Folic Acid and Folinic Acid Protect Hearts of Aging Triple-transgenic Alzheimer's Disease mice via IGF1R/PI3K/AKT and SIRT1/AMPK Pathways.

Patients with Alzheimer's disease have increased risk of developing heart disease, which therefore highlights the need for strategies aiming at reducing Alzheimer's disease-related cardiovascular disease. Folic acid and folinic acid are beneficial to the heart. We aimed to investigate the benefits of folic acid and folinic acid in heart of patients with late-stage Alzheimer's disease. Twelve 16-month-old mice of triple-transgenic late-stage Alzheimer's disease were divided into three groups: Alzheimer's disease group, Alzheimer's disease + folic acid group, and Alzheimer's disease + folinic acid group. The mice were administered 12 mg/kg folic acid or folinic acid once daily via oral gavage for 3 months. In the folic acid and folinic acid treatment groups, the intercellular space was reduced, compared with the Alzheimer's disease group. TUNEL assay and western blot images showed that the number of apoptotic cells and the apoptosis-related protein expression were higher in the Alzheimer's disease group than in other two treated groups. Folic acid and folinic acid induced the IGF1R/PI3K/AKT and SIRT1/ AMPK pathways in the hearts of mice with Alzheimer's disease. Our results showed that folic acid and folinic acid treatment increased survival and SIRT1 expression to reduce apoptotic proteins in the heart. The aging mice treated with folinic acid had more IGF1R and SIRT1/AMPK axes to limit myocardial cell apoptosis. In conclusion, folic acid and folinic acid promote cardiac cell survival and prevent apoptosis to inhibit heart damage in aging mice with triple-transgenic late-stage Alzheimer's disease. In particular, folinic acid provides a better curative effect than folic acid.

Induction of resistance to oxaliplatin in cancer by a microRNA/Fem1B/Gli1 pathway.

Colorectal cancer is among the most common cancers worldwide and a frequent cause of cancer related deaths. Oxaliplatin is the first line chemotherapeutics for treatment, but the development of resistance leads to recurrence of oxaliplatin insensitive tumors. To understand possible mechanisms of drug tolerance we developed oxaliplatin resistant derivatives (OR-LoVo) of the established LoVo cell line originally isolated from a metastatic colon adenocarcinoma. We compared the microRNA (miRNA) expression profile of the cell pair and found expression of miR-29a-3p significantly increased in OR-LoVo cells compared to parent cells. In addition, miR-29a-3p was significantly elevated in tumor tissue when compared to matched surrounding tissue in human, suggesting potential clinical importance. Ectopic miR-29-a-3p expression induced chemoresistance in a number of different cancer cell lines as well as colorectal tumors in mice. We further demonstrated that miR-29-a-3p downregulates expression of the ubiquitin ligase component FEM1B and that reduction of Fem1b levels is sufficient to confer oxaliplatin resistance. FEM1B targets the glioma associated oncogene Gli1 for degradation, suggesting that increased Gli1 levels could contribute to oxaliplatin tolerance. Accordingly, knockdown of GLI1 reverted chemoresistance of OR-LoVo cells. Mechanistically, resistant cells experienced significantly lower DNA damage upon oxaliplatin treatment, which can be partially explained by reduced oxaliplatin uptake and enhanced repair. These results suggest that miR-29-a-3p overexpression induces oxaliplatin resistance through misregulation of Fem1B and Gli1 levels. TCGA analyses provides strong evidence that the reported findings regarding induced drug tolerance by the miR-29a/Fem1B axis is clinically relevant. The reported findings can help to predict oxaliplatin sensitivity and resistance of colorectal tumors.

Edible folic acid and medicinal folinic acid produce cardioprotective effects in late-stage triple-transgenic Alzheimer's disease model mice by suppressing cardiac hypertrophy and fibrosis.

Some clinical studies have indicated the patients with Alzheimer's disease (AD) display an increased risk of cardiovascular disease (CVD). Here, to examine the relationship between AD and CVDs, we investigated the changes in heart function in triple-transgenic late-stage AD model mice (3× Tg-AD; APPSwe, PS1M146V, and tauP301L). We fed the AD mice folic acid (FA) or folinic acid (FN) and analyzed the protective effects of the compounds on the heart; specifically, 20-month-old triple-transgenic AD mice, weighing 34-55 g, were randomly allocated into three groups-the AD, AD + FA, and AD + FN groups-and subject to gastric feeding with FA or FN once daily at 12 mg/kg body weight (BW) for 3 months. Mouse BWs were assessed throughout the trial, at the end of which the animals were sacrificed using carbon dioxide suffocation. We found that BW, whole-heart weight, and left-ventricle weight were reduced in the AD + FA and AD + FN groups as compared with the measurements in the AD group. Furthermore, western blotting of excised heart tissue revealed that the levels of the hypertrophy-related protein markers phospho(p)-p38 and p-c-Jun were markedly decreased in the AD + FA group, whereas p-GATA4, and ANP were strongly reduced in the AD + FN group. Moreover, the fibrosis-related proteins uPA, MMP-2, MEK1/2 and SP-1 were decreased in the heart in both AD + FN group. In summary, our results indicate that FA and FN can exert anti-cardiac hypertrophy and fibrosis effects to protect the heart in aged triple-transgenic AD model mice, particular in FN.

Legislative preparedness for the control of pandemics - using Taiwan as an example.

At the early stage of an emerging disease, information is often insufficient for governments to determine what actions are necessary to contain its transmission. Taiwanese society was not prepared when the SARS epidemic hit in 2003. After the SARS epidemic, Taiwan began to overhaul its Communicable Disease Control Act authorising the government to act in a murky situation without the fear of violating due process. In hindsight, the new law has contributed a large part to the effective containment of Covid-19 in Taiwan. However, a new issue emerged concerning the conflict between an individual's freedom of confidential communication and the government's use of cell phone positioning to monitor self-quarantine. Although Taiwan's Council of Grand Justices previously resolved the concern over potential breaching of due-process, the legislature may have to strike a balance between public health emergency and the use of an electronic footprint to trace individual activities.

The Extent of Harm to the Victim as an Alternative Aggravating Factor for the Conviction of Felony Fraud in the Context of Food-Safety Violations.

Finding the intent to defraud or mislead for the conviction of felony fraud could be very tricky in the context of food regulation. As compared to the split among the US federal circuit courts on the interpretation of intent, Taiwan courts looked into the extent of harm to the victim to determine whether the defendant should be convicted of felony fraud. In order to limit the scope of felony liability, Taiwanese law requires an additional showing of the extent of harm to the victim. Recently, courts in Taiwan further expanded the scope of the statutory language, "harmful to human health," to include potential harm as demonstrated by animal studies. This approach provides courts in other jurisdiction with an alternative aggravating factor to assess criminal liability in nondisclosure cases arising out of non-compliance with food law.

When ethical reform became law: the constitutional concerns raised by recent legislation in Taiwan.

In an effort at ethical reform, Taiwan recently revised the Hospice Palliative Care Law authorising family members or physicians to make surrogate decisions to discontinue life-sustaining treatment if an incompetent terminally ill patient did not express their wishes while still competent. In particular, Article 7 of the new law authorises the palliative care team, namely the physicians, to act as sole decision-makers on behalf of the incompetent terminally ill patient's best interests if no family member is available. However, the law fails to provide guidance as to what constitutes the patient's best interests or what specific procedures the treating physicians should follow, and so has raised constitutional concerns. It may be difficult to translate ethical reform into law but it is not impossible if essential requirements are carefully followed. First, there must be substantial nexus between the purpose of the statute and the measures provided under the statute. Second, advocates need to convince the public that futility or waste has amounted to a public health emergency so as to justify lower procedural requirements. Third, a remedy or compensation should be available if the surrogate decisions have not been appropriately made. Fourth,minimum procedural safeguards are necessary even though the statute is intended to reduce the procedural burdens of making surrogate decisions on behalf of incompetent patients who lack family members and did not express their wishes while still competent.

Biohydrogen production from cellulosic hydrolysate produced via temperature-shift-enhanced bacterial cellulose hydrolysis.

A "temperature-shift" strategy was developed to improve reducing sugar production from bacterial hydrolysis of cellulosic materials. In this strategy, production of cellulolytic enzymes with Cellulomonas uda E3-01 was promoted at a preferable temperature (35 degrees C), while more efficient enzymatic cellulose hydrolysis was achieved under an elevated culture temperature (45 degrees C), at which cell growth was inhibited to avoid consumption of reducing sugar. This temperature-shift strategy was shown to markedly increase the reducing sugar (especially, monosaccharide and disaccharide) concentration in the hydrolysate while hydrolyzing pure (carboxymethyl-cellulose, xylan, avicel and cellobiose) and natural (rice husk, rice straw, bagasse and Napier-grass) cellulosic materials. The cellulosic hydrolysates from CMC and xylan were successfully converted to H(2) via dark fermentation with Clostridium butyricum CGS5, attaining a maximum hydrogen yield of 4.79 mmol H(2)/g reducing sugar.