News related to Science, Technology, Environment, Agriculture and Medicine in India

Therapeutics

1 June 2018

Treating Inflammation

Reducing side effects

To treat inflammation in chronic ailments, non-steroidal, anti-inflammatory drugs, such as aspirin and ibuprofen, are often prescribed. Long-term use is associated with side effects including stomach irritation, ulceration, and bowel dysfunction.

In May 2018, researchers from five different institutes in Karnataka came together to report a solution to the problem. “Non-steroidal anti-inflammatory drugs block a class of enzymes called cyclooxygenases. “Cyclooxygenase-2, a sub-type of the enzyme, is responsible for generating inflammation. So we thought that selective blocking of Cyclooxygenase-2 will help reduce the risk of side effects,” says Mahadev Kumbar, Karnatak University.

“We looked at the structure of celecoxib, a well-known selective cyclooxygenase-2 inhibitor”, says Shrinivas Joshi, SETs College of Pharmacy, Dharwad, “We introduced electron withdrawing substituents, such as chloro and bromo groups. And we added a methoxy group, an electron releasing group, on to the thiophene ring of celecoxib”.

Using such substituents, the scientists synthesised nine different derivatives of the compound. They investigated the structures of these derivatives using spectral and single crystal X-ray studies. The structures were visualised using Hirshfeld surface analysis, a technique to visualise the fidelity of crystal structures.

The researchers quantified the intermolecular interactions of these derivatives. Using computer simulation, they compared the docking of celecoxib and the newly designed molecules with the active site of the cyclooxygenase-2 enzyme. “Two of the derivatives seemed to exhibit selective inhibition of the enzyme, acting on the same site as celecoxib” says Hussien Ahmed Khamees, Mysore University.

But does it really work?

“We used the standard assay for nitric oxide production by macrophages to find out”, says Jagadeesh Prasad Dasappa, Mangalore University. In vitro studies confirmed the anti-inflammatory activity of the selected compounds. This means that, theoretically, the molecules should work as anti-inflammatory agents, without any gastrointestinal side effects.

“But is it safe? We check cell viability under the treatment with these compounds”, says Sunil Jalalpure from KLE Academy of Higher Education & Research, Belagavi. The researchers used colorimetric assay to assess cell viability.

“Of course, further studies in animals and humans need to be undertaken, and the effects and side effects compared with those of existing therapeutic options, before we can use these new drugs for treating inflammation in clinical settings” smiles Suneel Dodamani, his colleague.

The study is one more step to tackle inflammation – arthritis, cardiovascular disease, diabetes, Alzheimer’s disease, inflammatory bowel disease, … Without the consequent side-effects.

J. Mol.Structure, 1160: 63-72 (2018)

Pallavi Deshpande

19 June 2018

Anti-cancer Microbial Pigment

From silkworm gut

Silkworm is reared in large quantities in Karnataka. Shyam Kumar at the Karnatak University has been interested in silkworms for about a decade now. Just like us, the silkworm also harbours many bacteria in its gut. Understanding the role of gut bacteria in silkworm health and disease has implications not only for the silk industry, but also for many other biotechnological applications. That’s how Kumar came across Staphylococcus gallinarum KX912244.

When Delicia Barretto joined his team, as an INSPIRE Fellow, they started looking for areas where the bacterium can be put to use. From the colony growing in petri dishes, it was evident that the Staphylococcus gallinarum strain produces some golden-yellow pigment.

The researchers characterized the pigment using different biophysical methods such as Fourier Transform Infrared Spectroscopy, High Performance Liquid Chromatography, 1H NMR, Liquid chromatography-Mass spectrometry and Gas chromatography-Mass spectrometry to confirm the structure of the pigment as staphyloxanthin.

Staphyloxanthin is a carotenoid pigment produced by the Staphylococcus spp. In recent years, various carotenoid pigments from microbes have been found to possess antioxidant, chemoprotective and anticancer effects. So Shyam Kumar and Delicia Barretto extracted the pigment from Staphylococcus gallinarum KX912244, isolated from the gut of silkworm and checked its biological activities.

They found that staphyloxanthin produced significant antioxidant and anticancer activities in four different cell lines besides providing protection against DNA damage.

Cancer patients burdened with drug-induced toxicity can look forward to this complementary and alternative medicine in the form of natural compounds.

Staphyloxanthin, from the gut bacteria of silkworm, is part of silk industry waste. Now, we need to convert this waste to value by following up the in vitro studies with animal studies and clinical trials.

Indian J Microbiol., 58(2).146–158

K Venkatesh

25 December 2017

Nickel Chelates in Cancer

Overcomes multidrug resistance

Cancer is one of the world’s greatest healthcare challenges. We all want a cure for cancer. But the reality is that advances in cancer treatment rarely come in one big discovery. Rather, it is continued step-by-step progress that develops new therapies.

Now, researchers from the Chittaranjan National Cancer Institute in collaboration with the Ramakrishna Mission Residential College, Kolkata have come up with nickel chelates as therapeutic agent for cancer that can overcome multidrug resistance.

Nickel plays an important role in biological systems. It is a constituent of all organs of vertebrates. About 0.5 nM of nickel is present in the human bloodstream. We need about 500 μg per kilogram of nickel every day.

Nickel shows anticancer activity against hepatocellular carcinoma, leukaemia, and prostate cancer cells. Thus, nickel is a metal of choice for metallo drug synthesis.  The researchers synthesised a nickel chelate and investigated its antitumour activity in vivo against drug-resistant and sensitive cancer-bearing mice. The nickel complex showed less cytotoxicity in both in vitro and in vivo models suggesting its selectivity in killing tumour cells.

The researchers used five different cell types to determine the nickel complex targets. These complexes, when tested against drug-resistant and sensitive cells, did not show any side effects. Interestingly, in vitro studies showed that nickel complexes can overcome only drug resistance. On the other hand, in vivo, nickel complex overcomes protein 1 mediated drug resistance in cancer. This supports the possibility that a single insult may trigger parallel and separate pathways for in vivo and in vitro systems leading to apoptotic damages in different drug-resistant cells.

The nickel complex thus seems to be a potential therapeutic agent for cancer, irrespective of drug resistance phenotype and may prove to be a promising anticancer agent for reversing multidrug resistance.

J. Biol. Inorg. Chem., 22 (8): 1223–1249 (2017)

Mahadeva swamy H M

24 December 2017

Quick Healing of Wounds

A biocompatible hydrogel

Wound healing is a sequential process of restoring damaged tissues. Bacterial infections often delay wound healing, especially when deeper tissues are affected. This condition is worse in diabetics where wounds become intractable. Though wound dressing routines are available, they are ineffective in absolute healing.

Recently, a team led by Santanu Dhara from the IIT Kharagpur in collaboration with the IIEST, Shibpur, developed a hydrogel for quick healing of deep wounds. The scientists blended the commercially available biopolymer chitosan and synthetic polyurethane for the synthesis.

The team optimised the composition of the polymers of the hydrogel for enhanced biocompatible and antibacterial properties. They found that the hydrogel adsorbed more protein and water. This determines their ability to adhere to the wound surface and enhance cell regeneration.

They also noted the stability of hydrogel in biological surroundings, when treated with hydrolytic enzymes. The hydrogel exhibited hemocompatibility with no blood cell lysis observed.

The team assessed the antimicrobial potential of the hydrogel by growing microbes on its surface and found that the deacetylation property of chitosan inhibits microbial growth. In addition, this hydrogel is non-toxic and showed enhanced cell proliferation rate in rat fibroblast cells.

After laboratory based studies, the team analyzed the biocompatibility of the hydrogel by implanting it with dermal tissue. They observed matured blood vessels and enhanced collagen deposition on the wound surface – a crucial process in healing. Further studies on rat model revealed its ability to enhance the tissue regeneration rate of deep dermal damage. This was better than shown by commercially available products.

The hydrogel shows quick regeneration of epithelium and dermis on wound surfaces. The significant properties of this hydrogel recommend its use as skin graft. Now the entrepreneurs must come forward and commercialise this product to help diabetic patients.

Mat. Sci. Engi., 81: 133-143 (2017)

S Balaji

23 December 2017

Ulcerative Colitis

A spicy way to stay healthy

Ulcerative colitis is a major inflammatory ailment, affecting the large intestine and rectum. It is incurable, and, if not managed properly, can lead to colon cancer. Proper diet and medication are helpful.  However, long-term medication produces undue side effects and reduces the outcome of therapeutic interventions.

Sreeraj Gopi from the Aurea Biolabs (P) Ltd, Cochin, and collaborators from the Mahatma Gandhi University, Kottayam and the Gdansk University, Poland, recently came up with a spicy solution for this illness. The team used turmeric and asafoetida to make medicated dietary fibre for the purpose.

They used turmeric spent, a by-product obtained from Curcuma longa after extraction of curcumin, to develop turmeric nanofibres. The turmeric spent was washed many times over with acids and alkali to bleach, soften and remove undesirable oligosaccharides. The researchers used the resultant soft colourless nanofibres for curcumin and asafoetida coating along with a natural matrix, Q-Naturale.

They also sequentially used emulsification, homogenisation and spray drying techniques for coating. Electron-scanning microscopy confirmed proper coating.

The team assessed the bioactivity of the final product using a dextran sulphate sodium induced ulcerative colitis animal model. The gut of treated animals showed lesser ulcers, intact cell architecture and decreased colitis index than found in diseased animals. In addition, no toxic effect was observed during the animal study.

The scientists hope this gut health product will work equally well in clinical studies. This product can be co-administered with conventional drugs to reduce dose and side effects in severe colitis cases.

Mater. Sci. Eng., C, 81: 20-31 (2017)

Neeta Shrivastava

Natural Cure for Malaria

Malaria is a mosquito-borne infectious disease affecting humans and other animals. The World Health Organization reports that more than 2 million people died due to malaria in 2015. The highest death rate is reported in the African continent. India ranks 3rd in the death rate. Most of the cases are reported from Odisha and Meghalaya. Malaria is caused by a parasite known as Plasmodium. It has developed widespread resistance to different antimalarial drugs.

Last fortnight, researchers from the Indian Institute of Chemical Technology, Hyderabad in collaboration with the Centre for Cellular and Molecular Biology, Hyderabad developed a new anti-malarial drug using a natural product, neem oil. Neem oil showed modest anti-malarial activity. Researchers modified the structural moieties of this natural product to give it higher antimalarial activity.

To test the effect of these derivatives, the researchers administered these compounds to the mice having a malaria infection. Their results indicate that all the derivatives had higher antimalarial activity than the natural one. Moreover, these derivatives can break down antimalarial resistance in the resistant parasite. Additionally, this drug showed cytotoxic effects on cancer cells without affecting normal cells.

Despite enormous efforts to eradicate malaria in the last century, the disease remains a global health problem. Natural products play a pivotal role in developing new drug molecules. Natural derivatives can cause fewer side effects compared to synthetic compounds. Therefore, the neem derivatives developed by these researchers could perhaps serve as a potential alternative drug to overcome drug resistance in the malarial parasite to help eradicate malaria.

Eur. J. Med. Chem, 134: 242-257 (2017)

G. Sharath Chandra

8 November 2017

Drug Delivery in Cancer

Gold helps iron oxide nanoparticles

Iron oxide nanoparticles have unique properties – paramagnetism, high magnetic susceptibility and low curie temperature. These properties find applications in magnetic cell sorting and magnetic fluid hyperthermia. Now scientists are even considering these nanoparticles as candidates for drug delivery.

By themselves, iron oxide nanoparticles tend to aggregate. To reduce this tendency, they are often surface modified with gold. This makes them more stable and biocompatible. Now scientists from the Guru Gobind Singh Indraprastha University, and the National Physical Laboratory, New Delhi report using a gold coated iron oxide, further stabilized using thiol functionalized sodium alginate polymers, as a drug delivery platform. Alginates have been tested earlier for delivering drugs that are not very water soluble.

The scientists prepared gold doped iron oxide nanoparticles using co-precipitation, a simple and easy method to control the size of nanoparticles. The iron oxide-gold-alginate composite nanoparticles were about 8nanometers.

The scientists loaded these composites with curcumin, a potential anticancer drug. Curcumin is notorious for its non-bioavailability. The curcumin loaded nanoparticles exhibited chemical stability and biocompatibility. The team estimated the loading efficiency of curcumin for the nanoparticles to be around 72 μg drug/mg nanoparticle with encapsulation efficiency of more than 70 percent. The in vivo release showed that there is a peak release in the first one hour and then a sustained release for three days.

Further animal studies and clinical trials would be necessary to translate these results into clinical practice.

Mat. Sci & Eng. C, 80:  274-281

K Deva Arun Kumar

26 October 2017

Autophagy in Alzheimer’s

A cure for the disease?

Alzheimer’s is a degenerative disease of the brain. Researchers have noted the deposition of a protein, amyloid-beta, in a misfolded form in the brain of Alzheimer’s patients. The misfolding of the protein results in stress to neurons, followed by macromolecular damage and neuronal loss.

Our body has a mechanism to remove the misfolded proteins: autophagy – literally, self-eating. Indian scientists now claim that autophagic modulators can be used to cure Alzheimer’s.

512px-India_-_An_old_man_-_0800

Image: Jorge Royan (Wiki Commons)

Scientists from the University of Allahabad, the NIT and the Pt. JNM Medical College, Raipur exposed neurons to amyloid-beta and observed that it alters the redox status of the cells, resulting in impaired cell growth. This was generally followed by neurotoxicity and cell death. Next, they treated the cells with an autophagy enhancer, rapamycin, and monitored the reactive oxygen species and intracellular calcium ion levels, as markers for oxidative stress. They found that the increase in autophagy alleviated the oxidative damage caused by amyloid-beta treatment. The levels of reactive oxygen species, calcium ions, and antioxidant enzymes were restored.

Neuronal death is marked by alteration of membrane potential, increased membrane permeability, and reduced production of ATP by mitochondria. The team observed that autophagy activation reduced mitochondrial dysfunction and consequent cytotoxicity.  There was a marked reduction in the accumulation of toxic protein aggregates and damaged cell organelles.

The scientists also found that an autophagy inhibitor aggravated the deleterious effect of amyloid-beta.

These research results provide insights into plausible protection against amyloid-beta toxicity. Recently, increased autophagy has also been linked to the clearance of α-synuclein aggregates – the causative agent of Parkinson’s disease. Autophagy modulation has, thus, wider scope to be exploited as a therapeutic strategy for treating neurodegenerative diseases.

Neurotoxicity Res. 32: 351-361 (2017)

Divya Khatter

 

Coffee with Orlistat

Anti-obesity formulation

Orlistat is an important drug for obesity, prescribed by doctors worldwide. The drug inhibits intestinal lipases. Sibutramine, another oral anorexiant, was withdrawn from the market due to its harmful health effects and genotoxic nature. So orlisat has moved into number one position in this market segment. But orlisat too, is not without side effects. Now scientists from the University of Calcutta reported their findings about the drug.

Anita Mukherjee and team incubated human lymphocytes with different concentrations of orlistat and sibutramine to evaluate the extent of DNA damage. The results show that though orlistat induced lesser DNA damage compared to sibutramine, its increased use can also lead to cancer.

The researchers tested orlistat along with caffeine, the world’s most widely consumed psychoactive drug, and found that it decreases the genotoxic effects of orlistat further. The scientists claim that they are the first to study the effect of caffeine on orlistat induced DNA damage. To decrease the DNA damage, they suggest as an addition to treatment orlistat.

The study gives a solution to the problem faced by pharmaceutical industry. Treatment of obesity can be made less damaging by drinking coffee with orlisat.

Drug and Chemical Toxicology, 40 (3): 339-343 (2017)

Ashwathy Nair

Wound Healing

New technological interventions

The main intention of the wound dressing is to prevent infections, control the exudates and create a moist environment for quick healing. With the recent advances in the field of  fabrication of biopolymers and nanoparticles, new wound dressings have come up. The existing dressing material could be altered to markedly improve the wound healing process.

Recently, for example, scientists from the Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum claimed effectiveness of a combination of silver nanoparticles with hydrogel material for wound dressing 1. Silver nanoparticles are recognized for its antimicrobial properties even at low concentrations. In parallel, hydrogels are known to possess adequate moisture retention property. However, hydrogels have poor mechanical stability.

The research team examined the cytocompatibility and non-adherent character of dermal fibroblasts on the hydrogel matrix. They synthesized a copolymerized gelatin methacrylate with 2-hydroxypropyl methacrylate and added silver nanoparticles.

They determined the antimicrobial activity of the combination hydrogel using agar diffusion method: the therapeutic hydrogel kept in an agar medium suppresses bacterial growth.  They observed zone of inhibition against a bacteria – Staphylococcus aureus with agar diffusion. They also found that the resulting hydrogel possessed excellent mechanical stability with optimum water hydration property suitable for moist wound environment.

The wound dressing material should be of atraumatic, non-toxic, non-irritant, sterilized, replaceable, effective oxygen circulation low microbial attack and comfortable.   These are the properties that the hydrogel dressing seem to promise.

In another example, scientists from the Sastra University, Thanjavur investigated the prolonged effect of delivering the drug by loading microparticles into the hydrogel to enhance wound healing 2.

They started with simvastatin, known to speed up wound healing in diabetics. Simvastatin acts by stimulating vascular endothelial growth factor, which is normally low in diabetics. The research team developed simvastatin loaded chitosan microbeads. Chitosan is also known to have its own antibacterial properites. They prepared these microparticles with ionic gelation method using chitosan and surfactants.

Then they integrated simvastatin-chitosan microparticles with polyvinyl alcohol based hydrogel, known for its fluid retaining property. They optimised the hydrogels for 7 days of replacement in both in vitro and in vivo conditions. They tested the in vitro characteristics, such as entrapment efficiency, morphology and drug-polymer interactions. The results confirmed its suitability in vivo for a period of 21 days monitoring. They found that the optimum dose of 2.5mg of drug was released with 92% (n = 3) efficiency.

The controlled delivery of drug has enormous potential for patient-friendly wound management, especially in diabetic patients where wounds tend to fester and are difficult to treat.

Although, microspheres, nanoparticles, liposomes, solid lipid nanoparticles, microemulsions, and sponges are few other forms of carriers as a wound healing drugs.

Earlier, scientists from CSIR-Central Electrochemical Research Institute, Karaikudi investigated on the nanocomposite for wound dressings 3.  Their approach was to use Allium sativum, known to possess bactericidal property due to the presence of allicin molecules. They combined Allium sativum with redox activity of the nano-cerium. Cerium ions are well-known to have anti-apoptotic, anti-inflammatory and antioxidant properties. The research team coated the cerium oxide-allicin on woven and non-woven fabrics. They tested the antibacterial effect of CeO2/allicin nanocomposite impregnated fabrics using agar diffusion method to test microbicidal property. They determined leaching analysis of the nanocomposite incorporated woven and non-woven fabric during washing.

They observed that woven fabrics were more durable than the non-woven fabric cloth. And found that the fabrics were more effective against E. coli than S. aureus. Allicin incorporated CeO2 nanocomposite exhibited restricted protection from pathogens.

Perhaps, the biomedical field of wound care will expand with advances in technological interventions. And, new products would emerge to provide relief to patients. But, large-scale randomised and controlled clinical trials are needed to examine safety and efficacy to implement them in the day today practice.

References:
1. Resmi, R., Unnikrishnan, S., Krishnan, L.K., Krishnan, V.K. (2017). Synthesis and characterization of silver nanoparticle incorporated gelatin-hydroxypropyl methacrylate hydrogels for wound dressing applications. Journal of Applied Polymer Science. 134 (10): 44529 (1-9).
2. Yasasvini, S., Anusa, R. S., VedhaHari, B. N., Prabhu, P. C., RamyaDevi, D. (2017). Topical hydrogel matrix loaded with Simvastatin microparticles for enhanced wound healing activity. Materials Science and Engineering –C. 72:160–167.
3. Thanka Rajan, S., Karthika, M., Balaji, U., Muthappan, A., Subramanian, B. (2016). Functional finishing of medical fabrics using CeO2/allicin nanocompositeforwound dressings. Journal of Alloys and Compounds. 695: 747-752.

Pavithra P Nayak

Antibacterial Silver Nanofibres

Heal wounds the bitter way

Silver nanofibres have a wide range of applications in electronics and sensors. They are also used in biomedical devices, as silver ions provide protection against bacteria. In contrast to these cutting edge discoveries, we also have the humble bitter gourd, used in traditional herbal medicine to treat cough, skin diseases, wounds and ulcers.

Last fortnight, scientists from NIT Calicut and M.S. University, Gujarat reported that a combination of antibacterial silver and the healing properties of bitter gourd can be used in wound dressing. They synthesized silver nanofibres from silver nitrate by reducing it with bitter gourd extract as the eco- friendly reducing agent. Polylactide, a prominent biopolymer, was used as the stabilizing agent in the fabrication process. The team then characterized the nanofibres using electron microscopy and X- Ray diffraction.

The researchers used agar disc diffusion and discovered that the nanofibres showed appreciable antibacterial activity on screening against E. coli and S. aureus bacteria. They also found that the biofabricated silver nanofibres were compatible with fibroblast cells and did not impair cell growth.

Bitter gourd has antiallergic, antimicrobial properties. The scientists, therefore, claim that silver nanofibres produced using bitter gourd extract may have superior action. This method may inspire innovations for rapid wound healing.

Colloids and surfaces, 529: 771-782 (2017)

Ashwathy Nair

 

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