Chinese herbs and acupuncture to improve cognitive function in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease with a variety of causes. Traditional Chinese medicine (TCM), which includes the two main approaches of acupuncture and herbal medication, views the human body as a self-controlled system network. Fundamental theories, including "qi," the five elements, and the theory of viscera, form the basis for classification. Diseases in humans are considered to be caused by an imbalance of "yang qi" and "yin qi" that lead to the nonhomeostasis of organs. Acupuncture is derived from 12 main meridians and 365 acupuncture points characterized by "blood and qi." Needling of different positions corresponds to specific disease treatments to increase qi. Treatment with Chinese herbal medicines is based on syndrome differentiation characterized as "Zheng" which differs from the cause orientation approach of Western medicine. In this article, we review basic and clinical research studies that describe TCM herbs and acupuncture for the treatment of AD. Moreover, we propose that these two approaches be integrated to improve the outcomes for AD patients.

Induced Pluripotent Stem Cell (iPSC)-Based Neurodegenerative Disease Models for Phenotype Recapitulation and Drug Screening.

Neurodegenerative diseases represent a significant unmet medical need in our aging society. There are no effective treatments for most of these diseases, and we know comparatively little regarding pathogenic mechanisms. Among the challenges faced by those involved in developing therapeutic drugs for neurodegenerative diseases, the syndromes are often complex, and small animal models do not fully recapitulate the unique features of the human nervous system. Human induced pluripotent stem cells (iPSCs) are a novel technology that ideally would permit us to generate neuronal cells from individual patients, thereby eliminating the problem of species-specificity inherent when using animal models. Specific phenotypes of iPSC-derived cells may permit researchers to identify sub-types and to distinguish among unique clusters and groups. Recently, iPSCs were used for drug screening and testing for neurologic disorders including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), spinocerebellar atrophy (SCA), and Zika virus infection. However, there remain many challenges still ahead, including how one might effectively recapitulate sporadic disease phenotypes and the selection of ideal phenotypes and for large-scale drug screening. Fortunately, quite a few novel strategies have been developed that might be combined with an iPSC-based model to solve these challenges, including organoid technology, single-cell RNA sequencing, genome editing, and deep learning artificial intelligence. Here, we will review current applications and potential future directions for iPSC-based neurodegenerative disease models for critical drug screening.

Human-Induced Pluripotent Stem Cells and Herbal Small-Molecule Drugs for Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by extracellular amyloid plaques composed of the ß-amyloid peptides and intracellular neurofibrillary tangles and associates with progressive declines in memory and cognition. Several genes play important roles and regulate enzymes that produce a pathological accumulation of ß-amyloid in the brain, such as gamma secretase (γ-secretase). Induced pluripotent stem cells from patients with Alzheimer's disease with different underlying genetic mechanisms may help model different phenotypes of Alzheimer's disease and facilitate personalized drug screening platforms for the identification of small molecules. We also discuss recent developments by γ-secretase inhibitors and modulators in the treatment of AD. In addition, small-molecule drugs isolated from Chinese herbal medicines have been shown effective in treating Alzheimer's disease. We propose a mechanism of small-molecule drugs in treating Alzheimer's disease. Combining therapy with different small-molecule drugs may increase the chance of symptomatic treatment. A customized strategy tailored to individuals and in combination with therapy may be a more suitable treatment option for Alzheimer's disease in the future.

Epigenetic targeting DNMT1 of pancreatic ductal adenocarcinoma using interstitial control release biodegrading polymer reduced tumor growth through hedgehog pathway inhibition.

Annually, 48,000 people die from pancreatic ductal adenocarcinoma (PDAC), ranking it the fourth among cancer-related deaths in the United States. Currently, anti-cancer drugs are not effective against PDAC, and only extends survival by 3 months. Aberrant DNA methylation has been shown to play an important role during carcinogenesis in PDAC, with approximately 80% of tumor overexpressing the DNA methyltransferase 1 (DNMT1) protein. In the present study, we used DNMTs as a screening platform to find a new DNMT inhibitor, n-butylidenephthalide (n-BP), which is identified from a Chinese herbal drug. n-BP could inhibit DNMT1 expression in both dose-dependent and time-dependent manner. It also displays an effect in suppressing growth of PDAC cells and inducing cell cycle arrest at G0/G1 phase leading apoptosis. Growth suppression can be restored by the overexpression of DNMT1 in PDAC cells. Furthermore, we found n-BP-mediated DNMT1 suppression influenced the protein stability rather than changing the RNA expression. Through microarray studies, we found that the patched domain contained 4 (PTCHD4) is the potential downstream gene of DNMT1. Following silencing of PTCHD4 expression by siRNA, n-BP decreased tumor growth inhibition. Finally, in vivo, two animal models were used to evaluate the efficacy and survival after n-BP treatment by interstitial control release polymer delivery. The results show that n-BP could effectively inhibit PDAC tumor volume growth and extend animal survival. In summary, n-BP may inhibit the growth of human PDAC cells though reducing DNMT1 and increasing the expression of PTCHD4 both in vitro and in vivo.

Advances in Patient-Specific Induced Pluripotent Stem Cells Shed Light on Drug Discovery for Amyotrophic Lateral Sclerosis.

Induced pluripotent stem cells (iPSCs), which are generated through reprogramming adult somatic cells by expressing specific transcription factors, can differentiate into derivatives of the three embryonic germ layers and accelerate rapid advances in stem cell research. Neurological diseases such as amyotrophic lateral sclerosis (ALS) have benefited enormously from iPSC technology. This approach can be particularly important for creating iPSCs from patients with familial or sporadic forms of ALS. Motor neurons differentiated from the ALS-patient-derived iPSC can help to determine the relationship between cellular phenotype and genotype. Patient-derived iPSCs facilitate the development of new drugs and/or drug screening for ALS treatment and allow the exploration of the possible mechanism of ALS disease. In this article, we reviewed ALS-patient-specific iPSCs with various genetic mutations, progress in drug development for ALS disease, functional assays showing the differentiation of iPSCs into mature motor neurons, and promising biomarkers in ALS patients for the evaluation of drug candidates.

Effect of Cinnamomum osmophloeum Kanehira Leaf Aqueous Extract on Dermal Papilla Cell Proliferation and Hair Growth.

In this study, we explored the effect of the water extract of Cinnamomum osmophloeum Kanehira (COK) leaves on hair growth by in vitro and in vivo assays. Using an in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, it was found that the proliferation of rat vibrissae and human hair dermal papilla cells (hDPCs) was significantly enhanced by the COK leaf extract treatment. As determined by quantitative real-time polymerase chain reaction (RT-PCR), the messenger RNA (mRNA) levels of some hair growth-related factors including vascular endothelial growth factor, keratinocyte growth factor (KGF), and transforming growth factor-ß2 were found to be higher in the cultured hDPCs exposed to COK leaf extract than those in the untreated control group. In the hair-depilated C57BL/6 mouse model, the stimulation of hair growth was demonstrated in the group of COK leaf extract treatment. Both photographical and histological observations revealed the promotion of the anagen phase in the hair growth cycle by the COK leaf extract in the C57BL/6 mice. Finally, the ultra performance liquid chromatography (UPLC) showed that the COK extract contained mostly cinnamic aldehyde and a small amount of cinnamic acid. The results suggest that the COK leaf extract may find use for the treatment of hair loss.

Taiwanin A targets non-steroidal anti-inflammatory drug-activated gene-1 in human lung carcinoma.

Taiwanin A (α,ß-bis(piperonylidene)-γ-butyrolactone) is extracted from Taiwania cryptomerioides. Taiwanin A is extracted from tree bark and exhibits antitumor activity in breast, liver, and lung cancer cell lines. The objective of this study was to demonstrate the cytotoxicity of Taiwanin A against tumor cells by increasing the expression of non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1). NAG-1 has been reported to exhibit antitumor and proapoptotic activities, suggesting potential use in cancer therapy. Inhibiting NAG-1 mRNA expression in A549 reduced the cytotoxicity caused by Taiwanin A. Furthermore, the c-Jun-N-terminal kinase/Ste20-related protein proline/alanine-rich kinase (JNK/SPAK) pathway played a key role in the influence of NAG-1 on cell viability, whereas the addition of the JNK pathway inhibitor SP600125 resulted in an inhibitory effect on NAG-1 and recovery of Taiwanin-A-treated cells. A xenograft tumor model demonstrated that Taiwanin A dose-dependently significantly decreases tumor-mediated growth in nude mice by increasing the NAG-1 expression accompanying tumor apoptosis. These data supported the hypothesis that Taiwanin A inhibits lung carcinoma growth by increasing NAG-1 expression through the JNK pathway both in vivo and in vitro. This result can contribute to a compound design for increasing cytotoxicity activity in the future.

Food supplement 20070721-GX may increase CD34+ stem cells and telomerase activity.

Few rejuvenation and antiaging markers are used to evaluate food supplements. We measured three markers in peripheral blood to evaluate the antiaging effects of a food supplement containing placental extract. Samples were evaluated for CD34(+) cells, insulin-like growth factor 1 (IGF1), and telomerase activity, which are all markers related to aging. To control the quality of this food supplement, five active components were monitored. In total, we examined 44 individuals who took the food supplement from 1.2 months to 23 months; the average number of CD34(+) cells was almost 6-fold higher in the experimental group compared with the control group. Food supplement intake did not change serum IGF1 levels significantly. Finally, the average telomerase activity was 30% higher in the subjects taking this food supplement. In summary, our results suggest that the placental extract in the food supplement might contribute to rejuvenation and antiaging.

Inhibitory effect of n-butylidenephthalide on neointimal hyperplasia in balloon injured rat carotid artery.

This investigation was designed to determine the inhibitory effects and mechanisms of n-butylidenephthalide (BP) from Angelica sinensis on smooth muscle cell (SMC) proliferation in vitro and in balloon injured rat carotid artery. Treatment of cultured rat aorta SMC-derived A7r5 cells with 25-100 µg/mL BP significantly inhibited the proliferation and arrested the cell cycle in G(0)/G(1) phase. BP induced the expression and migration of Nur77 from the nucleus to the cytoplasm. Among signal pathways, JNK and p38 MAPK were phosphorylated after BP treatment. In vivo, the neointimal area of common carotid artery 2 weeks after balloon injury reduced significantly in Sprague-Dawley rats treated with 150-300 mg/kg BP compared with the control. The proliferative activity indicated by immunohistochemical detection of Ki-67 positive cells in the neointima was significantly decreased in the 60-300 mg/kg BP treatment groups. The apoptotic activity indicated by cleaved caspase-3 positive cells and Nur77 positive cells in the neointima was significantly increased in rats treated with 60-300 mg/kg BP. This study demonstrated BP inhibited neointimal hyperplasia in balloon injured rat carotid artery due to its dual effects of proliferative inhibition and apoptotic induction on SMCs. Up-regulation of Nur77 gene may partly explain the antihyperplasia activity of BP on the neointima.

Botanical drugs and stem cells.

The potential to generate virtually any differentiated cell type from stem cells offers the possibility of creating new sources of cells for regenerative medicine. To realize this potential, it will be essential to control stem cell differentiation. Chinese herbal medicine is a major aspect of traditional Chinese medicine and is a rich source of unique chemicals. As such, individual herbs or extracts may play a role in the proliferation and differentiation of stem cells. In this review, we discuss some of the Chinese herbal medicines that are used to treat human diseases such as neuronal degenerative diseases, cardiovascular diseases, and osteoporosis. We also describe the relationship between Chinese herbal medicines and stem cell regulation.