Akriti Srivastava

Bio: Akriti Srivastava is an academic researcher from Shiv Nadar University. The author has contributed to research in topics: Plasmodium falciparum & Video microscopy. The author has an hindex of 2, co-authored 6 publications receiving 13 citations.

Toxin-antitoxin systems and their medical applications: current status and future perspective

Abstract: Almost all bacteria synthesize two types of toxins-one for its survival by regulating different cellular processes and another as a strategy to interact with host cells for pathogenesis. Usually, "bacterial toxins" are contemplated as virulence factors that harm the host organism. However, toxins produced by bacteria, as a survival strategy against the host, also hamper its cellular processes. To overcome this, the bacteria have evolved with the production of a molecule, referred to as antitoxin, to negate the deleterious effect of the toxin against itself. The toxin and antitoxins are encoded by a two-component toxin-antitoxin (TA) system. The antitoxin, a protein or RNA, sequesters the toxins of the TA system for neutralization within the bacterial cell. In this review, we have described different TA systems of bacteria and their potential medical and biotechnological applications. It is of interest to note that while bacterial toxin-antitoxin systems have been well studied, the TA system in unicellular eukaryotes, though predicted by the investigators, have never been paid the desired attention. In the present review, we have also touched upon the TA system of eukaryotes identified to date. KEY POINTS: Bacterial toxins harm the host and also affect the bacterial cellular processes. The antitoxin produced by bacteria protect it from the toxin's harmful effects. The toxin-antitoxin systems can be targeted for various medical applications.

Integrative natural medicine inspired graphene nanovehicle-benzoxazine derivatives as potent therapy for cancer.

Abstract: Natural products from medicinal plants have always attracted a lot of attention due to their diverse and interesting therapeutic properties. We have employed the principles of green chemistry involving isomerization, coupling and condensation reaction to synthesize a class of compounds derived from eugenol, a naturally occurring bioactive phytophenol. The compounds were characterized structurally by 1H-, 13C-NMR, FT-IR spectroscopy and mass spectrometry analysis. The purity of compounds was detected by HPLC. The synthesized compounds exhibited anti-cancer activity. A 10–12-fold enhancement in efficiency of drug molecules (~ 1 µM) was observed when delivered with graphene oxide (GO) as a nanovehicle. Our data suggest cell death via apoptosis in a dose-dependent manner due to increase in calcium levels in specific cancer cell lines. Interestingly, the benzoxazine derivatives of eugenol with GO nanoparticle exhibited enhanced therapeutic potential in cancer cells. In addition to anti-cancer effect, we also observed significant role of these derivatives on parasite suggesting its multi-pharmacological capability.

Pathogenic Pore Forming Proteins of Plasmodium Triggers the Necrosis of Endothelial Cells Attributed to Malaria Severity.

Abstract: Severe malaria caused by Plasmodium falciparum poses a major global health problem with high morbidity and mortality. P. falciparum harbors a family of pore-forming proteins (PFPs), known as perforin like proteins (PLPs), which are structurally equivalent to prokaryotic PFPs. These PLPs are secreted from the parasites and, they contribute to disease pathogenesis by interacting with host cells. The severe malaria pathogenesis is associated with the dysfunction of various barrier cells, including endothelial cells (EC). Several factors, including PLPs secreted by parasites, contribute to the host cell dysfunction. Herein, we have tested the hypothesis that PLPs mediate dysfunction of barrier cells and might have a role in disease pathogenesis. We analyzed various dysfunctions in barrier cells following rPLP2 exposure and demonstrate that it causes an increase in intracellular Ca2+ levels. Additionally, rPLP2 exposed barrier cells displayed features of cell death, including Annexin/PI positivity, depolarized the mitochondrial membrane potential, and ROS generation. We have further performed the time-lapse video microscopy of barrier cells and found that the treatment of rPLP2 triggers their membrane blebbing. The cytoplasmic localization of HMGB1, a marker of necrosis, further confirmed the necrotic type of cell death. This study highlights the role of parasite factor PLP in endothelial dysfunction and provides a rationale for the design of adjunct therapies against severe malaria.

Pathogenic pore forming proteins of Plasmodium mediates the necrosis of Endothelial Cells

Abstract: Severe malaria caused by Plasmodium falciparum poses a major global health problem with high morbidity and mortality. The P. falciparum harbours a family of pore forming proteins (PFPs), known as perforin like proteins (PLPs), which are structurally equivalent to prokaryotic PFPs. These PLPs are secreted from the parasites and by interacting to host cells they contribute to disease pathogenesis. The severe malaria pathogenesis is associated with dysfunction of various barrier cells including endothelial cells. A number of factors, including PLPs, secreted by parasite contribute to the host cell dysfunction. Here in, we tested the hypothesis that the PLPs mediate dysfunction of barrier cells and might have a role in disease pathogenesis. We analysed various dysfunction in barrier cells following rPLP2 exposure and demonstrate that it causes an increase in intracellular Ca2+ levels. Additionally, rPLP2 exposed barrier cells displayed features of cell death including Annexin/PI positivity, depolarized mitochondrial membrane potential and ROS generation. We further performed the time lapse video microscopy of barrier cells and found the treatment of rPLP2 triggers their membrane blebbing. The cytoplasmic localization of HMGB1, a marker of necrosis, further confirmed the necrotic type of cell death. This study highlights the role of parasite factor PLP in endothelial dysfunction and provides a rational for the design of adjunct therapies against severe malaria.

A critical review on multifunctional smart materials ‘nanographene’ emerging avenue: nano-imaging and biosensor applications

Abstract: Smart electronic materials ‘nanographene’ stated, its significant authentication has undergone massive improvements and has emerged as a ‘material of the century’ in materialize fields of ‘Chemical...

Leishmania Protein Kinases: Important Regulators of the Parasite Life Cycle and Molecular Targets for Treating Leishmaniasis.

Abstract: Leishmania is a protozoan parasite of the trypanosomatid family, causing a wide range of diseases with different clinical manifestations including cutaneous, mucocutaneous and visceral leishmaniasis According to WHO, one billion people are at risk of Leishmania infection as they live in endemic areas while there are 12 million infected people worldwide Annually, 09–16 million new infections are reported and 20–50 thousand deaths occur due to Leishmania infection As current chemotherapy for treating leishmaniasis exhibits numerous drawbacks and due to the lack of effective human vaccine, there is an urgent need to develop new antileishmanial therapy treatment To this end, eukaryotic protein kinases can be ideal target candidates for rational drug design against leishmaniasis Eukaryotic protein kinases mediate signal transduction through protein phosphorylation and their inhibition is anticipated to be disease modifying as they regulate all essential processes for Leishmania viability and completion of the parasitic life cycle including cell-cycle progression, differentiation and virulence This review highlights existing knowledge concerning the exploitation of Leishmania protein kinases as molecular targets to treat leishmaniasis and the current knowledge of their role in the biology of Leishmania spp and in the regulation of signalling events that promote parasite survival in the insect vector or the mammalian host

Natural Product Inspired Novel Indole based Chiral Scaffold Kills Human Malaria Parasites via Ionic Imbalance Mediated Cell Death.

Abstract: Natural products offer an abundant source of diverse novel scaffolds that inspires development of next generation anti-malarials. With this vision, a library of scaffolds inspired by natural biologically active alkaloids was synthesized from chiral bicyclic lactams with steps/scaffold ratio of 1.7:1. On evaluation of library of scaffolds for their growth inhibitory effect against malaria parasite we found one scaffold with IC50 in low micro molar range. It inhibited parasite growth via disruption of Na+ homeostasis. P-type ATPase, PfATP4 is responsible for maintaining parasite Na+ homeostasis and is a good target for anti-malarials. Molecular docking with our scaffold showed that it fits well in the binding pocket of PfATP4. Moreover, inhibition of Na+-dependent ATPase activity by our potent scaffold suggests that it targets parasite by inhibiting PfATP4, leading to ionic imbalance. However how ionic imbalance attributes to parasite's death is unclear. We show that ionic imbalance caused by scaffold 7 induces autophagy that leads to onset of apoptosis in the parasite evident by the loss of mitochondrial membrane potential (ΔΨm) and DNA degradation. Our study provides a novel strategy for drug discovery and an insight into the molecular mechanism of ionic imbalance mediated death in malaria parasite.

Toxin-antitoxin systems and their medical applications: current status and future perspective

Abstract: Almost all bacteria synthesize two types of toxins-one for its survival by regulating different cellular processes and another as a strategy to interact with host cells for pathogenesis. Usually, "bacterial toxins" are contemplated as virulence factors that harm the host organism. However, toxins produced by bacteria, as a survival strategy against the host, also hamper its cellular processes. To overcome this, the bacteria have evolved with the production of a molecule, referred to as antitoxin, to negate the deleterious effect of the toxin against itself. The toxin and antitoxins are encoded by a two-component toxin-antitoxin (TA) system. The antitoxin, a protein or RNA, sequesters the toxins of the TA system for neutralization within the bacterial cell. In this review, we have described different TA systems of bacteria and their potential medical and biotechnological applications. It is of interest to note that while bacterial toxin-antitoxin systems have been well studied, the TA system in unicellular eukaryotes, though predicted by the investigators, have never been paid the desired attention. In the present review, we have also touched upon the TA system of eukaryotes identified to date. KEY POINTS: Bacterial toxins harm the host and also affect the bacterial cellular processes. The antitoxin produced by bacteria protect it from the toxin's harmful effects. The toxin-antitoxin systems can be targeted for various medical applications.

Recent advances in chemical reactivity and biological activities of eugenol derivatives

Abstract: Eugenol (4-allyl-2-methoxyphenol) is a volatile phenolic bioactive compound derived from a natural resource. This compound has been identified in several aromatic plants, among which Syzygium aromaticum (L.) Merr. and L.M. Perry contains between 45 and 90% of eugenol in its essential oil compared to other natural sources. Eugenol has been studied over the years and has shown to display a wide range of biological activities as antifungal, antimicrobial, anti-inflammatory, antioxidant, analgesic, anticancer, and antiparasitic. It has been extensively used in cosmetics, in food processing industry, and also as a starting material for total synthesis of several natural products. The 4-allyl-2-methoxyphenol has a simple structure, which presents three active sites: hydroxyl, allylic, and aromatic groups. Thus, the chemistry of this natural component emphasizes its potential impact in the synthesis of novel drugs, compounds that can be useful for human resources. Therefore, the present article reviews the latest developments in the methodologies of synthesis, pharmacological properties, and further applications of eugenol derivatives.