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  Ways to Stop Your iPhone from Spying on You

Submitter: [anonymous]
Category: Guides / Tutorials - Software
exhibition Date: 2018-08-08 01:49:24
Last Update: 2018-08-08 01:52:22
Views: 23
Score: 5.00 / 5.00 (Based on 1 votes.)
In an increasingly chaotic and frightening world, more people than ever are concerned about the government surveillance. Surveillance is probably easier than ever before thanks to the wealth of data captured and stored on devices like the iPhone. From our communications to the locations we visit to our social networks, our phones contain a lot of sensitive information about us and our activities.

Luckily, they also contain features that help us protect our digital privacy and prevent government spying. Check out these tips for keeping your data and your activities private.

Security for Web, Chat, and Email
Communications are one of the key things that surveillance seeks to gain access to. Encryption and taking certain precautions with the apps you use can help.

Use a VPN for Web Browsing
A Virtual Private Network, or VPN, routes all of your Internet browsings through a private "tunnel" which is protected with encryption from surveillance. While there have been reports of governments being able to crack some VPNs, using one will provide more protection than not. To use a VPN, you need two things: a VPN app and a subscription to a VPN service provider who provides the encrypted access to the internet. There's a VPN app built into the iOS, and numerous options available in the App Store, including:

ExpressVPN—Free app. Service costs US$8-13/month.
Download at the App Store
IPVanish VPN—Free app. Service costs $6.50-$10/month.
Download at the App Store
VPN by NordVPN—Free app. Service costs $5.75-$12/month.
Download at the App Store
Always Use Private Browsing
When you browse the web, Safari tracks your browsing history, information which can be relatively easy to access if someone gets access to your iPhone. Avoid leaving a trail of web browsing data by using Private Browsing. This feature built into Safari ensures that your browsing history isn't saved. Turn the feature on by following these steps:

Tap Safari
Tap the two-squares icon at the bottom right
Tap Private
Tap + to open a new Private Browsing window.
Use an Encrypted Chat App
Eavesdropping on conversations can net a ton of useful information—unless your conversations can't be cracked. To do that, you need to use a chat app with end-to-end encryption. This means that every step of a chat—from your phone to the chat server to the recipient's phone—is encrypted. Apple's iMessage platform works this way, as do a number of other chat apps. IMessage is a great option since Apple has taken a strong stand against creating a "backdoor" for the government to access conversations. Just make sure that no one in your iMessage group chats is using Android or another smartphone platform; that breaks encryption for the entire conversation.

The Electronic Frontier Foundation (EFF), a digital rights and policy organization, provides a useful Secure Messaging Scorecard to help you find the best chat app for your needs.

Ditch Email—Unless It's End-to-End Encrypted
As noted in the last section, encryption is a key way to keep prying eyes away from your private communications. While there are a number of totally encrypted chat apps, it's much harder to find unbreakably encrypted email. In fact, some encrypted email providers have shut down due to government pressure.

One good option includes ProtonMail, but just make sure that you're emailing someone who also uses it. Like with chat, if a recipient isn't using encryption, all of your communications are at risk.

Sign Out of Social Networks
Social networks are increasingly used for communication and organizing travel and events. Government access to your social networks will reveal your network of friends, activities, movements, and plans. Make sure to always sign out of your social networking apps when you're done using them. You should also sign out at an OS level, by following these steps:

Tap Settings
Tap Twitter or Facebook
Sign out of, or delete, your account (this won't delete the social networking account, just the data on your phone).
Passcode and Device Access
Spying doesn't just happen over the Internet. It can also happen when police, immigration and customs agents, and other governmental entities get physical access to your iPhone. These tips can help make it harder for them to view your data.

Set a Complex Passcode
Everyone should use a passcode to secure their iPhone, and the more complex your passcode, the harder it is to break into. We saw this in the showdown between Apple and the FBI over the iPhone in the San Bernardino terrorism case. Because a complex passcode was used, the FBI had an extremely difficult time accessing the device. A four-digit passcode isn't enough. Make sure to use the most complex passcode you can remember, combining numbers, letters (lowercase and uppercase). For tips on creating secure passwords, check out this article from the EFF.

Set a complex passcode by following these instructions:

Tap Settings
Tap Touch ID & Passcode
Enter your passcode, if needed
Tap Change Passcode
Tap Passcode Options
Tap Custom Alphanumeric Code and enter a new passcode.
Set Your Phone to Delete Its Data
The iPhone includes a feature that automatically deletes its data if an incorrect passcode is entered 10 times. This is a great feature if you want to keep your data private but no longer have possession of your phone. Enable this setting by following these steps:

Tap Settings
Tap Touch ID & Passcode
Enter your passcode, if needed
Move Erase Data slider to on/green.
Turn Off Touch ID in Some Cases
We think of the fingerprint-based security offered by Apple's Touch ID fingerprint scanner as very powerful. Unless someone can forge your fingerprint, they're locked out of your phone. Recent reports from protests have said that police are bypassing this restriction by physically forcing people who have been arrested to put their fingers on the Touch ID sensor to unlock their phones. If you're in a situation where you think you could be arrested, it's smart to turn off Touch ID. That way you can't be forced to put your finger on the sensor and can rely on a complex passcode to protect your data.

Turn it off by following these steps:

Tap Settings
Tap Touch ID & Passcode
Enter your passcode
Move all of the sliders in the Use Touch ID For: section to off/white.
Set Autolock to 30 Seconds
The longer your iPhone is unlocked, the more chance there is for someone with physical access to it to view your data. Your best bet is to set your phone to autolock as quickly as possible. You'll have to unlock it more frequently in day-to-day use, but it also means that the window for unauthorized access is much smaller. To change this setting, follow these steps:

Tap Settings
Tap Display & Brightness
Tap Auto-Lock
Tap 30 Seconds.
Disable All Lock Screen Access
Apple makes it easy to access data and features from the iPhone's lockscreen. In most situations, this is great—a few swipes or button clicks get at the features you need, without unlocking your phone. If your phone isn't in your physical control, though, these features can give others access to your data and apps. While turning off these features makes your phone a bit less convenient to use, it protects you, too. Change your settings by following these steps:

Tap Settings
Tap Touch ID & Passcode
Enter your passcode, if needed
Move the following sliders to off/white:
Voice Dial
Today View
Notifications View
Reply with Message
Only Use Camera From The Lockscreen
If you're taking pictures at an event—a protest, for instance—your phone is unlocked. If someone is able to grab your phone while it's unlocked, they can access your data. Having a very short autolock setting can help with this, but it's not foolproof in this scenario. Not unlocking your phone at all is a better security measure. You can do this, and still take pictures, by launching the Camera app from your lockscreen. When you do this, you can only use the Camera app and view the pictures you've just taken. Try to do anything else, and you'll need the passcode.

To launch the Camera app from the lockscreen, swipe from right to left.

Set Up Find My iPhone
Find My iPhone is extremely useful for protecting your data if you don't have physical access to your iPhone. That's because you can use it to delete all data on the phone over the Internet. To do that, make sure you've set up Find My iPhone.

Then, read this article about how to use Find My iPhone to delete your data.

Privacy Settings
The Privacy controls built into the iOS let you restrict apps, advertisers, and other entities from accessing data stored in apps. In the case of defending against surveillance and spying, these settings offer a few useful protections.

Disable Frequent Locations
Your iPhone tries to learn your habits. For instance, it tries to figure out the GPS location of your home and your job so that it can tell you when you wake up in the morning how long your commute is going to take. Learning these Frequent Locations can be helpful, but that data also tells a lot about where you go, when, and what you may be doing. To keep your movements harder to track, disable Frequent Locations by following these steps:

Tap Settings
Tap Privacy
Tap Location Services
Scroll to the very bottom and tap System Services
Tap Frequent Locations
Clear any existing locations
Move the Frequent Locations slider to off/white.
Prevent Apps from Accessing Your Location
Third-party apps may try to access your location data, too. This can be helpful—if Yelp can't figure out your location, it can't tell you what restaurants nearby offer the food you want—but it can also make it easier to track your movements. Stop apps from accessing your location by following these steps:

Tap Settings
Tap Privacy
Tap Location Services
Either move the Location Services slider to off/white or tap each individual app that you want to restrict and then tap Never.
Here are a few other tips that can generally serve you well in protecting your privacy.

Sign Out of iCloud
A lot of important personal data is likely stored in your iCloud account. Make sure to sign out of that account if you think there's a chance that you'll lose physical control of your device. To do that:

Tap Settings
Tap iCloud
Tap Sign Out at the bottom of the screen.
Delete Your Data Before Crossing Borders
Recently, the U.S. Customs and Border Patrol has begun asking people coming into the country—even legal permanent residents—to provide access to their phones as a condition of entering the country. If you don't want the government rooting through your data on your way into the country, don't leave any data on your phone in the first place.

Instead, before you travel back up all the data on your phone to iCloud (a computer can work, too, but if that's crossing the border with you, too, it might also be inspected).

Once you're sure that all of your data is safe, restore your iPhone to its factory settings. This deletes all of your data, accounts, and other personal information. As a result, there's nothing to inspect on your phone.

When your phone is no longer at risk of being examined, you can restore your iCloud backup and all of your data onto your phone.

Update to Latest OS
Hacking the iPhone is often accomplished by taking advantage of security flaws in older versions of the iOS, the operating system that runs the iPhone. If you're always running the latest version of the iOS, those security flaws are likely to have been fixed. Anytime there's a new version of the iOS, you should update—assuming it doesn't conflict with any other security tools you use.

To learn how to update your iOS, check out:

How to Update the iPhone Operating System
Install iOS Updates Without Connecting to iTunes

More Tips to Protect Your Privacy at

  NORML Action Center

Submitter: [anonymous]
Category: Guides / Tutorials - Health / Medical
exhibition Date: 2018-05-06 07:26:59
Last Update: 2018-05-06 07:27:29
Views: 151
Score: 5.00 / 5.00 (Based on 1 votes.)
NORML's Action Center

Register to Vote
Federal Priorities:
AG Jeff Sessions: Tell Congress to Reject Jeff Session's Reversal of the Cole Memo
MJ Justice: The Marijuana Justice Act of 2017 Introduced
Caucus: Tell Your Congressional Representative: Join the Cannabis Caucus
Protect Our Progress: Bipartisan Leaders Reintroduce the Respect State Marijuana Laws Act
Deschedule Marijuana: The Ending Marijuana Prohibition Act of 2017
Tell Your State Lawmakers To Put Marijuana On Their 2018 Agenda
2018 Legislation Pending Gubernatorial Action
Georgia: Legislation to Expand Medical CBD Access
Hawaii: Medical Marijuana Reciprocity Effort
Kansas: Legislation to Legalize the Retail Sale of CBD
Maine: Legislation to Expand Medical Marijuana Access
Maryland: Industrial Hemp Expansion Legislation
Missouri: Legislation to Allow Industrial Hemp Research
New Hampshire: Legislation to Expand Patient Access
2018 State Legislation: Legalization
Timely! New Jersey: Deschedule Marijuana
Connecticut: Marijuana Legalization Effort
Delaware: Marijuana Legalization Effort
Illinois: Legislation to Put Legalization to a Public Vote
Illinois: Marijuana Legalization Effort
Minnesota: Marijuana Legalization Effort
New Jersey: Marijuana Depenalization Effort
New Jersey: Marijuana Legalization Effort
New York: Marijuana Legalization Effort
Vermont: Legislation to Tax and Regulate Marijuana
2018 State Legislation: Decriminalization
Alabama: Marijuana Decriminalization Effort
Pennsylvania: Marijuana Decriminalization Effort
2018 State Legislation: Medical
Timely! New Jersey: Tell Regulators to Put Patients First
California: Protect Medical Marijuana Patients from Employment Discrimination
Colorado: Legislation to Protect Medical Marijuana Patients from Employment Discrimination
Delaware: Legislation to Expand Medical Marijuana Program
Florida: Medical Marijuana Reciprocity Effort
Illinois: Permit Doctors to Recommend Cannabis in Place of Opioids
Louisiana: Legislation to Expand Medical Cannabis Program
New Jersey: Legislation to Expand Patient Access
New Jersey: Let Doctors Decide When to Recommend Medical Marijuana
New Jersey: Protect Medical Marijuana Patients from Employment Discrimination
New York: Legislation to Expand Veteran Access to Medical Marijuana
New York: Let Doctors Decide When to Recommend Medical Marijuana
New York: Permit Physicians to Recommend Cannabis in Place of Opioids
Rhode Island: Protect Medical Marijuana Patients from Employment Discrimination
South Carolina: Medical Marijuana Legislation
Tennessee: Legislation to Establish Medical Marijuana Access
Tennessee: Legislation to Regulate Medical Marijuana Extracts
Tennessee: Medical Marijuana Exemption Bill
District of Columbia: Legislation to Expand Medical Cannabis Access
2018 State Legislation: Other
Alaska: Legislation to Seal Past Marijuana Convictions
Alaska: Legislation to Expand Banking Options to Cannabis Businesses
Alaska: Seeking Sanctuary State Status for Marijuana Operators
California: Legislation to Automatically Expunge Past Marijuana Convictions
California: Legislation to Expand Banking Options for Marijuana Businesses
California: Legislation to make California a Marijuana Industry Sanctuary State
California: Legislation to Temporarily Lower Cannabis Taxes
California: Protect Cannabis Delivery Services
Delaware: Legislation to Expunge Past Cannabis Possession Convictions
Illinois: Legislation to Expunge Past Cannabis Law Violations
Iowa: Legislation to Expand Medical CBD Program
Massachusetts: Bill Seeking Sanctuary State Status for Marijuana Operators
New Hampshire: Legislation to Allow Expungement of Certain Marijuana Convictions
New Jersey: Legislation to Allow Expungement of Marijuana Convictions
New Jersey: Legislation to Protect Cannabis Consumers from Employment Discrimination
Oklahoma: Establish the Oklahoma Cannabis Commission
Pennsylvania: Resolution Urging Congress to Deschedule Marijuana
Vermont: Legislation to Expunge Past Marijuana Convictions
Washington: Legislation to Expand Banking Options for Marijuana Businesses
2018 State Legislation: Hemp
Illinois: Industrial Hemp Expansion Legislation
Iowa: Industrial Hemp Research Legislation
2018 State Legislation NORML Opposes
Missouri: Oppose Unscientific Zero Tolerance DUI Drug Legislation
New Hampshire: Oppose Additional Possession Penalties
Oklahoma: Legislative Effort to Preemptively Amend Pending Medical Marijuana Legislation
Additional Federal Efforts:
Medical: Legislation to Protect Lawful Medical Marijuana Use From Housing Discrimination
Veterans: Legislation to Explicitly Authorize the Veterans Administration to Facilitate Medical Marijuana Research
Medical: Acknowledge the Role of Cannabis in Combating the Prescription Drug Overdose Epidemic
Judicial: Protect Legal Marijuana from Federal Interference
Legalization: The Marijuana Revenue and Regulation Act Introduced (Senate and House Bill)
Veterans: House Bill Introduced to Expand Veterans’ Access to Medical Marijuana
Medical: Legislation To Protect Medical Marijuana Patients Pending In Senate (CARERS Act)
Medical: Bill Seeks to Reschedule Marijuana Under the CSA
Medical: Remove Federal Restrictions on CBD
Judicial: Demand That The New US Attorney’s Respect State Marijuana Laws
Judicial: End Arbitrary License Suspensions For Minor Marijuana Possession (The Better Drive Act)
Economic: Legislation Pending To Halt Federal Forfeiture Actions Against Marijuana Facilities
Economic: Legislation Pending To Cease Penalizing State-Compliant Marijuana Businesses Under the Federal Tax Code
Economic: Support The Secure and Fair Enforcement Banking Act (SAFE Banking Act)
Economic: Support the State Marijuana And Regulatory Tolerance (SMART) Enforcement Act
Economic: Support the Sensible Enforcement Of Cannabis Act
Economic: House and Senate Measures Seek to Protect Marijuana Businesses and Consumers
Economic: The Stop Civil Asset Forfeiture Funding for Marijuana Suppression Act
Hemp: Exclude Hemp From the Controlled Substances Act
Research: Legislation Introduced to Facilitate Federally-Approved Cannabis Research
Science: Legislation To Facilitate Medical Marijuana Research
Advocacy: Tell AAA To Stop Lying About Legalization
Advocacy: Tell President Trump to Abolish the Office of the Drug Czar
Advocacy: Tell the ONDCP Opioid Commission: Medical Marijuana as an Alternative
2018 State Enacted Legislation
Alaska: Industrial Hemp Pilot Program Legislation
Indiana: Legislation to Expand CBD Access
Kansas: Industrial Hemp Pilot Program Legislation
Maine: Legislation Implements Retail Adult Use Sales, Amends Home Grow Limits
Massachusetts: Marijuana Expungement Bill Provision Signed Into Law
Oklahoma: Industrial Hemp Pilot Program Legislation
Utah: Legislation to Allow Medical Marijuana Research
Vermont: Marijuana Depenalization Effort
Virginia: Expand State's Medical CBD Law

  How To Grow Medicinal-Grade Cannabis Like the Pros

Submitter: [anonymous]
Category: Guides / Tutorials - Home / Gardening
exhibition Date: 2018-03-31 15:48:39
Views: 126
Score: 5.00 / 5.00 (Based on 1 votes.)
How To Grow Medicinal-Grade Cannabis – Like the Pros!
By Seshata
on March 13, 2018

  Practice Coin - Cryptocurrency Creation Guide Site

Submitter: [anonymous]
Category: Guides / Tutorials - Programming
exhibition Date: 2018-03-05 00:13:26
Last Update: 2018-03-07 03:48:27
Views: 178
Score: 5.00 / 5.00 (Based on 2 votes.)
This site is dedicated to a project we call Practice Coin, a new cryptocoin. Its aim is to cut through FUD of Altcoin creation process. Specifically, to go through all the steps of doing and launching and running a coin, from scratch, and documenting it all, in detail. Read more about Practice Coin.

  Cloning Litecoin - How to Create Your Own Crypto

Submitter: Limitless
Category: Guides / Tutorials - Business / Finance
exhibition Date: 2018-03-05 00:05:06
Last Update: 2018-03-05 00:05:41
Views: 214
Score: 5.00 / 5.00 (Based on 2 votes.)
Cloning Litecoin Table of Contents

Pre Installers.
1a. Winrar
1b. Compression
1c. MinGW
Windows Deps.
2a. OpenSSL
2b.Berkeley DB
2c. Boost
2d. MiniUPNP
2e. Protoc and Libprotobuf
2f. Libpng
2g. qrencode
Download and Compile QT.
The Clone
4a. Source Code
4b. Copy and Replace Litecoin
4c. Copy and Replace LTC
4d. Change rpc and port numbers.
4e. Change starting letter for addresses.
4f. Update client version number.
4g. Change Litecoin example addresses to Clonecoin Addresses.
4h. Change char pchMessageStart and ParseHex.
4i. Change alert keys.
4j. Remove Merkel root and Genesis Block.
4k. Remove Nonce and testnet genesis.
4l. Add Epoochtime and Timestamp.
4m. Fixing the checkpoints.
4n. Change max money supply and coinbase maturity.
4o. Change block times from 2.5 minutes to 30 seconds.
4p. Change re-targeting
4q. Add premine and change block rewards.
4r. Update Images.
4s. Update Seed node/ AWS Seed node guide.
Hashing the Genesis Block and Merkel Root.
5a. Ability to hash Genesis Block.
5b. Compiling Clonecoin Windows QT.
5c. Generating Merkel Root
5d. Hashing the Genesis Block.
Connecting your nodes.
6a. Create a conf.
6b. Connect- server and home network.
Checkpointing the premine.
Clean up Your Code.
Compiling Clonecoind.
9a. Compile Clonecoind.
9b. Remove and cleanup.
Github for release, made easy.
10a. Easy Pushing Commits/Launch code.
10b. Easy Revert Commits
10c. Easy Pushing Updates.
Common Errors
Quick Logos
The Website.
13a. The Template.
13b. Upload to a website.
The Launch. Ninja vs Pumped vs ICO.
14a. Prelaunch
14b. The Ninja
14c. The Pumped.
14d. The ICO.

  Ad Campaign Feature Described on Steemit

Submitter: Limitless
Category: Guides / Tutorials - Web Design / Development
exhibition Date: 2018-03-03 18:43:20
Last Update: 2018-03-03 19:23:08
Views: 130
Score: 5.00 / 5.00 (Based on 3 votes.)
I made an article describing how the Ad Network feature works on Steemit

  Ripple Coinbase listing Rumor

Submitter: [anonymous]
Category: Guides / Tutorials - Business / Finance
exhibition Date: 2018-02-17 23:51:49
Last Update: 2018-03-01 23:07:07
Views: 122
Score: (not yet rated)

  Earning Free Interest on Your XLM (Lumens)

Submitter: Limitless
Category: Guides / Tutorials - Business / Finance
exhibition Date: 2018-02-13 04:38:32
Last Update: 2018-02-13 07:01:54
Views: 150
Score: 5.00 / 5.00 (Based on 1 votes.)
What is inflation
The Stellar network has a build-in inflation mechanism which distributes new lumens at a rate of 1% per year. The new coins are added to the network weekly, so each week around 0.0191% of the total current amount of XLM is distributed on the network.
Who gets inflation

The inflation lumens are distributed using a voting mechanism. Any account that gets over 0.05% of the votes, gets a share of the new lumens. The number of votes you have is equal to your balance. So if you have 500XLM you have 500 votes. You can vote for any account you like, but remember, only accounts with more than 0.05% of the votes get their share. That means that an account needs at least 51.8 million votes to get inflation lumens.
Why use a pool

You cannot get a share of the inflation lumens if you posses less than 51.8 million XLM. But we can work together in a pool. If you vote for MoonPool or Lumenauts, they will get a part of the inflation lumens, and pay you back based on your number of votes. The payout is done automatically as soon as we got our share of the inflation lumens, and also your votes are recorded automatically.

How to vote
Voting is done by setting a certain option in your account, called the inflation destination. The value is the account ID you vote for. This account information is public on the network, and they periodically record all account IDs that vote for their pool, together with their balance. The balance is used to calculate the amount of lumens you get when an inflation operation is run on the network, and this amount will be paid to the corresponding account ID.

To join the Lumenaut Community Pool, vote for their inflation destination address:


You cannot earn inflation on an exchange (and you should not use exchanges as wallets). Use a Ledger Nano S or create a paper wallet to store your lumens first.

If you have 1,000 Lumens, weekly payout should be about 1,000*0.0019; with comes out to 1.91 lumens.
If you have 2,000 as your balance for the week, you should earn about 3.82 in a week just from setting an inflation address in your wallet.
A balance of 10,000 would earn you 19.1 lumens per week and increasing as the balance gets bigger.

  Marijuana Risks vs Benefits for Seizure Treatment

Submitter: Limitless
Category: Guides / Tutorials - Health / Medical
exhibition Date: 2018-02-11 03:22:56
Last Update: 2018-03-10 02:07:22
Views: 183
Score: 5.00 / 5.00 (Based on 3 votes.)
Cannabinoids are inherently neuroprotective substances—in fact, our brain produces its own cannabinoids when injured to reduce damage and promote healing. Cannabinoids have a superior safety profile compared to most anti-epileptic drugs, many of which have been shown to impair brain function and development.

  Cryptocurrency Market Capitalizations

Submitter: [anonymous]
Category: Guides / Tutorials - Business / Finance
exhibition Date: 2018-01-23 04:38:22
Last Update: 2018-01-23 04:48:49
Views: 145
Score: (not yet rated)
View Cryptocurrency Ranking Data, Charts and other important information for potential investors.

  Gordon Dentistry

Submitter: Limitless
Category: Guides / Tutorials - Health / Medical
exhibition Date: 2017-03-20 08:31:22
Last Update: 2017-03-20 08:33:54
Views: 308
Score: (not yet rated)
5 stars Dennis P Customer since 2013

Very professional doctor and staff. Pleasant, warm and carrying professionals! My family are warmly received and cared for.

10 days ago
5 stars Roger G Customer since 2010

Great experience. Very thorough and considerate.

13 days ago
5 stars Linda J Verified customer

Painless, kind, wonderful care!

18 days ago
5 stars Anonymous Verified customer

Dr. Gordon & staff are always professional and polite. Dr. Gordon truly cares for her patients.

19 days ago
5 stars Sarah B Customer since 2016

I have never felt more cared for in any dentistry setting than I have with Dr. Gordon and her team, Her knowledge and compassion for the patient blended with her dental skills took away any fears of dental work.

25 days ago
5 stars Anonymous Verified customer

Great service and teamwork!

a month ago
5 stars Beverly O Verified customer

First visit. Nice people. Clean, nicely decorated office. Dr. Gordon was professional. Good experience.

a month ago
5 stars Robert L Customer since 2012

Very nice

a month ago

Submitter: Nicholai
Category: Guides / Tutorials - Arts / Crafts
exhibition Date: 2017-01-24 19:27:53
Views: 363
Score: 5.00 / 5.00 (Based on 1 votes.)
Holiday Help For your Hardwood Floors

  PPARδ agonist GW501516 for enhancing running

Submitter: [anonymous]
Category: Guides / Tutorials - Health / Medical
exhibition Date: 2017-01-24 01:00:29
Views: 424
Score: 5.00 / 5.00 (Based on 1 votes.)
A metabolomic study of the PPARδ agonist GW501516 for enhancing running endurance in Kunming mice
Wei Chen, Rong Gao[…]Lili Wang
Scientific Reports 5, Article number: 9884 (2015)

Published online:
06 May 2015


This study demonstrated that GW501516 increases exhaustive running performance and the proportion of SDH-positive muscle fibres in both trained and untrained mice. Slow-twitch myofibres are rich in mitochondria and have a high oxidative capacity. Formation of slow-twitch muscle fibres revolves around PGC-1α and its transcripts17,18. Like exercise, GW501516 alone is sufficient to improve running endurance of untrained mice, even after only 1 week of administration (Supplementary Fig. S1 online). Enhanced running endurance is the results of increased fatty acid utilization after PPARδ activation that upregulates PDK4 and other key components of fatty acid oxidation pathways. Accordingly, blood glucose levels of GW501516-treated mice were significantly higher after exercise while blood lactate was lower compared to untrained controls. Although GW501516 or exercise each enhanced fatty acid oxidation in skeletal muscle, GW501516 predominately induces fatty acid metabolism, while training also induced protein metabolism as an energy source.

Studies have demonstrated that GW501516 significantly increased the running performance of trained C57Bl/6J mice5, but not in untrained mice that were treated with 5 mg/kg over periods lasting 4 weeks to 5 months, or 3–30 mg/kg/day gavaged for 2 months5. Our study found that GW501516 increased running performance in KM mice regardless of training and the magnitude of improvement was unexpectedly greater for untrained mice. This finding could be due to different GW501516 administration protocols, exhaustive running protocols, or strain differences. In this study, running performance was determined by wheel running rather than treadmill running because it is more natural for mice, which are specialized climbers, and better measures their natural running abilities. Additionally, studies have shown significant differences in aerobic capacity, treadmill performance, and exercise training responses between different inbred and hybrid rodent strains19,20. The running distance of untreated trained mice (TN) was relatively higher than that of GW501516-treated untrained mice (NG). The effects of wheel training and the skills acquired during the training period cannot be ignored, but are difficult to control for.

PPARδ is the principle isoform involved in regulating muscle fuel utilization. Previous studies demonstrated that changes in expression of genes regulated by PPARδ occurred after 3 days of GW501516 treatment5. We also found that expression of PGC1α, PDK4, and selective biomarkers for fatty acid β oxidation in skeletal muscle were significantly increased by GW501516 treatment. Both palmitic acid and the earlier intermediate in the fatty acid oxidation pathway, 3-hydroxy-hexadecanoic acid, were elevated compared to untrained control mice. However, why the downstream products of fatty acid oxidation were not found to be increased in the GW501516-treated group warrants further investigation. Additionally, GW17046 (another PPARδ agonist) treatment in ob/ob mice markedly reduced levels of saturated long chain fatty acids (15–24 carbon atoms) in untrained GW501516-treated (NG) mice compared to untreated untrained (NN) mice21. This result suggests that unlike exercise, GW501516 is limited to promoting hydrolysis of triglycerides and that the increased serum palmitic acid observed in GW501516-treated (NG) mice may be due to the catabolism of saturated fatty acids. In contrast, the decrease in serum saturated fatty acids was completely reversed when GW501516 treatment was combined with training. Presumably, this is because of enhanced fat metabolism. GW501516 also increased blood glucose and lowered blood lactate compared to control mice, particularly after running tests and in trained mice. This suggests that glycolysis in muscle tissue is reduced after treatment with GW501516, and becomes more apparent immediately after the exhaustive running (Fig. 1 and Supplementary Fig. S1 online). Consistent with this reduced glucose metabolism, increased serum galactose was also only observed after GW501516 treatment. Although glycolytic metabolism of galactose yields no net adenosine triphosphate (ATP), previous research demonstrated that galactose induces a metabolic shift towards a more oxidative phenotype and enhances aerobic mitochondrial metabolism in myotubes22.

PPARδ is intricately involved in enhanced running endurance. It mediates oxidative adaption following exercise training and increased expression in skeletal muscle was reported after both acute exercise and endurance training12,23,24. Similar to chemical activation of PPARδ, endurance training increases fatty acid metabolism in skeletal muscle and reduced lactate production during exercise25. Accordingly, the running distance of untreated trained (TN) mice is over 100% greater of that of untreated untrained (NN), blood glucose levels in the TN group are significantly higher and blood lactate levels are significantly lower than those measured in the NN group. Enhanced fatty acid oxidation in skeletal muscle was also observed by measuring elevated components of the fatty acid oxidation pathway including palmitic acid and octanoic acid. Caproic acid and butyric acid were not significantly different between groups in our assay, but the sensitivity to detect these metabolites may be insufficient. The underlying mechanism for PPARδ and PPARα activation to increase fatty acid oxidation in skeletal muscle is by upregulating components of the electron transport chain (CYT-C and UCP3) and CPT1b in the mitochondria. Serum inositol is also increased by training and may help increase endurance in trained mice. Inositol can help transport fat from the liver and improve the distribution of fat throughout the body, allowing it to be used more efficiently as an energy source. Our results further corroborate that exercise training promotes fat mobilization and fatty acid oxidation as energy substrates during running. Furthermore, this is likely mediated through exercised-induced PPARδ expression in a way that is similar to what was reported previously in human skeletal muscle following exercise training12.

One of the most striking differences between drug treatment and exercise was the increase of serum PUFA and hydroxybutyrate. Compared to training, GW501516 increased levels of UFA, especially PUFA, and they were further increased by the combination of GW501516 and training. This is in agreement with previous studies that showed increases of enzymes that produce UFA after treatment with a PPARδ agonist5,21. Our study demonstrated GW501516 increased levels of 3 PUFA (α-linolenic acid, arachidonic acid, and its precursor 8,  11,  14-Eicosatrienoic acid) regardless of exercise training. Previous studies have demonstrated that all long-chain fatty acids and their derivatives are putative PPAR ligands2,26,27. Endogenous fatty acids that have been shown to activate PPAR include PUFAs such as some ω-3 PUFA (e.g. α-linolenic acid and docosahexaenoic acid), some ω-6 PUFA (e.g. linoleic acid and arachidonic acid), and some saturated fatty acids (e.g. stearic acid)2,3,26,27. UFA and PUFA in particular, could act as activators of PPARδ after being increased by GW501516. Additionally they are sensed by the liver which then mobilizes fatty acids and stimulates hepatic fatty acid oxidation28. We observed hydroxybutyrate, the major constituent of ketone bodies, was significantly increased by GW501516, but not exercise. Leucine, a ketogenic amino acid, was also increased by GW501516 only. However, exercise did increase other BCAA. Increased hepatic synthesis of ketone bodies would be expected during increased release of fatty acids from fat stores and further suggests that GW501516 promotes hepatic fatty acid oxidation that can provide muscle with an alternative energy source during exercise. Ketone bodies are an important energy substrate under stress and hydroxybutyrate can freely enter muscle mitochondria and be metabolized to acetyl CoA.

The impacts of training or GW501516 treatment on essential amino acids were slightly different. The glycogenic amino acids that can be metabolized to form pyruvate (alanine, serine and threonine) were only significantly increased after training alone. This suggests more energy is utilized from pyruvate after training. Elevations in these amino acids were reversed by GW501516 treatment suggesting that GW501516 inhibits gluconeogenesis or the conversion of glycogenic amino acids into pyruvate that was induced by training. This indirectly suggests that GW501516-treated mice specifically rely on fatty acids as energy. Three BCAA (valine, leucine, and isoleucine) were increased by both GW501516 and training. Long-distance running involves mobilization of BCAA29 and many studies demonstrate that BCAA concentrations immediately after exercise are reduced in the serum, but not in muscle30. We found that training or GW501516 treatment, preserved serum BCAA levels after exhaustive running. As essential amino acids, BCAA are primarily metabolized in muscle and are important for protein synthesis, neurotransmitter synthesis, and repair of exercise-induced skeletal muscle damage31,32. Increased BCAA may both act as an energy source (Supplementary Fig. S3 online) and protect mitochondria from exercise-induced damage to preserve mitochondrial function. In addition, increased serum BCAA may reduce tryptophan uptake in the brain and delay fatigue by competitively inhibiting 5-hydroxytryptamine (5-HT) synthesis31,32.

Metabolomic analyses are relatively new technology. It is limited by the complexity of techniques, high inter- and intra- subject variability, incomplete metabolite databases, and incomplete understanding of metabolic pathways. Although there are a total of 122 peaks measured in serum samples, only 43 peaks could be matched to known metabolites.

In conclusion,this study demonstrated that 3-week treatment with GW501516 increased running performance of both trained and untrained mice. Like training, GW501516 promoted mitochondrial fatty acid oxidation and increased fat metabolism in muscle tissue (Summarized in Supplementary Fig. S4 online). However, exercise increased energy supply by promoting catabolism of protein, glycolysis and glucogenesis from amino acids, while GW501516 increased fatty acid oxidation through BCAA and ketone body pathways.


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