Department of Bioscience & Bioengineering

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IIT Jodhpur

Apoptosis associated speck like protein containing CARD (ASC) is widely researched and recognized as an adaptor protein participating in inflammasome assembly and pyroptosis. It contains a bipartite structure comprising of a pyrin and a caspase recruitment domain (CARD) domain. These two domains help ASC function as an adaptor molecule. ASC is encoded by the gene PYCARD. ASC plays pivotal role in various diseases as well as different homeostatic processes. ASC plays a regulatory role in different cancers showing differential regulation with respect to tissue and stage of disease. Besides cancer, ASC also plays a central role in sensing, regulation, and/or disease progression in bacterial infections, viral infections and in varied inflammatory diseases. ASC is expressed in different types of immune and non-immune cells. Its localization pattern also varies with different kinds of stimuli encountered by cell. This review will summarize the literature on the structure cellular and tissue expression, localization and disease association of ASC. © 2020, Springer Nature B.V.

World University root node

Molecular Biology Reports

Comprehensive review of ASC structure and function in immune homeostasis and disease

Triple-negative breast cancer (TNBC), defined as loss of estrogen, progesterone, and Her2 receptors, is a subtype of highly aggressive breast cancer with worse prognosis and poor survival rate. Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory cytokine aberrantly expressed in many solid tumors and known to promote tumor progression and metastasis. However, its role in TNBC progression and metastasis is unexplored. Here we have shown that in TNBC patients, MIF expression was significantly enriched in the tumor compared to adjacent normal tissue. Using publically available patient datasets, we showed that MIF overexpression correlates with worse survival in TNBC compared to other hormonal status. Orthotopic implantation of TNBC cells into MIF knockout mice showed reduced tumor growth compared to wild-type mice. In addition, we have shown that MIF downregulation inhibits TNBC growth and progression in a syngeneic mouse model. We further showed that CPSI-1306, a small-molecule MIF inhibitor, inhibits the growth of TNBC cells in vitro. Mechanistic studies revealed that CPSI-1306 induces intrinsic apoptosis by alteration in mitochondrial membrane potential, cytochrome c (Cyt c) release, and activation of different caspases. In addition, CPSI-1306 inhibits the activation of cell survival and proliferation-related molecules. CPSI-1306 treatment also reduced the tumor growth and metastasis in orthotopic mouse models of mammary carcinoma. CPSI-1306 treatment of tumor-bearing mice significantly inhibited TNBC growth and pulmonary metastasis in a dose-dependent manner. Histological analysis of xenograft tumors revealed a higher number of apoptotic cells in CPSI-1306-treated tumors compared to vehicle controls. Our studies, for the first time, show that MIF overexpression in TNBC enhances growth and metastasis. Taken together, our results indicate that using small molecular weight MIF inhibitors could be a promising strategy to inhibit TNBC progression and metastasis. © 2020, The Author(s).

Cell death \& disease

Macrophage migration inhibitory factor inhibition as a novel therapeutic approach against triple-negative breast cancer

Fulltext

Current Science

APOBEC3B and ACE1 indel polymorphisms as prima facie candidates for protection from COVID-19

We recently reported a novel, heterozygous, and non-synonymous ACTC1 mutation (p.Gly247Asp or G247D) in a large, multi-generational family, causing atrial-septal defect followed by late-onset dilated cardiomyopathy (DCM). We also found that the G247D ACTC1 mutation negatively regulated serum response (SRF)-signaling thereby contributing to the late-onset DCM observed in human patients carrying this mutation (“A cardiac α-actin (ACTC1) p. Gly247Asp mutation inhibits SRF-signaling in vitro in neonatal rat cardiomyocytes” [1]). There are some ACTC1 mutations known to date, majority of which, though, have not been investigated for their functional consequence. We thus aimed at determining the functional impact of various ACTC1 gene mutations on SRF-signaling using SM22-response element driven firefly luciferase activity assays in C2C12 cells. © 2019 The Author(s)

Data in Brief

Data on the role of cardiac α-actin (ACTC1) gene mutations on SRF-signaling

The gelation of the vegetable oils using fat crystals has gained significant attention in recent years. These formulations have been explored for food and pharmaceutical applications. The alteration in the properties of palmitic acid (20–40% w/w) and safflower oil oleogels is extensively studied at microscopic and macroscopic levels. The thermal and mechanical stability of the oleogels is improved when the proportion of the palmitic acid content is increased. However, under stress, the fat crystal network junction zones of the oleogels with higher proportions of palmitic acid undergo disruption. The changes in the properties of the oleogels are due to the alteration in the molecular packing, crystallite size, and lattice strain of the fat crystal network. The alteration in the properties is governed by the changes in the extent of inter- and intramolecular hydrogen bonding within the components of the oleogels. The oleogels can demonstrate the ability to deliver the drug, voriconazole, across the corneal tissue. Further, the prepared oleogels are biocompatible to murine fibroblast cells and do not elicit adverse reactions when instilled within the ocular sac of rabbits. The results suggest that the oleogels can be tried as ocular delivery vehicles. Practical Applications: The delivery of drug into the internal structure of the eye is a great challenge for the ophthalmologists. Usually no more than 1% of the drug can be delivered through conventional techniques. Various researchers have proposed the use of lipid-based ocular drug delivery systems. Some of them include solid liquid nanoparticles, emulsions, and liposomes. However, the preparation of these formulations requires a tedious process. Keeping this in mind, it is proposed to synthesize oleogel as probable ocular drug delivery system. © 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

European Journal of Lipid Science and Technology

Oleogels Based on Palmitic Acid and Safflower Oil: Novel Formulations for Ocular Drug Delivery of Voriconazole

Hydrogels are three-dimensional cross-linked networks generally composed of hydrophilic polymers having the capability to hold high volume of aqueous fluids devoid of altering the matrix structure. Recent years, various kinds of hydrogels have already achieved the attention for the use in drug-releasing applications. Hydrogels made of natural gums such as chitosan, alginate, gellan gum, pectin, tamarind gum, sterculia gum, guar gum, and locust bean gum have been investigated as effectual drug-releasing carriers to control the releasing of numerous drugs. This chapter deals with an inclusive discussion of a number of gum-based hydrogels for the application in drug delivery. Besides this, sources and classifications of gum have been explained, in detail. © 2020 Elsevier Inc. All rights reserved.

Biopolymer-Based Formulations: Biomedical and Food Applications

Gum-based hydrogels in drug delivery

In this work, oleogels of cocoa butter (CB), rice bran oil (RBO), and graphene oxide (GO) were prepared. The prepared oleogels were subjected to various characterization techniques such as bright-field microscopy, X-ray diffraction (XRD), crystallization kinetics, differential scanning calorimetry (DSC), and mechanical studies. The influence of increasing GO content on the in vitro drug release and ex vivo corneal permeation of the model drug (ciprofloxacin HCl—CPH) from the oleogels was also investigated. Bright-field micrographs showed that increment in GO content reduced the size of the globular particles of CB. XRD analysis revealed that CB was crystallized in its β’ and β polymorphic forms in the oleogels, which was in agreement with thermal studies. The mechanical characterization demonstrated that the presence of GO improved the elastic nature and stress-bearing properties of the oleogels. Moreover, GO altered the crystallization kinetics of CB in the oleogels in a composition-dependent manner. The in vitro release of CPH from the oleogels occurred through either Fickian diffusion or fat network relaxation or a combination thereof. Furthermore, the inclusion of GO enhanced the ex vivo permeation of CPH molecules across the caprine cornea. Hence, we concluded that the prepared oleogels could be explored as potential delivery systems for ophthalmic applications. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Gels

Graphene oxide increases corneal permeation of ciprofloxacin hydrochloride from oleogels: A study with cocoa butter-based oleogels

Although upconversion nanoparticle (UCNP) has shown promising role as a near infra-red (NIR) excitation triggered theranostic agent, its application in dermatology is limited due to skin permeation issues. Herein, we report the delivery of UCNP to the inner skin structure in transdermal fashion using oleogel based topical formulation. For this purpose, we have developed a series of oleylamine coated UCNP (OA-UCNP) incorporated oleogel through a simple two-step heat-cool procedure by varying the weight % of OA-UCNP and keeping the weight ratio of soybean oil:stearic acid constant. The UCNP-oleogels were characterized by various microscopic techniques as well as XRD and FTIR in order to understand the changes occurring in the microstructures of the oleogels with the incorporation of OA-UCNP in a concentration-dependent manner. The photoluminescence (PL) spectroscopy studies revealed that the UCNP-oleogel with the highest concentration of OA-UCNP (UG4) showed maximum luminescence among all the other compositions. The skin tissue penetration ability of UCNP was validated using UG4 as a topical agent through in vitro PL experiments involving agarose gel and animal skin models. The permeation of UCNP across the full thickness of intact pig ear skin was evident when UCNP was incorporated in oleogel, whereas UCNP itself in the form of OA-UCNP did not show any detectable skin permeation. The inner layer of animal skins were imaged by capturing the PL of the UCNP under NIR (980 nm) laser excitation. © 2019 Elsevier B.V.

Chemical Engineering Journal

Upconversion nanoparticle incorporated oleogel as probable skin tissue imaging agent

The design and development of an efficacious tumor-specific drug-delivery system is a challenging task. In this study, we have synthesized target-specific small peptide substrates on an octaguanidine sorbitol scaffold, named small molecular targeted drug-delivery conjugate (SMTDDC). The SMTDDC fabrication, with dual targeting cRGD and Cathepsin B (Cath B)-specific tripeptide (Glu-Lys-Phe), altered the microtubule network of glioblastoma cells by the orchestrated release of the cytotoxic paclitaxel (PTX). Cath B assisted PTX delivery was monitored by high-performance liquid chromatography and Surface-Enhanced Raman Scattering (SERS) modalities. The time-dependent SERS fingerprinting and imaging revealed a fast and accurate PTX release profile and subsequent in vitro cytotoxicity as well as the apoptotic events and microtubule network alteration in U-87 MG glioblastoma cells. Furthermore, SMTDDC displayed adequate stability under physiological conditions and demonstrated biocompatibility toward red blood cells and lymphocytes. This study indicated a new insight on SERS-guided peptidomimetic sorbitol molecular transporter, enabling a greater promise with high potential for the further development of PTX delivery in glioblastoma treatment. Copyright © 2020 American Chemical Society.

ACS Biomaterials Science and Engineering

Tracking the Footprints of Paclitaxel Delivery and Mechanistic Action via SERS Trajectory in Glioblastoma Cells

The labyrinth of intricate circuitry makes the central nervous system quite inept to regenerate its functionality after a devastating injury. Apart from targeting the major inhibitory effect of glial scar associated proteoglycans like chondroitin sulfate and the reactive glial cell secreted inflammatory and growth inhibitory molecules, the other major regeneration stalling component that arises after severe CNS injury is myelin and its associated proteinaceous debris comprising myelin-associated glycoprotein (MAG), neurite outgrowth inhibitor protein (NOGO), and oligodendrocyte myelin glycoprotein (OMgp). Various experiments revealed that, upon neutralization of those myelin inhibitors, regeneration could occur satisfactorily. Any therapeutic intervention which can obliterate the myelin-associated axonal growth-inhibitory protein components will be successful in revival and normal restoration of a patient's life. The sole purpose of this Viewpoint is to address the inhibitory role of these myelin-associated proteins, usually located at the lesion site, and few recent research trends to explore the scope of therapeutically overcoming the regeneration barrier in healing massive CNS injury. © 2020 American Chemical Society.