Improved Potency

“If it’s a bad habit for your heart, it’s probably bad for your sex life too,” says epidemiologist Henry Feldman of the New England Research Institute in Watertown, Massachusetts. improved potency Feldman and his colleagues recently re-examined 513 middle-aged men nine years after enrolling them in the Massachusetts Male Aging Study. All were free of heart disease, diabetes, and erectile difficulties when they joined the study. But nine years later, 14 percent had become moderately or completely impotent. “The cigarette smokers were nearly twice as likely to experience erectile dysfunction (ED) as those who didn’t smoke,” says Feldman. “Being exposed to a double dose of passive smoke — at home and at work — also doubled the risk,” he adds. The other risk factor for impotence: a Body Mass Index (BMI) greater than 28. (Your BMI is 28 if you’re 5’6” tall and weigh 173 lbs. It’s also 28 if you’re 153 lbs. at 5’2”, 163 lbs. at 5’4”, 184 lbs. at 5’8”, or 195 lbs. at 5’10”.) Feldman’s study didn’t find any connection between high blood cholesterol and erectile difficulties. But in an earlier study of more than 3,000 Texans, for every 40 points higher a man’s total cholesterol, his risk of developing erectile dysfunction during the next two years increased by 32 percent.² Lower HDL (“good”) cholesterol was also linked to ED. Why? High cholesterol can lead to improved potency clogged arteries...and not just ones that feed the heart. Israeli researchers found, for example, that men with serious blockages in two of their coronary arteries were likely to experience more erectile difficulties than men with only one blocked artery.³ “Our new data tighten the noose of evidence suggesting that at least some of the risk factors for cardiovascular disease are also risk factors for ED,” says Feldman. improved potency

And women? “Blood flow is important for women too,” adds Feldman. “Since we know that what’s bad for men’s hearts is also bad for women’s hearts, it would follow that tobacco smoke, being overweight, and perhaps having high cholesterol levels would interfere with women’s sexual function too.” improved potency

improved potency

Erection Quality Over Time

It’s been said that men reach their sexual peak at 18. The quality and size of erections can decrease over time. Some causes for this are poor sleeping habits, smoking, alcohol, poor nutrition, and a lack of exercise. Sometimes, however, it’s simply a part of one’s genetics. Fortunately, it’s a part of genetics, that, in many cases, can be improved.improved potency

In fact, many men report a decrease in erection quality with age.In fact, many men report a decrease in erection quality with age. For some, it may even start before they’re 35. For a number of reasons, men can experience a decrease in natural blood flow during arousal that can lead to difficulties in getting and maintaining erections. The natural catalyst Ziozpher helps restore blood flow and create fuller, firmer erections.improved potency

While there is no known ingestible proven to alter the natural size or shape of the penis, Ziozpher can help your body achieve the fullest, strongest erections you are physically capable of achieving. And that just may make your confidence levels rise over time. improved potency

Are penis enlargement pills like Viagra?

A major benefit of a penis enlargement pill is larger and fuller erections, and potentially more frequent erections and an increase in sex drive. Viagra™ is a compound that is taken just before sexual activity whereas penis supplements are taken at any point during the day. penis enlargement pills, such as Maxyte™, let you go with the moment, and avoid the embarrassing and un-romantic aspect of having to ‘schedule’ your lovemaking.improved potency
Can taking a penis enlargement pill or other male supplements affect my sleep patterns?improved potency
Not likely. Some people even report better improved potency sleep when taking a male supplement such as the Male Sexual Health System since they do not need to urinate as much throughout the night. While we can not speak to every male enhancement product or supplement promoting a bigger erection, a penis enlargement pill in general should not affect your sleep. improved potency

How quickly will I see results in my erection size?

This depends on which penis enlargement pill you are using, and which penis enlargement techniques you are using. Some people report results as early as three weeks, and the average seems to be 2-3 months. Your results would also depend on your following the instructions for each male supplement explicitly, and performing any required enlargement exercises. improved potency

At high dose (50 nM), all of the duplexes suppressed EGFP fluorescence. improved potency When dose was decreased to sub-nanomolar levels (50-200 pM), the longer duplexes continued to suppress EGFP while the 21mer was inactive. Improved potency has also been described for 29mer stem short hairpin RNAs (shRNAs) when compared with 19mer stem hairpins¹⁵, suggesting that length-related effects may reflect some aspect of RNAi biochemistry that is common to both the siRNA and shRNA pathways.improved potency

The basis for this increased potency was explored in a series of experiments. RNA duplexes 23 bases and longer were found to be substrates for Dicer and were processed to 21-22mer size duplexes, both in vitro using recombinant human Dicer and in cells. Thus, even though the 27mer showed improved potency, 21mer duplexes were still the final active compounds. improved potency

Why did the 27mer in this case show such improved potency? Shifting a 21mer siRNA by even a single base along a target mRNA sequence can produce a 10-fold or greater change in potency. Kim tested every possible 21mer that could be "diced" from the parent 27mer to see if any of these species could account for its improved performance. None of the 21mers showed sub-nanomolar potency like the 27mer, indicating that some specific benefit resulted from using a sequence of this length. improved potency

However, several of the 21mers tested did show potency that was as much as 10-fold better than the original 21mer studied at this site (effective in the low nanomolar range). improved potency

Electrospray ionization mass spectrometry (ESI-MS) was used to identify the specific products that result from Dicer digestion of this 27mer in vitro; two distinct 21mers were found to result from dicing, one of which was significantly more active than the original 21mer tested at that site in EGFP. improved potency

Thus, the 100-fold improvement in activity seen with the 27mer resulted from the additive effects of Dicer processing producing "a better 21mer" (10-fold boost) and some other effect that is dependent upon intact 27mer being provided to the cells (another 10-fold boost). improved potency

Design Rules for Dicer-substrate RNAi Duplexes

Unfortunately, not all 27mers show this effect. In a series of studies done at Integrated DNA Technologies (IDT) to establish design rules for Dicer-substrate RNAi duplexes, examples were identified where 27mers designed around a known effective 21mer showed improved, equivalent, or worse potency than the "parent" 21mer. improved potency

One example of this kind of experiment is shown in Figure 3, where two blunt 27mers were tested at the site of a previously identified effective 21mer siRNA in the human STAT1 gene. This 21mer is a potent duplex that results in 90% suppression of STAT1 mRNA levels at 1 nM concentration and 80% suppression at 100 pM concentration. improved potency

If "27mer conversion" is done at this site by adding bases to the left side of the 21mer, the resulting duplex (27a) has low potency (worse than the 21mer), whereas if bases are added to the right side of the 21mer, the resulting duplex (27b) has high potency (slightly better than the 21mer). improved potency

Why is this large variation in potency seen between 27mers "at the same site" and can design rules be established that ensure that the most potent 27mer is obtained? improved potency

The problem is that a given 27mer can produce a variety of different 21mers after dicing and sometimes these 21mers are potent and sometimes they are not. For example, the EGFP 27mer studied in Figure 2 was diced into a "good" 21mer that was more potent than the original parent 21mer at that site. improved potency

In the STAT1 examples shown in Figure 3, duplex 27a was functionally diced into "bad" 21mer(s), even though a known "good" 21mer was present within the 27mer sequence. To effectively use 27mer Dicer-substrates in RNAi, design rules must be available to obtain duplexes that consistently result in high-activity 21mer products after Dicer processing. improved potency

To better understand the biochemistry of Dicer processing, cleavage patterns for a series of different 27mer RNA duplexes were studied using ESI-MS¹⁶. Blunt duplexes generally give rise to multiple 21mer species, and the precise cleavage patterns are unpredictable. improved potency

Through testing a number of design variants, a strategy was developed that gives predictable results. Asymmetric duplexes that have a single 2-base 3¢-overhang on one end and are blunt on the other end usually have a single cleavage event 21-22 bases from the overhang. Substitution of two DNA residues at the 3¢-end of the blunt side of an asymmetric duplex further helps limit heterogeneity in dicing patterns. improved potency

Currently, the combination of asymmetric single 3¢-overhang with a DNA-modified blunt end is the preferred design for Dicer-substrate RNA duplexes. It is likely that the single 3¢-overhang provides a binding site for the PAZ domain in Dicer, which serves to anchor the duplex with cleavage occurring 21-22 bases away. improved potency

Conversely, the opposing blunt end with DNA residues offers an unfavorable site for PAZ binding, further helping to ensure the orientation of Dicer processing¹⁶.

Using this approach, two different 27mers can be designed that are each cleaved to produce the same active 21mer siRNA product after Dicer processing. An example of the relationship between these sequences is shown for a target site in hnRNPH in Figure 4A. The "L-form" 27mer has the 3¢-overhang on the sense (top) strand with added bases (which will later be removed by Dicer) on the "left" side while the "R-form" 27mer has the 3¢-overhang on the antisense (bottom) strand with added bases on the "right" side. improved potency

Given that both 27mers produce the same 21mer after processing (confirmed by ESI-MS), it would be predicted that they should have similar functional potency. Interestingly, this is not the case. The duplexes shown in Figure 4A were co-transfected into HEK293 cells with a plasmid that expresses an EGFP-hnRNPH fusion protein and cells were examined for EGFP fluorescence (Figure 4B, adapted from Rose et al). improved potency

The "L-form" duplex performed about the same as the 21mer while the "R-form" duplex was significantly more potent. This same pattern where functional potency was biased by the direction of Dicer processing was observed in several sites in different genes. improved potency

improved potency

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