DNA replication

WESTERN BLOT

NORTHERN BLOT

SDS PAGE GEL ELECTROPHORESIS

Protein Transcription

How to Detect the IDENTITY by Using an IMAGE !!

Friends..

This post is just to help you in finding
1) the name of any Famous Personality... if you have their image !
2) To detect any PROFILE in FACEBOOK, ORKUT or any Social Network Sites.. whether they are
GENUINE or FAKE


Google has developed IMAGE SEARCH !!

Just open the GOOGLE IMAGE SEARCH !   Drag and Drop the image need to found on the GOOGLE IMAGE SEARCH BAR !!

Thats It !!  You will have the results !!

If the Facebook profile user is FAKE, the image used for that profile will be given in search !!

 

Stay Alert !!   Stay Updated !!!

Akcent - My Passion (Lyrics Encoded) By Me ...

HOW TO KEEP YOUR FACEBOOK ACCOUNT SAFE AND SECURE

Facebook recently announced that they're adding full HTTPS support for the site, to keep you protected from attacks like Firesheep. The feature's finally rolling out, and here's how you can turn it on.

HTTPS is going to keep you a lot safer on the net, and after lots of waiting, Facebook finally announced support for HTTPS all over the site. It wasn't available at the time of the announcement, but we've seen it pop up in our settings menus this week, so it might be time to take another look at yours. To enable it, just hit "Account" in the upper-right hand corner of any Facebook window and go to "Account Settings".

Under "Account Security", hit the change button and check the box that says "Browse Facebook on a secure connection (https) whenever possible". Hit save and exit that window. From now on, whenever you connect to Facebook, it will default to an SSL-encrypted connection, keeping you safe on open Wi-Fi networks from Firesheep-like attacks. Check out the video below for a quick demo. If you don't have it yet, you should have it pretty soon—so check back frequently to see if it pops up.

Facebook comes with some cool security features that let you prevent any phishing attacks to your profile. You can set your account to ask for computer name every time you login from other device. Also you can remotely remove any associated device to your account.

This feature is beneficial in case if any hacker successfully cracks your Facebook account. You’ll immediately came to know about it and takes proper action (changing your password). Here’s how you can do that:

How to set Facebook to send you email and SMS in case other user login into your account

1. Go to your Facebook account.

2. On the top right go to Account –> Account settings

 

3. Click on the change link next to Account Security.

 

You’ll see Login notifications is set to “off”. Click on the circle next to “On” option.

 

Now your Login notification is “ON”. It means you will be prompted to name your device during your next login.

Note: If you are using public computer don’t check the box next to “Don’t ask me again from this computer”.

It also means that if anyone finds your password and tries to login into your account from any device then he’ll get a “Name New Computer”. page. Without entering the Computer name he can’t get into your account.

 

As soon he enters the the name of his computer (any text), you’ll get a notification as email and SMS that a person login from his computer... If you Connect your moblie and email to FACEBOOK.

How to remotely remove devices associated to your Facebook account

Suppose by mistake you added any public computer as your trusted device. It means if any user using this device login to your account mistakenly then he won’t get the “Name new computer page” and also you won’t get the email and SMS notification after he logged in. Facebook keeps record of all the trusted devices and anytime you can remove those devices from your account. Here’s how you can do that:

1. Go to Facebook account.

2. Go to Account –> Account settings.

3. From the Account Settings page, select “Change” Account Security.

4. You’ll see all the computers and devices associated with your account. It means that these are those devices in which you check the box next to “Don’t ask me again from this computer” after filling your computer name in the box when “Name new computer” page appeared.

In the screenshot given below you can see that it shows time of registering the device. It also has “Remove” link next to it. Click on it to remove the devices associated with your account.

 

That’s all. After removing the account, user won’t be able to login into your account without getting the “Name new computer” page on the removed device.

KEEP SAFE ! ENJOY SOCIALLY !!

Many Things .. Many Lessons .. Amazing Week !!

This Week, I have experienced a Lot .. Felt Better .. and Learned some Morals !!

To Start, Letter from the Institution regarding my Admission in Canada made me Jump in Joy !! I kept my Faith in GOD, this Happened !!  Praise the Lord ! Glory  be to GOD !

The Next Day, my Family went out of station for a Couple of Days.. leaving me in the House as a Guardian !

I thought this would be boring for me. But They all made my days easy going..
Some of my B.pharm Frends ..Came to my House for giving me Company..  We Enjoyed, Played well.
After the Completion of B.pharm, This is first time, some of we met for the first time. I was happy for my House, as it was the Venue for the Happy Moments.

Taking Care of Friends, Remembering those past B.pharm Days that we enjoyed .. made me feel so Happy !
Thanks Avi, Sunny, Shaik and Mahe for being with me... You all rock Guys !!

Started Playing POOL in Facebook !! Lost Some pools, Won some..
The Happiest Part is that I got intro to "Jamela" ...

Learning a new language .. Have known some basic cute Words...  Totally this week, Till Now, I enjoyed every moment of it ! 

Guys .. GOD is Really Awesome !! 
He  makes us Cry,,,, and when we are ready to Cry.... He keeps a Chocolate in our Hand !!
He Loves Us the Most !!  Thank you Saviour !!

High-fat diet may injure brain cells regulating weight

Obesity among people who eat a high-fat diet may injure neurons, or nerve cells, in a key part of the brain that controls body weight.

“The possibility that brain injury may be a consequence of the overconsumption of a typical American diet offers a new explanation for why sustained weight loss is so difficult to achieve for most obese individuals,” said study author Joshua Thaler.

Thaler and his colleagues at the Obesity Centre of Excellence at the University of Washington in Seattle, studied the brains of rodents for the short-term and long-term effects of eating a high-fat diet.

After giving groups of six to 10 rats and mice a high-fat diet for periods from one day to eight months, researchers performed detailed biochemical, imaging and cell sorting analyses on the animals’ brains, according to Washington University release.

Within the first three days of consuming a diet that had a similar fat content to the typical American diet, rats consumed nearly double their usual daily amount of calories, Thaler reported.

Rats and mice fed the high-fat diet and gained weight throughout the study. These rodents developed inflammation in the hypothalamus, the part of the brain containing neurons that control body weight.

At the same time, a group of support cells called glia and scavenger cells called microglia accumulated in the hypothalamus and appeared to become activated. Although this collective response to brain inflammation-called gliosis-subsided days later, it recurred after four weeks.

“Gliosis is thought to be the brain equivalent of wound healing and is typically seen in conditions of neuronal injury, such as stroke and multiple sclerosis,” Thaler said. “We speculate that the early gliosis that we saw may be a protective response that fails over time.”

The results were presented at the Endocrine Society’s 93rd Annual Meeting in Boston.

Source : Bioscholar

MF Husain passes away in London - Lifestyle - DNA

MF Husain passes away in London - Lifestyle - DNA

Frog skin for treating cancer?

Scientists at Queen's University Belfast have discovered proteins in frog skins which could be used to treat cancer, diabetes, stroke and transplant patients by regulating the growth of blood vessels.

The award-winning research, led by Professor Chris Shaw at Queen's School of Pharmacy, has identified two proteins, or 'peptides', which can be used in a controlled and targeted way to regulate 'angiogenesis' -- the process by which blood vessels grow in the body. The discovery holds the potential to develop new treatments for more than seventy major diseases and conditions that affect more than one billion people worldwide.

The proteins are found in secretions on the skins of the Waxy Monkey Frog and the Giant Firebellied Toad. Scientists capture the frogs and gently extract the secretions, before releasing them back in to the wild. The frogs are not harmed in any way during this process.

Professor Shaw said: "The proteins that we have discovered have the ability to either stimulate or inhibit the growth of blood vessels. By 'switching off' angiogenesis and inhibiting blood vessel growth, a protein from the Waxy Monkey Frog has the potential to kill cancer tumours. Most cancer tumours can only grow to a certain size before they need blood vessels to grow into the tumour to supply it with vital oxygen and nutrients. Stopping the blood vessels from growing will make the tumour less likely to spread and may eventually kill it. This has the potential to transform cancer from a terminal illness into a chronic condition.

"On the other hand, a protein from the Giant Firebellied Toad has been found to 'switch on' angiogenesis and stimulate blood vessel growth. This has the potential to treat an array of diseases and conditions that require blood vessels to repair quickly, such as wound healing, organ transplants, diabetic ulcers, and damage caused by strokes or heart conditions."

Explaining how his research team looks to the natural world to solve problems where other methods of drug discovery have failed, Professor Shaw said: "Because of its huge potential, angiogenesis has been a prime target for drugs development research over the past forty years. But despite an investment of around $4-5 billion by scientists and drugs companies around the world, they have yet to develop a drug that can effectively target, control and regulate the growth of blood vessels.

"The aim of our work at Queen's is to unlock the potential of the natural world -- in this case the secretions found on frog and toad skins -- to alleviate human suffering. We are absolutely convinced that the natural world holds the solutions to many of our problems, we just need to pose the right questions to find them.

"It would be a great shame to have something in nature that is potentially the wonder drug to treat cancer and not aim to do everything in our power to make it work."

The Queen's researchers will receive the Commendation in the Cardiovasular Innovation Award at the Medical Futures Innovation Awards in London June 6, 2011. The Awards are one of Europe's most prestigious healthcare and business awards, rewarding innovative ideas from front line clinicians, scientists and entrepreneurs. Professor Shaw's team are the only entry from Northern Ireland to be successful at this year's awards.

Congratulating Professor Shaw and his colleagues, Professor Brian Walker and Dr Tianbao Chen, on their commendation award, Queen's Vice-Chancellor Professor Peter Gregson said: "This award is not only an honour for Professor Shaw and his team, it is recognition of the world-class research taking place at Queen's School of Pharmacy, and the life-changing potential of the University's work in drug discovery."

Large-Scale Adsorption and Chromatography, Volumes 1-2

Loved Todays Google Doodle !

Today is 96th birthday of Les Paul—was an American jazz andcountry guitarist, songwriter and inventor. He was a pioneer in the development of the solid-body electric guitar which "made the sound of rock and roll possible". He is credited with many recording innovations. Although he was not the first to use the technique, his early experiments with overdubbing (also known as sound on sound), delay effectssuch as tape delay, phasing effects and multitrack recording were among the first to attract widespread attention.

His innovative talents extended into his playing style, including licks, trills, chording sequences, fretting techniques and timing, which set him apart from his contemporaries and inspired many guitarists of the present day. He recorded with his wife Mary Ford in the 1950s, and they sold millions of records.

Among his many honors, Paul is one of a handful of artists with a permanent, stand-alone exhibit in the Rock and Roll Hall of Fame. He is prominently named by the music museum on its website as an "architect" and a "key inductee" along with Sam Phillips and Alan Freed.

STOP VIOLENCE AGAINST WOMEN

Investigative IL-6 Inhibitor Sirukumab Reduces Symptoms in Patients With Rheumatoid Arthritis

LONDON -- May 31, 2011 -- Rheumatoid arthritis patients failing to respond to the disease-modifying agent methotrexate appear to achieve a reduction in symptoms when treated with the investigational interleukin-6 inhibitor sirukumab, researchers said here at the 2011 Annual Meeting of the European League Against Rheumatism (EULAR).

“Not all patients respond to initial treatment, and in my experience a proportion of patients receiving currently available therapies will either have an inadequate response or lose response over time,” said Josef Smolen, MD, Medical University of Vienna, Vienna, Austria.

“There continues to be a need for additional therapeutic options for the treatment of rheumatoid arthritis -- a serious, progressive autoimmune disease. The results we have seen to date with sirukumab are promising, and we look forward to seeing future data from the ongoing clinical studies,” he said.

Results from the phase 2 multicentre, randomised, double-blind, dose-finding study showed that patients treated with sirukumab achieved a significantly greater reduction in Disease Activity Score 28 (DAS28 CRP) at week 12, the primary endpoint of the study, researchers reported on May 27.

At week 12, in this proof-of-concept trial, the 19 patients on methotrexate plus placebo achieved a score reduction 0.65 while the 17 patients on methotrexate and sirukumab showed a reduction of 1.66 (P =.001).

All patients remained on their background medication of methotrexate and were randomised to receive subcutaneous injections of sirukumab 100 mg or placebo once every 2 weeks from week 0 to week 10. At week 12, an interim analysis showed that 82% of patients in the sirukumab group achieved good or moderate DAS28 C-reactive protein (CRP) response compared with 32% of patients receiving placebo plus methotrexate (P =.015).

By week 12, at least a 20% improvement in American College of Rheumatology scores (ACR20) was seen in 75% of sirukumab-treated patients compared with 21% of patients receiving placebo plus methotrexate patients (P =.002).

Treatment with sirukumab was generally well tolerated through 10 weeks of treatment. Three patients discontinued the study before week 12 due to an adverse event -- one being a serious case of staphylococcal cellulitis. The infection resolved. Another patient was withdrawn after developing pneumonia and the third patient -- in the placebo group -- quit the study due to worsening rheumatoid arthritis. No deaths, cardiovascular events, or gastrointestinal perforations were reported.

The study was funded by Centocor Ortho Biotech Inc.

By Alex Morrisson
Presented at EULAR

[Presentation title: Proof-of-Concept for CNTO 136, a Human Anti-Interleukin-6 Monoclonal Antibody, in a Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study in Patients With Active Rheumatoid Arthritis Despite Methotrexate Therapy. Abstract FRI0345]

Cancer drug can reverse heart failure

A promising cancer drug can reverse a heart failure resulting from high blood pressure (BP).

The drug, a type of histone deacetylase (HDAC) inhibitor being evaluated in ongoing clinical trials, has been shown to reverse the harmful effects of autophagy in heart muscle cells of mice, according to a recent study.

Autophagy is a natural process by which cells eat their own proteins to provide needed resources in times of stress, the journal Proceedings of the National Academy of Sciences reports.

"This opens the way for a new therapeutic strategy in hypertensive (BP related) heart disease, one we can test for potential to promote regression of heart disease," said Joseph Hill, chief of cardiology at the University of Texas Southwestern Medical Centre, who led the study.

Hill, senior study author, and other researchers have shown previously that all forms of heart disease involve either too much or too little autophagy, according to a Texas statement.

For example, in the presence of high BP, the heart enlarges, or hypertrophies and autophagy is turned on. Ultimately, the hypertension-stressed heart can go into failure.

Prior research from Hill's laboratory has shown that HDAC inhibitors blunt disease-associated heart growth, so researchers designed this study to determine what impact a particular type of HDAC inhibitor had on autophagy.

The researchers engineered mice with overactive autophagy and induced hypertrophy leading to heart failure. Scientists then gave the mice an HDAC inhibitor known to limit autophagy.

"The heart decreased back to near its normal size, and heart function that had previously been declining went back to normal," Hill said. "That is a powerful observation where disease regression, not just disease prevention, was seen." 

Source :  Research brain tumour : www.anticancer.de/astrocytoma-study - Phase III study for anaplastic astrocytoma accepts patients.

Thank you All !!!

Killing a Pregnant Lady for Having a Baby Girl is INSANE !! Giving birth to a Baby Girl is not in Her Hand !!

Recently, This incident happened in Andhra Pradesh, INDIA.. 

Now a Dayz.... In this New Modern World too....there are many instances happening all around like this !!

A Husband killed his Pregnant Wife for Having a Baby Girl..

Although, Scanning is Prohibited and Illegal in INDIA, He has Done Scanning to his Wife, to confirm whether He will be having a BABY girl/ Baby Boy..

A Scanning Centre & A Doctor for Money... Done Scanning and Revealed the reports that He is going to have a BABY GIRL..

Husband who already had two daughters by his WIFE, has lost his patience, Killed his WIFE that She is the REASON for this Whole thing.

Let me Clear to you all that Birth of a BABY is completely dependent on the Husband !!

The chromosomes of a Man --- X, Y

The Chromosomes of a Woman ---  X, X

So, by the above picture,, you can clearly understand that Only MAN is Responsible for the BIRTH of a BABY .. no matter whether it may be a Girl or a Boy !!

Vancomycin mechanism of action: an animation

Vancomycin is a tricyclic glycopeptide that has gained clinical importance thanks to its effectiveness against organisms such as MRSA and enterococci. It has activity against Gram-positive rods and cocci, Gram-negative rods are resistant to its bactericidal action.

Some clinical uses of IV vancomycin include treatment of infective endocarditis and sepsis caused by MRSA. Since vancomycin is poorly absorbed,  it is used only in treatment of enterocolitis caused by C. difficile.

Vancomycin adverse effects include skin flushing (red-man syndrome), fever, chills and phlebitis at the infusion site. Ototoxicity and nephrotoxicity must be kept in mind when treating patients that are receiving other drugs.

As you can see in the animation below, vancomycin binds to the pentapeptides of the peptidoglycan monomers and prevents the transglycosylation step in peptidoglycan polymerization. This weakens the cell wall and damages the underlying cell membrane.

Mechanism of action

About the animation author

Dr. Gary Kaiser is a Professor of Microbiology at The Community College of Baltimore County, Catonsville Campus located in Baltimore, Maryland.

Make sure you visit his excellent microbiology website: The Grapes of Staph.

References


Golan, David E (editor). “Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy”, 2nd edition. LWW: 2008.


Harvey, R; Champe, P (series editors). “Lippincott illustrated reviews: Pharmacology”, 4th edition. LWW: 2009.

Gilbert, D; Moellering R (editors) “Sanford Guide to Antimicrobial Therapy”, 39th edition. Antimicrobial therapy: 2009

Hauser, A. “Antibiotic Basics for Clinicians: Choosing the Right Antibacterial Agent”.1st edition. LWW:2007

Gallagher, J. “Antibiotics Simplified”. 1st edition. Jones & Bartlett Publishers: 2008

Botulinum toxin type A (Botox) mechanism of action

Botox mechanism of action

The presynaptic neuromuscular nerve ending contains vesicles prepared to release the neurotransmitter acetylcholine. Neuronal stimulation initiates a cascade of events that leads to the fusion of the neurotransmitter containing vesicle with the nerve membrane. This process is facilitated by a group of proteins comprising the SNARE complex. The membrane fusion results in the release of acetylcholine into the synaptic cleft by a process of exocytosis.




Acetylcholine diffuses and eventually binds to acetylcholine receptors in the muscle, leading to muscle contraction.
Botox (botulinum toxin type A) consists of a heavy chain of 100 kDa and a light chain of 50 kDa making up the 150 kDa core type A molecule. The toxin is protected by accessory hemaglutinin and non-toxic non- hemaglutinin proteins.
This illustration shows a cross section of the spine, with a motor neuron extending into the muscle and a sensory neuron extending out of the muscle. After injection of Botox it would be expected that most of the neurotoxin would remain in the injection site. The Botox core molecule dissociates from the accessory proteins and targets the nerve endings. The binding domain of the Botox core molecule is the C-terminal portion of the heavy chain.
The Botox core molecule enters the nerve cell by a process of receptor mediated endocytosis. It is the heavy chain that contains the binding domain. The toxin is now contained in a membranous vesicle inside the cell. Soon after, the light chain is released into the cytoplasm of nerve terminal, where it begins to cleave one of the SNARE proteins.


In motor neurons, the light chain of the Botox core molecule blocks the release of acetylcholine by cleaving SNAP-25, which is an essential component of the SNARE complex. When acetylcholine cannot be released, muscle contraction cannot occur. In sensory neurons, the light chain is believed to cleave SNAP-25 by a similar mechanism, thereby blocking the release of neuropeptide neurotransmitters and inhibiting the desensitation of pain nerves.
The toxin does not appear to affect the conduction along the nerve fiber or the synthesis or storage of acetylcholine.

Renal physiology and diuretics mechanism of action.

Mechanism of action of loop diuretics ( Source: Bertram Katzung, Basic and Clinical Pharmacology, Mc Graw Hill Medical, 2007):

Pharmacodynamics

These drugs inhibit NKCC2, the luminal Na⁺/K⁺/2Cl^- transporter in the thick ascending limb of Henle’s loop. By inhibiting this transporter, the loop diuretics reduce the reabsorption of NaCl and also diminish the lumen-positive potential that comes from K⁺ recycling (Figure 15-3). This positive potential normally drives divalent cation reabsorption in the loop (Figure 15-3), and by reducing this potential, loop diuretics cause an increase in Mg²⁺ and Ca²⁺ excretion. Prolonged use can cause significant hypomagnesemia in some patients. Since vitamin D-induced intestinal absorption of Ca²⁺ can be increased and Ca²⁺ is actively reabsorbed in the DCT, loop diuretics do not generally cause hypocalcemia. However, in disorders that cause hypercalcemia, Ca²⁺ excretion can be usefully enhanced by treatment with loop diuretics combined with saline infusions.

Loop diuretics induce synthesis of renal prostaglandins, which participate in the renal actions of these diuretics. NSAIDs (eg, indomethacin) can interfere with the actions of the loop diuretics by reducing prostaglandin synthesis in the kidney. This interference is minimal in otherwise normal subjects but may be significant in patients with nephrotic syndrome or hepatic cirrhosis.

In addition to their diuretic activity, loop agents have direct effects on blood flow through several vascular beds. Furosemide increases renal blood flow. Both furosemide and ethacrynic acid have also been shown to reduce pulmonary congestion and left ventricular filling pressures in heart failure before a measurable increase in urinary output occurs, and in anephric patients.

Mechanism of action of tiazide diuretics ( Source: Bertram Katzung, Basic and Clinical Pharmacology, Mc Graw Hill Medical, 2007):

Pharmacodynamics

Thiazides inhibit NaCl reabsorption from the luminal side of epithelial cells in the DCT by blocking the Na⁺/Cl^- transporter (NCC). In contrast to the situation in the TAL, where loop diuretics inhibit Ca²⁺ reabsorption, thiazides actually enhance Ca²⁺ reabsorption. This enhancement has been postulated to result from effects in both the proximal and distal convoluted tubules. In the proximal tubule, thiazide-induced volume depletion leads to enhanced Na⁺ and passive Ca²⁺ reabsorption. In the DCT, lowering of intracellular Na⁺ by thiazide-induced blockade of Na⁺ entry enhances Na⁺/Ca²⁺ exchange in the basolateral membrane (Figure 15-4), and increases overall reabsorption of Ca²⁺. While thiazides rarely cause hypercalcemia as the result of this enhanced reabsorption, they can unmask hypercalcemia due to other causes (eg, hyperparathyroidism, carcinoma, sarcoidosis). Thiazides are useful in the treatment of kidney stones caused by hypercalciuria.

The action of thiazides depends in part on renal prostaglandin production. As described above for the loop diuretics, the actions of thiazides can also be inhibited by NSAIDs under certain conditions.

Mechanism of action of potasium sparing diuretics ( Source: Bertram Katzung, Basic and Clinical Pharmacology, Mc Graw Hill Medical, 2007):

Pharmacodynamics

Potassium-sparing diuretics reduce Na⁺ absorption in the collecting tubules and ducts. Na⁺ absorption (and K⁺ secretion) at this site is regulated by aldosterone, as described above. Aldosterone antagonists interfere with this process. Similar effects are observed with respect to H⁺ handling by the intercalated cells of the collecting tubule, in part explaining the metabolic acidosis seen with aldosterone antagonists (Table 15-2).

Spironolactone and eplerenone bind to aldosterone receptors and may also reduce the intracellular formation of active metabolites of aldosterone. Amiloride and triamterene do not block the aldosterone receptor but instead directly interfere with Na⁺ entry through the epithelial sodium ion channels (ENaC) in the apical membrane of the collecting tubule. Since K⁺ secretion is coupled with Na⁺ entry in this segment, these agents are also effective potassium-sparing diuretics.

The actions of the aldosterone antagonists depend on renal prostaglandin production. As described above for loop diuretics and thiazides, the actions of K⁺-sparing diuretics can be inhibited by NSAIDs under certain conditions.

Mechanism of action of osmotic diuretics ( Source: Bertram Katzung, Basic and Clinical Pharmacology, Mc Graw Hill Medical, 2007):

Pharmacodynamics

Osmotic diuretics have their major effect in the proximal tubule and the descending limb of Henle’s loop. Through osmotic effects, they also oppose the action of ADH in the collecting tubule. The presence of a nonreabsorbable solute such as mannitol prevents the normal absorption of water by interposing a countervailing osmotic force. As a result, urine volume increases. The increase in urine flow rate decreases the contact time between fluid and the tubular epithelium, thus reducing Na⁺ as well as water reabsorption. The resulting natriuresis is of lesser magnitude than the water diuresis, leading eventually to excessive water loss and hypernatremia.

P-glycoprotein: animation showing its role in chemotherapy resistance

Some introductory information about MDR1, the protein that mediates resistance to chemotherapeutic agents, from Wikipedia:

P-glycoprotein (plasma gycoprotein, abbreviated as P-gp or Pgp) is a well-characterized ABC-transporter of the MDR/TAP subfamily. P-gp is also called ABCB1, ATP-binding cassette sub-family B member 1, MDR1, and PGY1. P-glycoprotein has also recently been designated CD243 (cluster of differentiation 243). In humans, P-glycoprotein is encoded by the ABCB1 gene.
Pgp is extensively distributed and expressed in the intestinal epithelium, hepatocytes, renal proximal tubular cells, and capillary endothelial cells comprising the blood-brain barrier.

The animation below, produced by CancerQuest, shows how the MDR protein ejects drugs once they have entered the cell.

G protein-coupled receptors: Description & 3-D video

G protein-coupled receptors are the most abundant class of receptors in the human body. These receptors are exposed at the extracellular surface of the cell membrane, traverse the membrane, and possess intracellular regions that activate a unique class of signaling molecules called G proteins. (G proteins are so named because they bind the guanine nucleotides GTP and GDP.) G protein-coupled signaling mechanisms are involved in many important processes, including vision, olfaction, and neurotransmission.

G protein-coupled receptors all have seven transmembrane regions within a single polypeptide chain. Each transmembrane region consists of a single α helix, and the α helices are arranged in a characteristic structural motif that is similar in all members of this receptor class. The extracellular domain of this class of proteins usually contains the ligand-binding region, although some G protein-coupled receptors bind ligands within the transmembrane domain of the receptor. In the resting (unstimulated) state, the cytoplasmic domain of the receptor is noncovalently linked to a G protein that consists of α and βγ subunits. Upon activation, the α subunit exchanges GDP for GTP. The α-GTP subunit then dissociates from the βγ subunit, and the α or βγ subunit diffuses along the inner leaflet of the plasma membrane to interact with a number of different effectors.

These effectors include adenylyl cyclase, phospholipase C, various ion channels, and other classes of proteins. Signals mediated by G proteins are usually terminated by the hydrolysis of GTP to GDP, which is catalyzed by the inherent GTPase activity of the α subunit .

One major role of the G proteins is to activate the production of second messengers, that is, signaling molecules that convey the input provided by the first messenger—usually an endogenous ligand or an exogenous drug—to cytoplasmic effectors . The activation of cyclases, such as adenylyl cyclase, which catalyzes the production of the second messenger cyclic adenosine-3′,5′-monophosphate (cAMP), and guanylyl cyclase, which catalyzes the production of cyclic guanosine-3′,5′-monophosphate (cGMP), constitutes the most common pathway linked to G proteins. In addition, G proteins can activate the enzyme phospholipase C (PLC) which, among other functions, plays a key role in regulating the concentration of intracellular calcium. Upon activation by a G protein, PLC cleaves the membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2) to the second messengers diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP3). IP3 triggers the release of Ca2+ from intracellular stores, thereby dramatically increasing the cytosolic Ca2+ concentration and activating downstream molecular and cellular events. DAG activates protein kinase C, which then mediates other molecular and cellular events, including smooth muscle contraction and transmembrane ion transport. All of these events are dynamically regulated, so that the different steps in the pathways are activated and inactivated with characteristic kinetics.

A large number of Gα protein isoforms have now been identified, each of which has unique effects on its targets. A few of these G proteins include G-stimulatory (Gs), G-inhibitory (Gi), Gq, Go, and G12/13. Examples of the effects of these isoforms are shown in Table 1-4. The differential functioning of these G proteins, some of which may couple in different ways to the same receptor in different cell types, is likely to be important for the potential selectivity of future drugs. The βγ subunits of G proteins can also act as second messenger molecules, although their actions are not as thoroughly characterized.

One important class in the G protein-coupled receptor family is the β-adrenergic receptor group. The most thoroughly studied of these receptors have been designated β1, β2, and β3. As discussed in more detail in Chapter 9, Adrenergic Pharmacology, β1 receptors play a role in controlling heart rate; β2 receptors are involved in the relaxation of smooth muscle; and β3 receptors play a role in the mobilization of energy by fat cells. Each of these receptors is stimulated by the binding of endogenous catecholamines, such as epinephrine and norepinephrine, to the extracellular domain of the receptor. Epinephrine binding induces a conformational change in the receptor, activating G proteins associated with the cytoplasmic domain of the receptor. The activated (GTP-bound) form of the G protein activates adenylyl cyclase, resulting in increased intracellular cAMP levels and downstream cellular effects.

Source of text: David Golan: Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 2nd Edition

Mechanism of ionotropic receptors or ligand-gated ion channels (LGICs)

In pharmacology, receptors can be divided into 4 general groups:
1. Ion channels:

• Ligand gatedace

• Voltage gated

• Second messenger regulated

2. G protein coupled receptors
3. Receptor tyrosine kinase
4. Intracellular hormone receptors: like  the glucocorticoid receptor

The video animation below shows the activation of a ionotropic receptor or ligand-gated ion channel (LGIC):

An excerpt on the topic from Katzung’s textbook:

Ligand-Gated Channels
Many of the most useful drugs in clinical medicine act by mimicking or blocking the actions of endogenous ligands that regulate the flow of ions through plasma membrane channels. The natural ligands include acetylcholine, serotonin, GABA, and glutamate. All of these agents are synaptic transmitters.
Each of their receptors transmits its signal across the plasma membrane by increasing transmembrane conductance of the relevant ion and thereby altering the electrical potential across the membrane. For example, acetylcholine causes the opening of the ion channel in the nicotinic acetylcholine receptor (AChR), which allows Na⁺ to flow down its concentration gradient into cells, producing a localized excitatory postsynaptic potential-a depolarization.

Mechanisms that Bacteria Use to develop antibiotic resistance

Mechanisms of Antimicrobial Resistance

Mutation

Destruction or Inactivation

Efflux ( 1:00)

Genetic Transfer

Conjugation

Transformation

Transduction

Cisplatin and its Mechanism of Action

Mechanism of Action.

Cisplatin, carboplatin, and oxaliplatin enter cells by diffusion, and by an active Cu2+ transporter (Kruh, 2003). Inside the cell, the chloride atoms of cisplatin may be displaced and the compound may be inactivated directly by reaction with nucleophiles such as thiols. Chloride is replaced by water, yielding a positively charged molecule. In the primary cytotoxic reaction, the aquated species of the drug then reacts with nucleophilic sites on DNA and proteins. Aquation is favored at the low concentrations of chloride inside the cell and in the urine. High concentrations of chloride stabilize the drug, explaining the effectiveness of chloride diuresis in preventing nephrotoxicity (see below). Hydrolysis of carboplatin removes the bidentate cyclobutanedicarboxylato group; this activation reaction occurs slowly.

The platinum complexes can react with DNA, forming both intrastrand and interstrand cross-links. The N7 of guanine is a particularly reactive site, leading to platinum cross-links between adjacent guanines on the same DNA strand; guanine-adenine cross-links also readily form and may be critical to cytotoxicity (Parker et al., 1991). The formation of interstrand cross-links is less favored. DNA adducts formed by cisplatin inhibit DNA replication and transcription and lead to breaks and miscoding, and if recognized by p53 and other checkpoint proteins, induction of apoptosis. Although no conclusive association between platinum-DNA adduct formation and efficacy has been documented, the ability of patients to form and sustain platinum adducts appears to be an important predictor of clinical response (Reed et al., 1986). Preclinical data suggest that the formation of the platinum-adenosine-to-guanosine adduct may be the most critical adduct in terms of cytotoxicity.

The specificity of cisplatin with regard to phase of the cell cycle appears to differ among cell types, although the effects of cross-linking are most pronounced during the S phase. Cisplatin is mutagenic, teratogenic, and carcinogenic. The use of cisplatin- or carboplatin-based chemotherapy for women with ovarian cancer is associated with a fourfold increased risk of developing secondary leukemia (Travis et al., 1999).

Source:Goodman And Gilman’s The Pharmacological Basis of Therapeutics

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Development and evaluation of xyloglucan matrix release tabs contaning glipizide

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Pharmacodynamic Animation : full agonists, partial agonists, inverse agonists, competitive antagonists and irreversible antagonists.

 

Agonist dose response curve in the presence of competitive and irreversible antagonists

Some pharmacodynamic definitions related to the animation:

Full Agonists: Compounds that are able to elicit a maximal response following receptor occupation and activation.

Partial Agonists: Compounds that can activate receptors but are unable to elicit the maximal response of the receptor system.

Inverse agonist: an agent which binds to the same receptor binding-site as an agonist for that receptor and reverses constitutive activity of receptors. Inverse agonists exert the opposite pharmacological effect of a receptor agonist.

Competitive and Irreversible Pharmacologic Antagonists

Competitive antagonists are drugs that bind to the receptor in a reversible way without activating the effector system for that receptor. In the presence of a competitive antagonist, the log dose-response curve is shifted to higher doses (ie, horizontally to the right on the dose axis) but the same maximal effect is reached (Figure 2-5A).

In contrast, an irreversible antagonist causes a downward shift of the maximum, with no shift of the curve on the dose axis unless spare receptors are present (Figure 2-5B). The effects of competitive antagonists can be overcome by adding more agonist. Irreversible antagonists cannot be overcome by adding more agonist. Competitive antagonists increase the ED50; irreversible antagonists do not (unless spare receptors are present).

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