Monday, 24 April 2017

Indian Origin Scientists at Hopkins Discover Birth-And-Death Life Cycle of Intestinal Neurons

A new study refutes the long-held scientific belief that we have the same set of gut neurons throughout the life.

By Ratneshwar Thakur

    The green shapes are new neurons emerging from their precursor cells, highlighted in red.
         Photo Credit: Dr. Subhash Kulkarni

A team led by Indian-origin researchers, Pankaj Jay Pasricha, M.B.B.S., M.D., Professor of Medicine and Director of the Johns Hopkins Center for Neurogastroenterology, and Subhash Kulkarni, M.S., Ph.D., Assistant Professor at the Johns Hopkins University School of Medicine, have discovered the birth-and-death cycle of the gut neurons which are present throughout the digestive tract. The study was published in the Journal "Proceedings of the National Academy of Sciences (PNAS)."

The gut has its own mind known as the Enteric Nervous System (ENS), the largest collection of neurons outside the brain, and is located in the sheaths of the tissue lining of the digestive tract. “It regulates core functions of gustation, digestion, and metabolic regulation that help us stay alive. To have that high rate of turnover, wherein a course of three weeks all of the neurons in this system are completely renewed is an exciting finding”, says Dr. Kulkarni. 

For a long time, it was a common scientific belief that gut neurons don’t regenerate and that gut’s ‘brain,’ remained relatively static shortly after birth. However, Hopkins study suggests that not only do they regenerate, but the entire network turns completely over every few weeks in adult animals. 

The investigating team confined their research to the small intestines of healthy adult mice model and studied various proteins associated with neural cell death. Eight year-long research work provided irrefutable evidence of ongoing neuronal death due to apoptosis in the adult gut. “Of course, breaking dogma brings with it its own challenges, and at such times only perseverance and belief in the scientific method help overcome them’’, says the investigators. 

The significant rate of nerve cell loss left the research team with the question that how the gut maintains its relatively constant number of neurons. “In addition, understanding how the healthy enteric nervous system is maintained despite an ongoing and significant mechanical, chemical, and microbial insult was a very intriguing question. These thoughts inspired and motivated throughout the course of this study”, says Dr. Pasricha. 

“Despite having many patients who suffer from gut motility disorders due to dysfunctions or deficits in their enteric neurons, we have no current treatments on how to best treat and cure their diseases’’, says Dr. Pasricha. He says, “While stem cell transplantation to generate new neurons in their gut gives us hope of creating cures, we were hamstrung by not knowing whether there is a true neural stem cell in the adult gut, and what kind of potential to generate neurons it has.” 

Dr. Pasricha and Dr. Kulkarni says that “With this study, we have set a new paradigm of a dynamic enteric nervous system, where cells rapidly turnover to ensure that the system remains the same. We now know what happens in the state of health and this framework sets a platform for us and the scientific community to understand how various diseases that afflict the ENS in humans originate and what cell types they specifically target”. 

Here is a link to published article:

Friday, 14 April 2017

Breaking The Barrier Of The Skin For Better Management Of Skin Health

Entry of nano-complexes into skin layers may eliminate the need of painful needles and injections.

BY Ratneshwar Thakur

 (Dr. Manika and Dr. Munia Ganguli, Image Credit: Munia Ganguli)

A team led by Dr. Munia Ganguli, Scientist at Institute of Genomics and Integrative Biology (IGIB)-New Delhi, -- from the field of Nanobiotechnology -- is the first to develop a unique approach whereby pretreatment of skin with silicone oil can improvise the entry of nano-complexes, comprising of plasmid DNA and a peptide carrier, up to deeper layers of skin just by a topical application. The results of the study were published in the journal Molecular Therapy. 

Large surface area of the skin makes it convenient for skin care formulation to treat a multitude of skin conditions. Skin is a major barrier against absorption of external agents in our body. Therefore aiming for topical/transdermal delivery across such interface is itself a challenging task. A topical medication is intended to have an effect at the site of application. Transdermal medications are absorbed through the skin to have an effect in areas of the body away from the site of application. 

“Recently there has been an upsurge in the number of individuals affected by skin related disorders which in turn affects their overall quality of life,’’ says Manika Vij, one of the authors of the paper. She says this motivated her to focus her research on understanding of the intricacies of biomolecule delivery in the skin and to develop an effective treatment modality for such individuals whereby they can regain the confidence and are no more ostracized for skin related issues’’.

The group has been working on the peptide-mediated delivery of DNA to cells and organs for many years. The motivation of Dr. Ganguli and her team was to develop a non-invasive and non-toxic method of nucleic acid delivery to the skin. 

“In this study, we have used, in a synergistic manner, a chemical enhancer namely silicone oil and a peptide to allow large negatively charged molecules like DNA to get into the skin layers,’’ says Dr. Ganguli. “Usually the techniques that are used for DNA delivery to the skin are harsh, toxic and often cumbersome to use. Thus it was very exciting for us to observe that we could efficiently deliver DNA to deeper skin layers in a simple manner,’’ she said. 

Getting under the skin has always been challenging prospect for life-saving therapy in cutaneous disorders. “Nucleic acids (DNA or RNA) have potential to be used as therapeutics for different skin disorders. Our method is simple to use, non-invasive and does not damage the skin integrity, and hence possibly patient compliant”, says the study leader. 

The study leader and her team believe that a detailed study of this method could dramatically redefine this strategy for transdermal delivery of other such molecules that can eliminate the need for painful needles and injections. 

“We can extend this strategy for easy delivery of other large molecules which can be important for anti-aging applications, and cosmeceuticals, the combination of cosmetics and pharmaceuticals. There is also a possibility of easier delivery of growth factors for improved skin health. These are of course long term projections and a lot more validations will be needed to reach there”, Dr. Ganguli explained about the future perspectives of her finding. 

Here is a link to published article: 

Saturday, 8 April 2017

Bio-Conjugates: Upcoming Therapeutic Platform Against Bacterial Infections

The key powers of both antibody and antibiotic in a single conjugate molecule used against bacterial infection.

By Ratneshwar Thakur

In 2015, Sophie M. Lehar et al; reported in the journal “Nature”, their new antibody-antibiotic conjugate (AAC) killed Staphylococcus aureus in mice that frontline antibiotics like vancomycin failed to kill. Such treatment works by loading antibiotics onto antibodies with the help of linker which delivers a lethal dose of drug directly to the site of infection. An antibody is a protein used by the immune system to recognize and neutralize pathogens such as bacteria and viruses. Antibiotics are powerful medicines that fight bacterial infections.

Developments of these newer types of interventions are of utmost importance as many common infections, with the passage of time, are becoming resistant to antibiotics worldwide. At the same time, not many novel antibiotics or therapeutics have been developed for clinical use because of poor pharmacokinetic properties or toxicities.

Many antibiotics have potential to kill the variety of microorganisms and they are known as broad-spectrum antibiotics. But such antibiotics can also kill body’s good bacteria in our gut and intestine, which can lead to serious health risks. On one hand, as AAC, broad spectrum antibiotics might be used for targeted antimicrobial therapies to kill the harmful bacteria. On the other hand, many antibodies might become more useful in AAC, because, in spite of having exquisite specificity for the microbial target, they have not been successful as therapy in the clinic.

The concept of AAC is a variant of the antibody–drug conjugate (ADC) model that has been applied successfully to cancer treatment. In the case of cancer treatment, ADC uses the antibody to selectively deliver potent cytotoxic payloads to antigen-expressing tumor cells, whereas the AAC uses the antibody to deliver an antibiotic payload to bacteria. The AAC design has three building blocks: antibiotic payload to kill bacteria, an antibody to target the delivery of the payload to the bacteria, and a linker to attach the payload to the antibody. 

Sophie M. Lehar et al reported that many intracellular pathogens like S. aureus residing within host cells are protected from attack by extracellular host defenses. To escape the antibiotic therapy, these pathogens also become intrinsically resistant by adopting the semi-dormant state. The AAC therapeutic provides the possibility to specifically tag and kill pathogens like S. aureus because they periodically escape from their intracellular niches. The direct delivery of a high concentration of antibiotic by AAC at the site of infection can eliminate the harmful bacteria that are not effectively eliminated by traditional antibiotic treatment. 

For many reasons, scientists believe that the key powers of both antibody and antibiotic in a single conjugate molecule have the potential to be expanded to other hard-to-treat bacterial infections such as tuberculosis. First, the therapeutic index can be improved by maximizing efficacy and minimizing off-target toxicity. Second, due to the antibody specificity, the AAC has potential to transform a broad-spectrum antibiotic into a pathogen-specific antibiotic. Third, a potential use of a linker might be to release a high local concentration of active antibiotic at the target. 

AAC approach is very promising, as it has robust potential to cut the emergence of antibiotic resistance by reducing exposure of other bacteria to the active drug. Future developments of bio-conjugates should focus on technologies that permit the attachment of more antibiotics per antibody without affecting the pharmacokinetic properties of the AAC. Also, to limit the damage of body's beneficial microbes, it is important to design an efficacious AAC by developing advanced conjugation strategies to maximize specific binding, internalization, and payload release at the site of infection.

Here is a link to published article: