Vinpocetine from the periwinkle plant, as a potent anti-inflammatory agent....

Vinpocetine (ethyl apovincaminate (see chemical structure,   is  a  semisynthetic   derivative   of  alkaloid   vincamine - an  extract  from the  periwinkle plant (see picture) Vinca minor) is a well-known natural product that was originally discovered nearly 30 years ago and is currently used as a dietary supplement for the prevention and treatment of cognitive disorders, such as stroke and memory loss, in Europe, Japan and China.

 

The therapy has no evidence of toxicity or noticeable side effects in human patients. Now scientists at the University of Rochester hope to reposition this compound as an anti-inflammatory agent for the treatment of COPD, and potentially other inflammatory conditions, such as asthma, otitis media, rheumatoid arthritis, atherosclerosis and psoriasis in the future.

As per the claim by the lead researcher Dr. Jian-Dong Li,  vinpocetine decreases inflammation by targeting the activity of a specific enzyme, known as IKK. IKK is responsible for regulating inflammation, and does so through the activation of a key protein, nuclear-factor kappaB (NF-κB). By directly inhibiting IKK, vinpocetine is able to switch off NF-κB, which normally produces pro-inflammatory molecules that cause inflammation. Halting the activity of NF-κB ultimately reduces inflammation. 

"Given vinpocetine's efficacy and solid safety profile, we believe there is great potential to bring this drug to market." claims co-author,  Dr. Bradford C. Berk...

Inflammatory diseases are a major cause of illness worldwide. For example, chronic obstructive pulmonary disease is the fourth leading cause of death in the United States. In people with COPD, airflow is blocked due to chronic bronchitis or emphysema, making it increasingly difficult to breathe. Most COPD is caused by long-term smoking, although genetics may play a role as well.....

Ref : http://www.urmc.rochester.edu/news/story/index.cfm?id=2836

Eliminating inherent drug resistance in tuberculosis....

In continuation of my update on drug resistant TB and the drug development for TB, I found this info interesting to share with.

Dr. John Blanchard of the Albert Einstein College of Medicine has come up with really  interesting  findings about how to "eliminate inherent drug resistance in tuberculosis".   

When the M. tuberculosis genome was sequenced a few years ago, the presence of  beta-lactamase enzyme was discovered. Most scientists didn't pay much attention to this discovery and beta-lactams   never have been systematically used to treat TB. However Dr. John,  thought it would be an attractive therapeutic target, considering several beta-lactamase inhibitors had been developed for other bacteria.

If we could inactivate this inactivator enzyme, it would expose TB bacteria to a whole new range of antibiotics," he says. 

While M. tuberculosis was resistant to most beta-lactamase inhibitors,  Blanchard's group found that the drug clavulanate was effective in shutting down the TB enzyme. 

The combination of clavulanate (see above right structure- its potassium salt) with the beta-lactam   meropenem (see below: left structure) could effectively sterilize laboratory cultures of TB within two weeks, including several XDR-strains (XDR strains are even more resilient than multi-drug resistant (MDR) strains).  Blanchard notes this finding was exciting since, despite such high rates of drug resistance, research into new TB drugs is not a high priority in industrialized countries (for socio-economic reasons), and thus the best short-term approach might be identifying other already FDA approved antibiotics that are effective against TB -like meropenem and clavulanate.

Blanchard is currently progressing with the next steps of the therapeutic process, which includes both detailed animal studies and setting up some small-scale trials with XDR-TB patients in developing nations...

(Source : a presentation at the American Society for Biochemistry and Molecular Biology’s annual meeting, titled “Drug resistance in tuberculosis,” by Dr. John Blanchard).

Ref : http://www.asbmb.org/News.aspx?id=7470&terms=John+Blanchard

Useful chemistry resources.....

If you are looking for interesting and informative blogs  and  other  chemistry  resources in one place,  you  can  visit  the site where in, Anna Miller (staff) has listed nearly 50 sites (chemistry blogs and chemical resources), which in my opinion are very good resources and most of the blogs I do follow on regular basis. 

Though the  website is for online degree, in my opinion its useful for each and every one who yearns for more...

The Secret of Lowering Cholesterol Through Diet...

I am really happy to share an interesting and important article  'the secret of lowering cholesterol through diet' by  Deborah Land, who has written this article exclusively for the readers of  my blog.......

The Secret of Lowering Cholesterol Through Diet

a. The Myth of Cholesterol - the Bad and the Good:

Most people think that cholesterol is always bad, but there are actually two types of cholesterol. LDL is  considered the "bad" cholesterol, and HDL is considered the "good" cholesterol. If there is too much LDL in our bloodstream, it will form plaque on our arteries. Over time, this narrows our arteries and can eventually block blood flow completely. Dietary cholesterol actually isn't the primary reason for high cholesterol in the blood; it is high amounts of saturated fat and trans fat. To keep cholesterol low, you should eat unsaturated fats, eat fibrous foods, and exercise more.

b. Number Relevance in Cholesterol :
Every adult should have their cholesterol checked at least every 5 years. When you get a cholesterol test, you'll usually get back four different results. Here are the 4 categories and the healthy range you want to be in.

Total Cholesterol - less than 200 mg/dL (5.2 mmol/L);
LDL Cholesterol - less than 100 mg/dL (2.6 mmol/L);
HDL Cholesterol - greater than 40 mg/dL (1.0 mmol/L) &
Triglycerides - less than 150 mg/dL (1.7 mmol/L).

If you are over or under the desired level on any category, it is usually indicative that a diet or exercise change is needed.

c. Heart Protection and Vitamin E:
Vitamin E, an important vitamin, is sourced in vegetable oils, nuts and leafy vegetables. Vitamin E can decrease your heart disease risk, but it will not prevent a heart attack.

d. Lowering Cholesterol with these Five Foods :
1. Oatmeal and Oat Bran: These contain a high amount of soluble fiber, which can lower LDL.
2. Fish: Fish is a great source of omega 3 fatty acids, which lowers LDL and raises HDL.
3. Nuts: Not only are nuts high in fiber, but they contain the healthy fats you need to keep LDL in check.
4. Plant Sterols: This is found in foods like margarine, salad dressing, orange juice, and functional cookies. 2  grams per day will lower your LDL by 10-15%.
5. Soy: This popular meat replacement can lower LDL by up to 3%.

e. Plant Sterols and Benefits to Health :
Foods such as VitaTops Muffin Tops, Benecol Spread, granola bars and fat free milk are rich sources of plant sterols. You can easily help your heart when you start eating foods packed with plant sterols and avoid eating foods that contain saturated fats. A saturated fat-filled diet is not canceled out by this. Exercising often as well as eating healthy food will keep your cholesterol in check.

About the Author - Deborah Land writes for Cholesterol Lowering Diet Blog  ,  her personal hobby blog focused on tips to eat healthy to prevent high cholesterol. I find the blog very informative, do visit for more details...

Hormone Spray improves male Sensitivity.....

A study by Dr. Ren- Hurlemann of Bonn University's Clinic for Psychiatry,  has revealed for the first time that emotional empathy is modulated by oxytocin (see structure), and that this applies similarly to learning processes with social multipliers.. Researchers claim that, this hormone might thus be useful as medication for diseases such as schizophrenia, which are frequently associated with reduced social approachability and social withdrawal......

Ref : http://www3.uni-bonn.de/Press-releases/hormone-spray-improves-male-sensitivity

New Data on NovaBay’s Aganocide compounds ( first-in-class anti-infectives) as presentations...

NovaBay Pharmaceuticals, Inc.  recently announced that, it is will be  presenting the latest public data on its Aganocide^® compounds (see structures : a new class of broad-spectrum antimicrobials). 

Data will be presented during three poster sessions at the Association for Research in Vision and Ophthalmology (ARVO) annual meeting in Fort Lauderdale, Florida. NovaBay's Aganocide compounds are first-in-class anti-infectives being developed for the treatment and prevention of antibiotic-resistant infections. NovaBay and Alcon, Inc., the world's leading eye care company, have a licensing and research collaboration agreement for the use of NovaBay's Aganocide compounds in the eye, ear and sinus, and for contact lens care.

The three presentations are :

1. Dichloro analog (AL-46383A) (see structure) as a Novel Topical Ophthalmic Agent, 2. In vitro evaluation of dichloro analog as an Antiviral Agent Against Adenovirus and HSV-1 and 3. topical dichloro analog,  Inhibits Adenovirus Replication in the Ocular Ad5/NZW Rabbit Replication Model.

NVC-422, or AL-46383A, is a stable compound based on the chemical structures of N-chlorotaurine (NCT) and N,N-dichlorotaurine, which are naturally occurring antimicrobial agents produced by the body's white blood cells to fight invasive pathogens.

Alcon is conducting a Phase 2 clinical trial of this compound for the treatment of viral conjunctivitis, a form of "pink eye". The randomized, placebo-controlled trial is enrolling approximately 250 patients at more than 30 medical centers in the United States and worldwide. It is designed to determine the safety and efficacy of NVC-422 or AL-46383A. 

Ref : http://www.novabaypharma.com/investors/release/apr_30_2010

Some new insights into the molecular mechanisms of pain perception....

UT Health Science Center researchers,  lead by Dr. Kenneth M. Hargreaves,  found a new family of fatty acids  produced by the body itself, that play an important role in the biology of pain.

Researchers evaluated the hypothesis that,  the heat sensitivity of TRPV1 is regulated by the generation of endogenous ligands and they found that heat-generated linoleic acid metabolites comprise a family of physiologically relevant TRPV1 agonists that contribute to the heat responsiveness of this channel. More interestingly the results also suggest, a previously unknown mechanism by which TRPV1 might mediate biological actions of oxidized linoleic acid metabolites in conditions such as inflammation and hypotension.

Encouraged by the facts that,  heat activation of TRPV1 (mechanistically distinct from capsaicin sensitivity) appears to occur in a membrane-delimited fashion (during short periods), its dependence on C terminus or voltage gating and their  own results, researchers proposed that heating leads to the generation of oxidized linoleic acid products in the plasma membrane that are important for TRPV1 responses to noxious thermal stimuli. It should be noted that in inflammatory diseases, relatively high levels of HODEs are observed even in extracellular compartments.

The data indicate that 9-HODE and 13-HODE substantially contribute to the heat responsiveness of TRPV1 in vitro and in vivo (apart from intrinsic heat sensitivity of TRPV1). Researchers claim that, heat directly activates TRPV1 with a subsequent generation of endogenous ligands that further amplifies the heat response and biological actions occur only in WT neurons and not neurons from TRPV1.

Researchers conclude by their in vitro and in vivo results that, blockade of the endogenous linoleic acid metabolites substantially decreased responses to thermal stimuli and the heat sensitivity of another member of the TRP family, TRPV4, is mediated via generation of a soluble ligand.

Previous studies have demonstrated that leukotrienes activate TRPV1, epoxyeicosatrienoic acids activate TRPV4, and 4-hydroxynonenal and 15d-PGJ₂ activate TRPA1. These results by UT researchers add HODEs as endogenous ligands for TRPV1. It is noteworthy that all these TRP ligands are lipid oxidation products and therefore encouraged the researchers to speculate that, one of the major roles of certain TRP channels in mammals is to act as sensors of membrane lipid oxidation as a surrogate for cellular damage. ..

Ref : http://www.uthscsa.edu/hscnews/singleformat2.asp?newID=3419

Combination antibiotics effective against chlamydia-induced arthritis, study finds

Combination antibiotics effective against chlamydia-induced arthritis, study finds

Peppers may increase energy expenditure in people tying to lose weight....

We know that, Capsinoids, which include capsiate, dihydrocapsiate,  and nordihydrocapsiate, are substances naturally present in chili peppers. Although they are structurally similar to capsaicin, the substance that causes pungency in hot peppers, they largely lack that characteristic. Capsinoids have an estimated “hot taste threshold” which is about 1000 times lower than of that of capsaicin. Many health effects have been ascribed to capsaicin and capsinoids, both anecdotally and through scientific study, including anticancer, anti-inflammatory, analgesic activity, and weight management.

Now researchers form UCLA's Center for Human Nutrition in Los Angeles, CA, lead by Dr. David Heber have come up with more interesting findings, i.e., "peppers may increase energy expenditure in people tying to lose weight". 


In a study designed to test the weight-loss potential of this DCT containing, non-spicy cousin of hot peppers, researchers at the UCLA Center for Human Nutrition set out to document its ability to increase heat production in human subjects consuming a weight-loss diet.

Under the direction of Dr. David Heber (Professor of Medicine and Public Health), they recruited 34 men and women who were willing to consume a very low-calorie liquid meal replacement product for 28 days. The researchers then randomized the subjects to take either placebo pills or supplements containing the non-burning DCT pepper analog. Two dosage levels of dihydrocapsiate DCT (see above structure ) were tested. At the beginning and end of the study, body weight and body fat were assessed, and the researchers determined energy expenditure (heat production) in each subject after he or she consumed one serving of the test meal.

The data provided convincing evidence that, at least for several hours after the test meal was consumed, energy expenditure was significantly increased in the group consuming the highest amount of DCT. In fact, it was almost double that of the placebo group. This suggests that eating this pepper-derived substance that doesn't burn can have the same potential benefit as hot peppers at least in part by increasing food-induced heat production. They were also able to show that DCT significantly increased fat oxidation, pushing the body to use more fat as fuel. This may help people lose weight when they consume a low-calorie diet by increasing metabolism. 


However, that a limitation to this study was that, the researchers only tested the effect of DCT on the thermic response to a single meal. Heber and colleagues also point out that that there might be a different effect in lean vs. obese subjects. But to their credit, this was the first study ever conducted to examine the potential health benefits of DCT consumed together with a very low calorie diet....

Ref : Dr. David Heber et. al., FASEB Journal 

New study confirms 98.9% specificity of the T-SPOTspan TB assay

The study highlights the very high specificity of the T-SPOT.TB assay and confirms its utility in the identification of latent TB infection....

New study confirms 98.9% specificity of the T-SPOTspan style="vertical-align:super; font-size:80%;"®/span.iTB/i assay

Rib-X Pharmaceuticals to demonstrate three presentations at Antibacterial Drug Development Conference

Rib-X Pharmaceuticals, Inc, is presenting three separate presentations at the Cambridge Healthtech Institute's 4^th Annual Antibacterial Drug Development Conference, Resistance is Futile: The Challenge of Antibacterial Drug Development, April 27 - 28, in San Diego,

The presentations include overviews on radezolid (see below structure)  

delafloxacin  (see  right  structure) and the Company's proprietary platform for unlocking the bacterial ribosome, which has allowed for the design and generation of three novel classes of antibiotics that have been tuned for both multi-drug resistant Gram-negative and Gram-positive activity and have shown efficacy in multiple animal models of infection. 

Hope these results will  lead to relief from multi-drug–resistant infections (e.g., MRSA, uSSSI  and community acquired pneumonia,CAP).


Ref : http://www.rib-x.com/news_and_events/release_2010_04_12

Chokeberry extract reduces weight gain in insulin-resistant animals.....

Chokeberries (Aronia) are a great example of those fruits that both  taste good and show a number of health benefits for the body. Chokeberries' rich antioxidant content may be beneficial as a dietary preventative for reducing the risk of diseases caused by oxidative stress. Among the models under evaluation where preliminary results show benefits of chokeberry anthocyanins are colorectal cancer, chronic inflammation, gastric mucosal disorders (peptic ulcer),eye inflammation (uveitis) and liver failure cardiovascular disease.

Now Drs. Bolin Qin and Richard Anderson from the US Department of Agriculture in Beltsville, MD, have come up with some more interesting info about chokeberries, i.e., "chokeberry extract reduces weight gain in insulin-resistant animals". 

Qin and Anderson found that at the end of the study,  the rats consuming the chokeberry-spiked water weighed less than the controls; both levels of chokeberry had the same effect in this regard. Similar beneficial effects of chokeberry consumption were found for body fat (specifically, that of the lower abdominal region). They also discovered that animals that had been drinking chokeberry extract had lower blood glucose and reduced levels of plasma triglycerides, cholesterol, and low-density lipoprotein (LDL) cholesterol when compared to the control animals. These alterations would theoretically lead to lower risk for diabetes and cardiovascular disease in humans.

To add even more evidence for a healthful impact of this super-berry, the researchers documented numerous alterations in expression of genes that would likely lead to reduced chronic inflammation and perhaps even lower cancer risk. For instance, drinking chokeberry extract lowered expression of the gene coding for interleukin-6 (IL-6), a protein that normally triggers inflammation following trauma or infection. Chronic overproduction of IL-6 has been documented in many diseases such as diabetes, arthritis, and atherosclerosis and is thought to be a partial cause of these conditions.

Researchers conclude that though human trials are essential to further substantiate their claim,  they believe their study "provides evidence that the chokeberry extract inhibits weight gain in insulin-resistant animals and that it modulates multiple genes associated with adipose tissue growth, blood glucose regulation, and inflammatory pathways."....

Ref : Bolin Qin and Richard A Anderson, :  Abstract in FASEB, 

(those interested can read other benefits and other details at the link)

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.