MIF (Macrophage migration Inhibitory Factor) - a new molecular target for the treatment of depressant and anxiety...

Clinical depression affects 121 million people around the world,  according to the World Health Organization, but only 60% to 80% of cases are effectively treated with current medication and psychotherapy.  Now researchers from Ecole Polytechnique Fédérale de Lausann, (EPFL), have come up with an interesting target, i.e., macrophage migration inhibitory factor, MIF. 

MIF(see strucutre : wikipedia : a pro-inflammatory cytokine that is expressed in the CNS) is normally thought to play a role in tissue swelling (inflammatory mediator possibly associated with rheumatoid arthritis,  RA-severity) and even cancer development (metastatic potential in speculative models of cancer), but its precise location and function in the brain remained a mystery before Carmen Sandi's (lead researcher) study. 

 The research team, first detected a concentration of MIF protein in stem cells in the hippocampus, (a key area for memory formation and neuron generation during adulthood). New neurons are thought to be linked to the creation of new memories but they may also play an important role in curbing anxiety  (previous studies have shown that prolonged periods of stress reduce neurogenesis, and many anti-depressants actually boost the production of new neurons).

By genetically and pharmaceutically manipulating the level of MIF in the hippocampus of rats, the researchers discovered that the absence of MIF significantly reduced the production of neurons and increased anxiety They also found that the lack of MIF decreases the ability of anti-depressants to stimulate neurogenesis. 

Researchers, identified  MIF expression in neurogenic cells  (in stem cells, cells undergoing proliferation, and in newly proliferated cells undergoing maturation) in the subgranular zone of the rodent dentate gyrus. A causal function for MIF in cell proliferation was shown using genetic (MIF gene deletion) and pharmacological (treatment with the MIF antagonist Iso-1 - see (right side) chemical structure : (S,R)-3-(4-Hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid, methyl ester) approaches. 

As per the claim by the researchers,  genetic deletion of MIF resulted in increased anxiety and depression-like behaviors, as well as of impaired hippocampus-dependent memory. Researchers conclude that,   MIF as a potentially relevant molecular target for the development of treatments linked to deficits in neurogenesis, as well as to problems related to anxiety, depression, and cognition....

Ref : Carmen Sandi et. al., Molecular Psychiatry, 23 February 2010

 

HAMLET (found in breast milk) may target molecules in specific membrane regions.....

We know that HAMLET (human α-lactalbumin made lethal to tumor cells) is a molecular complex of α-lactalbumin and oleic acid (see structure courtesy : Lunds Univ). It induces apoptosis in tumor cells, but normal differentiated cells are resistant to its effect . The activity of HAMLET was discovered by serendipity, while using human milk fractions to investigate bacteria adherence to lung carcinoma cell lines. In addition to blocking adherence, one milk fraction actually killed the cells by inducing apoptosis. Cell death was accompanied by changes in morphology, nuclear condensation, cytoplasmic blebbing, and formation of apoptotic bodies, similar to cells that undergo classical apoptosis.

Further studies showed that HAMLET comprises a protein and a fatty acid that are both found naturally in breast milk. So far, however, it has not been proven that the HAMLET complex is spontaneously formed in the milk. It is speculated, however, that HAMLET can form in the acidic environment of the babies´ stomachs. Laboratory experiments have shown that HAMLET kills 40 different types of cancer, and the researchers are studying  its effect on skin cancer, tumours in the mucous membranes and brain tumours. Importantly, HAMLET kills only cancer cells and does not affect healthy cells.

Although the substance was found several years ago, it is only now that it has been possible to test it on humans. Patients with cancer of the bladder who were treated with the substance excreted dead cancer cells in their urine after each treatment, which has given rise to hopes that it can be developed into medication for cancer care in the future.

Researchers at the University of Gothenburg are focussed on how HAMLET can be taken up into tumour cells. Researchers  lead by,  Roger Karlsson attempting to gain an in-depth understanding of how the substance interacts with cell membranes. 

In their study, researchers examined the interactions of HAMLET with in vitro generated membranes of known composition, and compared HAMLET to the native or partially unfolded, fatty acid free proteins. They also examined the effect of HAMLET on plasma membrane vesicles (PMVs) obtained from tumor cells. Researchers could show that HAMLET interacts with membranes and disturbs their integrity under physiological conditions. Binding to intact tumor cell membranes showed a patchy distribution, indicating that HAMLET may target molecules in specific membrane regions.

Researchers conclude that, HAMLET engages membranes by a mechanism requiring both the protein and the fatty acid. HAMLET binding alters the morphology of the membrane and compromises its integrity, suggesting that membrane perturbation could be an initial step in inducing cell death...

Ref : Roger Karlsson et.al.,  PLoS One., February 23, 2010

PA-824 - Aerosol: New Tool Against Tuberculosis?

We know the epidemic rates of HIV/TB coinfection as well as emerging multidrug-resistant  (MDR) and extensively drug-resistant (XDR) TB strains those are contributing to increased TB-associated deaths worldwide. 

Now PA-824 (see structure), a compound capable of being formulated into a dry powder, has not only shown promising activity against MDR (multidrug-resistant tuberculosis) and XDR (extensively drug-resistant tuberculosis, or latent TB) but has also proven safe and effective in patients coinfected with HIV and TB. Previous studies showed that PA-824 was well-tolerated in tablet form, however, side effects such as headache and stomach discomfort were reported. Aerosol delivery of PA-824 directly to the primary site of infection would limit systemic exposure and ultimately eliminate potentially bothersome side effects.

About  PA-824 :

Nitroimidazoles are widely used drugs in humans for a variety of primarily anaerobic microbial infections. Metronidazole, a 5-nitroimidazole, is an important bactericidal agent for the treatment of anaerobic infections  and shows excellent selective toxicity toward anaerobic bacterial and protozoal pathogens. This class of compounds has only recently begun to be explored for Mtb, because only anaerobic activity of metronidazole against Mtb has been reported. Bicyclic 4-nitroimidazoles such as PA-824 (a nitroimidazo-oxazine) and CGI-17341 (a nitroimidazo-oxazole) have inhibitory activity against aerobically growing and nonreplicating anaerobic Mtb. Although anaerobic conditions have not been demonstrated during TB disease in humans, various authors have suggested that an anaerobic microenvironment may contribute to a nonreplicating state that may be linked with latent disease in humans. Thus, PA-824 has been developed, in part, because it may be a promising lead for therapy against latent disease that may be linked to anaerobically persisting bacilli. The Global Alliance for TB Drug Development has recently initiated phase-I clinical trials with PA-824 

Researchers from the University of North Carolina School of Pharmacy, Chapel Hill, North Carolina; and Harvard School of Engineering and Applied Sciences, Cambridge, Massachusetts, lead by  Dr. Anthony J Hickey  have achieved this interesting finding, i.e., potential use of PA-824 dry powder aerosols in the treatment of TB.

In the study guinea pigs were used to evaluate the effects of PA-824 aerosols on TB infection. One month following infection with TB some guinea pigs received high daily aerosol treatments while others received low daily treatments for 4 weeks. Lung and spleen analysis of guinea pigs receiving the high dose of aerosol PA-284 showed less inflammation, bacterial burden and tissue damage.

"The present studies indicate the potential use of PA-824 dry powder aerosols in the treatment of TB,” say the researchers".

Ref : http://aac.asm.org/cgi/content/abstract/54/4/1436.

Chitosan could repair spinal damage - first evidence....

Polyethylene glycol (PEG) was reported to seal and repair damaged spinal cord nerve cells,  by repairing the damaged membranes of nerve cells. Researchers lead by  Richard Borgens and his team claimed that, PEG can restore the spinal cord's ability to transmit signals to the brain. However, there is one possible clinical drawback: PEG's breakdown products are potentially toxic. 

So, is there a biodegradable non-toxic compound that is equally effective at targeting and repairing damaged nerve membranes? Borgens teamed up with physiologist Riyi Shi and chemist Youngnam Cho, who pointed out that some sugars are capable of targeting damaged membranes. Borgens and his team  has  now come up with an interesting finding i.e.,  chitosan (see structure; source  : Wikipedia) can repair damaged nerve cell membranes. 

Having initially tested mannose and found that it did not repair spinal cord nerve membranes, Cho decided to test a modified form of chitin, one of the most common sugars that is found in crustacean shells. Converting chitin into chitosan, Cho isolated a segment of guinea pig spinal cord, compressed a section, applied the modified chitin and then added a fluorescent dye that could only enter the cells through damaged membranes.  Viewing a section of the spinal cord under the microscope, Cho was amazed to see that the spinal cord was completely dark and none of the dye had entered the nerve cells and Cho concluded that Chitosan had repaired the damaged cell membranes.

Borgens is extremely excited by this discovery that chitosan is able to locate and repair damaged spinal cord tissue and is even more enthusiastic by the prospect that nanoparticles of chitosan could also target delivery of neuroprotective drugs directly to the site of injury.

'giving us a dual bang for our buck,' says Borgens....

 Ref :  http://jeb.biologists.org/cgi/content/full/213/9/i-a

Positive results from second phase 3 Study of Fidaxomicin for the treatment of Clostridium difficile Infection..

Fidaxomicin  is the first in a new class of narrow spectrum macrocyclic  antibiotic drugs.  It is non-systemic (minimally absorbed into the bloodstream)  bactericidal, and  has demonstrated selective eradication of pathogenic Clostridium difficile with minimal disruption to the multiple species of bacteria that make up the normal, healthy intestinal flora. The maintenance of normal physiological conditions in the colon can reduce the probability of clostridium difficile infection recurrence.

Now Optimer Pharmaceuticals, Inc.,  announced the top-line results from its second fidaxomicin Phase 3 clinical study in patients with Clostridium difficile infection (CDI) at the 20th Annual European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) in Vienna, Austria. 

As per the claim by the company, in the trial, fidaxomicin met the primary endpoint of non-inferiority in clinical cure compared to Vancocin®.  Importantly, fidaxomicin also had significantly lower recurrence rates compared to Vancocin (p = 0.002), and significantly higher global cure rates (defined as cure with no recurrence within four weeks of completing therapy) compared to Vancocin (p < 0.001).  Interestingly  the se robust results from this second fidaxomicin Phase 3 trial confirm the results from the first fidaxomicin Phase 3 trial.  Together these trials enrolled more than 1,100 subjects thus making them the two largest comparative studies ever conducted against Vancocin in CDI.

"Fidaxomicin offers potential advantages over existing therapies as a single agent that can provide a high cure rate and fewer recurrences for Clostridium difficile infection," said Dr. Crook, M.D., Consultant Microbiologist/Infectious Diseases and Professor of Infectious Diseases and Microbiology, Experimental Medicine Division, Nuffield Department of Clinical Medicine (NDM), University of Oxford"...  

Ref :  http://www.optimerpharma.com/news.asp?news_story=113&page_num=

Anti-cancer agent stops metastasis in its tracks....

Like microscopic inchworms, cancer cells slink away from tumors to travel and settle elsewhere in the body. Now, researchers at Weill Cornell Medical College, have found  that new anti-cancer agent, i.e., macroketone (see structure) break down the loping gait these cells use to migrate, stopping them in their tracks.

As per the claim by the lead researcher, Dr. Xin-Yun Huang, a professor in the Department of Physiology and Biophysics at Weill Cornell Medical College, mice implanted with cancer cells and treated with the small molecule macroketone lived a full life without any cancer spread, compared with control animals, which all died of metastasis. When macroketone was given a week after cancer cells were introduced, it still blocked greater than 80 percent of cancer metastasis in mice. He further adds that, these findings provide a very encouraging direction for development of a new class of anti-cancer agents, the first to specifically stop cancer metastasis. 

Dr. Huang and his research team have been working on macroketone since 2003. Their work started after researchers in Japan isolated a natural substance, dubbed migrastatin, secreted by Streptomyces bacteria, that is the basis of many antibiotic drugs. The Japanese researchers noted that migrastatin had a weak inhibitory effect on tumor cell migration. After a lot of modifications, researchers made several versions that were a thousand-fold more potent than the original. In 2005, they published a study showing that several of the new versions, including macroketone, stopped cancer cell metastasis in laboratory animals, but they didn't know how the agent worked. 

Interestingly, in the current study, the researchers revealed the mechanism. As per the claim  macroketone targets an actin cytoskeletal protein known as fascin that is critical to cell movement. In order for a cancer cell to leave a primary tumor, fascin bundles actin filaments together like a thick finger. The front edge of this finger creeps forward and pulls along the rear of the cell. Cells crawl away in the same way that an inchworm moves. Macroketone latches on to individual fascin, preventing the actin fibers from adhering to each other and forming the pushing leading edge Because individual actin fibers are too soft when they are not bundled together, the cell cannot move.

Researchers conclude that, the new animal experiments detailed in the study confirmed the power of macroketone. The agent did not stop the cancer cells implanted into the animals from forming tumors or from growing.

"This suggests to us that an agent like macroketone could be used to both prevent cancer spread and to treat it as well," Dr. Huang says. "Of course, because it has no effect on the growth of a primary tumor, such a drug would have to be combined with other anti-cancer therapies acting on tumor cell growth."

 Ref : http://weill.cornell.edu/news/releases/wcmc/wcmc_2010/04_14_10.shtml

Chinese Wolfberries (as dietary supplement) may improve vision imperfections caused by Type-2 diabetes..

Wolfberry, commercially called goji berry, is the common name for the  fruit of two very closely related species: Lycium barbarum. 

It is also known as Chinese wolfberry, mede berry, barbary matrimony vine, bocksdorn, Duke of Argyll's tea tree, Murali (in India), red medlar, or matrimony vine.  Unrelated to the plant's geographic origin, the names Tibetan goji and Himalayan goji are in common use in the health food market for products from this plant.

Marketing literature for wolfberry products including several "goji juices" suggest that wolfberry polysaccharides have extensive biological effects and health benefits, although none of these claims have been supported by peer-reviewed research.

Interestingly, now Dingbo "Daniel" Lin a researcher from Kansas State University, is studying wolfberries and their potential to improve damage to the retina. His findings show that the fruit can lower the oxidative stress that the eye undergoes as a result of type-2 diabetes.

Lin and his colleagues have found that wolfberries have high levels of zeaxanthin, lutein, polysaccharides and polyphenolics, which have been shown to improve vision, including the prevention of age-related macular degeneration and diabetic retinopathy. 

By using type-2 diabetic mice, the researchers are studying the effects of wolfberries on oxidative stress, one of the factors that occurs in diabetic retinopathy.

"I would not say that wolfberries are a medicine, but they can be used as a dietary supplement to traditional treatments to improve vision," Lin said. "Wolfberries have high antioxidant activity and are very beneficial to protect against oxidative stress caused by environmental stimuli and genetic mutations."

Ref : http://www.k-state.edu/media/newsreleases/mar10/wolfberry33010.html

Flaxseed lowers high cholesterol in men.....

Flax (also known as common flax or linseed) (Linum  usitatissimum) is a member of the genus Linum in the family Linaceae. It is native to the region extending from the eastern Mediterranean to India.  This is called as Agasi/Akshi in Kannada, Jawas/Javas (जवस) or Alashi (अळशी) in Marathi.  

Flax seeds come in two basic varieties brown yellow or golden. Most types have similar nutritional characteristics and equal amounts of short-chain omega-3 fatty acids. The exception is a type of yellow flax called Linola or solin, which has a completely different oil profile and is very low in omega-3. Although brown flax can be consumed as readily as yellow, and has been for thousands of years, it is better known as an ingredient in paints, fiber and cattle feed. Flax seeds produce a vegetable oil known as flaxseed or linseed oil, which is one of the oldest commercial oils and solvent-processed flax seed oil has been used for centuries as a drying oil in painting and varnishing. 

Flaxseeds are rich in alpha linolenic acid (ALA), an omega-3 fat that is a precursor to the form of omega-3 found in fish oils called eicosapentaenoic acid or EPA. Many benefits like 1. anti-iflammatory benefits, 2. omega-3-rich flaxseeds protect bone health, 3.protection against heart disease, cancer and diabetes, 4. flaxseeds help prevent and control high blood pressure. And even it helps to control some types of cancers.

Earlier report says,  Flaxseed provides comparable cholesterol-lowering benefits to statin drugs. Now this has been further substantiated by researchers from Iowa State University's (ISU) Nutrition and Wellness Research Center (NWRC).

Suzanne Hendrich, an ISU professor in food science and human nutrition, led a study that examined the effects of flaxseed lignan in 90 people diagnosed with high cholesterol. The results showed that consuming at least 150 milligrams of flaxseed lignans per day (about three tablespoons) decreased cholesterol in men, but not women, by just under 10 percent over the three months that they were given the flaxseed.  Suzanne concludes that though the result is  considerably less than the expected outcome from cholesterol-lowering drugs -- approximately 10 to20 percent for three months, depending on the individual -- it's still enough to make flaxseed a more natural option for some men. While the study found that the flaxseed lignans lowered cholesterol in men, it did not produce a significant change in women. More.... 

Ref : http://www.news.iastate.edu/news/2010/mar/flaxseed

(Those interested in knowing the other benefits of flax seed can read the article..)

miRNAs' Therapeutic Potential

miRNAs' Therapeutic Potential

New pyrimidine compounds may lead to improved treatments for childhood brain cancer

New pyrimidine compounds may lead to improved treatments for childhood brain cancer

2-aminoimidazole/triazole conjugate re-sensitizes multi-drug resistant strains of bacteria to the effects of conventional antibiotics...

We know that infections from antibiotic-resistant bacteria such as MRSA  are especially difficult to get rid of because the bacteria can attach to surfaces and then create biofilms, sticky layers of cells that act as a shield and prevent antibiotics from destroying the bacteria underneath. While a limited number of existing antibiotics may destroy part of the biofilm, enough bacteria survive to create a recurring infection as soon as antibiotic therapy stops, and over time the surviving bacteria build resistance to that antibiotic. Though I have covered some recent developments in the MRSA field, the following findings are  really interesting for me...

Now researchers lead by Dr. Christian Melander, from North Carolina State University have found that, 2-aminoimidazole/triazole conjugate will  re-sensitize multi-drug resistant strains of bacteria to the effects of conventional antibiotics (including MRSA and multi-drug resistant Acinetobacter baumannii), apart from the synergistic effect between  the  conjugate and antibiotics toward dispersing pre-established biofilms. 

Melander and his team, in collaboration with NC State biochemist John Cavanagh, found that pre-treating the bacteria with their compound and then introducing the antibiotic penicillin one hour later increased the penicillin's effectiveness 128-fold, even when the bacteria was penicillin resistant. The antibiotics also provided a 1,000-fold enhancement to the ability of the 2-aminoimidazole to disperse biofilms. 

Researchers conclude that, compound cooperates with conventional antibiotics, overcoming an infectious threat that would otherwise persist if treated with either agent individually.....

Ref : http://aac.asm.org/cgi/content/abstract/AAC.01418-09v1

Minocycline - Effective defense against HIV ?

We know that Minocycline hydrochloride, also known as minocycline (structure), is a broad spectrum tetracycline antibiotic, and has a broader spectrum than the other members of the group. It is a bacteriostatic antibiotic. It is primarily used to treat acne and other skin infections as well as lyme disease. It may be used to treat certain strains of MRSA infection and disease caused by drug resistant Acinetobacter. Its also used in DMARD (Disease-Modifying Anti-Rheumatic Drug) for RA. 

Now, Johns Hopkins scientists have found that this safe and inexpensive antibiotic (minocycline),   effectively targets infected immune cells in which HIV, the virus that causes AIDS, lies dormant and prevents them from reactivating and replicating. 

As per the claim by the researchers, minocycline, likely will improve on the current treatment regimens of HIV-infected patients if used in combination with a standard drug cocktail known as HAART (Highly Active Antiretroviral Therapy).  Though HART is really effective in keeping down active replication, minocycline is another arm of defense against the virus. 

Dr. Janice Clements lead researcher claims that,  unlike the drugs used in HAART which target the virus, minocycline homes in on, and adjusts T cells, major immune system agents and targets of HIV infection. and  minocycline reduces the ability of T cells to activate and proliferate, both steps crucial to HIV production and progression toward full blown AIDS. 

The idea for using minocycline as an adjunct to HAART resulted when the Hopkins team learned of research by others on rheumatoid arthritis patients showing the anti-inflammatory effects of minocycline on T cells. Interestingly the same researchers earlier found that  minocycline treatment had multiple beneficial effects in monkeys infected with SIV, the primate version of HIV. In monkeys treated with minocycline, the virus load in the cerebrospinal fluid, the viral RNA in the brain and the severity of central nervous system disease were significantly decreased. The drug was also shown to affect T cell activation and proliferation.  

The team used molecular markers to discover that minocycline very selectively interrupts certain specific signaling pathways critical for T cell activation. However, the antibiotic doesn't completely obliterate T cells or diminish their ability to respond to other infections or diseases, which is crucial for individuals with HIV. Researchers conclude that,  this new understanding about minocyline's effects on a T cell  might help to find even more drugs that target its signaling pathways.

At Johns Hopkins and elsewhere, scientists are now testing whether giving HIV patients minocycline benefits them, let us hope for the positive results....

Ref : http://www.usnews.com/science/articles/2010/03/26/existing-antibiotic-might-help-keep-wraps-on-aids-virus.html

UT Southwestern researchers find clues to TB drug resistance.....

In continuation of my update on TB and its challenges...

Now researchers from the University of Texas Southwestern Medical Center at Dallas, have come up with some interesting info. i.e.,  a type of blood pressure medication shows promise at overcoming some drug-resistant tuberculosis, at least in the laboratory. 

Dr. Gumbo (lead researcher) and his colleagues used an experimental apparatus to simulate the way TB bacteria grow in the human lung. When they exposed the bacteria to drugs commonly used to treat the disease (ethambutol and isoniazid),  the bacterial cells activated a cellular mechanism that pumps each drug out of the cells. 

"The pumping action enables the rapid emergence of high-level resistance to the drugs whether administered together as well as individually, Dr. Gumbo said".

As per the claim by the researchers, resistance was drastically reduced  when the researchers gave the blood-pressure drug reserpine – which is known to block this pumping action – to the TB cells before administering ethambutol and isoniazid.

Researchers now want to test all the first-line drug treatments together with the pump blocker in humans. Hope they will come up with positive results.....

Ref  : http://www.utsouthwestern.edu/utsw/cda/dept37389/files/582308.html

Telaprevir-based regimens increase rates of SVR in patients with genotype 1 HCV infection

In continuation of my update on telaprevir-based regimens, I found this article interesting to share with.....

In a clinical trial known as PROVE 3 published in this week's New England Journal of Medicine, treatment with telaprevir-based regimens significantly increased rates of sustained viral response (SVR) in patients with genotype 1 hepatitis C virus (HCV) infection who did not achieve SVR with at least one prior course of pegylated-interferon and ribavirin therapy. In the trial, 51 percent and 53 percent of patients who received telaprevir in combination with pegylated-interferon and ribavirin as part of a 24-week or 48-week regimen, respectively, achieved SVR.   More...

Scientists show carbon nanotubes can be broken down by MPO

Carbon nanotubes were once considered biopersistent in that they did not break down in body tissue or in nature. In recent years, research has shown that laboratory animals exposed to carbon nanotubes via inhalation or through injection into the abdominal cavity develop severe inflammation. A combined study by a team of Swedish and American scientists have come up with an interesting finding, which will be a breakthrough in nanotechnology and nanotoxicology. As per the claim by the researchers, "endogenous MPO can break down carbon nanotubes". This enzyme is expressed in certain types of white blood cell (neutrophils), which use it to neutralise harmful bacteria. Now, however, the researchers have found that the enzyme also works on carbon nanotubes, breaking them down into water and carbon dioxide. The researchers also showed that carbon nanotubes that have been broken down by MPO no longer give rise to inflammation in mice. More....

Scientists show carbon nanotubes can be broken down by MPO