Education & Certifications

  • Doctor of Philosophy, University of Madras, Chemistry-Bioorganic (2006)
  • Master of Science, University of Madras, Chemistry (1999)
  • Bachelor of Science, University of Madras, Chemistry (1995)


  • David K. Stevenson, Jayakumar Rajadas, Cecilia Espadas, Ronald James Wong, David Lechuga, Mohammed Inayathullah Nazir Ahmed. "United States Patent US20170035778, WO/2017/023970A1 Formulations and uses for microparticle delivery of metalloporphyrins", The Board of Trustees of the Leland Stanford Junior University, Feb 9, 2017


Work Experience

  • Research Associate/Scientist, Stanford University (December 2010 - Present)


    300 Pasteur drive, Stanford, CA 94305

  • Postdoctoral Scholar, University of California, Los Angeles (UCLA) (October 2006 - November 2010)


    635 Charles E. Young Drive south, Los Angeles, California

  • Ph.D Research Scholar, Bioorganic and Neurochemistry Laboratory, CLRI, CSIR. (2000 - 2006)

    University of Madras


    Adyar, Chennai, India.

Professional Affiliations and Activities

  • Editorial Board, Novel Approaches in Drug Designing & Development (NAPDD) (2017 - Present)
  • Editorial Board, American Journal of Advanced Drug Delivery (2016 - Present)
  • Editorial Board, International Journal of Nanotechnology and Nanomedicine (2016 - Present)
  • Editorial Board, Radiology Open Journal (2015 - Present)
  • Editorial Board, SM Journal of Clinical and Medical Imaging (2015 - Present)


All Publications

  • Microhemorrhage-associated tissue iron enhances the risk forAspergillus fumigatusinvasion in a mouse model of airway transplantation. Science translational medicine Hsu, J. L., Manouvakhova, O. V., Clemons, K. V., Inayathullah, M., Tu, A. B., Sobel, R. A., Tian, A., Nazik, H., Pothineni, V. R., Pasupneti, S., Jiang, X., Dhillon, G. S., Bedi, H., Rajadas, J., Haas, H., Aurelian, L., Stevens, D. A., Nicolls, M. R. 2018; 10 (429)


    Invasive pulmonary disease due to the moldAspergillus fumigatuscan be life-threatening in lung transplant recipients, but the risk factors remain poorly understood. To study this process, we used a tracheal allograft mouse model that recapitulates large airway changes observed in patients undergoing lung transplantation. We report that microhemorrhage-related iron content may be a major determinant ofA. fumigatusinvasion and, consequently, its virulence. Invasive growth was increased during progressive alloimmune-mediated graft rejection associated with high concentrations of ferric iron in the graft. The role of iron inA. fumigatusinvasive growth was further confirmed by showing that this invasive phenotype was increased in tracheal transplants from donor mice lacking the hemochromatosis gene (Hfe -/- ). The invasive phenotype was also increased in mouse syngrafts treated with topical iron solution and in allograft recipients receiving deferoxamine, a chelator that increases iron bioavailability to the mold. The invasive growth of the iron-intolerantA. fumigatusdouble-knockout mutant (?sreA/?cccA) was lower than that of the wild-type mold. Alloimmune-mediated microvascular damage and iron overload did not appear to impair the host's immune response. In human lung transplant recipients, positive staining for iron in lung transplant tissue was more commonly seen in endobronchial biopsy sections from transplanted airways than in biopsies from the patients' own airways. Collectively, these data identify iron as a major determinant ofA. fumigatusinvasive growth and a potential target to treat or preventA. fumigatusinfections in lung transplant patients.

    View details for DOI 10.1126/scitranslmed.aag2616

    View details for PubMedID 29467298

  • Prolonged survival of transplanted stem cells after ischaemic injury via the slow release of pro-survival peptides from a collagen matrix Nature Biomedical Engineering Lee, A. S., Inayathullah, ., Lijkwan, . A., Zhao, X., Sun, W., Park, S., Hong, W. X., Parekh, M. B., Malkovskiy, A. V., Lau, E., Qin, X., Pothineni,, . R., Sanchez-Freire, ., Kooreman, N. G., Ebert, A. D., Chan, C. K., Nguyen, P. K., Rajadas, J., Wu, J. C. 2018; 2 (2)
  • Nordihydroguaiaretic acid, a lignan from Larrea tridentata (Creosote bush) protects against ALIOS diet-induced metabolic dysfunction in mice. The Journal of pharmacology and experimental therapeutics Chan, J. K., Bittner, S., Bittner, A., Atwal, S., Shen, W. J., Inayathullah, M., Rajada, J., Nicolls, M. R., Kraemer, F. B., Azhar, S. 2018


    To determine the effects of NDGA on metabolic and molecular changes in response to feeding mice typical American fast food or Western diet, mice were fed with ALIOS diet and subjected to metabolic analysis. Male C57BL/6J mice were randomly assigned to: ALIOS, ALIOS + NDGA, or control diet and maintained on the specific diet for 8 weeks. Mice fed ALIOS diet, showed increased body, liver and epididymal fat pad weight, plasma ALT and AST levels (a measure of liver injury), and liver triglyceride (TG) content. Co-administration of NDGA normalized body and epididymal fat pad weight, ALT and AST levels, and liver TG. NDGA treatment also improved insulin sensitivity but not glucose intolerance in ALIOS diet fed mice. In ALIOS diet fed mice, NDGA supplementation induced PPAR? (the master regulator of fatty acid oxidation) and mRNA levels of Cpt1c and Cpt2, key genes involved in fatty acid oxidation as compared to ALIOS diet. NDGA significantly reduced liver ER stress response CHOP protein, as compared to chow or ALIOS diet and also ameliorated ALIOS diet-induced elevation of apoptosis signaling protein, CASP3. Likewise, NDGA downregulated the ALIOS-diet induced mRNA levels of Pparg, Fasn, and Dgat2. NDGA treatment of ALIOS fed mice upregulated the hepatic expression of antioxidant enzymes, GPX4 and PRDX3 proteins. In conclusion, we provide evidence that NDGA improves metabolic dysregulation by simultaneously modulating PPAR? transcription factor and key genes involved in fatty acid oxidation, key antioxidant and lipogenic enzymes, and apoptosis and ER stress signaling pathways.

    View details for DOI 10.1124/jpet.117.243733

    View details for PubMedID 29472517

  • PEG/Dextran Double Layer Influences Fe Ion Release and Colloidal Stability of Iron Oxide Nanoparticles. Scientific reports Mohammadi, M. R., Malkovskiy, A. V., Jothimuthu, P., Kim, K. M., Parekh, M., Inayathullah, M., Zhuge, Y., Rajadas, J. 2018; 8 (1): 4286


    Despite preliminary confidence on biosafety of polymer coated iron oxide nanoparticles (SPIONs), toxicity concerns have hampered their clinical translation. SPIONs toxicity is known to be due to catalytic activity of their surface and release of toxic Fe ions originating from the core biodegradation, leading to the generation of reactive oxygen species (ROS). Here, we hypothesized that a double-layer polymeric corona comprising of dextran as an interior, and polyethylene glycol (PEG) as an exterior layer better shields the core SPIONs. We found that ROS generation was cell specific and depended on SPIONs concentration, although it was reduced by sufficient PEG immobilization or 100?ÁM deferoxamine. 24?h following injection, PEGylated samples showed reduction of biodistribution in liver, heterogenous biodistribution profile in spleen, and no influence on NPs blood retention. Sufficient surface masking or administration of deferoxamine could be beneficial strategies in designing and clinical translation of future biomedical SPIONs.

    View details for DOI 10.1038/s41598-018-22644-8

    View details for PubMedID 29523826

  • Screening of NCI-DTP library to identify new drug candidates for Borrelia burgdorferi. journal of antibiotics Pothineni, V. R., Wagh, D., Babar, M. M., Inayathullah, M., Watts, R. E., Kim, K., Parekh, M. B., Gurjarpadhye, A. A., Solow-Cordero, D., Tayebi, L., Rajadas, J. 2017; 70 (3): 308-312

    View details for DOI 10.1038/ja.2016.131

    View details for PubMedID 27826144

  • Endothelial APLNR regulates tissue fatty acid uptake and is essential for apelin's glucose-lowering effects. Science translational medicine Hwangbo, C., Wu, J., Papangeli, I., Adachi, T., Sharma, B., Park, S., Zhao, L., Ju, H., Go, G. W., Cui, G., Inayathullah, M., Job, J. K., Rajadas, J., Kwei, S. L., Li, M. O., Morrison, A. R., Quertermous, T., Mani, A., Red-Horse, K., Chun, H. J. 2017; 9 (407)


    Treatment of type 2 diabetes mellitus continues to pose an important clinical challenge, with most existing therapies lacking demonstrable ability to improve cardiovascular outcomes. The atheroprotective peptide apelin (APLN) enhances glucose utilization and improves insulin sensitivity. However, the mechanism of these effects remains poorly defined. We demonstrate that the expression of APLNR (APJ/AGTRL1), the only known receptor for apelin, is predominantly restricted to the endothelial cells (ECs) of multiple adult metabolic organs, including skeletal muscle and adipose tissue. Conditional endothelial-specific deletion of Aplnr (Aplnr(ECKO) ) resulted in markedly impaired glucose utilization and abrogation of apelin-induced glucose lowering. Furthermore, we identified inactivation of Forkhead box protein O1 (FOXO1) and inhibition of endothelial expression of fatty acid (FA) binding protein 4 (FABP4) as key downstream signaling targets of apelin/APLNR signaling. Both the Apln(-/-) and Aplnr(ECKO) mice demonstrated increased endothelial FABP4 expression and excess tissue FA accumulation, whereas concurrent endothelial Foxo1 deletion or pharmacologic FABP4 inhibition rescued the excess FA accumulation phenotype of the Apln(-/-) mice. The impaired glucose utilization in the Aplnr(ECKO) mice was associated with excess FA accumulation in the skeletal muscle. Treatment of these mice with an FABP4 inhibitor abrogated these metabolic phenotypes. These findings provide mechanistic insights that could greatly expand the therapeutic repertoire for type 2 diabetes and related metabolic disorders.

    View details for DOI 10.1126/scitranslmed.aad4000

    View details for PubMedID 28904225

  • Identification of key regions and residues controlling A? folding and assembly. Scientific reports Hayden, E. Y., Hoi, K. K., Lopez, J., Inayathullah, M., Condron, M. M., Teplow, D. B. 2017; 7 (1): 12434


    Amyloid ?-protein (A?) assembly is hypothesized to be a seminal neuropathologic event in Alzheimer's disease (AD). We used an unbiased D-amino acid substitution strategy to determine structure-assembly relationships of 76 different A?40 and A?42 peptides. We determined the effects of the substitutions on peptide oligomerization, secondary structure dynamics, fibril assembly dynamics, and fibril morphology. Our experiments revealed that the assembly of A?42 was more sensitive to chiral substitutions than was A?40 assembly. Substitutions at identical positions in the two peptides often, but not always, produced the same effects on assembly. Sites causing substantial effects in both A?40 and A?42 include His14, Gln15, Ala30, Ile31, Met35, and Val36. Sites whose effects were unique to A?40 include Lys16, Leu17, and Asn 27, whereas sites unique to A?42 include Phe20 and Ala21. These sites may be appropriate targets for therapeutic agents that inhibit or potentiate, respectively, these effects.

    View details for DOI 10.1038/s41598-017-10845-6

    View details for PubMedID 28974765

    View details for PubMedCentralID PMC5626695

  • Nanoparticles hybridization to engineer biomaterials for drug delivery Nanobiomaterials Science, Development and Evaluation Mohammadi, M., Sun, W., Inayathullah, M., Rajadas, J. Elsevier. 2017: 147?161
  • Nanomaterials engineering for drug delivery: a hybridization approach Journal of Materials Chemistry B Mohammadi, M., Nojoomi, A., Mozafari, M., Dubnika, A., Inayathullah, M., Rajadas, J. 2017; 5 (22): 3995-4018

    View details for DOI 10.1039/C6TB03247H

  • Attenuation of synaptic toxicity and MARK4/PAR1-mediated Tau phosphorylation by methylene blue for Alzheimer's disease treatment SCIENTIFIC REPORTS Sun, W., Lee, S., Huang, X., Liu, S., Inayathullah, M., Kim, K., Tang, H., Ashford, J. W., Rajadas, J. 2016; 6


    Alzheimer's disease (AD) is a neurodegenerative disease characterized by genotypic and phenotypic heterogeneity. Critical components of the two AD pathological pathways, A?-amyloidosis and Tauopathy, have been considered as therapeutic targets. Among them, much effort is focused on aberrant Tau phosphorylation and targeting Tau-phosphorylating kinases. Methylene blue (MB), a phenothiazine dye that crosses the blood-brain barrier, has been shown to hit multiple molecular targets involved in AD and have beneficial effects in clinical studies. Here we present evidence that microtubule affinity-regulating kinase (MARK4) is a novel target of MB. MB partially rescued the synaptic toxicity in Drosophila larva overexpressing PAR1 (MARK analog). In 293T culture, MB decreased MARK4-mediated Tau phosphorylation in a dose dependent manner. Further studies revealed a two-fold mechanism by MB including down-regulation of MARK4 protein level through ubiquitin-proteasome pathway and inhibition of MARK4 kinase activity in vitro. This study highlights the importance of MARK4 as a viable target for Tauopathy and provides fresh insight into the complex mechanism used by MB to treat AD.

    View details for DOI 10.1038/srep34784

    View details for Web of Science ID 000384762100001

    View details for PubMedID 27708431

  • Conformational dynamics of a hydrophobic prion fragment (113-127) in different pH and osmolyte solutions NEUROPEPTIDES Inayathullah, M., Rajadas, J. 2016; 57: 9-14


    Prion diseases are characterized by a conformational change in prion protein from its native state into beta-sheet rich aggregates that are neurotoxic. The central domain that contain a highly conserved hydrophobic region of the protein play an important role in the toxicity. The conformation of the proteins is largely influenced by various solvent environments. Here we report results of study of hydrophobic prion fragment peptide PrP(113-127) under different pH and osmolytes solution conditions. The secondary structure and the folding of PrP(113-127) was determined using circular dichroism and fluorescence spectroscopic methods. The results indicate that PrP(113-127) adopts a random coil conformation in aqueous buffer at neutral pH and that converted into beta sheet on aging. Even though the initial random coil conformation was similar in different pH conditions, the acidic as well as basic pH conditions delays the conformational transition to beta sheet. FRET results indicate that the distance between N and C-terminal regions increased on aging due to unfolding by self-assembly of the peptide into an organized beta sheet structure. Presence of osmolytes, prevented or decelerated the aggregation process of PrP(113-127) peptide.

    View details for DOI 10.1016/j.npep.2016.02.004

    View details for Web of Science ID 000378193100002

    View details for PubMedID 26919915

  • Effect of osmolytes on the conformation and aggregation of some amyloid peptides: CD spectroscopic data. Data in brief Inayathullah, M., Rajadas, J. 2016; 7: 1643-1651


    Protein misfolding and aggregation are responsible for a large number of diseases called protein conformational diseases or disorders that include Alzheimer?s disease, Huntington?s diseases, Prion related encephalopathies and type-II diabetes (á(Kopito and Ron, 2000) [1]. A variety of studies have shown that some small organic molecules, known as osmolytes have the ability to stabilize native conformation of proteins and prevent misfolding and aggregation ( (Zhao et al., 2008) [2]. It has been shown that certain short segment or fragment of respective proteins can also form amyloids, and the segments also promote the aggregation in the full-length protein ( (Gazit, 2002) [3]. This article presents circular dichroism spectroscopic data on conformational analysis and effect of osmolytes on A? peptide fragments, different lengths of polyglutamine peptide and the amyloidogenic segment of islet amyloid polypeptide.

    View details for DOI 10.1016/j.dib.2016.04.070

    View details for PubMedID 27222868

  • Self-assembly and sequence length dependence on nanofibrils of polyglutamine peptides NEUROPEPTIDES Inayathullah, M., Tan, A., Jeyaraj, R., Lam, J., Cho, N., Liu, C. W., Manoukian, M. A., Ashkan, K., Mahmoudi, M., Rajadas, J. 2016; 57: 71-83


    Huntington's disease (HD) is recognized as a currently incurable, inherited neurodegenerative disorder caused by the accumulation of misfolded polyglutamine (polyQ) peptide aggregates in neuronal cells. Yet, the mechanism by which newly formed polyQ chains interact and assemble into toxic oligomeric structures remains a critical, unresolved issue. In order to shed further light on the matter, our group elected to investigate the folding of polyQ peptides - examining glutamine repeat lengths ranging from 3 to 44 residues. To characterize these aggregates we employed a diverse array of technologies, including: nuclear magnetic resonance; circular dichroism; Fourier transform infrared spectroscopy; fluorescence resonance energy transfer (FRET), and atomic force microscopy. The data we obtained suggest that an increase in the number of glutamine repeats above 14 residues results in disordered loop structures, with different repeat lengths demonstrating unique folding characteristics. This differential folding manifests in the formation of distinct nano-sized fibrils, and on this basis, we postulate the idea of 14 polyQ repeats representing a critical loop length for neurotoxicity - a property that we hope may prove amenable to future therapeutic intervention. Furthermore, FRET measurements on aged assemblages indicate an increase in the end-to-end distance of the peptide with time, most probably due to the intermixing of individual peptide strands within the nanofibril. Further insight into this apparent time-dependent reorganization of aggregated polyQ peptides may influence future disease modeling of polyQ-related proteinopathies, in addition to directing novel clinical innovations.

    View details for DOI 10.1016/j.npep.2016.01.011

    View details for Web of Science ID 000378193100010

    View details for PubMedID 26874369

  • Identification of new drug candidates against Borrelia burgdorferi using high-throughput screening DRUG DESIGN DEVELOPMENT AND THERAPY Pothineni, V. R., Wagh, D., Babar, M. M., Inayathullah, M., Solow-Cordero, D., Kim, K., Samineni, A. V., Parekh, M. B., Tayebi, L., Rajadas, J. 2016; 10: 1307-1322


    Lyme disease is the most common zoonotic bacterial disease in North America. It is estimated that >300,000 cases per annum are reported in USA alone. A total of 10%-20% of patients who have been treated with antibiotic therapy report the recrudescence of symptoms, such as muscle and joint pain, psychosocial and cognitive difficulties, and generalized fatigue. This condition is referred to as posttreatment Lyme disease syndrome. While there is no evidence for the presence of viable infectious organisms in individuals with posttreatment Lyme disease syndrome, some researchers found surviving Borrelia burgdorferi population in rodents and primates even after antibiotic treatment. Although such observations need more ratification, there is unmet need for developing the therapeutic agents that focus on removing the persisting bacterial form of B. burgdorferi in rodent and nonhuman primates. For this purpose, high-throughput screening was done using BacTiter-Glo assay for four compound libraries to identify candidates that stop the growth of B. burgdorferi in vitro. The four chemical libraries containing 4,366 compounds (80% Food and Drug Administration [FDA] approved) that were screened are Library of Pharmacologically Active Compounds (LOPAC1280), the National Institutes of Health Clinical Collection, the Microsource Spectrum, and the Biomol FDA. We subsequently identified 150 unique compounds, which inhibited >90% of B. burgdorferi growth at a concentration of <25 ÁM. These 150 unique compounds comprise many safe antibiotics, chemical compounds, and also small molecules from plant sources. Of the 150 unique compounds, 101 compounds are FDA approved. We selected the top 20 FDA-approved molecules based on safety and potency and studied their minimum inhibitory concentration and minimum bactericidal concentration. The promising safe FDA-approved candidates that show low minimum inhibitory concentration and minimum bactericidal concentration values can be chosen as lead molecules for further advanced studies.

    View details for DOI 10.2147/DDDT.S101486

    View details for Web of Science ID 000373575000001

    View details for PubMedID 27103785

  • Enhanced Electrochemical Sensing with Carbon Nanotubes Modified with Bismuth and Magnetic Nanoparticles in a Lab-on-a-Chip. ChemNanoMat : chemistry of nanomaterials for energy, biology and more Jothimuthu, P., Hsu, J. L., Chen, R., Inayathullah, M., Pothineni, V. R., Jan, A., Gurtner, G. C., Rajadas, J., Nicolls, M. R. 2016; 2 (9): 904?10


    Iron plays an especially important role in human physiological functions and pathological impairments. The superior properties of carbon nanotubes (CNTs) and their modification with bismuth and magnetic nanoparticles as developed in this work have led to an extraordinary and novel material to facilitate ultrasensitive detection in the nanomolar range. Here, we present the development of an electrochemical sensor for detection of ferrous (Fe(2+)) and ferric (Fe(3+)) iron by means of CNTs modified with bismuth and magnetic nanoparticles for higher sensitivity of detection. The sensor fabrication includes microfabrication methodologies, soft lithography, and electrodeposition. Cyclic voltammetry and differential pulse voltammetry are used for the electroanalytical studies and detection of the ions in samples. The sensor has a dynamic range of detection from 0.01 nm to 10 mm. The performance of the sensor with modified CNTs was explored for sensitivity and specificity. CNTs, modified with bismuth and magnetic nanoparticles by means of electrodeposition, enhanced the detection limit significantly down to 0.01 nm.

    View details for DOI 10.1002/cnma.201600174

    View details for PubMedID 27857882

  • Transdermal Delivery of Functional Collagen Via Polyvinylpyrrolidone Microneedles ANNALS OF BIOMEDICAL ENGINEERING Sun, W., Inayathullah, M., Manoukian, M. A., Malkovskiy, A. V., Manickam, S., Marinkovich, M. P., Lane, A. T., Tayebi, L., Seifalian, A. M., Rajadas, J. 2015; 43 (12): 2978-2990


    Collagen makes up a large proportion of the human body, particularly the skin. As the body ages, collagen content decreases, resulting in wrinkled skin and decreased wound healing capabilities. This paper presents a method of delivering type I collagen into porcine and human skin utilizing a polyvinylpyrrolidone microneedle delivery system. The microneedle patches were made with concentrations of 1, 2, 4, and 8% type I collagen (w/w). Microneedle structures and the distribution of collagen were characterized using scanning electron microscopy and confocal microscopy. Patches were then applied on the porcine and human skin, and their effectiveness was examined using fluorescence microscopy. The results illustrate that this microneedle delivery system is effective in delivering collagen I into the epidermis and dermis of porcine and human skin. Since the technique presented in this paper is quick, safe, effective and easy, it can be considered as a new collagen delivery method for cosmetic and therapeutic applications.

    View details for DOI 10.1007/s10439-015-1353-0

    View details for Web of Science ID 000363941300013

    View details for PubMedID 26066056

  • A Thermo-Sensitive Delivery Platform for Topical Administration of Inflammatory Bowel Disease Therapies. Gastroenterology Sinha, S. R., Nguyen, L. P., Inayathullah, M., Malkovskiy, A., Habte, F., Rajadas, J., Habtezion, A. 2015; 149 (1): 52-55 e2


    Systemic therapies for inflammatory bowel disease are associated with increased risk of infections and malignancies. Topical therapies reduce systemic exposure, but can be difficult to retain or have limited proximal distribution. To mitigate these issues, we developed a thermo-sensitive platform, using a polymer-based system that is liquid at room temperature but turns into a viscous gel upon reaching body temperature. Following rectal administration to mice with dextran sulphate sodium-induced colitis, the platform carrying budesonide or mesalamine becomes more viscoelastic near body temperature. Mice given the drug-containing platform gained more weight and had reduced histologic and biologic features of colitis than mice given the platform alone or liquid drugs via enema. Image analysis showed that enemas delivered with and without the platform reached similar distances in the colons of mice, but greater colonic retention was achieved by using the platform.

    View details for DOI 10.1053/j.gastro.2015.04.002

    View details for PubMedID 25863215

  • Transdermal deferoxamine prevents pressure-induced diabetic ulcers. Proceedings of the National Academy of Sciences of the United States of America Duscher, D., Neofytou, E., Wong, V. W., Maan, Z. N., Rennert, R. C., Inayathullah, M., Januszyk, M., Rodrigues, M., Malkovskiy, A. V., Whitmore, A. J., Walmsley, G. G., Galvez, M. G., Whittam, A. J., Brownlee, M., Rajadas, J., Gurtner, G. C. 2015; 112 (1): 94-99


    There is a high mortality in patients with diabetes and severe pressure ulcers. For example, chronic pressure sores of the heels often lead to limb loss in diabetic patients. A major factor underlying this is reduced neovascularization caused by impaired activity of the transcription factor hypoxia inducible factor-1 alpha (HIF-1?). In diabetes, HIF-1? function is compromised by a high glucose-induced and reactive oxygen species-mediated modification of its coactivator p300, leading to impaired HIF-1? transactivation. We examined whether local enhancement of HIF-1? activity would improve diabetic wound healing and minimize the severity of diabetic ulcers. To improve HIF-1? activity we designed a transdermal drug delivery system (TDDS) containing the FDA-approved small molecule deferoxamine (DFO), an iron chelator that increases HIF-1? transactivation in diabetes by preventing iron-catalyzed reactive oxygen stress. Applying this TDDS to a pressure-induced ulcer model in diabetic mice, we found that transdermal delivery of DFO significantly improved wound healing. Unexpectedly, prophylactic application of this transdermal delivery system also prevented diabetic ulcer formation. DFO-treated wounds demonstrated increased collagen density, improved neovascularization, and reduction of free radical formation, leading to decreased cell death. These findings suggest that transdermal delivery of DFO provides a targeted means to both prevent ulcer formation and accelerate diabetic wound healing with the potential for rapid clinical translation.

    View details for DOI 10.1073/pnas.1413445112

    View details for PubMedID 25535360

  • [Pyr-1]-Apelin-13 delivery via nano-liposomal encapsulation attenuates pressure overload-induced cardiac dysfunction BIOMATERIALS Serpooshan, V., Sivanesan, S., Huang, X., Mahmoudi, M., Malkovskiy, A. V., Zhao, M., Inayathullah, M., Wagh, D., Zhang, X. J., Metzler, S., Bernstein, D., Wu, J. C., Ruiz-Lozano, P., Rajadas, J. 2015; 37: 289-298


    Nanoparticle-mediated sustained delivery of therapeutics is one of the highly effective and increasingly utilized applications of nanomedicine. Here, we report the development and application of a drug delivery system consisting of polyethylene glycol (PEG)-conjugated liposomal nanoparticles as an efficient inávivo delivery approach for [Pyr1]-apelin-13 polypeptide. Apelin is an adipokine that regulates a variety of biological functions including cardiac hypertrophy and hypertrophy-induced heart failure. The clinical use of apelin has been greatly impaired by its remarkably short half-life in circulation. Here, we investigate whether [Pyr1]-apelin-13 encapsulation in liposome nanocarriers, conjugated with PEG polymer on their surface, can prolong apelin stability in the blood stream and potentiate apelin beneficial effects in cardiac function. Atomic force microscopy and dynamic light scattering were used to assess the structure and size distribution of drug-laden nanoparticles. [Pyr1]-apelin-13 encapsulation in PEGylated liposomal nanocarriers resulted in sustained and extended drug release both inávitro and inávivo. Moreover, intraperitoneal injection of [Pyr1]-apelin-13 nanocarriers in a mouse model of pressure-overload induced heart failure demonstrated a sustainable long-term effect of [Pyr1]-apelin-13 in preventing cardiac dysfunction. We concluded that this engineered nanocarrier system can serve as a delivery platform for treating heart injuries through sustained bioavailability of cardioprotective therapeutics.

    View details for DOI 10.1016/j.biomaterials.2014.08.045

    View details for Web of Science ID 000346541100028

    View details for PubMedID 25443792

  • Infrared Imaging Tools for Diagnostic Applications in Dermatology. SM journal of clinical and medical imaging Gurjarpadhye, A. A., Parekh, M. B., Dubnika, A., Rajadas, J., Inayathullah, M. 2015; 1 (1): 1-5


    Infrared (IR) imaging is a collection of non-invasive imaging techniques that utilize the IR domain of the electromagnetic spectrum for tissue assessment. A subset of these techniques construct images using back-reflected light, while other techniques rely on detection of IR radiation emitted by the tissue as a result of its temperature. Modern IR detectors sense thermal emissions and produce a heat map of surface temperature distribution in tissues. Thus, the IR spectrum offers a variety of imaging applications particularly useful in clinical diagnostic area, ranging from high-resolution, depth-resolved visualization of tissue to temperature variation assessment. These techniques have been helpful in the diagnosis of many medical conditions including skin/breast cancer, arthritis, allergy, burns, and others. In this review, we discuss current roles of IR-imaging techniques for diagnostic applications in dermatology with an emphasis on skin cancer, allergies, blisters, burns and wounds.

    View details for PubMedID 26691203

  • Recent Developments in Diffusion Tensor Imaging of Brain Radiol Open J. Parekh, M. B., Gurjarpadhye, A. A., Manoukian, M. A., Dubnika, A., Rajadas, J., Inayathullah, M. 2015; 1 (1): 12
  • Borreliacidal activity of Borrelia metal transporter A (BmtA) binding small molecules by manganese transport inhibition. Drug design, development and therapy Wagh, D., Pothineni, V. R., Inayathullah, M., Liu, S., Kim, K., Rajadas, J. 2015; 9: 805-816


    Borrelia burgdorferi, the causative agent of Lyme disease, utilizes manganese (Mn) for its various metabolic needs. We hypothesized that blocking Mn transporter could be a possible approach to inhibit metabolic activity of this pathogen and eliminate the infection. We used a combination of in silico protein structure prediction together with molecular docking to target the Borrelia metal transporter A (BmtA), a single known Mn transporter in Borrelia and screened libraries of FDA approved compounds that could potentially bind to the predicted BmtA structure with high affinity. Tricyclic antihistamines such as loratadine, desloratadine, and 3-hydroxydesloratadine as well as yohimbine and tadalafil demonstrated a tight binding to the in silico folded BmtA transporter. We, then, tested borreliacidal activity and dose response of the shortlisted compounds from this screen using a series of in vitro assays. Amongst the probed compounds, desloratadine exhibited potent borreliacidal activity in vitro at and above 78 ?g/mL (250 ?M). Borrelia treated with lethal doses of desloratadine exhibited a significant loss of intracellular Mn specifically and a severe structural damage to the bacterial cell wall. Our results support the possibility of developing a novel, targeted therapy to treat Lyme disease by targeting specific metabolic needs of Borrelia.

    View details for DOI 10.2147/DDDT.S77063

    View details for PubMedID 25709405

  • Polymeric Nanoparticles to Combat Squamous Cell Carcinomas in Patients with Dystrophic Epidermolysis Bullosa. Recent patents on nanomedicine Manoukian, M. A., Ott, S. V., Rajadas, J., Inayathullah, M. 2014; 4 (1): 15-24


    Skin cancer is the leading cause of malignancy in the United States, with Basal Cell Carcinoma, Squamous Cell Carcinoma , and Melanoma being the three most common diagnoses, respectively. Squamous Cell Carcinoma (SCC) is a particular concern for patients suffering from Dystrophic Epidermolysis Bullosa (DEB), a disease that affects the production and function of collagen VII, a protein that forms the anchoring fibrils which bind the epidermis to the dermis. Patients with DEB suffer from chronic blistering and wounds that have impaired healing capabilities, often leading to the development of SCC and eventual mortality. Nanomedicine is playing an increasing role in the delivery of effective therapeutics to combat a wide range of diseases, including the imaging and treatment of SCC. In this review, we discuss the role of nanoparticles in the treatment of SCC with an emphasis on PLGA nanoparticles and SCCs found in patients suffering from DEB, and address recent patents that are pertinent to the development of novel nanomedical therapeutics.

    View details for PubMedID 25506404

  • Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension. Science translational medicine Tian, W., Jiang, X., Tamosiuniene, R., Sung, Y. K., Qian, J., Dhillon, G., Gera, L., Farkas, L., Rabinovitch, M., Zamanian, R. T., Inayathullah, M., Fridlib, M., Rajadas, J., Peters-Golden, M., Voelkel, N. F., Nicolls, M. R. 2013; 5 (200): 200ra117-?


    Pulmonary hypertension (PH) is a serious condition that affects mainly young and middle-aged women, and its etiology is poorly understood. A prominent pathological feature of PH is accumulation of macrophages near the arterioles of the lung. In both clinical tissue and the SU5416 (SU)/athymic rat model of severe PH, we found that the accumulated macrophages expressed high levels of leukotriene A4 hydrolase (LTA4H), the biosynthetic enzyme for leukotriene B4 (LTB4). Moreover, macrophage-derived LTB4 directly induced apoptosis in pulmonary artery endothelial cells (PAECs). Further, LTB4 induced proliferation and hypertrophy of human pulmonary artery smooth muscle cells. We found that LTB4 acted through its receptor, BLT1, to induce PAEC apoptosis by inhibiting the protective endothelial sphingosine kinase 1 (Sphk1)-endothelial nitric oxide synthase (eNOS) pathway. Blocking LTA4H decreased in vivo LTB4 levels, prevented PAEC apoptosis, restored Sphk1-eNOS signaling, and reversed fulminant PH in the SU/athymic rat model of PH. Antagonizing BLT1 similarly reversed established PH. Inhibition of LTB4 biosynthesis or signal transduction in SU-treated athymic rats with established disease also improved cardiac function and reopened obstructed arterioles; this approach was also effective in the monocrotaline model of severe PH. Human plexiform lesions, one hallmark of PH, showed increased numbers of macrophages, which expressed LTA4H, and patients with connective tissue disease-associated pulmonary arterial hypertension exhibited significantly higher LTB4 concentrations in the systemic circulation than did healthy subjects. These results uncover a possible role for macrophage-derived LTB4 in PH pathogenesis and identify a pathway that may be amenable to therapeutic targeting.

    View details for DOI 10.1126/scitranslmed.3006674

    View details for PubMedID 23986401

  • Polyvinylpyrrolidone microneedles enable delivery of intact proteins for diagnostic and therapeutic applications ACTA BIOMATERIALIA Sun, W., Araci, Z., Inayathullah, M., Manickam, S., Zhang, X., Bruce, M. A., Marinkovich, M. P., Lane, A. T., Milla, C., Rajadas, J., Butte, M. J. 2013; 9 (8): 7767-7774


    We present a method of fabricating microneedles from polyvinylpyrrolidone (PVP) that enables delivery of intact proteins (or peptides) to the dermal layers of the skin. PVP is known to self-assemble into branched hollow fibers in aqueous and alcoholic solutions; we utilized this property to develop dissolvable patches of microneedles. Proteins were dissolved in concentrated PVP solution in both alcohol and water, poured into polydimethylsiloxane templates shaped as microneedles and, upon evaporation of solvent, formed into concentric, fibrous, layered structures. This approach of making PVP microneedles overcomes problems in dosage, uniform delivery and stability of protein formulation as compared to protein-coated metallic microneedles or photopolymerized PVP microneedles. Here we characterize the PVP microneedles and measure the delivery of proteins into skin. We show that our method of fabrication preserves the protein conformation. These microneedles can serve as a broadly useful platform for delivering protein antigens and therapeutic proteins to the skin, for example for allergen skin testing or immunotherapy.

    View details for DOI 10.1016/j.actbio.2013.04.045

    View details for Web of Science ID 000322207700017

    View details for PubMedID 23648574

  • Solvent microenvironments and copper binding alters the conformation and toxicity of a prion fragment. PloS one Inayathullah, M., Satheeshkumar, K. S., Malkovskiy, A. V., Carre, A. L., Sivanesan, S., Hardesty, J. O., Rajadas, J. 2013; 8 (12)


    The secondary structures of amyloidogenic proteins are largely influenced by various intra and extra cellular microenvironments and metal ions that govern cytotoxicity. The secondary structure of a prion fragment, PrP(111-126), was determined using circular dichroism (CD) spectroscopy in various microenvironments. The conformational preferences of the prion peptide fragment were examined by changing solvent conditions and pH, and by introducing external stress (sonication). These physical and chemical environments simulate various cellular components at the water-membrane interface, namely differing aqueous environments and metal chelating ions. The results show that PrP(111-126) adopts different conformations in assembled and non-assembled forms. Aging studies on the PrP(111-126) peptide fragment in aqueous buffer demonstrated a structural transition from random coil to a stable ?-sheet structure. A similar, but significantly accelerated structural transition was observed upon sonication in aqueous environment. With increasing TFE concentrations, the helical content of PrP(111-126) increased persistently during the structural transition process from random coil. In aqueous SDS solution, PrP(111-126) exhibited ?-sheet conformation with greater ?-helical content. No significant conformational changes were observed under various pH conditions. Addition of Cu(2+) ions inhibited the structural transition and fibril formation of the peptide in a cell free in vitro system. The fact that Cu(2+) supplementation attenuates the fibrillar assemblies and cytotoxicity of PrP(111-126) was witnessed through structural morphology studies using AFM as well as cytotoxicity using MTT measurements. We observed negligible effects during both physical and chemical stimulation on conformation of the prion fragment in the presence of Cu(2+) ions. The toxicity of PrP(111-126) to cultured astrocytes was reduced following the addition of Cu(2+) ions, owing to binding affinity of copper towards histidine moiety present in the peptide.

    View details for DOI 10.1371/journal.pone.0085160

    View details for PubMedID 24386462

  • Enhanced A▀(1-40) production in endothelial cells stimulated with fibrillar A▀(1-42). PloS one Rajadas, J., Sun, W., Li, H., Inayathullah, M., Cereghetti, D., Tan, A., de Mello Coelho, V., Chrest, F. J., Kusiak, J. W., Smith, W. W., Taub, D., Wu, J. C., Rifkind, J. M. 2013; 8 (3)


    Amyloid accumulation in the brain of Alzheimer's patients results from altered processing of the 39- to 43-amino acid amyloid ? protein (A?). The mechanisms for the elevated amyloid (A?(1-42)) are considered to be over-expression of the amyloid precursor protein (APP), enhanced cleavage of APP to A?, and decreased clearance of A? from the central nervous system (CNS). We report herein studies of A? stimulated effects on endothelial cells. We observe an interesting and as yet unprecedented feedback effect involving A?(1-42) fibril-induced synthesis of APP by Western blot analysis in the endothelial cell line Hep-1. We further observe an increase in the expression of A?(1-40) by flow cytometry and fluorescence microscopy. This phenomenon is reproducible for cultures grown both in the presence and absence of serum. In the former case, flow cytometry reveals that A?(1-40) accumulation is less pronounced than under serum-free conditions. Immunofluorescence staining further corroborates these observations. Cellular responses to fibrillar A?(1-42) treatment involving eNOS upregulation and increased autophagy are also reported.

    View details for DOI 10.1371/journal.pone.0058194

    View details for PubMedID 23505467

    View details for PubMedCentralID PMC3591408

  • Glucose Oxidase Incorporated Collagen Matrices for Dermal Wound Repair in Diabetic Rat Models: A Biochemical Study JOURNAL OF BIOMATERIALS APPLICATIONS Arul, V., Masilamoni, J. G., Jesudason, E. P., Jaji, P. J., Inayathullah, M., John, D. G., Vignesh, S., Jayakumar, R. 2012; 26 (8): 917-938


    Impaired wound healing in diabetes is a well-documented phenomenon. Emerging data favor the involvement of free radicals in the pathogenesis of diabetic wound healing. We investigated the beneficial role of the sustained release of reactive oxygen species (ROS) in diabetic dermal wound healing. In order to achieve the sustained delivery of ROS in the wound bed, we have incorporated glucose oxidase in the collagen matrix (GOIC), which is applied to the healing diabetic wound. Our in vitro proteolysis studies on incorporated GOIC show increased stability against the proteases in the collagen matrix. In this study, GOIC film and collagen film (CF) are used as dressing material on the wound of streptozotocin-induced diabetic rats. A significant increase in ROS (p?

    View details for DOI 10.1177/0885328210390402

    View details for Web of Science ID 000303649700002

    View details for PubMedID 21363874

  • Pullulan Hydrogels Improve Mesenchymal Stem Cell Delivery into High-Oxidative-Stress Wounds MACROMOLECULAR BIOSCIENCE Wong, V. W., Rustad, K. C., Glotzbach, J. P., Sorkin, M., Inayathullah, M., Major, M. R., Longaker, M. T., Rajadas, J., Gurtner, G. C. 2011; 11 (11): 1458-1466


    Cell-based therapies for wound repair are limited by inefficient delivery systems that fail to protect cells from the acute inflammatory environment. Here, a biomimetic hydrogel system is described that is based on the polymer pullulan, a carbohydrate glucan known to exhibit potent antioxidant capabilities. It is shown that pullulan hydrogels are an effective cell delivery system and improve mesenchymal stem cell survival and engraftment in high-oxidative-stress environments. The results suggest that glucan hydrogel systems may prove beneficial for progenitor-cell-based approaches to skin regeneration.

    View details for DOI 10.1002/mabi.201100180

    View details for Web of Science ID 000297555500002

    View details for PubMedID 21994074

  • Structural dynamics of the Delta E22 (Osaka) familial Alzheimer's disease-linked amyloid beta-protein AMYLOID-JOURNAL OF PROTEIN FOLDING DISORDERS Inayathullah, M., Teplow, D. B. 2011; 18 (3): 98-107


    A familial form of Alzheimer disease recently was described in a kindred in Osaka, Japan. This kindred possesses an amyloid ?-protein (A?) precursor mutation within the A? coding region that results in the deletion of Glu22 (?E22). We report here results of studies of [?E22]A?40 and [?E22]A?42 that sought to elucidate the conformational dynamics, oligomerization behavior, fibril formation kinetics, fibril morphology, and fibril stability of these mutant peptides. Both [?E22]A? peptides had extraordinary ?-sheet formation propensities. The [?E22]A?40 mutant formed ?-sheet secondary structure elements ?400-fold faster. Studies of ?-sheet stability in the presence of fluorinated alcohol cosolvents or high pH revealed that the ?E22 mutation substantially increased stability, producing a rank order of [?E22]A?42 >A?42 > [?E22]A?40 > A?40. The mutation facilitated formation of oligomers by [?E22]A?42 (dodecamers and octadecamers) that were not observed with A?42. Both A?40 and A?42 peptides formed nebulous globular and small string-like structures immediately upon solvation from lyophilizates, whereas short protofibrillar and fibrillar structures were evident immediately in the ?E22 samples. Determination of the critical concentration for fibril formation for the [?E22]A? peptides showed it to be ?1/2 that of the wild type homologues, demonstrating that the mutations causes a modest increase in fibril stability. The magnitude of this increase, when considered in the context of the extraordinary increase in ?-sheet propensity for the ?E22 peptides, suggests that the primary biophysical effect of the mutation is to accelerate conformational changes in the peptide monomer that facilitate oligomerization and higher-order assembly.

    View details for DOI 10.3109/13506129.2011.580399

    View details for Web of Science ID 000294117300003

    View details for PubMedID 21668291

  • Rationally Designed Turn Promoting Mutation in the Amyloid-beta Peptide Sequence Stabilizes Oligomers in Solution PLOS ONE Rajadas, J., Liu, C. W., Novick, P., Kelley, N. W., Inayathullah, M., LeMieux, M. C., Pande, V. S. 2011; 6 (7)


    Enhanced production of a 42-residue beta amyloid peptide (A?(42)) in affected parts of the brain has been suggested to be the main causative factor for the development of Alzheimer's Disease (AD). The severity of the disease depends not only on the amount of the peptide but also its conformational transition leading to the formation of oligomeric amyloid-derived diffusible ligands (ADDLs) in the brain of AD patients. Despite being significant to the understanding of AD mechanism, no atomic-resolution structures are available for these species due to the evanescent nature of ADDLs that hinders most structural biophysical investigations. Based on our molecular modeling and computational studies, we have designed Met35Nle and G37p mutations in the A?(42) peptide (A?(42)Nle35p37) that appear to organize A?(42) into stable oligomers. 2D NMR on the A?(42)Nle35p37 peptide revealed the occurrence of two ?-turns in the V24-N27 and V36-V39 stretches that could be the possible cause for the oligomer stability. We did not observe corresponding NOEs for the V24-N27 turn in the A?(21-43)Nle35p37 fragment suggesting the need for the longer length amyloid peptide to form the stable oligomer promoting conformation. Because of the presence of two turns in the mutant peptide which were absent in solid state NMR structures for the fibrils, we propose, fibril formation might be hindered. The biophysical information obtained in this work could aid in the development of structural models for toxic oligomer formation that could facilitate the development of therapeutic approaches to AD.

    View details for DOI 10.1371/journal.pone.0021776

    View details for Web of Science ID 000293097300006

    View details for PubMedID 21799748

    View details for PubMedCentralID PMC3142112

  • Efficient gene delivery of primary human cells using peptide linked polyethylenimine polymer hybrid BIOMATERIALS Dey, D., Inayathullah, M., Lee, A. S., LeMieux, M. C., Zhang, X., Wu, Y., Nag, D., De Almeida, P. E., Han, L., Rajadas, J., Wu, J. C. 2011; 32 (20): 4647-4658


    Polyethylenimine (PEI) based polymers are efficient agents for cell transfection. However, their use has been hampered due to high cell death associated with transfection thereby resulting in low efficiency of gene delivery within the cells. To circumvent the problem of cellular toxicity, metal binding peptides were linked to PEI. Eight peptide-PEI derivatives were synthesized to improve cell survival and transfection efficiency. TAT linked PEI was used as a control polymer. Peptides linked with PEI amines formed nanogels as shown by electron microscopy and atomic force microscopic measurements. Polymers were characterized by spectroscopic methods and their ability to form complexes with plasmids was tested using electrophoretic studies. These modifications improved polymer biocompatibility as well as cell survival markedly, when compared to PEI alone. A subset of the modified peptide-polymers also showed significantly higher transfection efficiency in primary human cells with respect to the widely used transfection agent, lipofectamine. Study of the underlying mechanism of the observed phenomena revealed lower levels of 'reactive oxygen species' (ROS) in the presence of the peptide-polymers when compared to PEI alone. This was further corroborated with global gene expression analysis which showed upregulation of multiple genes and pathways involved in regulating intracellular oxidative stress.

    View details for DOI 10.1016/j.biomaterials.2011.03.016

    View details for Web of Science ID 000291193700019

    View details for PubMedID 21477858

    View details for PubMedCentralID PMC3090516

  • Amino Acid Position-specific Contributions to Amyloid beta-Protein Oligomerization JOURNAL OF BIOLOGICAL CHEMISTRY Maji, S. K., Loo, R. R., Inayathullah, M., Spring, S. M., Vollers, S. S., Condron, M. M., Bitan, G., Loo, J. A., Teplow, D. B. 2009; 284 (35): 23580-23591


    Understanding the structural and assembly dynamics of the amyloid beta-protein (Abeta) has direct relevance to the development of therapeutic agents for Alzheimer disease. To elucidate these dynamics, we combined scanning amino acid substitution with a method for quantitative determination of the Abeta oligomer frequency distribution, photo-induced cross-linking of unmodified proteins (PICUP), to perform "scanning PICUP." Tyr, a reactive group in PICUP, was substituted at position 1, 10, 20, 30, or 40 (for Abeta40) or 42 (for Abeta42). The effects of these substitutions were probed using circular dichroism spectroscopy, thioflavin T binding, electron microscopy, PICUP, and mass spectrometry. All peptides displayed a random coil --> alpha/beta --> beta transition, but substitution-dependent alterations in assembly kinetics and conformer complexity were observed. Tyr(1)-substituted homologues of Abeta40 and Abeta42 assembled the slowest and yielded unusual patterns of oligomer bands in gel electrophoresis experiments, suggesting oligomer compaction had occurred. Consistent with this suggestion was the observation of relatively narrow [Tyr(1)]Abeta40 fibrils. Substitution of Abeta40 at the C terminus decreased the population conformational complexity and substantially extended the highest order of oligomers observed. This latter effect was observed in both Abeta40 and Abeta42 as the Tyr substitution position number increased. The ability of a single substitution (Tyr(1)) to alter Abeta assembly kinetics and the oligomer frequency distribution suggests that the N terminus is not a benign peptide segment, but rather that Abeta conformational dynamics and assembly are affected significantly by the competition between the N and C termini to form a stable complex with the central hydrophobic cluster.

    View details for DOI 10.1074/jbc.M109.038133

    View details for Web of Science ID 000269180000044

    View details for PubMedID 19567875

    View details for PubMedCentralID PMC2749133

  • Synthesis, pharmacological screening, quantum chemical and in vitro permeability studies of N-Mannich bases of benzimidazoles through bovine cornea EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY Jesudason, E. P., Sridhar, S. K., Malar, E. J., Shanmugapandiyan, P., Inayathullah, M., Arul, V., Selvaraj, D., Jayakumar, R. 2009; 44 (5): 2307-2312


    A novel series of N-Mannich bases of benzimidazole derivatives were synthesized and characterized by (1)H NMR, IR spectral studies and elemental analysis. The compounds were screened for analgesic and anti-inflammatory activity. 1-((Diethylamino)-methyl)-2-styryl benzimidazole 4 at 40mg/kg was found to be equipotent to paracetamol. 1-((Piperidin-1-yl) methyl)-2-styryl-benzimidazole 6 at 40mg/kg was found to be more potent than Diclofenac. Corneal permeability and quantum chemical calculations were performed to correlate the hydrogen bonding ability with permeability and activity. The energies of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) were correlated with pharmacological activity. The semi-empirical PM3 calculations (quantum chemical calculations) revealed that E(LUMO) and energy gap DeltaE were capable of accounting for the high in vitro bovine corneal permeability and activity of the compounds.

    View details for DOI 10.1016/j.ejmech.2008.03.043

    View details for Web of Science ID 000265339900062

    View details for PubMedID 18486995

  • Conformational polymorphism and cellular toxicity of IAPP and beta AP domains JOURNAL OF STRUCTURAL BIOLOGY Andrews, M. E., Inayathullah, N. M., Jayakumar, R., Malar, E. J. 2009; 166 (2): 116-125


    The principal component of the amyloid deposits in Alzheimer's disease is the beta-amyloid polypeptide, while in type II diabetes the deposits consist primarily of Islet amyloid polypeptide. These amyloid forming polypeptides consist of highly polymorphic domains, which take different conformations including random coil, helical and beta strand depending upon the microenvironment. We have studied major fibril-forming components of IAPP and beta AP and demonstrated that conformational polymorphism of these peptides in different microenvironments correlate with cellular toxicity and proteasomal inhibitory activity. On treating with trifluoroethanol (TFE) the peptide fragments undergo structural transition from a random coil to a helical conformation. Even though these domains share the same gross amyloid structural characteristic, their proteasomal activities differ. We found that even the tetrapeptides have significant proteasomal inhibitory activity indicating that the amyloid formation is involved in the enhanced life of the smaller aggregates of full-length and fragment peptides, which could explain the toxicity of these sequences.

    View details for DOI 10.1016/j.jsb.2008.12.011

    View details for Web of Science ID 000265560900002

    View details for PubMedID 19374013

  • Alzheimer disease macrophages shuttle amyloid-beta from neurons to vessels, contributing to amyloid angiopathy ACTA NEUROPATHOLOGICA Zaghi, J., Goldenson, B., Inayathullah, M., Lossinsky, A. S., Masoumi, A., Avagyan, H., Mahanian, M., Bernas, M., Weinand, M., Rosenthal, M. J., Espinosa-Jeffrey, A., de Vellis, J., Teplow, D. B., Fiala, M. 2009; 117 (2): 111-124


    Neuronal accumulation of oligomeric amyloid-beta (Alphabeta) is considered the proximal cause of neuronal demise in Alzheimer disease (AD) patients. Blood-borne macrophages might reduce Abeta stress to neurons by immigration into the brain and phagocytosis of Alphabeta. We tested migration and export across a blood-brain barrier model, and phagocytosis and clearance of Alphabeta by AD and normal subjects' macrophages. Both AD and normal macrophages were inhibited in Alphabeta export across the blood-brain barrier due to adherence of Abeta-engorged macrophages to the endothelial layer. In comparison to normal subjects' macrophages, AD macrophages ingested and cleared less Alphabeta, and underwent apoptosis upon exposure to soluble, protofibrillar, or fibrillar Alphabeta. Confocal microscopy of stained AD brain sections revealed oligomeric Abeta in neurons and apoptotic macrophages, which surrounded and infiltrated congophilic microvessels, and fibrillar Abeta in plaques and microvessel walls. After incubation with AD brain sections, normal subjects' monocytes intruded into neurons and uploaded oligomeric Abeta. In conclusion, in patients with AD, macrophages appear to shuttle Abeta from neurons to vessels where their apoptosis may release fibrillar Abeta, contributing to cerebral amyloid angiopathy.

    View details for DOI 10.1007/s00401-008-0481-0

    View details for Web of Science ID 000262784500002

    View details for PubMedID 19139910

  • Amyloid beta-Protein Assembly as a Therapeutic Target of Alzheimer's Disease CURRENT PHARMACEUTICAL DESIGN Yamin, G., Ono, K., Inayathullah, M., Teplow, D. B. 2008; 14 (30): 3231-3246


    Alzheimer's disease (AD), the most common neurodegenerative disorder in the aged, is characterized by the cerebral deposition of fibrils formed by the amyloid beta-protein (Abeta), a 40-42 amino acid peptide. The folding of Abeta into neurotoxic oligomeric, protofibrillar, and fibrillar assemblies is hypothesized to be the key pathologic event in AD. Abeta is formed through cleavage of the Abeta precursor protein by two endoproteinases, beta-secretase and gamma-secretase, that cleave the Abeta N-terminus and C-terminus, respectively. These facts support the relevance of therapeutic strategies targeting Abeta production, assembly, clearance, and neurotoxicity. Currently, no disease-modifying therapeutic agents are available for AD patients. Instead, existing therapeutics provide only modest symptomatic benefits for a limited time. We summarize here recent efforts to produce therapeutic drugs targeting Abeta assembly. A number of approaches are being used in these efforts, including immunological, nutraceutical, and more classical medicinal chemical (peptidic inhibitors, carbohydrate-containing compounds, polyamines, "drug-like" compounds, chaperones, metal chelators, and osmolytes), and many of these have progressed to phase III clinical trails. We also discuss briefly a number of less mature, but intriguing, strategies that have therapeutic potential. Although initial trials of some disease-modifying agents have failed, we argue that substantial cause for optimism exists.

    View details for Web of Science ID 000261916000004

    View details for PubMedID 19075703

  • Isolation and partial characterization of antifungal protein from Bacillus polymyxa strain VLB16 PROCESS BIOCHEMISTRY Kavitha, S., Senthilkumar, S., Gnanamanickam, S., Inayathullah, M., Jayakumar, R. 2005; 40 (10): 3236-3243
  • Effect of osmolyte on the micellization of SDS at different temperatures LANGMUIR Inayathullah, N. M., Jasmine, G. J., Jayakumar, R. 2003; 19 (22): 9545-9547

    View details for DOI 10.1021/la034403z

    View details for Web of Science ID 000186177200068

  • Effect of Ca2+ on the self assembly of a nonionic peptide aggregate LETTERS IN PEPTIDE SCIENCE Moses, J. P., Inayathullah, N. M., Murugesan, M., Andrews, M. E., Balasubramanian, M. P., Jayakumar, R. 2003; 10 (1): 25-32

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