Friday, 24 November 2017

Indian Scientists Find Novel Target For Developing The Drugs Of Malaria

The new study provides the template for designing new molecules that may play a very important role in the prevention of the malaria pathogenesis.

By Ratneshwar Thakur    Published in The Hawk Journal Ref.: Nature Communications

(Dr. Pawan Malhotra and Dr. Anand Ranganathan)

Malaria is one of the deadliest diseases which give you experiences like fever, chills, and flu-like illness. Despite a gradual decline in the number of malaria cases worldwide, since 2000 the rate of this decline is not encouraging, with nearly half of the world population living in conditions highly susceptible to malaria. A major challenge which scientists and physicians face nowadays is the upsurge of drug-resistant parasites. Indian researchers are looking for alternative drug targets as well as druggable molecules that could be used for targeting such parasites.

In a collaborative effort, Scientists from New Delhi based institutions ICGEB, JNU, and NIPGR- have discovered the new mechanism of parasite invasion process into the RBC and reveals novel targets for the development of drugs against malaria.

The study, published in “Nature Communications,” reveals a novel host-pathogen interaction between human Cyclophilin B and Plasmodium (parasite) PfRhopH3 proteins. Cyclophilin B protein is present on the RBC surface and binds to the PfRhopH3 during the invasion and facilitates the entry of the parasite into the RBC.

In this study, Dr. Ranganathan’s teams have also reported an interaction between Cyclophilin B and another parasite receptor on the RBC (blood cells) surface named as Basigin. Basigin acts as a receptor for the PfRH5 protein of the parasite. “We report that PfRhopH3 and PfRH5 also interact with each other on the parasite surface. Thus, a multi-protein complex involving Human Cyclophilin B and Basigin interacting with parasite proteins PfRhopH3 and PfRh5 respectively- sets the stage for parasite entry in the RBC,” said Dr. Anand Ranganathan. He added, “We also found that Cyclophilin B - PfRhopH3 interaction is crucial for entry of Plasmodium in host cells and inhibiting this interaction can help in inhibiting parasite entry.”

According to the study, Cyclosporin A is a drug that binds to the cyclophilin B and blocks the interaction between Cyclophilin B and PfRhopH3 resulting in the blocking of the invasion process and reduction of the parasite load in the RBCs. “Interestingly, we discovered a long peptide molecule named as CDP3 that efficiently binds to Cyclophilin B. When the efficacy of CDP3 was tested for the prevention of the invasion process, we observed that CDP3 can block the invasion by up to 80%,” said Prem Prakash and Mohammad Zeeshan, first authors of this paper.

“Our study takes us one step ahead in understanding the pathogenesis of malaria and parasite biology at the host-pathogen junction because till now very few host-pathogen interactions have been documented in case of malaria,” said Dr. Pawan Malhotra.

Dr. Ranganathan’s teams have clearly shown that inhibitors of Cyclophilin B and Basigin are able to prevent the invasion of tested P. falciparum strains and it could provide an alternative option for future development of therapeutics.

“Finally, our study provides the template for designing new molecules like CDP3 that may play a very important role during prevention of the malaria pathogenesis,” said Anand Ranganathan about the future perspective of this study.

Thursday, 16 November 2017

Here Is How To Get Rid Of Bacterial Assemblages

Glycolipid-based surfactants derived from renewable resources could be potentially used in products for washing hands for clinicians, surface cleansing in hospitals and eradicating preformed biofilm in food processing industries.

BY Ratneshwar Thakur Published in India Science Wire Journal Ref. ACS
Also appeared in BusinessLine BioTechTimes Scroll FIRSTPOST BioVoice

(Left to right -- Mr. Siva Prasad, Dr. Nagarajan, Mr. Sandeep and, Dr. Srinandan)

Biofilms are dense, sticky mat like assemblies formed by communities of bacteria in critical medical equipment such as catheters and implants. Such microbial biofilms are hard to eliminate because bacteria build barriers using sugars, proteins and DNA molecules that prevent antibiotics to reach their target sites within microbes. It is also a problem in food processing industry.

Now a team of Indian scientists have figured out to disrupt such microbial assemblies and prevent them from forming.

Researchers from SASTRA University at Thanjavur have synthesized a new class of glycolipid based surfactant from renewable feedstocks, monosaccharide, and cashew nut shell liquid. The term “surfactant” stands for “surface active agents” often used in detergents, wetting agents, emulsifiers and foaming agents.

“We have developed a simple method to produce non-ionic surfactant from cardanol, which is present in cashew nut shell - a waste material from the cashew-nut industry. The glycolipid surfactant production from waste motivated us to test its capacity to disrupt pathogenic biofilms,” said Dr. C. S. Srinandan, who led the research team along with Dr. Subbaiah Nagarajan.

When researchers performed the reaction of cardanol derivatives and monosaccharides (carbohydrates like glucose and galactose) under mild conditions, it resulted in the formation of glycolipids. Glycolipids derived from glucose displayed exclusive formation of cyclic form, while in case of galactose both cyclic and acyclic structures are formed. This suggested that the nature of monosaccharide determines the existence of cyclic or acyclic or both in solution form. 

“Glycolipids having cyclic structure self-assemble into the gel in highly hydrophobic solvents and vegetable oils, and display foam formation in water. These glycolipids can have greater significance because commercially used anionic and cationic surfactants have the adverse effect on the biological system,” researchers said.

Biofilm bacteria display resilience towards environmental factors including antibiotics. Around 80% and more bacterial chronic infections are caused by biofilms that are tolerant to 1000 times more antibiotic concentrations than free-living cells of bacteria. 

The new findings hold the promise of developing new strategies to control hospital-acquired infections like pneumonia and urinary tract infection. The study results have been published in journal ACS Applied Materials & Interfaces.

“Glycolipid-based surfactants derived from renewable resources could be potentially used in products for washing hands for clinicians, surface cleansing in hospitals and eradicating preformed biofilm in food processing industries,” said Dr. Srinandan.

Dr. Praveen Kumar Vemula, a scientist at the Institute for Stem Cell Biology and Regenerative Medicine, Bangalore, who is not connected with the study, said “disruption of biofilms is a much-needed strategy to fight against pathogens. Demonstration of biofilm disruption using glycolipid amphiphiles is very encouraging. Such supramolecular self-assembled materials could be used as compositions for the cleaning surfaces at public places such as hospitals, schools, and public transport areas.”

The research team included Y. Siva Prasad, M. Sandeep, K. Lalitha, K. Ranjitha, B. Shehnaz, V. Sridharan, and C. Uma Maheswari. Both study leaders-Dr. C. S. Srinandan and Dr. Subbaiah Nagarajan have contributed equally to this finding.

Thursday, 9 November 2017

Scientists Decipher How Salmonella Survives In Human Cells

Pathogens like Salmonella have evolved several tactics to manipulate the activity of host proteins, all in an effort to create their intracellular replicative niche.

BY Ratneshwar Thakur Published in India Science Wire Journal Ref. PLOS Pathogens
Also appeared in  BusinessLine    Scroll   FIRSTPOST   BioVoice  DownToEarth

(Dr. Mahak Sharma and her team members at IISER-Mohali)

Many disease-causing bacteria are insidious. They try to imitate or manipulate intracellular structures of human cells for their own growth and survival. Indian biologists are trying to decipher how these pathogens manipulate host cell proteins to survive and proliferate inside human cells.

Among the bacterial pathogens which use human proteins for thriving are- Mycobacterium tuberculosis which causes tuberculosis and Salmonella enterica typhimurium, the causative agent of typhoid and gastroenteritis.

A team led by Dr. Mahak Sharma at Indian Institute of Science Education and Research (IISER), Mohali has uncovered the mechanism of how Salmonella manages access to membranes and nutrients in human cells through structures (known as lysosomes) that hold a variety of proteins for its own growth and survival.

According to the study, pathogens have evolved several tactics to manipulate the activity of host proteins, all in an effort to create their intracellular replicative niche (also known as a vacuole). For example, M. tuberculosis arrests maturation of its vacuole to prevent its degradation while continuously acquiring iron and other nutrients from the host cell. On the other hand, Salmonella acquires both membrane and nutrients within a mature acidic vacuole. It avoids bactericidal host proteases (enzymes) by rerouting them out of the host cell as well as by forming an extensive network of membranes continuous with its vacuole that dilutes these proteases.

“We are trying to understand how lysosomal proteins; specifically the small GTP-binding proteins and their effectors facilitate cargo delivery to lysosomes. Previous studies have shown that Salmonella vacuole acquires several characteristics of the host cell lysosomes for nutrient access from this organelle but the mechanism at play was not known,” Dr. Mahak Sharma told India Science Wire. The work on Salmonella biology is being carried out in collaboration with Dr. Amit Tuli’s group at CSIR-IMTECH, Chandigarh.

“Salmonella-containing vacuole (SCV) does not inhibit maturation of its vacuole but rather acquires several features of host lysosomes. Indeed, acidification of the vacuole is required for the production of virulence factors that in turn help Salmonella to acquire both membranes and nutrients from the host endosomes and lysosomes,” explained Dr. Amit Tuli.

Researchers say Salmonella secretes a protein known as SifA that recruits a host chemical, HOPS complex, to SCV membranes. Recruitment of HOPS complex is key step promoting docking and fusion of SCVs with host late endosomes and lysosomes. Blocking HOPS function prevents Salmonella replication inside its vacuolar niche, as it cuts off the supply of membranes and nutrients to the SCV.

“Based on our findings, we envision that small molecules or peptide-based inhibitors that specifically block the interaction of Salmonella protein SifA with host factors including HOPS complex can potentially prevent Salmonella replication and infection in the human host,” added Dr. Sharma.

The research team included – Aastha Sindhwani, Subhash B. Arya, Harmeet Kaur, Divya Jagga, Amit Tuli, Mahak Sharma. The results of the study have been published in journal PLOS Pathogens.

Sunday, 5 November 2017

Indian Scientists Find Histone Proteins Might Influence Cancer Progress

Changes in expression of the various histone isoforms might play a role in cancer development and changes in cellular functions.

 Ratneshwar Thakur Published in The Hawk

(Saikat Bhattacharya (Standing), Dr. Sanjay Gupta (Standing) and Ms. Divya Reddy)

The genome is the master blueprint of life- fortified by spool-like proteins known as Histones. Histones are present in many identical forms which are arranged in an octameric repeating structure around the genetic material-DNA and helps in packaging and arrangements of nearly seven feet long DNA in the microscopic cells. Scientists are trying to discover how changes in expression of the various histone isoforms might play a role in cancer development and changes in cellular functions.

The findings by researchers at the ACTREC-TMC, Mumbai – by Dr. Sanjay Gupta and his team members, provide novel insights into how different histone H2A isoforms, owing to slight alterations in amino acid substitution, dramatically bring about subtle differences in the stability of nucleosome. These differences alter gene expression and therefore phenotype.

These results were published in the journal “Epigenetics & Chromatin.”

“Liver being a visceral organ, its cancer is often difficult to treat. Hence, our lab has been working on identifying new candidate biomarkers and drug targets to tackle this disease. Our previous efforts led to the identification of the changes in the composition of a class of proteins known as histone isoforms. However, the molecular basis of how the highly similar isoforms contribute to disease development remained elusive. Hence, we decided to take up this challenge,” says Dr. Sanjay Gupta.

Researchers say the small differences in the amino acid composition of the histone isoforms makes it difficult to study them. “We used a holistic approach and collaboratively employed expertise in varied fields to address our questions,” added Dr. Gupta.

In this study, Dr. Gupta and his team members have shown that substitution of amino acids like Methionine (M51L) by Leucine and Lysine (K99R) by arginine alters the stability of histone-histone and histone–DNA complexes resulting in increased cell proliferation during cancer development.

“Our study in liver cancer suggests that although, the difference brought about by the isoforms is subtle, yet the epigenetic landscape of cells changes due to their sheer abundance in cells resulting in different gene expression pattern affecting the normal phenotype of the cell. The subtle nature of the epigenetic differences makes them more amenable to reversion and a potential target for future drug discoveries,” says Dr. Gupta about future perspectives of this study. 

The multiple expertise’s to work out the intricacies of the project was provided by Integrated Biophysics and Structural Biology Group led by Dr. Kakoli Bose, in silico and bioinformatics experiments were carried out with support of Dr. Rajendra Joshi’s Bioinformatics Group at Centre for Development of Advanced Computing (C‑DAC), Pune and Mr. Nikhil Gadewal, BTIS, ACTREC.