The interaction among different ingredients in a compound medicine has long been recognized in traditional Chinese medicine. This interaction may lead to strengthening or weakening the efficiency relative to any single ingredient, even creating a novel effect. The art of formulating a compound Chinese medicine is to manipulate these interactions to yield a regime with highest efficiency and lowest side effect. The dose of QSYQ used in the present study was its equivalent clinic dose, while the doses of ASIV, DLA and R1 were those that contained in QSYQ used. The content of DO in QSYQ is very low (0.4%). More than 20 different components are so far isolated from DO, none of which is reported having potential to protect against cardiac hypertrophy. The only beneficial role observed for DO in QSYQ is to help absorb other components and potentiate their effects43. These facts led us to use DO but not it’s any individual ingredient in the present study. The result of the present study provides an example showing how the interactions among the different ingredients look like. To this end, ASIV+DLA intensified the effect of ASIV on ALDOA and SODM; ASIV+R1 intensified the effect of ASIV on SODM; ASIV+DLA+R1 intensified the effect of ASIV and R1 on ATP/ADP and ATP/AMP, the effect of ASIV on ALDOA, the effect of DLA on ENOβ, the effect of R1 on HIF1, the effect of DLA on MDA and the effect of ASIV and R1 on SODM (Table 1). On the contrary, we found that although ASIV mono-therapy could modulate ECH1, CPT1A and SODM, these effects lost when ASIV combined with other ingredient, for example, ASIV+DLA lost the effect on ECH1 and CPT1A; ASIV+R1 lost the effect on CPT1A; ASIV+DO lost the effect on SODM (Table 1). Interestingly, we found that two or more ingredients combined together exerted some effects that any single one alone did not have, such as DLA and R1 mono-therapy had no effect on CPT1A, while DLA+R1 could modulate CPT1A; ASIV, DLA and DO mono-therapy had no effect on HIF1 and HSP70, while ASIV+DLA and ASIV+DO could modulate these two proteins; ASIV and R1 mono-therapy had no effect on MDA, while ASIV+R1 could modulate MDA (Table 1). More importantly, QSYQ, a combination of all the ingredients, always revealed the highest efficiency regardless of evaluating by variables of CH or energy metabolism or oxidative stress, demonstrating the rationality of QSYQ formula.

The additional 3.8% “net investment income tax” (described below) may apply to dividends received by certain U.S. Holders who meet certain modified adjusted gross income thresholds.

        At the inception of each arrangement that includes precommercial milestone payments, the Company evaluates whether the milestones are considered probable of being reached and estimates the amount to be included in the transaction price using the most likely amount method. If it is probable that a significant cumulative revenue reversal would not occur, the associated milestone value is included in the transaction price. Milestone payments that are not within the Company’s control, such as regulatory approvals, are not considered probable of being achieved until the uncertainty related to the milestone is resolved. The transaction price is then allocated to each performance obligation on a relative selling price basis, for which the Company recognizes revenue as or when the performance obligations under the contract are satisfied. At the end of each subsequent reporting period, the Company reevaluates the probability of achievement of such development milestones and any related constraint, and if necessary, adjust its estimate of the overall transaction price.

        Even if they are unchallenged, our licensed patents and pending patent applications, if issued, may not provide us with any meaningful protection or prevent competitors from designing around our patent claims to circumvent our licensed patents by developing similar or alternative technologies or therapeutics in a non-infringing manner. For example, a third party may develop a competitive therapy that provides benefits similar to one or more of our product candidates but that uses a vector, expression construct or delivery modality that falls outside the scope of our patent protection or license rights. If the patent protection provided by the patents and patent applications we hold or pursue with respect to our product candidates is not sufficiently broad to impede such competition, our ability to successfully commercialize our product candidates could be negatively affected, which would harm our business. These risks apply to patents and patent applications which we have in-licensed as well as those we own now or in the future.

We entered into written employment agreements with each of our executive officers. These agreements provide for notice periods of varying duration for termination of the agreement by us or by the relevant executive officer, during which time the executive officer will continue to receive base salary and benefits. These agreements also contain customary provisions regarding non-competition, confidentiality of information and assignment of inventions. However, the enforceability of the non-competition and assignment of inventions provisions may be limited under applicable law. See “Item 3. Key Information—Risk Factors—Risks Related to Our Business, Industry and Regulatory Requirements.”

Moreover, adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate (AMP) contents in cardiac tissue from different groups were assessed by enzyme-linked immuno sorbent assay (ELISA). As shown in Fig. 6e,f, both ATP/ADP and ATP/AMP were significantly down-regulated in AAS groups compared to Sham. Except DLA and DO alone, all the treatments protected this down-regulation significantly with QSYQ being most effective. Noticeably, QSYQ exhibited more effective than any other combination treatments except ASIV+DLA+R1, which showed more significant effect than its any composition.

Data are represented as the mean ± SEM of at least three independent experiments. Statistical analysis was performed using Student’s t-test or one-way ANOVA as appropriate. P < 0.05 was considered significant.

On your last post you wrote about another cardiac glycoside, Proscillaridin A, which must be in the same class of drugs as digoxin, and would probably do the same thing.

A mark-to-market election will not apply to our ordinary shares held by a U.S. Holder for any taxable year during which we are not a PFIC, but will remain in effect with respect to any subsequent taxable year in which we become a PFIC. Such election will not apply to any PFIC subsidiary that we own. Each U.S. Holder is encouraged to consult its own tax advisor with respect to the availability and tax consequences of a mark-to-market election with respect to our ordinary shares.

The mistletoe extract is known as Iscador. USA physicians are allowed to order and administer Iscador under “compassionate care act” rules.

Generally, if for any taxable year 75% or more of our gross income is passive income, or at least 50% of the average value of our assets are held for the production of, or produce, passive income, we would be characterized as a passive foreign investment company, or PFIC, for U.S. federal income tax purposes. Based upon our review of our financial data, we believe that we were not a PFIC for our 2018 taxable year however we expect to be a PFIC for the 2019 taxable year. Because the PFIC determination is highly fact intensive, there can be no assurance that we will be a PFIC in 2019 or for any other taxable year. If we were to be characterized as a PFIC for U.S. federal income tax purposes in any taxable year during which a U.S. Holder (as defined below) owns ordinary shares, such U.S. Holder could face adverse U.S. federal income tax consequences. For example, such U.S. Holder could be subject to additional taxes and interest charges upon certain distributions by us and any gain recognized on a sale, exchange or other disposition of our shares, whether or not we continue to be characterized as a PFIC. Certain adverse consequences of PFIC status can be mitigated if a U.S. Holder makes an election to treat us as a qualified electing fund, or QEF However, it is not expected that a U.S. Holder will be able to make a QEF election because we do not intend to provide U.S. Holders with the information necessary to make a QEF election. See also “Item 10. Additional Information—E. Taxation— Certain U.S. Federal Income Tax Considerations.” 

In blood stasis rats, in OGD treated HUEVC cells, the protective effect of β-BA was attenuated by knockdown of eNOS. In conclusion, the findings convincingly support the protective effects of β-BA on blood stasis induced endothelial dysfunction by eNOS signaling pathway.