, year = {2024}, month = {2024 Jan 08}, pages = {77-88}, abstract = {

-Nitrosamines are well established motifs to release nitric oxide (NO) under photoirradiation. Herein, a series of amphiphilic -nitrosamine-based block copolymers () are developed to attain controlled NO release under photoirradiation (365 nm, 3.71 mW/cm). The water-soluble forms micellar architecture in aqueous medium and exhibits a sustained NO release of 92-160 μM within 11.5 h, which is 36.8-64.0\% of the calculated value. To understand the NO release mechanism, a small molecular NO donor () resembling the NO releasing functional motif of is synthesized, which displays a burst NO release in DMSO within 2.5 h. The radical nature of the released NO is confirmed by electron paramagnetic resonance (EPR) spectroscopy. The gradual NO release from micellar enhances antibacterial activity over and exhibits a superior bactericidal effect on Gram-positive . In relation to biomedical applications, this work offers a comprehensive insight into tuning light-triggered NO release to improve antibacterial activity.

}, keywords = {Anti-Bacterial Agents, Micelles, Nitric Oxide, Polymers, Staphylococcus aureus}, issn = {1526-4602}, doi = {10.1021/acs.biomac.3c00822}, author = {Paul, Soumya and Ashrit, Priya and Kumar, Manish and Mete, Sourav and Ghosh, Shilpendu and Vemula, Praveen Kumar and Mukherjee, Arindam and De, Priyadarsi} } @article {2424, title = {Flow Cytometry Analysis of Planarian Stem Cells Using DNA and Mitochondrial Dyes.}, journal = {Bio Protoc}, volume = {12}, year = {2022}, month = {2022 Jan 20}, pages = {e4299}, abstract = {

Planarians are free-living flatworms that emerged as a crucial model system to understand regeneration and stem cell biology. The ability to purify neoblasts, the adult stem cell population of planaria, through fluorescence-activated cell sorting (FACS) has tremendously increased our understanding of pluripotency, specialization, and heterogeneity. To date, the FACS-based purification methods for neoblasts relied on nuclear dyes that discriminate proliferating cells (\>2N), as neoblasts are the only dividing somatic cells. However, this method does not distinguish the functional states within the neoblast population. Our work has shown that among the neoblasts, the pluripotent stem cells (PSCs) are associated with low mitochondrial content and this property could be leveraged for purification of the PSC-enriched population. Using the mitochondrial dye MitoTracker Green (MTG) and the nuclear dye SiR-DNA, we have described a method for isolation of PSCs that are viable and compatible with downstream experiments, such as transplantation and cell culture. In this protocol, we provide a detailed description for sample preparation and FACS gating for neoblast isolation in planaria.

}, issn = {2331-8325}, doi = {10.21769/BioProtoc.4299}, author = {Haroon, Mohamed Mohamed and Vemula, Praveen Kumar and Palakodeti, Dasaradhi} } @article {3642, title = {Intermittent scavenging of storage lesion from stored red blood cells by electrospun nanofibrous sheets enhances their quality and shelf-life.}, journal = {Nat Commun}, volume = {13}, year = {2022}, month = {2022 Dec 01}, pages = {7394}, abstract = {

Transfusion of healthy red blood cells (RBCs) is a lifesaving process. However, upon storing RBCs, a wide range of damage-associate molecular patterns (DAMPs), such as cell-free DNA, nucleosomes, free-hemoglobin, and poly-unsaturated-fatty-acids are generated. DAMPs can further damage RBCs; thus, the quality of stored RBCs declines during the storage and limits their shelf-life. Since these DAMPs consist of either positive or negative charged species, we developed taurine and acridine containing electrospun-nanofibrous-sheets (Tau-AcrNFS), featuring anionic, cationic charges and an DNA intercalating group on their surfaces. We show that Tau-AcrNFS are efficient in scavenging DAMPs from stored human and mice RBCs ex vivo. We find that intermittent scavenging of DAMPs by Tau-AcrNFS during the storage reduces the loss of RBC membrane integrity and reduces discocytes-to-spheroechinocytes transformation in stored-old-RBCs. We perform RBC-transfusion studies in mice to reveal that intermittent removal of DAMPs enhances the quality of stored-old-RBCs equivalent to freshly collected RBCs, and increases their shelf-life by ~22\%. Such prophylactic technology may lead to the development of novel blood bags or medical device, and may therefore impact healthcare by reducing transfusion-related adverse effects.

}, keywords = {Acridines, Animals, Drug-Related Side Effects and Adverse Reactions, Erythrocytes, Humans, Mice, Nanofibers, Research Personnel}, issn = {2041-1723}, doi = {10.1038/s41467-022-35269-3}, author = {Pandey, Subhashini and Mahato, Manohar and Srinath, Preethem and Bhutani, Utkarsh and Goap, Tanu Jain and Ravipati, Priusha and Vemula, Praveen Kumar} } @article {2883, title = {Microbial metabolite restricts 5-fluorouracil-resistant colonic tumor progression by sensitizing drug transporters via regulation of FOXO3-FOXM1 axis.}, journal = {Theranostics}, volume = {12}, year = {2022}, month = {2022}, pages = {5574-5595}, abstract = {

The survival rate of colorectal cancer patients is adversely affected by the selection of tumors resistant to conventional anti-cancer drugs such as 5-fluorouracil (5FU). Although there is mounting evidence that commensal gut microbiota is essential for effective colon cancer treatment, the detailed molecular mechanisms and the role of gut microbial metabolites remain elusive. The goal of this study is to decipher the impact and mechanisms of gut microbial metabolite, urolithin A (UroA) and its structural analogue, UAS03 on reversal of 5FU-resistant (5FUR) colon cancers. We have utilized the SW480 and HCT-116 parental (5FU-sensitive) and 5FUR colon cancer cells to examine the chemosensitization effects of UroA or UAS03 by using both and models. The effects of mono (UroA/UAS03/5FU) and combinatorial therapy (UroA/UAS03 + 5FU) on cell proliferation, apoptosis, cell migration and invasion, regulation of epithelial mesenchymal transition (EMT) mediators, expression and activities of drug transporters, and their regulatory transcription factors were examined using molecular, cellular, immunological and flowcytometric methods. Further, the anti-tumor effects of mono/combination therapy (UroA or UAS03 or 5FU or UroA/UAS03 + 5FU) were examined using pre-clinical models of 5FUR-tumor xenografts in NRGS mice and azoxymethane (AOM)-dextran sodium sulfate (DSS)-induced colon tumors. Our data showed that UroA or UAS03 in combination with 5FU significantly inhibited cell viability, proliferation, invasiveness as well as induced apoptosis of the 5FUR colon cancer cells compared to mono treatments. Mechanistically, UroA or UAS03 chemosensitized the 5FUR cancer cells by downregulating the expression and activities of drug transporters (MDR1, BCRP, MRP2 and MRP7) leading to a decrease in the efflux of 5FU. Further, our data suggested the UroA or UAS03 chemosensitized 5FUR cancer cells to 5FU treatment through regulating FOXO3-FOXM1 axis. Oral treatment with UroA or UAS03 in combination with low dose i.p. 5FU significantly reduced the growth of 5FUR-tumor xenografts in NRGS mice. Further, combination therapy significantly abrogated colonic tumors in AOM-DSS-induced colon tumors in mice. In summary, gut microbial metabolite UroA and its structural analogue UAS03 chemosensitized the 5FUR colon cancers for effective 5FU chemotherapy. This study provided the novel characteristics of gut microbial metabolites to have significant translational implications in drug-resistant cancer therapeutics.

}, keywords = {Animals, Antimetabolites, Antineoplastic, ATP Binding Cassette Transporter, Subfamily G, Member 2, Azoxymethane, Cell Line, Tumor, Colonic Neoplasms, Coumarins, Drug Resistance, Neoplasm, Fluorouracil, Forkhead Box Protein M1, Forkhead Box Protein O3, Gastrointestinal Microbiome, Humans, Mice, Neoplasm Proteins}, issn = {1838-7640}, doi = {10.7150/thno.70754}, author = {Ghosh, Sweta and Singh, Rajbir and Vanwinkle, Zachary Matthew and Guo, Haixun and Vemula, Praveen Kumar and Goel, Ajay and Haribabu, Bodduluri and Jala, Venkatakrishna Rao} } @article {2399, title = {Microscale engineering of hollow microneedle tips: design, manufacturing, optimization and validation.}, journal = {Drug Deliv Transl Res}, volume = {12}, year = {2022}, month = {2022 Feb}, pages = {350-367}, abstract = {

Transdermal and intradermal drug delivery utilizing microneedles is an emerging front in painless therapeutics. Drug delivery using hollow microneedles is the most preferred method for delivering generic transdermal drugs in the clinical setup. The needle tip must be extremely short as the drug is administered to sub-millimeter depths. Also, they need to be sharp enough to pierce through the skin with minimal skin flexing. There are multiple challenges in engineering a tip profile that is short and sharp at the same time. Stainless steel (SS) hypodermic needles with the lancet tip profile are ubiquitous in subcutaneous and intramuscular injections. They have long bevel lengths that make them inappropriate as microneedles. Thus, designing a unique tip profile and developing the manufacturing technology for microneedle applications are necessary. This article presents the design and optimization of microneedle tip profiles through analytical models. Further, manufacturing strategies for reliably obtaining designed profiles are discussed. The article concludes with experimental validation of improved piercing performance of the optimized tip profile compared to other tip profiles. The article discusses about tip geometries of stainless steel needles for microneedle applications, where depth of delivery is less than 1 mm. Through series of analyses, the optimum needle tip geometry evolved from single plane bevel (SPB) to hex plane bevel (HPB) progressively improving piercing performance.

}, issn = {2190-3948}, doi = {10.1007/s13346-021-01062-w}, author = {Badnikar, Kedar and Jayadevi, Shreyas Nataraja and Pahal, Suman and Vemula, Praveen Kumar and Nayak, Mangalore Manjunatha and Subramanyam, Dinesh Narasimhaiah} } @article {2474, title = {Skin-Permeable Nano-Lithocholic Lipidoid Efficiently Alleviates Psoriasis-like Chronic Skin Inflammations.}, journal = {ACS Appl Mater Interfaces}, year = {2022}, month = {2022 Mar 29}, abstract = {

Long-term application of topical therapeutics for psoriasis has a plethora of side effects. Additionally, skin-permeating agents used in their formulations for deeper dermal delivery damage the skin. To address these limitations, we developed novel lithocholic acid analogues that could form lipid nanoparticles (nano-LCs) spontaneously in the aqueous milieu, permeate through the skin, penetrate the deeper dermal layers, and exert anti-inflammatory effects against psoriasis-like chronic skin inflammations. Prior findings demonstrated that lithocholic acid acts as a vitamin D receptor agonist without affecting the Ca metabolism and also as an antagonist for ephrin type-A receptor 2 (EphA2). Taking cues from the previous findings, lithocholic acid derivatives with twin alkyl chains (LC6, LC8, LC10, and LC-12) were synthesized, nanoparticles (nano-LCs) were prepared, and they were evaluated for their skin permeability and anti-inflammatory properties. Among these nano-LCs, nano-LC10 demonstrated superior anti-inflammatory properties and inhibition of keratinocyte proliferation in various cell-based evaluations. Furthermore, the therapeutic efficiency of nano-LC10 was evaluated in an imiquimod-induced psoriasis-like mouse model and demonstrated comparable efficiency with the standard topical formulation, Sorvate, in reducing skin inflammations. Nano-LC10 also reduced systemic inflammation, organ toxicity, and also proinflammatory serum cytokine levels. Overall, nano-lithocholic lipidoid (nano-LC10) can be a potential novel class of therapeutics for topical application in treating psoriasis.

}, issn = {1944-8252}, doi = {10.1021/acsami.1c19180}, author = {Rachamalla, Hari Krishnareddy and Voshavar, Chandrashekhar and Arjunan, Porkizhi and Mahalingam, Gokulnath and Chowath, Rashmi Praksash and Banerjee, Rajkumar and Vemula, Praveen Kumar and Marepally, Srujan} } @article {2214, title = {iRGD conjugated nimbolide liposomes protect against endotoxin induced acute respiratory distress syndrome.}, journal = {Nanomedicine}, volume = {33}, year = {2021}, month = {2021 Jan 05}, pages = {102351}, abstract = {

Acute respiratory distress syndrome (ARDS) is a deadly respiratory illness associated with refractory hypoxemia and pulmonary edema. The recent pandemic outbreak of COVID-19 is associated with severe pneumonia and inflammatory cytokine storm in the lungs. The anti-inflammatory phytomedicine nimbolide (NIM) may not be feasible for clinical translation due to poor pharmacokinetic properties and lack of suitable delivery systems. To overcome these barriers, we have developed nimbolide liposomes conjugated with iRGD peptide (iRGD-NIMLip) for targeting lung inflammation. It was observed that iRGD-NIMLip treatment significantly inhibited oxidative stress and cytokine storm compared to nimbolide free-drug (f-NIM), nimbolide liposomes (NIMLip), and exhibited superior activity compared to dexamethasone (DEX). iRGD-NIMLip abrogated the LPS induced p65 NF-κB, Akt, MAPK, Integrin β3 and β5, STAT3, and DNMT1 expression. Collectively, our results demonstrate that iRGD-NIMLip could be a promising novel drug delivery system to target severe pathological consequences observed in ARDS and COVID-19 associated cytokine storm.

}, issn = {1549-9642}, doi = {10.1016/j.nano.2020.102351}, author = {Pooladanda, Venkatesh and Thatikonda, Sowjanya and Sunnapu, Omprakash and Tiwary, Shristy and Vemula, Praveen Kumar and Talluri, M V N Kumar and Godugu, Chandraiah} } @article {2212, title = {Microneedles for Extended Transdermal Therapeutics: A Route to Advanced Healthcare.}, journal = {Eur J Pharm Biopharm}, volume = {159}, year = {2021}, month = {2021 Feb}, pages = {151-169}, abstract = {

Sustained release of drugs over a pre-determined period is required to maintain an effective therapeutic dose for variety of drug delivery applications. Transdermal devices such as polymeric microneedle patches and other microneedle-based devices have been utilized for sustained release of their payload. Swift clearing of drugs can be prevented either by designing a slow-degrading polymeric matrix or by providing physiochemical triggers to different microneedle-based devices for on-demand release. These long-acting transdermal devices prevent the burst release of drugs. This review highlights the recent advances of microneedle-based devices for sustained release of vaccines, hormones, and antiretrovirals with their prospective safe clinical translation.

}, issn = {1873-3441}, doi = {10.1016/j.ejpb.2020.12.020}, author = {Pahal, Suman and Badnikar, Kedar and Ghate, Vivek and Bhutani, Utkarsh and Nayak, Mangalore Manjunatha and Subramanyam, Dinesh Narasimhaiah and Vemula, Praveen Kumar} } @article {2274, title = {Mitochondrial state determines functionally divergent stem cell population in planaria.}, journal = {Stem Cell Reports}, volume = {16}, year = {2021}, month = {2021 May 11}, pages = {1302-1316}, abstract = {

Mitochondrial state changes were shown to be critical for stem cell function. However, variation in the mitochondrial content in stem cells and the implication, if any, on differentiation is poorly understood. Here, using cellular and molecular studies, we show that the planarian pluripotent stem cells (PSCs) have low mitochondrial mass compared with their progenitors. Transplantation experiments provided functional validation that neoblasts with low mitochondrial mass are the true PSCs. Further, the mitochondrial mass correlated with OxPhos and inhibiting the transition to OxPhos dependent metabolism in cultured cells resulted in higher PSCs. In summary, we show that low mitochondrial mass is a hallmark of PSCs in planaria and provide a mechanism to isolate live, functionally active, PSCs from different cell cycle stages (G0/G1 and S, G2/M). Our study demonstrates that the change in mitochondrial metabolism, a feature of PSCs is conserved in planaria and highlights its role in organismal regeneration.

}, issn = {2213-6711}, doi = {10.1016/j.stemcr.2021.03.022}, author = {Mohamed Haroon, Mohamed and Lakshmanan, Vairavan and Sarkar, Souradeep R and Lei, Kai and Vemula, Praveen Kumar and Palakodeti, Dasaradhi} } @article {2146, title = {Differential flexibility leading to crucial microelastic properties of asymmetric lipid vesicles for cellular transfection: A combined spectroscopic and atomic force microscopy studies.}, journal = {Colloids Surf B Biointerfaces}, volume = {196}, year = {2020}, month = {2020 Sep 21}, pages = {111363}, abstract = {

The role of microscopic elasticity of nano-carriers in cellular uptake is an important aspect in biomedical research. Herein we have used AFM nano-indentation force spectroscopy and F{\"o}rster resonance energy transfer (FRET) measurements to probe microelastic properties of three novel cationic liposomes based on di-alkyl dihydroxy ethyl ammonium chloride based lipids having asymmetry in their hydrophobic chains (Lip1818, Lip1814 and Lip1810). AFM data reveals that symmetry in hydrophobic chains of a cationic lipid (Lip1818) imparts higher rigidity to the resulting liposomes than those based on asymmetric lipids (Lip1814 and Lip1810). The stiffness of the cationic liposomes is found to decrease with increasing asymmetry in the hydrophobic lipid chains in the order of Lip1818 \> Lip1814 \> lip1810. FRET measurements between Coumarin 500 (Donor) and Merocyanine 540 (Acceptor) have revealed that full width at half-maxima (hw) of the probability distribution (P(r)) of donor-acceptor distance (r), increases in an order Lip1818 \< Lip1814 \< Lip1810 with increasing asymmetry of the hydrophobic lipid chains. This increase in width (hw) of the donor-acceptor distance distributions is reflective of increasing flexibility of the liposomes with increasing asymmetry of their constituent lipids. Thus, the results from AFM and FRET studies are complementary to each other and indicates that an increase in asymmetry of the hydrophobic lipid chains increases elasticity and or flexibility of the corresponding liposomes. Cell biology experiments confirm that liposomal flexibility or rigidity directly influences their cellular transfection efficiency, where Lip1814 is found to be superior than the other two liposomes manifesting that a critical balance between flexibility and rigidity of the cationic liposomes is key to efficient cellular uptake. Taken together, our studies reveal how asymmetry in the molecular architecture of the hydrophobic lipid chains influences the microelastic properties of the liposomes, and hence, their cellular uptake efficiency.

}, issn = {1873-4367}, doi = {10.1016/j.colsurfb.2020.111363}, author = {Mukherjee, Dipanjan and Rakshit, Tatini and Singh, Priya and Mondal, Suman and Paul, Debashish and Ahir, Manisha and Adhikari, Arghya and Puthiyapurayil, Theja P and Vemula, Praveen Kumar and Senapati, Dulal and Das, Ranjan and Pal, Samir Kumar} } @article {2107, title = {Microbial Metabolite Urolithin B Inhibits Recombinant Human Monoamine Oxidase A Enzyme.}, journal = {Metabolites}, volume = {10}, year = {2020}, month = {2020 Jun 19}, abstract = {

Urolithins are gut microbial metabolites derived from ellagitannins (ET) and ellagic acid (EA), and shown to exhibit anticancer, anti-inflammatory, anti-microbial, anti-glycative and anti-oxidant activities. Similarly, the parent molecules, ET and EA are reported for their neuroprotection and antidepressant activities. Due to the poor bioavailability of ET and EA, the in vivo functional activities cannot be attributed exclusively to these compounds. Elevated monoamine oxidase (MAO) activities are responsible for the inactivation of monoamine neurotransmitters in neurological disorders, such as depression and Parkinson{\textquoteright}s disease. In this study, we examined the inhibitory effects of urolithins (A, B and C) and EA on MAO activity using recombinant human MAO-A and MAO-B enzymes. Urolithin B was found to be a better MAO-A enzyme inhibitor among the tested urolithins and EA with an IC value of 0.88 {\textmu}M, and displaying a mixed mode of inhibition. However, all tested compounds exhibited higher IC (\>100 {\textmu}M) for MAO-B enzyme.

}, issn = {2218-1989}, doi = {10.3390/metabo10060258}, author = {Singh, Rajbir and Chandrashekharappa, Sandeep and Vemula, Praveen Kumar and Haribabu, Bodduluri and Jala, Venkatakrishna Rao} } @article {1582, title = {Urolithin A, a Novel Natural Compound to Target PI3K/AKT/mTOR Pathway in Pancreatic Cancer.}, journal = {Mol Cancer Ther}, volume = {18}, year = {2019}, month = {2019 Feb}, pages = {301-311}, abstract = {

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy and is highly resistant to standard treatment regimens. Targeted therapies against , a mutation present in an overwhelming majority of PDAC cases, have been largely ineffective. However, inhibition of downstream components in the KRAS signaling cascade provides promising therapeutic targets in the management of PDAC and warrants further exploration. Here, we investigated Urolithin A (Uro A), a novel natural compound derived from pomegranates, which targets numerous kinases downstream of KRAS, in particular the PI3K/AKT/mTOR signaling pathways. We showed that treatment of PDAC cells with Uro A blocked the phosphorylation of AKT and p70S6K successfully inhibited the growth of tumor xenografts, and increased overall survival of Ptf1a;LSL-Kras;Tgfbr2 (PKT) mice compared with vehicle or gemcitabine therapy alone. Histologic evaluation of these Uro A-treated tumor samples confirmed mechanistic actions of Uro A via decreased phosphorylation of AKT and p70S6K, reduced proliferation, and increased cellular apoptosis in both xenograft and PKT mouse models. In addition, Uro A treatment reprogrammed the tumor microenvironment, as evidenced by reduced levels of infiltrating immunosuppressive cell populations such as myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Overall, this work provides convincing preclinical evidence for the utility of Uro A as a therapeutic agent in PDAC through suppression of the PI3K/AKT/mTOR pathway.

}, issn = {1538-8514}, doi = {10.1158/1535-7163.MCT-18-0464}, author = {Totiger, Tulasigeri M and Srinivasan, Supriya and Jala, Venkatakrishna R and Lamichhane, Purushottam and Dosch, Austin R and Gaidarski, Alexander A and Joshi, Chandrashekhar and Rangappa, Shobith and Castellanos, Jason and Vemula, Praveen Kumar and Chen, Xi and Kwon, Deukwoo and Kashikar, Nilesh and VanSaun, Michael and Merchant, Nipun B and Nagathihalli, Nagaraj S} } @article {1592, title = {Local release of tacrolimus from hydrogel-based drug delivery system is controlled by inflammatory enzymes in vivo and can be monitored non-invasively using in vivo imaging.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0203409}, abstract = {

BACKGROUND: Local drug delivery systems that adjust the release of immunosuppressive drug in response to the nature and intensity of inflammation represent a promising approach to reduce systemic immunosuppression and its side effects in allotransplantation. Here we aimed to demonstrate that release of tacrolimus from triglycerol monostearate hydrogel is inflammation-dependent in vivo. We further report that by loading the hydrogel with a near-infrared dye, it is possible to monitor drug release non-invasively in an in vivo model of vascularized composite allotransplantation.

MATERIALS AND METHODS: Inflammation was induced by local challenge with lipopolysaccharides in na{\"\i}ve rats 7 days after injection of tacrolimus-loaded hydrogel in the hind limb. Tacrolimus levels in blood and tissues were measured at selected time points. A near-infrared dye was encapsulated in the hydrogel together with tacrolimus in order to monitor hydrogel deposits and drug release in vitro and in vivo in a model of vascularized composite allotransplantation.

RESULTS: Injection of lipopolysaccharides led to increased blood and skin tacrolimus levels (p = 0.0076, day 7 vs. day 12 in blood, and p = 0.0007 in treated limbs, 48 h after injection compared to controls). Moreover, lipopolysaccharides-injected animals had higher tacrolimus levels in treated limbs compared to contralateral limbs (p = 0.0003 for skin and p = 0.0053 for muscle). Imaging of hydrogel deposits and tacrolimus release was achieved by encapsulating near-infrared dye in the hydrogel for 160 days. The correlation of tacrolimus and near-infrared dye release from hydrogel was R2 = 0.6297 and R2 = 0.5619 in blood and grafts of transplanted animals respectively and R2 = 0.6066 in vitro.

CONCLUSIONS: Here we demonstrate the inflammation-responsiveness of a tacrolimus-loaded hydrogel in vivo. Moreover, we show that encapsulating a near-infrared dye in the hydrogel provides a reliable correlation of tacrolimus and dye release from the hydrogel, and an accessible non-invasive method for monitoring drug release from hydrogel deposits.

}, keywords = {Animals, Drug Delivery Systems, Humans, Hydrogels, Immunosuppressive Agents, Inflammation, Male, Rats, Rats, Inbred BN, Rats, Inbred Lew, Tacrolimus}, issn = {1932-6203}, doi = {10.1371/journal.pone.0203409}, author = {Dzhonova, Dzhuliya and Olariu, Radu and Leckenby, Jonathan and Dhayani, Ashish and Vemula, Praveen Kumar and Prost, Jean-Christophe and Banz, Yara and Taddeo, Adriano and Rieben, Robert} } @inbook {1193, title = {Prevention of Metal Exposure: Chelating Agents and Barrier Creams}, booktitle = {Metal Allergy: From Dermatitis to Implant and Device Failure}, year = {2018}, pages = {227{\textendash}246}, publisher = {Springer International Publishing}, organization = {Springer International Publishing}, address = {Cham}, abstract = {

Metals are a group of elements which are ubiquitous in modern life. They are used in the fields of cosmetics, water purification, medicine, paint, food products, pesticides, and almost innumerable others. As the use of metals has increased in recent decades, so has human exposure to these elements. Metals such as mercury, lead, arsenic, nickel, and others have been implicated in negatively affecting human homeostasis by causing chronic inflammatory diseases, among other serious conditions. Both acute and chronic metal toxicity in vital organs could arise from local or systemic exposure to numerous metals. Although some metals have health benefits, overaccumulation of metals in body tissues can result in deleterious, toxic effects. Most exposure to metals occurs via cutaneous, inhalation, or oral routes. At the highest risk of negative effects of exposure are pregnant women and children. To ameliorate or prevent the toxic effects of metals, chelating agents and barrier creams are used widely in medical practice today. In this chapter, we will discuss preventing metal toxicity from overexposure via chelation therapy and skin barrier creams.

}, isbn = {978-3-319-58503-1}, doi = {10.1007/978-3-319-58503-1_18}, url = {https://doi.org/10.1007/978-3-319-58503-1_18}, author = {Mahato, Manohar and Sherman, Nicholas E. and Kiran Kumar Mudnakudu, N. and Joshi, Nitin and Briand, Elisabeth and Karp, Jeffrey M. and Vemula, Praveen Kumar}, editor = {Chen, Jennifer K and Thyssen, Jacob P.} } @article {1199, title = {The miR-124 family of microRNAs is crucial for regeneration of the brain and visual system in the planarian Schmidtea mediterranea}, journal = {Development}, volume = {144}, year = {2017}, pages = {3211{\textendash}3223}, abstract = {

Brain regeneration in planarians is mediated by precise spatiotemporal control of gene expression and is crucial for multiple aspects of neurogenesis. However, the mechanisms underpinning the gene regulation essential for brain regeneration are largely unknown. Here, we investigated the role of the miR-124 family of microRNAs in planarian brain regeneration. The miR-124 family (miR-124) is highly conserved in animals and regulates neurogenesis by facilitating neural differentiation, yet its role in neural wiring and brain organization is not known. We developed a novel method for delivering anti-miRs using liposomes for the functional knockdown of microRNAs. Smed-miR-124 knockdown revealed a key role for these microRNAs in neuronal organization during planarian brain regeneration. Our results also demonstrated an essential role for miR-124 in the generation of eye progenitors. Additionally, miR-124 regulates Smed-slit-1, which encodes an axon guidance protein, either by targeting slit-1 mRNA or, potentially, by modulating the canonical Notch pathway. Together, our results reveal a role for miR-124 in regulating the regeneration of a functional brain and visual system.

}, issn = {0950-1991}, doi = {10.1242/dev.144758}, url = {http://dev.biologists.org/content/144/18/3211}, author = {Sasidharan, Vidyanand and Marepally, Srujan and Elliott, Sarah A. and Baid, Srishti and Lakshmanan, Vairavan and Nayyar, Nishtha and Bansal, Dhiru and S{\'a}nchez Alvarado, Alejandro and Vemula, Praveen Kumar and Palakodeti, Dasaradhi} } @article {1165, title = {Morphology transition in helical tubules of a supramolecular gel driven by metal ions.}, journal = {Chem Commun (Camb)}, volume = {53}, year = {2017}, month = {2017 Jan 26}, pages = {1538-1541}, abstract = {

Our aim to access a particular chemical functionality on helical tubules has been achieved by the rational molecular design and synthesis of glucono-appended cardanol derivatives. For the first time, we report a chiral molecular packing with α-helical tubules, and chiral symmetry-breaking upon exposure to Cu that generated the final ordered structure via an in situ morphological transition without undergoing any phase change.

}, issn = {1364-548X}, doi = {10.1039/c6cc09120b}, author = {Lalitha, Krishnamoorthy and Sridharan, Vellaisamy and Maheswari, C Uma and Vemula, Praveen Kumar and Nagarajan, Subbiah} } @article {1201, title = {Scaling the effect of hydrophobic chain length on gene transfer properties of di-alkyl{,} di-hydroxy ethylammonium chloride based cationic amphiphiles}, journal = {RSC Adv.}, volume = {7}, year = {2017}, pages = {25398-25405}, abstract = {

The success of gene therapy critically depends on the availability of efficient transfection vectors. Cationic lipids are the most widely studied non-viral vectors. The molecular architecture of the cationic lipid determines its transfection efficiency. Variations in alkyl chain lengths of lipids influence self-assembly and liposomal fusion with the cell membrane. These factors determine the transfection ability of the lipid. Thus{,} to probe the effect of asymmetry in hydrophobic chains on transfection efficiency{,} we designed and synthesized a series of cationic lipids by systematically varying one of the two alkyl chains linked to the quaternary nitrogen centre from C18 to C10 and keeping the other alkyl C18 chain constant (Lip1818-Lip1810). Transfection studies in multiple cultured mammalian cells (CHO{,} B16F10 and HeLa) revealed that the lipids with C18:C14 and C18:C12 alkyl chains (Lip1814 \& Lip1812) showed 20-30\% higher transfection efficacies than their counterparts at 2 : 1 and 4 : 1 lipid to pDNA charge ratios. Cryo-transmission electron images showed unilamellar vesicle structures for the liposomes of lipids. Mechanistic studies involving Small Angle X-ray Scattering (SAXS) revealed that asymmetry in the hydrophobic region has a significant impact on liposomal fusion with the plasma membrane model. Collectively{,} these findings demonstrate that chain length asymmetry in the hydrophobic region of cationic lipids has an important role in their liposome-DNA interactions at optimal 2 : 1 and 4 : 1 lipid to pDNA charge ratios{,} which in turn modulates their gene transfer properties.

}, doi = {10.1039/C7RA02271A}, url = {http://dx.doi.org/10.1039/C7RA02271A}, author = {Hiwale, Ankita A. and Voshavar, Chandrashekhar and Dharmalingam, Priya and Dhayani, Ashish and Mukthavaram, Rajesh and Nadella, Rasajna and Sunnapu, Omprakash and Gandhi, Sivaraman and Naidu, V. G. M. and Chaudhuri, Arabinda and Marepally, Srujan and Vemula, Praveen Kumar} } @article {1166, title = {Water-mediated intermolecular interactions in 1,2-O-cyclohexylidene-myo-inositol: a quantitative analysis.}, journal = {Acta Crystallogr C Struct Chem}, volume = {73}, year = {2017}, month = {2017 Jan 01}, pages = {20-27}, abstract = {

The syntheses of new myo-inositol derivatives have received much attention due to their important biological activities. 1,2-O-Cyclohexylidene-myo-inositol is an important intermediate formed during the syntheses of certain myo-inositol derivatives. We report herein the crystal structure of 1,2-O-cyclohexylidene-myo-inositol dihydrate, CHO{\textperiodcentered}2HO, which is an intermediate formed during the syntheses of myo-inositol phosphate derivatives, to demonstrate the participation of water molecules and hydroxy groups in the formation of several intermolecular O-H...O interactions, and to determine a low-energy conformation. The title myo-inositol derivative crystallizes with two water molecules in the asymmetric unit in the space group C2/c, with Z = 8. The water molecules facilitate the formation of an extensive O-H...O hydrogen-bonding network that assists in the formation of a dense crystal packing. Furthermore, geometrical optimization and frequency analysis was carried out using density functional theory (DFT) calculations with B3LYP hybrid functionals and 6-31G(d), 6-31G(d,p) and 6-311G(d,p) basis sets. The theoretical and experimental structures were found to be very similar, with only slight deviations. The intermolecular interactions were quantitatively analysed using Hirshfeld surface analysis and 2D (two-dimensional) fingerplot plots, and the total lattice energy was calculated.

}, issn = {2053-2296}, doi = {10.1107/S2053229616018581}, author = {Purushothaman, Gayathri and Juvale, Kapil and Kirubakaran, Sivapriya and Vemula, Praveen Kumar and Thiruvenkatam, Vijay} } @article {617, title = {Gut Microbiota Conversion of Dietary Ellagic Acid into Bioactive Phytoceutical Urolithin A Inhibits Heme Peroxidases.}, journal = {PLoS One}, volume = {11}, year = {2016}, month = {2016}, pages = {e0156811}, abstract = {

Numerous studies signify that diets rich in phytochemicals offer many beneficial functions specifically during pathologic conditions, yet their effects are often not uniform due to inter-individual variation. The host indigenous gut microbiota and their modifications of dietary phytochemicals have emerged as factors that greatly influence the efficacy of phytoceutical-based intervention. Here, we investigated the biological activities of one such active microbial metabolite, Urolithin A (UA or 3,8-dihydroxybenzo[c]chromen-6-one), which is derived from the ellagic acid (EA). Our study demonstrates that UA potently inhibits heme peroxidases i.e. myeloperoxidase (MPO) and lactoperoxidase (LPO) when compared to the parent compound EA. In addition, chrome azurol S (CAS) assay suggests that EA, but not UA, is capable of binding to Fe3+, due to its catechol-like structure, although its modest heme peroxidase inhibitory activity is abrogated upon Fe3+-binding. Interestingly, UA-mediated MPO and LPO inhibition can be prevented by innate immune protein human NGAL or its murine ortholog lipocalin 2 (Lcn2), implying the complex nature of host innate immunity-microbiota interactions. Spectral analysis indicates that UA inhibits heme peroxidase-catalyzed reaction by reverting the peroxidase back to its inactive native state. In support of these in vitro results, UA significantly reduced phorbol myristate acetate (PMA)-induced superoxide generation in neutrophils, however, EA failed to block the superoxide generation. Treatment with UA significantly reduced PMA-induced mouse ear edema and MPO activity compared to EA treated mice. Collectively, our results demonstrate that microbiota-mediated conversion of EA to UA is advantageous to both host and microbiota i.e. UA-mediated inhibition of pro-oxidant enzymes reduce tissue inflammation, mitigate non-specific killing of gut bacteria, and abrogate iron-binding property of EA, thus providing a competitive edge to the microbiota in acquiring limiting nutrient iron and thrive in the gut.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0156811}, author = {Saha, Piu and Yeoh, Beng San and Singh, Rajbir and Chandrasekar, Bhargavi and Vemula, Praveen Kumar and Haribabu, Bodduluri and Vijay-Kumar, Matam and Jala, Venkatakrishna R} } @article {1169, title = {In Situ Synthesis of Metal Nanoparticle Embedded Hybrid Soft Nanomaterials.}, journal = {Acc Chem Res}, volume = {49}, year = {2016}, month = {2016 Sep 20}, pages = {1671-80}, abstract = {

The allure of integrating the tunable properties of soft nanomaterials with the unique optical and electronic properties of metal nanoparticles has led to the development of organic-inorganic hybrid nanomaterials. A promising method for the synthesis of such organic-inorganic hybrid nanomaterials is afforded by the in situ generation of metal nanoparticles within a host organic template. Due to their tunable surface morphology and porosity, soft organic materials such as gels, liquid crystals, and polymers that are derived from various synthetic or natural compounds can act as templates for the synthesis of metal nanoparticles of different shapes and sizes. This method provides stabilization to the metal nanoparticles by the organic soft material and advantageously precludes the use of external reducing or capping agents in many instances. In this Account, we exemplify the green chemistry approach for synthesizing these materials, both in the choice of gelators as soft material frameworks and in the reduction mechanisms that generate the metal nanoparticles. Established herein is the core design principle centered on conceiving multifaceted amphiphilic soft materials that possess the ability to self-assemble and reduce metal ions into nanoparticles. Furthermore, these soft materials stabilize the in situ generated metal nanoparticles and retain their self-assembly ability to generate metal nanoparticle embedded homogeneous organic-inorganic hybrid materials. We discuss a remarkable example of vegetable-based drying oils as host templates for metal ions, resulting in the synthesis of novel hybrid nanomaterials. The synthesis of metal nanoparticles via polymers and self-assembled materials fabricated via cardanol (a bioorganic monomer derived from cashew nut shell liquid) are also explored in this Account. The organic-inorganic hybrid structures were characterized by several techniques such as UV-visible spectroscopy, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Utilization of silver nanoparticle-based hybrid nanomaterials as an antimicrobial material is another illustration of the advantage of hybrid nanomaterials. We envision that the results summarized in this Account will help the scientific community to design and develop diverse organic-inorganic hybrid materials using environmentally benign methods and that these materials will yield advanced properties that have multifaceted applications in various research fields.

}, issn = {1520-4898}, doi = {10.1021/acs.accounts.6b00201}, author = {Divya, Kizhmuri P and Miroshnikov, Mikhail and Dutta, Debjit and Vemula, Praveen Kumar and Ajayan, Pulickel M and John, George} }