Showing papers by "Sudipta Saha published in 2021"

Fabrication of Imatinib Mesylate-Loaded Lactoferrin-Modified PEGylated Liquid Crystalline Nanoparticles for Mitochondrial-Dependent Apoptosis in Hepatocellular Carcinoma.

Abstract: Hepatocellular carcinoma (HCC) is a major cause of concern as it has substantial morbidity associated with it. Previous reports have ascertained the antiproliferative activity of imatinib mesylate (IMS) against diverse types of carcinomas, but limited bioavailability has also been reported. The present study envisaged optimized IMS-loaded lactoferrin (LF)-modified PEGylated liquid crystalline nanoparticles (IMS-LF-LCNPs) for effective therapy of IMS to HCC via asialoglycoprotein receptor (ASGPR) targeting. Results displayed that IMS-LF-LCNPs presented an optimum particle size of 120.40 ± 2.75 nm, a zeta potential of +12.5 ± 0.23 mV, and 73.94 ± 2.69% release. High-resolution transmission electron microscopy and atomic force microscopy were used to confirm the surface architecture of IMS-LF-LCNPs. The results of cytotoxicity and 4,6-diamidino-2-phenylindole revealed that IMS-LF-LCNPs had the highest growth inhibition and significant apoptotic effects. Pharmacokinetics and biodistribution studies showed that IMS-LF-LCNPs have superior pharmacokinetic performance and targeted delivery compared to IMS-LCNPs and plain IMS, which was attributed to the targeting action of LF that targets the ASGPR in hepatic cells. Next, our in vivo experiment established that the HCC environment existed due to suppression of BAX, cyt c, BAD, e-NOS, and caspase (3 and 9) genes, which thus owed upstream expression of Bcl-xl, iNOS, and Bcl-2 genes. The excellent therapeutic potential of IMS-LF-LCNPs began the significant stimulation of caspase-mediated apoptotic signals accountable for its anti-HCC prospect. 1H nuclear magnetic resonance (serum) metabolomics revealed that IMS-LF-LCNPs are capable of regulating the disturbed levels of metabolites linked to HCC triggered through N-nitrosodiethylamine. Therefore, IMS-LF-LCNPs are a potentially effective formulation against HCC.

Assessments of in vitro and in vivo antineoplastic potentials of β-sitosterol-loaded PEGylated niosomes against hepatocellular carcinoma.

Abstract: β-sitosterol (BS), a phytosterol, exhibits ameliorative effects on hepatocellular carcinoma (HCC) due to its antioxidant activities. However, its poor aqueous solubility and negotiated bioavailability and short elimination half-life is a huge limitation for its therapeutic applications. To overcome these two shortcomings, BS-loaded niosomes were made to via, film hydration method and process parameters were optimized using a three-factor Box-Behnken design. The optimized formulation (BSF) was further surface-modified with polyethylene glycol (PEG). The resulting niosomes (BSMF) have spherical shapes, particle sizes, 219.6 ± 1.98 nm with polydispersity index (PDI) and zeta potential of 0.078 ± 0.04 and -19.54 ± 0.19 mV, respectively. The drug loading, entrapment efficiency, and drug release at 24 h of the BSMF were found to be 16.72 ± 0.09%, 78.04 ± 0.92%, and 75.10 ± 3.06%, respectively. Moreover, BSMF showed significantly greater cytotoxic potentials on Hep G2 cells with an enhanced cellular uptake relative to pure BS and BSF. The BSMF also displayed potentially improved curative property of HCC in albino wistar rat. Thus, the BSMF could be one of the promising therapeutic modalities for HCC treatment in terms of targeting potential resulting in enhanced therapeutic efficacy.

Hepatic Regulator of G Protein Signaling 6 (RGS6) drives non-alcoholic fatty liver disease by promoting oxidative stress and ATM-dependent cell death.

Abstract: The pathophysiological mechanism(s) driving non-alcoholic fatty liver disease, the most prevalent chronic liver disease globally, have yet to be fully elucidated. Here, we identify regulator of G protein signaling 6 (RGS6), up-regulated in the livers of NAFLD patients, as a critical mediator of hepatic steatosis, fibrosis, inflammation, and cell death. Human patients with high hepatic RGS6 expression exhibited a corresponding high inflammatory burden, pronounced insulin resistance, and poor liver function. In mice, liver-specific RGS6 knockdown largely ameliorated high fat diet (HFD)-driven oxidative stress, fibrotic remodeling, inflammation, lipid deposition and cell death. RGS6 depletion allowed for maintenance of mitochondrial integrity restoring redox balance, improving fatty acid oxidation, and preventing loss of insulin receptor sensitivity in hepatocytes. RGS6 is both induced by ROS and increases ROS generation acting as a key amplification node to exacerbate oxidative stress. In liver, RGS6 forms a direct complex with ATM kinase supported by key aspartate residues in the RGS domain and is both necessary and sufficient to drive hyperlipidemia-dependent ATM phosphorylation. pATM and markers of DNA damage (γH2AX) were also elevated in livers from NAFLD patients particularly in samples with high RGS6 protein content. Unsurprisingly, RGS6 knockdown prevented ATM phosphorylation in livers from HFD-fed mice. Further, RGS6 mutants lacking the capacity for ATM binding fail to facilitate palmitic acid-dependent hepatocyte apoptosis underscoring the importance of the RGS6-ATM complex in hyperlipidemia-dependent cell death. Inhibition of RGS6, then, may provide a viable means to prevent or reverse liver damage by mitigating oxidative liver damage.

Curdlan-based nanomaterials in drug delivery applications

Abstract: Biopolymer-based polysaccharides such as chitosan, guar gum, pectin, hyaluronic acid, sodium alginate, and dextran are commonly used for the development of various types of drug delivery systems Among these polysaccharides, dextran has received immense interest in accomplishing nanoscale drug carriers because of its easy availability, hydrophilicity, biocompatibility, nontoxicity, nonimmunogenicity, and biodegradability However, the native dextran possesses several limitations regarding its physicochemical properties, restricting its wide applications as nanocarriers of drugs These drawbacks could be conquered by suitably modifying its backbone through carboxymethylation, acetylation, amidation, conjugation with drugs, cross-linking, and grafting with other natural, synthetic, or semisynthetic polymers The resulting tailor-made dextran derivatives have widely been utilized to develop different types of nanoscale drug delivery systems This chapter mainly reviews on the sources, compositions, characteristics, chemical modifications, pharmacokinetics, and clinical safety of dextran with special emphasis on its various nanomaterials, particularly designed for drug delivery applications

Albumin-based nanomaterials in drug delivery and biomedical applications

Abstract: Among various natural biopolymers, gelatin has gained attention of scientists and researchers in various biomedical fields. Gelatin as a biopolymer is bestowed with numerous advantages, such as ease of availability from the natural resources, excellent stability, biocompatibility, biodegradability, facile fabrication, ability to modify drug release behavior, and capacity to restrain drug degradation by arresting their release before reaching to the target sites. These benefits eventually make gelatin a potential biomaterial for a variety of biomedical applications including drug delivery, biocompatibility, biodegradability, etc. In recent years, numerous gelatin-based nanomaterials in the form of nanoparticles, nanofibers, nanocomplexes, nanocomposites, etc., have been fabricated and their efficacy to deliver various therapeutic agents like small-molecule drugs, proteins and peptides, genes, etc., has been evaluated. These nanoscaffolds have also been used for tissue regeneration, toxicity minimization, and antimicrobial applications. This chapter describes several gelatin-based nanomaterials specifically developed for drug delivery and biomedical applications.

G protein β5-ATM complexes drive acetaminophen-induced hepatotoxicity.

Abstract: Excessive ingestion of the common analgesic acetaminophen (APAP) leads to severe hepatotoxicity. Here we identify G protein β5 (Gβ5), elevated in livers from APAP overdose patients, as a critical regulator of cell death pathways and autophagic signaling in APAP-exposed liver. Liver-specific knockdown of Gβ5 in mice protected the liver from APAP-dependent fibrosis, cell loss, oxidative stress, and inflammation following either acute or chronic APAP administration. Conversely, overexpression of Gβ5 in liver was sufficient to drive hepatocyte dysfunction and loss. In hepatocytes, Gβ5 depletion ameliorated mitochondrial dysfunction, allowed for maintenance of ATP generation and mitigated APAP-induced cell death. Further, Gβ5 knockdown also reversed impacts of APAP on kinase cascades (e.g. ATM/AMPK) signaling to mammalian target of rapamycin (mTOR), a master regulator of autophagy and, as a result, interrupted autophagic flux. Though canonically relegated to nuclear DNA repair pathways, ATM also functions in the cytoplasm to control cell death and autophagy. Indeed, we now show that Gβ5 forms a direct, stable complex with the FAT domain of ATM, important for autophosphorylation-dependent kinase activation. These data provide a viable explanation for these novel, G protein-independent actions of Gβ5 in liver. Thus, Gβ5 sits at a critical nexus in multiple pathological sequelae driving APAP-dependent liver damage.

Differences in phase, microstructural, and electrical characteristics of quartz-substituted alumina porcelain insulator

Abstract: In the present study, total quartz content (30 wt%) of a standard porcelain body was progressively substituted with two different kinds of aluminas (active alumina and calcined alumina) keeping active alumina constant at 5 wt% and varying calcined alumina content to the extent of 5–25 wt%. The alumina incorporated compositions (AP1 to AP7), along with the standard quartz containing porcelain body (SP0), were processed following common ceramic processing techniques. Two types of forming techniques were used to make samples, namely extrusion of plastic mass to get cylinder of desired dimensions and the other one was hydraulic compaction to produce rectangular bars. The extruded and compacted samples were properly dried and then heated in an electrically operated furnace in the temperature range of 1170–1260 °C. The fully densified samples heated at 1260 °C were subjected to various tests, namely phase identification by X-ray diffraction (XRD) pattern studies; scanning electron microscopic (SEM) analysis; and measurement for electrical properties such as dielectric strength (kV/mm), dielectric loss (tanδ), electrical resistivity (ohm-cm), and dielectric constant to confirm suitability of the samples for application in high-tension power transmission system. The results revealed that the body AP6, wherein 25 wt% quartz was substituted by 5 wt% active alumina and 20 wt% calcined alumina and heated at 1260 °C, may be considered the most suitable sample for porcelain insulator.

Functional Defense Signals in Plants

Abstract: Plants live in a complex environment where they interact with a number of microbial pathogens with varying lifestyles and infection strategies. Numerous morphological, biochemical, and molecular mechanisms exist to cope with the effects of pathogen infection. Some mechanisms are preexisting and others induced upon infection of pathogens or attack of herbivores. Phytohormones have been shown to play key role in plant defense, and they mediate defense signaling cascades in plants. Phytohormones such as salicylic acid, jasmonic acid, and ethylene have been shown to play crucial role in the regulation of defense signaling. Understanding of function of complex defense signaling network is important. The present chapter is aimed to study about the role of phytohormones in induction of defense mechanism in plants. Moreover, this study covers the defense mechanisms (existing/induced) in the plants against the phytopathogens.

Involvement of Synergistic Interactions Between Plant and Rhizospheric Microbes for the Removal of Toxic/Hazardous Contaminants

Abstract: The abundance of toxic heavy metals, organic and inorganic pollutants, xenobiotic chemicals and contaminants pose a major threat to the environment which is linked to the health of the living systems including human beings and needs an eco-friendly remediation technology. This technology may not only reduce the pollution level by degradation or detoxification of such hazardous pollutants but also does not generate any secondary or intermediate pollutants. Phytoremediation is an advanced and efficient plant-based treatment technology that takes advantage of the remarkable ability of the plants to tolerate and grow at higher concentration of pollutants/contaminants. The mechanisms used by the plants for the removal of toxic components from the surroundings include accumulation, absorption or transformation of the toxic compounds in their tissues, leaf, stem and roots. In addition to this, plant-associated microbes also play an important role to enhance the efficiency of phytoremediation process. In recent years, understanding the knowledge of the synergistic relationship between plants and microbes for the removal of unwanted chemicals becomes an interesting area of research. Understanding the physiological and molecular mechanisms of plant–microbe interaction helps the environmentalists to get an insight of this technology and to improve and expand new horizons of phytoremediation.

Giant Scalp Metastasis: an Unusual Presentation of Cutaneous Malignant Melanoma

Abstract: Cutaneous metastases from primary malignant melanoma of the skin are fairly common. However, distant cutaneous metastasis to the scalp is unusual. We present a case of giant scalp metastasis secondary to primary cutaneous nodular malignant melanoma of the heel in the setting of disseminated disease. Majority of melanomas occurring over the feet are acral lentiginous type, nodular melanomas being extremely uncommon. An association of a rare site of primary nodular melanoma with a rare site of metastases makes this case extremely unusual and, hence, worth reporting. Besides the atypical and rare manifestation of a common disease, the main aim of presenting this report is to highlight that scalp metastasis may rarely be the initial presentation of an occult cutaneous melanoma, and in such cases, a thorough head-to-toe cutaneous examination is essential to identify the primary lesion. Although prognosis of metastatic cutaneous melanoma is poor, awareness about the aggressive course of such lesions will assist clinicians in prompt diagnosis and early initiation of palliative treatment options.