Berberine glow 15

Berberine glow 15 DEFAULT

Good State Glyco-X 500 with Berberine HCL (500mg per capsule - 6

But first, sex education

From the very beginning, we started by surveying women from all around the world. On an ongoing basis, we keep gathering insights and feedbacks on vulva owners' fantasies, desires, pleasure preferences and questions about sex. We use this information not only for our design process to create products that vulva owners love but also to develop educational content about vulva sexuality that is reliable and relevant.
This is how we have built a sex education program focused on vulva pleasure. We have found consistently in studies we have conducted that having access to pleasure positive sex education plays a key role n our sexual satisfaction. Answering questions from our community with expert insights from sexual health professionals, the program is available for free.


Creating products for female pleasure

To create our vibrators and intimate lubricants, we use insights from thousands of vulva owners, and we update as we go with our customer's feedbacks.
We also partner with doctors and sexologists to design products that are the most anatomically relevant. For our clitoral and vaginal vibrators, this translates into every measurement and every angle. For our sex lubricants, this guides the choice of ingredients. From safety to pleasure, all we do is intended to respect the female body!


Vibrators for first-timers, and beyond!

To create our collection of first-time vibrators, we started by surveying the market to understand what was the shopping experience and where did vulva owners want to find their pleasure toys. Turned out, the majority wanted to find them in their favourite beauty or fashion retailers, out in the open. Many also found the offering limited and could not find something that felt empowering and pampering.
To create a collection that would remove roadblocks for vi-curious vulva-owners (vi-curious: curious to try vibrators), we did 2 things. The first one is that we discussed with people with vulvas all over the world to explore the most popular female fantasies and we based our naming conventions on this. The purpose was to use humour to break the ice while validating the idea that vulva-owners have fantasies. The second is that we worked hand-in-hand with gynecologists and sexologists to design the best vibrators.
Made of the softest silicone we import from Japan, their touch is irresistibly smooth. Phtalate-free, our vibrators for women are completely safe for your body. We work with a high-end manufacturer to make sure we provide you with the best quality products. Thanks to their expertise, our personal massagers are the most discreet sex toys for women you can find, below 40 dB. And their sophisticated looks have won design competition against the most prestigious brands, proving that sexual wellness products belong with other consumer goods products, and should no longer be framed like a taboo.
As we were seeing more and more users entering the category with our friendly toys, we expanded our collection to premium vibrators for more experienced users.
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The best lubricant for sex

There are a lot of myths around vaginal lubrication. Sexual arousal is not the only factor at play: stress, hydration, hormones also have an impact on natural lubrication. But what is certain is that the lack of vaginal lubrication has a negative impact on how your sensual moments will feel.
Personal lubricants are mostly used to solve a problem of lubrication, but it doesn’t mean they should look like a medication! After all, you use them in glamourous moments and they should live up to that! They should also treat your intimate skin with the greatest care possible. And that is not the case of most lubes.
This is why, at Smile Makers, we have formulated the best water-based lubricant , using the purest ingredients. We have selected ingredients that are used in luxury skincare products to soothe and help your intimate skin regenerate. Following gynecologists’ recommendation, our lubricant is only water-based since these are the safest for the vagina. And we have worked with prestigious designers to create a packaging worthy of the romantic setting of your love moments. When tested against our competitors, 8 out of 10 vulva owners prefer Smile Makers’: this is why we can say with pride we are bringing you the best lubricant for women.

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Description

Berberine's superpower is its ability to produce biological effects similar to those of exercise. Grown throughout Asia, berberine has been used for centuries as an alternative medicine. In studies, berberine has been shown to benefit diabetes, metabolic syndrome, gut health, and a positive effect on fat

Features

  • Helps kick start autophagy
  • Helps improve metabolism through activating a key enzyme (AMPK)
  • Helps improve blood sugar levels within the body
  • Can assist in weight-loss: A 12-week study individuals taking 500mg of berberine experience 3.6% of body fat

It's unlikely to find significant changes in price, we expect this product to remain within its Average price. Our advice is Buy now.

Buy on Amazon

Product details

EAN

857826008044

UPC

857826008044

ASIN

B07K79L757

FAQs

Glow15 Berberine A Helpful Digestive And Blood Sug, is it available on Amazon?

Yes! But at Pricepulse we inform you when is the lowest price to buy the Glow15 Berberine A Helpful Digestive And Blood Sug

Should I buy the Glow15 Berberine A Helpful Digestive And Blood Sug now?

It's unlikely to find significant changes in price, we expect this product to remain within its Average price. Our advice is Buy now.

What is the current price of Glow15 Berberine A Helpful Digestive And Blood Sug?

Its current price is $29.99

What was the lowest price for the Glow15 Berberine A Helpful Digestive And Blood Sug?

The lowest historical price was $28.49

Sours: https://www.pricepulse.app/glow15-berberine-a-helpful-digestive-and-blood-sug_us_9084465
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Drop a dress size and look years younger in 15 days

We're all the same. Every year, summer swings round and we desperately diet in a bid to lose those pounds that pile on over winter.

But what if I told you there was a new, revolutionary, scientifically proven plan that could help you to not only drop a dress size, improve your health and strength and supercharge your energy levels, but also make you look younger, reducing your wrinkles by up to 30 per cent — and all in just 15 days?

I know it sounds too good to be true, but this is an easy-to-follow lifestyle plan based on Nobel Prize-winning science, developed with world-leading researchers and scientists who have studied the missing link in anti-ageing. And it’s been tested on real women, who were so impressed with the results and how easy it was to incorporate into their lives that they stuck with it long after the trial finished.

My 15-day plan combines clever nutrition, exercise and sleep aides that can slow down — and even reverse — the ageing process, opening the pathway to a happier, healthier, slimmer and, more youthful version of you.

Wellness pioneer: Naomi Whittel (pictured) has crafted a revolutionary 15 days plan for improving health whilst dropping a dress size 

Wellness pioneer: Naomi Whittel (pictured) has crafted a revolutionary 15 days plan for improving health whilst dropping a dress size 

So, what’s the secret? The answer lies in one of the body’s natural processes, something called autophagy (pronounced aw-toff-uh-gee). It’s the cleansing process that removes the toxins from our cells and repairs the damage caused by natural wear and tear and environmental aggressors.

And why is this important? Quite simply, because there is a large body of research that suggests a lot of the ageing process — from wrinkles to weight gain — is actually down to an accumulation of damage in our cells, which results in them working less effectively.

Autophagy literally means ‘self-eating’, because your cells eat away their own rubbish. But, like everything else in the body, this process becomes less efficient with age. So, not only are your cells accumulating more junk, they can’t keep up with the clear-up.

And that’s something else worth bearing in mind — cells can’t always be in clear-up mode, they also have to do their main job, the one they are made to do. It’s like someone constantly bringing you plates to wash up and then wondering why you’re not cooking a meal.

My revolutionary plan stops autophagy sitting in maintenance mode, where it doesn’t really do anything useful, and shows you how to turn it on and off, boosting your cellular clean-up crew’s productivity so you look and feel younger.

Because, while a certain amount of the ageing process is inevitable, you can control up to 70 per cent of related symptoms and problems by controlling external factors — diet, pollution, UV exposure, lack of sleep, a sedentary lifestyle — and by optimising autophagy.

Research has shown that autophagy is turned on when the body is in stress-response mode. The easiest way to achieve this is through high-intensity exercise, potent antioxidant supplements and a way of eating that combines intermittent fasting with protein cycling, where you alternate between low protein consumption and normal to high protein consumption. Let me explain . . .

Naomi (pictured) revealed intermittent fasting is a key practice for giving cells a chance to repair and clean toxins

Naomi (pictured) revealed intermittent fasting is a key practice for giving cells a chance to repair and clean toxins

HERE’S WHAT TO EAT — AND WHEN

Intermittent fasting is the practice of shifting between unrestricted and restricted eating and is a key activator of autophagy.

If you’re constantly eating — which is the case for many of us as we graze throughout the day — it doesn’t give your cells a chance to repair and clean up the waste and toxins they have accumulated. Short periods of not eating give them the time to take care of those tasks.

In practical terms, on three non-consecutive days (your Low Days), you will fast for 16 hours and eat only during an eight-hour period.

But you can begin your intermittent fast after dinner the night before, so the majority of your fasting happens while you’re asleep.

For example, if you stop eating at 8pm one evening, your first meal will be at noon the next day. So, essentially, you’ll just skip breakfast.

As long as your fast lasts 16 hours, you can adapt it to suit your schedule. If you prefer to eat breakfast, you can start your intermittent fast earlier, by skipping dinner the night before.

Make the hours work for you, your body and your lifestyle.

Research shows 16 hours is optimal for creating the caloric restriction that happens during intermittent fasting, allowing your body to activate autophagy through different nutrient pathways.

However, to really supercharge the efficacy of intermittent fasting, I suggest supplementing it with protein cycling.

The idea is that you limit your protein intake to around 25g on the same three days you practice fasting (your Low Days), while on the other four days (your High Days), you eat normal to high amounts of protein (45g to 150g).

To give you some context, there’s around 6g protein in an egg, 34g in a skinless chicken breast, 14g in a portion of cottage cheese and around 2g in a tablespoon of cooked lentils.

Protein cycling is a particularly effective anti-ager because your body can’t create its own protein. Instead, it is forced to find every possible way to recycle the existing amounts you’ve already provided. If you deprive your body of protein, it will enhance autophagy, kicking your body’s recycling programme into overdrive.

Naomi claims protein cycling is essential for anti-ageing as your body can't create it's own protein (file image) 

Naomi claims protein cycling is essential for anti-ageing as your body can't create it's own protein (file image) 

The problem is, we don’t normally deprive ourselves of protein. The 70g we average daily is around one-and-a-half times the amount recommended for women and it’s enough to keep autophagy in maintenance mode.

But our bodies can handle periods without protein — after all, our hunter-gatherer ancestors often had to survive when deprived of it after unsuccessful hunts.

To be clear, low is not always the way to go. Being in a constant state of low protein will actually contribute to ageing in the form of muscle wasting, increasing weakness and immune deficiencies. So you need to have both high and low protein days — that’s the cycling part — to force your body to regulate autophagy.

There is also evidence protein cycling can help to reduce the risk of developing diseases including diabetes, cancer and heart disease.

Most of the women who tried this plan found it worked best to make their Low Days Monday, Wednesday and Friday, so they had fewer restrictions over the weekend.

But you should choose the days that best work for you.

FAT AND CARBS DON’T HAVE TO BE DIET DEMONS

As you might have guessed, some foods are better than others when it comes to boosting autophagy.

The good news is that we don’t demonise any one food group, but we might suggest there are better times to eat one over another and I would always advocate choosing high-quality, pure foods over more processed varieties.

Take fats, for example. Fat is essential for optimal health and can promote autophagy — but we’re talking about natural, unprocessed fats that are found in foods such as avocados, butter, nuts, salmon, mackerel, sardines, coconut oil and olive oil.

On this plan, you should incorporate these types of fats into every meal and, crucially, you want to start every day — High Days and Low Days — with fat.

The easiest way to do this is with my AutophaTea. This kick-starts your metabolism and keeps you satiated throughout the day — as fat carries flavour, the more fat you eat, the less sugar and salt your taste receptors require to register satisfaction.

Naomi recommends incorporating fats into every meal to lower your need for sugar and salt. Her AutophaTea combines coconut oil, green tea, Earl Grey and cinnamon (file image)

Naomi recommends incorporating fats into every meal to lower your need for sugar and salt. Her AutophaTea combines coconut oil, green tea, Earl Grey and cinnamon (file image)

Unlike many eating plans, this one doesn’t see carbs as the enemy — they provide energy and help you to relax — but in order to make them work hardest, choose them carefully.

Look for high-fibre carbs, such as vegetables, fruit, legumes (including lentils, pulses and grains) and wholewheat bread and pasta.

Again, it’s a question of timing: save them for later in the day because ketosis — a natural metabolic state in which your body uses fat as fuel in the absence of carbohydrates — is one of the best ways to boost autophagy.

But your body does not need to be in a constant state of ketosis for this to happen. When you wake up, your body is already high in ketones, so skipping carbs for at least the first half of the day prolongs this, maximising the benefit.

And being pro-carb is not the only surprising thing about this plan. While I advocate a wide range of fruit, veg, herbs, spices, nuts and seeds, I also give you the go-ahead to indulge in red wine and dark chocolate, as both are rich in antioxidants, which help start autophagy.

Naomi believes less is more when it to comes to exercise and two days of the plan should be spent doing High Intensity Interval Training (file image) 

Naomi believes less is more when it to comes to exercise and two days of the plan should be spent doing High Intensity Interval Training (file image) 

HIT THE GYM FOR ONLY 30 MINUTES

Exercise is important, as it puts your body under stress and powers up autophagy. But the best part of the workouts on my plan is that they’re based on the idea that less is more — you don’t need hours and hours to get results, just half-an-hour four times a week, on your High Days.

Your exercise sessions should be split. Two days should be spent doing High-Intensity Interval Training (HIIT) and the other two doing Resistance Exercise Training (RET).

HIIT involves alternating moderate-intensity exercise (say, three or four out of ten on a scale of how hard you’re working) with high-intensity exercise (six to eight) every minute for half-an-hour — this works whether you’re walking, running, swimming, rowing or doing anything that gets you out of breath during those high-intensity minutes.

RET is about strength training — that can mean lifting weights or doing push-ups, lunges, squats or a yoga session. Research has shown that regular resistance training activates autophagy and helps prevent the loss of muscle mass, while improving muscle strength.

THE NEW POWER SUPPLEMENTS

While eating the right things at the right time is a good start, I’m a big fan of supplementing my diet with what I call ‘powerphenols’, to ensure I’m getting all the nutrients I need.

These are polyphenols (or antioxidant-rich micronutrients) that protect cells and promote autophagy, but also optimise metabolism, increase beneficial bacteria in your gut and improve overall health and appearance.

You may have heard of some of them, such as resveratrol (in red wine) and curcumin (in turmeric), but you’d have to drink a lot of wine and eat a lot of curry to get the levels that a supplement can provide.

Also on my list are berberine, derived from an Asian plant and thought to help burn fat, and EGCG, found in green tea, which increases metabolism and reduces anxiety.

Make sure you’re getting good-quality supplements by buying them from a reputable source and checking for the Traditional Herbal Registration certification mark.

Always check with your doctor before taking them if you are pregnant or on prescription medication.

My power quartet:

Resveratrol: Up to 1,000mg a day.

Organic curcumin: 500mg twice a day.

Berberine: 500mg, three times a day with food.

EGCG: Up to 200mg, three times a day with food.

Adapted by CLAIRE COLEMAN from Glow 15: A Science-based Plan To Lose Weight, Rejuvenate Your Skin And Invigorate Your Life, by Naomi Whittel (Aster, £9.99) out May 3, 2018. © Naomi Whittel 2018. To order a copy for £7.49 (offer valid to May 6, 2018), visit mailshop.co.uk/books or call 0844 571 0640. P&P is free on orders over £15.

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The Amazing Benefits of Berberine

Dr. Whitaker's Berberine 1,500 mg Supplement (270 Capsules)

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Glow 15 berberine

Toxicological Effects of Berberine and Sanguinarine

Introduction

Alkaloids are a group of naturally occurring chemical compounds that mostly contain basic nitrogen atoms (Figure 1). Sometimes alkaloids also include some related chemical compounds with weakly acidic and neutral properties. A large variety of organisms produces (bacteria, fungi, plants, and animals) alkaloids that can be purified by acid-base extraction from crude extracts of these organisms. A number of pharmacological activities such as antimalarial (e.g., quinine), antiasthma (e.g., ephedrine), anticancer (e.g., homoharringtonine), cholinomimetic (e.g., galantamine), vasodilatory (e.g., vincamine), antiarrhythmic (e.g., quinidine), analgesic (e.g., morphine), antibacterial (e.g., chelerythrine), and antihyperglycemic activities (vincristine and vinblastine) of alkaloids has been reported. Berberine and sanguinarine both are isoquinoline derivatives and belong to protoberberines and benzophenanthridienes, respectively. Some chelerythrine isolated from Argemone mexicana alkaloids such as N-demethyloxysanguinarine, pancorine, (+)-argenaxine, (+)-higenamine, (+)-reticuline, angoline, and chelerythrine isolated from A. mexicana and have been reported for their cytotoxic activities against human nasopharyngeal carcinoma (HONE-1) and human gastric cancer (NUGC) cell lines (Chang et al., 2003). Berberamine, berberine, palmatine, columbamine, oxyberberine, isocorydine, lambertinea, and magniflorine have been isolated from different species of berries (Berberies vulgaris, Berberies candidula etc.). These alkaloids are reported to exert anti-cancer, anti-inflammatory, antioxidant, antidiabetic, antibacterial, analgesic and anti-nociceptive, and hepatoprotective effects. Several pharmacological activities of berberine and sanguinarine are similar. The aromatic amino acid such as tyrosine or phenylalanine is a common precursor for the biosynthesis of both. The molecular formula of berberine and sanguinarine are C20H19NO5 and C2H15NO5, respectively (Chao et al., 2013; Yatoo et al., 2018).

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Figure 1. Molecular structures of berberine (A) and sanguinarine (B) (Source: Hao et al., 2014).

Berberine, an isoquinoline alkaloid, belongs to the class of protoberberine alkaloids (Ikuta and Itokawa, 1988). The genus Berberis with more than 500 species belongs to Berberidaceae family (Rounsaville and Ranney, 2010). Berberine is also present in plants of Papaveraceae and Ranunculaceae families. Berberies are an evergreen shrub which possesses yellow, spiny, angled or sulcated bark, oblong, obovate, or elliptic leaves, yellow flowers and red, oblong fruits (Ahrendt, 1961). Berberine is crystal bright yellow in color and present in different parts such as roots, stem, bark, rhizome, fruit and leaves (rarely) of several plant species (mostly in barberry), the Thalictrum rochebrunianum (meadow rue), the Chelidonium majus (celandine), the Hydrastis canadensis (goldenseal), and the Phellodendron amurense (Amur cork tree), etc. Among these berberine are mainly present in a variety of barberry species and goldenseal species which are native to Asia and America, respectively (Manske and Holmes, 1995). Some workers have reported berberine (5.2–7.7%) as a major active component of Rhizoma coptidis (Huang Lian) which is traditional herb of china (Yina et al., 2012). First time in 1988 hypoglycemic effect of berberine has been reported during the treatment of diarrhea in diabetic patients. Since then, berberine as an anti-diabetic agent has been used on large scale and known as folk medicine of China. A number of research workers reported the use of this alkaloid in treatment of various diseases including problems in cardiovascular, endocrine, gastrointestinal, renal and central nervous system (Imanshahidi and Hosseinzadeh, 2008). Recent publications demonstrate the anti-oxidant (Abd El-Wahab et al., 2013), anti-inflammatory (Lin et al., 2013), anti-tumor (Yu et al., 2007), anti-mutagenic (Cernakova et al., 2002), and anti-diabetic (Abd El-Wahab et al., 2013) properties of berberine. The potential antitumor activity of berberine hydrochloride has always been a subject of considerable interest because of the known capability of berberine to bind with nucleic acids. Its ability to bind specifically to oligonucleotides and to stabilize DNA triplexes or G-quadruplexes via telomerase and topoisomerase inhibition accounts for its antiproliferative activity (Tan et al., 2011; Hao et al., 2014). In addition, berberine is reported to induce a significant hormetic dose response, in which the low dose of berberine strongly stimulates the growth of cancer cells, while at high doses it acts as anticancer agents (Bao et al., 2015). Moreover, its extensive occurrence in various plant species and low toxicity suggest that berberine hydrochloride has the potential to become an effective antitumor agent in future.

Sanguinarine [13-methyl (1,3) benzodioxolo (5,6-c)-1,3-dioxolo (4,5) phenanthridinium] derived from the root of Sanguinaria canadensis and other poppy-fumaria species of Papaveraceae family, is the most widely used benzophenanthridine alkaloid (Laster and Lobene, 1990). Sanguinarine is a benzophenanthridine structural homolog of chelerythrine (Pi et al., 2008). A positive moiety is present in the aromatic ring of the molecule. In similarity to berberine, sanguinarine also have antimicrobial, antioxidant and anti-inflammatory properties (Firatli et al., 1994). The cytotoxic and cytostatic effects of sanguinarine on a variety of human cancer cells, including human epidermoid carcinoma, erythroleukemia, prostate cancer, pancreatic carcinoma, colon cancer, breast cancer, lung cancer, promyelocytic leukemia, and bone cancer (Weerasinghe et al., 2001a,b; Matkar et al., 2008; Vrba et al., 2009; Park et al., 2010), have been reported. Sanguinarine exhibits the highest cytotoxicity among benzophenanthridine alkaloids (Slaninová et al., 2001; Vogel et al., 2010).

Sanguinarine is a toxin that kills animal cells through its action on the Na+-K+-ATPase transmembrane protein. The normal physiological functions of Na+-K+-ATPase are to maintain the resting potential and to regulate cellular volume by pumping sodium out of cells and potassium into the cells, both against their concentration gradients. The pumping of Na+-K+ is mediated through active transport, uses energy in the form of ATP and also plays significant role in cell physiology. The Na+-K+-ATPase is known to play key role in regulating mitogen activating protein kinases (MAPK) pathway, reactive oxygen species (ROS) and intracellular calcium by acting as signal transducer. Thus, the sanguinarine mediated toxicity to Na+-K+-ATPase can result into development of abnormal cellular functions (Pitts and Meyerson, 1981; Horisberger and Geering, 2009).

Epidemic dropsy is a disease that results from ingesting sanguinarine. Benzophenanthridine sanguinarine alkaloids involves cell death signaling pathway and apoptosis induction mechanism in cancer cell lines. Induction of apoptosis by sanguinarine targeted through mitochondrial damage, nuclear factor kappa-light-chain enhancer of activated B cells activation, and cell cycle arrest (Malikova et al., 2006b). Sanguinarine has been reported to inhibit microtubule polymerization and benzophenanthridine cytotoxic activity involves intercalation of double-stranded deoxyribonucleotide (DNA) (Lopus and Panda, 2006; Matkar et al., 2008) and induces fragmentation of DNA. Recent studies stated that the cytotoxicity and DNA damaging effect of sanguinarine is more specific to cancer cells than to normal cells (Ahmad et al., 2000; Matkar et al., 2008). Cell death mechanism of sanguinarine particularly involves cytotoxic and apoptotic effects occurring by changing the apoptotic gene expressions in human SH-SY5Y and Kelly neuroblastoma cell lines (Cecen et al., 2014). Toxicity of sanguinarine (other than inhibition of Na+/K+ATPase) have been explained in the form of cell membrane damage by lipid peroxidation by free radicals including ROS and r active nitrogen species (RNS). It also indicates DNA polymarase activity inhibition and accumulation of pyruvate due to increased glycogenolysis (Verma et al., 2001). Sanguinarine inhibits the growth of tumor through different molecular pathways. Sanguinarine also inhibits the proliferation and invasiveness of tumor cells i.e., called as the complex phenomena of tumor angiogenesis. In particular, owing to its pro-apoptotic potential, sanguinarine is a good candidate for the development of new anticancer therapeutics either when used alone or in combination with other chemotherapeutic regimens (Gaziano et al., 2016).

Keeping in view the toxicological implications of these two plant-based alkaloids i.e., berberine and sanguinarine, it was considered imperative to update the information on their impacts on the biochemical, cellular and molecular indices in biological systems. The rational for choosing the berberine and sanguinarine (Figure 1) for their toxicological properties are its structural similarity and both are belonging to the isoquinoline group. The structural formulas of berberine and sanguinarine molecules are C20H19NO5 and C20H15NO5, respectively. Usually, isoquinoline alkaloids interact with DNA as intercalators, or they are arranged in a small groove; their external binding with phosphate groups is also possible. The present review article illustrates a recent account of varied aspects of these two alkaloids and their roles in biological systems.

Toxicological Effects of Berberine

On the basis of the amount of berberine present in any compound, rout of administration and type of organism LD50 value varies. Some data accumulated by Kulkarni et al. (1972), which gives following information. The LD50 value of powdered root Berberis vulgaris which is known as barberry is 2,600 mg/kg in mice on oral administration (Table 1). On orally administration of root extract fraction of B. vulgaris, the LD50 values are 1,280 and 520 mg/kg in rat and mice, respectively (Table 1). In mice the LD50 value of pure berberine on intraperitoneal (IP) and orally administration are 23 and 329 mg/kg, respectively (Table 1). Berberine sulfate isolated from Berberis aristata on intraperitoneal administration in rats have LD50 value equal to 205 mg/kg. However, administration of 50 mg/kg of Berberine sulfate causes diarrhea in 40 % of rats which directly effects the gastrointestinal track (Kulkarni et al., 1972).

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Table 1. LD50 of berberine and sanguinarine (of extract and pure compound) as determined in different animals through different routes of exposure (S.No.1-6 Kulkarni et al., 1972 and S.No.7-9 Becci et al., 1987).

In cats 100 mg/kg (orally) of berberine evokes vomiting in 6–8 h and the same dose for 8–10 days caused death of all animals. In cats 50/100 mg/kg for 10 days oral administration of berberine sulfate caused hemorrhagic inflammatory problems in both small and large intestine. Some mild symptom of low amount of berberine and its compounds poisoning has been seen in dogs. These symptoms are salivation, nausea, diarrhea, emesis, muscular tremor, and sometimes paralysis also appeared in dogs (Lampe, 1992). The sub-acute toxicity of berberine shows gastric ulcers (Kupeli et al., 2002), Freund's complete adjuvant-induced chronic arthritis, liver and kidney enlargement, increase in body weight (up to 30%) (Yesilada and Kupeli, 2002), decreases bilirubin protein binding in adult rats (Ho et al., 2014). Mahmoudi et al. (2016) has been reported some immunotoxic effects of berberine. It is reported that, 10 mg/kg of berberine administration responsible for reduced number of leukocytes, neutrophils, lymphocytes (blood cell count), and spleen weight. Significant decrease generation/differentiation of B- and T-cells and splenic CD19+ B-cells, CD4+ and CD8+ T-cells is also associated with berberine. Totally, 5 mg/kg of berberine is responsible for only influence the proliferation of lymphocytes and delayed-type hypersensitivity response while 10 mg/kg of berberine is responsible for suppressed both cellular and humoral immune functions (Mahmoudi et al., 2016) (Table 2).

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Table 2. Dose dependent effects of berberine and sanguinarine.

Sub-chronic toxicity of berberine has reported to damages lung and liver by increasing alanine aminotransferase (ALT) and aspartate aminotransferase (AST), significantly (Ning et al., 2015). In another study on mosquito larvae of Aedes atropatpus, effects of berberine showed chronic toxicity and significantly increased cumulative mortality (Philogene et al., 1984). Another study has revealed that in diabetic rats after 16 weeks of berberine administration at concentrations >50, 100, and 150 mg/kg induces liver tissue damages but these symptoms do not appear in healthy rats (Zhou et al., 2008). Berberine in ApoE-/- mice evokes atherosclerosis after IP treatment for 15 weeks with 5 mg/kg/day (Li et al., 2009). Further, exposure to berberine results into uterine contraction and also may lead to teratogenic effects (the substances responsible for inducing developmental toxicity in an organism from the time of conception till birth) (Table 2).

Experimental studies validated by docking studies has been reported the mode of action (through hydrophobic interactions) and inhibitory effect of berberine against main neurological enzymes namely acetylcholinesterase (AChE), butyryl cholinesterase (BChE), and monoamine oxidase (MAO) (Ji and Shen, 2012). An LD50 of berberine that can inhibit AChE, BChE, MAO-A, and MAO-B are 0.44, 3.44, 126, and 98.2 μM, respectively (Ji and Shen, 2012). It was reported that treatment of 10 and 30 μM of berberine exposure to PC12 cells increased cyto-toxicity that was indicated by increase in apoptotic cell death. The in vitro (5 and 30 mg/kg, i.p. for 21days) and in vivo (10 and 30 μM up to 48 h) studies with berberine against 6-hydroxydopamine (6-OHDA) induced neuro-toxicity in rats and PC-12 cells, respectively, have demonstrated inhibition of dopamine biosynthesis, accompanied by reduced levels of norepinephrine (NE) and dopamine (DA) (Kwon et al., 2010).

Toxicological Effects of Sanguinarine

The short-term toxicity of sanguinarine, a benzophenanthridine alkaloid, and two other alkaloids of S. canadensis L. extracts have been reported. The acute oral LD50 in rats were reported to be about 1,658 mg/kg of sanguinarine. When given through intra-venous route, the acute LD50 in rats was observed to be 29 mg/kg of sanguinarine (Table 1). However, the acute dermal LD50 of sanguinarine in rabbits was found to be greater than 200 mg/kg (Becci et al., 1987) (Table 1). Occurrences of epidemic dropsy in the tropics have been examined for its hepatotoxic potential in rats which was due to administration of the alkaloid sanguinarine. In some studies, it was found that a single IP dose of about 10 mg/kg of sanguinarine was responsible for increase in the activity of serum glutamic pyruvic transaminase (SGPT) and serum glutamic-oxaloacetic transaminase (SGOT) substantially as well as it was responsible for the drastic loss in microsomal cytochrome P-450 and benzphetamine N-demethylase activity. Furthermore, in the same study, significant decrease in body and liver weights and slightly enlargement in livers with fibrinous material and peritoneal edema were recorded in the treated rats. Progressive degeneration of cells and necrosis has been examined by microscopy in the liver tissue. Further, all these changes substantiating that sanguinarine is a potential hepatotoxic alkaloid (Dalvi, 1985). Moreover, depending on the dosage sanguinarine and its derivative dihydrosanguinarine were found to induce HL60 cell death through apoptotic or necrotic processes (Vrba et al., 2009). In addition, sanguinarine exhibits antiproliferative and pro-apoptotic properties on normal and cancer cells (Slunská et al., 2010).

Some workers have reported the effect of sanguinarine on cell viability. According to this study, IC50 value of 0.9 μM of sanguinarine decreased the cell viability in human gingival fibroblasts (Malikova et al., 2006a) determined by using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] MTT assay after 4 h of exposure (Vrba et al., 2009) (Table 2). Another study revealed that with an IC50 value of 0.95 μM, sanguinarine triggered mouse embryonic stem cell (ESC) apoptosis in a dose-dependent manner. The IC50 value of sanguinarine was determined by using the MTT assay after 24 h exposure to the material. On the basis of above study, the cytotoxic effects of 0.5–2 μM sanguinarine on pre- and post-implantation embryonic development was determined. Sanguinarine in dose dependent manner caused apoptosis in mouse blastocysts as determined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. These workers have also discovered primary occurrence of sanguinarine mediated cellular loss and apoptosis in the inner cell mass (ICM) by dual differential staining. They have demonstrated in their in vivo and in vitro studies that sanguinarine at 0.5–2 μM may induce apoptosis and exert negative effect on the mouse embryonic development (Chan, 2011). The workers have concluded that sanguinarine even at physiological doses can adversely influence both the pre-implantation and post-implantation embryonic development in rats (Vrba et al., 2009) (Table 2).

Cytotoxicity or antiproliferative properties of sanguinarine in normal or cancer cell lines, such as rat hepatocytes (Choy et al., 2008), human gingival fibroblasts (Malikova et al., 2006b), human osteosarcoma cells (Park et al., 2010), and human promyelocytic leukemia HL-60 cells (Vrba et al., 2009) have been reported by several investigators. A number of alkaloids isolated and evaluated from A. mexicana for cytotoxic activity have been evaluated. The N-demethyloxysanguinarine was reported to cause nasopharyngeal carcinoma (HONE-1) to human and human gastric cancer (NUGC) cell lines (Chang et al., 2003). In another study, Uddin et al. (2011) revealed the cytotoxic activity against healthy mouse fibroblasts (NIH3T3) and three human cancer-cell lines (AGS, HT-29, and MDA-MB-435S) of methanolic extract of A. mexicana leaves by using the MTT assay. One of the cancer cell lines such as MDAMB-435S exhibited more cytotoxic effects of extracts from A. mexicana leaves (IC50 1.82 mg/ml) (Brahmachari et al., 2013).

Conclusion

Berberine and sanguinarine are traditionally used alkaloids with multispectrum pharmacodynamic properties. On the basis of extensive literature survey, berberine, and sanguinarine have been reported to cause toxicity in different living system. In molecular structure of berberine and sanguinarine, both contains a positive moiety which interacts with a number of nucleophilic and anionic moieties of many biomolecules that distort their structure and further resulted in to altered function of biomolecules. Instead of antitumor activity of berberine, it has potential to treat diabetes mellitus. They have been implicated in the occurrence of dropsy. The toxicity of pure compound is greater than the toxicity of plant extract or plant extract fractions. The sub-acute concentrations of berberine lead to altered liver function, gastric troubles, hepato and hematotoxicity, hemorrhagic inflammatory consequences, damage to immune cells and induced apoptosis. The in vivo and in vitro studies have reported that sanguinarine may induce apoptosis and adversely influence the embryonic development (both in the pre-implantation and post-implantation conditions) of mouse. Sanguinarine toxicity is also reflected in terms of increased SGPT and SGOT activities and reduced microsomal cytochrome P-450 and benzphetamine N-demethylase activities. On the other hand, the cytotoxic properties of both of these alkaloids reveal the use of these alkaloids in treatment of cancer. Berberine treatment may improve insulin resistance, promote insulin secretion, inhibit gluconeogenesis in liver, stimulate glycolysis in peripheral tissue cells, modulate gut microbiota, reduce intestinal absorption of glucose, and perturb lipid metabolism. However, more work is required to assess their anticancer potential under different environmental and clinical conditions to ascertain this possibility.

Author Contributions

NS: Wrote the review article prepared and assembled the figure and table; BS: Critically organized and revised the manuscript by incorporating significant reports.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

NS is grateful to the University Grant Commission (UGC), New Delhi, India for providing financial assistance in the form of a Research Fellowship. The authors also acknowledge the support received from DST-FIST and UGC-SAP, New Delhi India to the Department.

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Keywords: berberine, sanguinarine, alkaloids, toxicity, pharmacological properties

Citation: Singh N and Sharma B (2018) Toxicological Effects of Berberine and Sanguinarine. Front. Mol. Biosci. 5:21. doi: 10.3389/fmolb.2018.00021

Received: 21 November 2017; Accepted: 20 February 2018;
Published: 19 March 2018.

Copyright © 2018 Singh and Sharma. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Bechan Sharma, [email protected]

Sours: https://www.frontiersin.org/articles/10.3389/fmolb.2018.00021/full
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