Natural-product-based, carrier-free, noncovalent nanoparticles for tumor chemo-photodynamic combination therapy.

Cancer, with its diversity, heterogeneity, and complexity, is a significant contributor to global morbidity, disability, and mortality, highlighting the necessity for transformative treatment approaches. Photodynamic therapy (PDT) has aroused continuous interest as a viable alternative to conventional cancer treatments that encounter drug resistance. Nanotechnology has brought new advances in medicine and has shown great potential in drug delivery and cancer treatment. For precise and efficient therapeutic utilization of such a tumor therapeutic approach with high spatiotemporal selectivity and minimal invasiveness, the carrier-free noncovalent nanoparticles (NPs) based on chemo-photodynamic combination therapy is essential. Utilizing natural products as the foundation for nanodrug development offers unparalleled advantages, including exceptional pharmacological activity, easy functionalization/modification, and well biocompatibility. The natural-product-based, carrier-free, noncovalent NPs revealed excellent synergistic anticancer activity in comparison with free photosensitizers and free bioactive natural products, representing an alternative and favorable combination therapeutic avenue to improve therapeutic efficacy. Herein, a comprehensive summary of current strategies and representative application examples of carrier-free noncovalent NPs in the past decade based on natural products (such as paclitaxel, 10-hydroxycamptothecin, doxorubicin, etoposide, combretastatin A4, epigallocatechin gallate, and curcumin) for tumor chemo-photodynamic combination therapy. We highlight the insightful design and synthesis of the smart carrier-free NPs that aim to enhance PDT efficacy. Meanwhile, we discuss the future challenges and potential opportunities associated with these NPs to provide new enlightenment, spur innovative ideas, and facilitate PDT-mediated clinical transformation.

Biochanin A as a modulator of the inflammatory response: An updated overview and therapeutic potential.

Uncontrolled inflammation and failure to resolve the inflammatory response are crucial factors involved in the progress of inflammatory diseases. Current therapeutic strategies aimed at controlling excessive inflammation are effective in some cases, though they may be accompanied by severe side effects, such as immunosuppression. Phytochemicals as a therapeutic alternative can have a fundamental impact on the different stages of inflammation and its resolution. Biochanin A (BCA) is an isoflavone known for its wide range of pharmacological properties, especially its marked anti-inflammatory effects. Recent studies have provided evidence of BCA's abilities to activate events essential for resolving inflammation. In this review, we summarize the most recent findings from pre-clinical studies of the pharmacological effects of BCA on the complex signaling network associated with the onset and resolution of inflammation and BCA's potential protective functionality in several models of inflammatory diseases, such as arthritis, pulmonary disease, neuroinflammation, and metabolic disease.

Natural bioactive constituents from herbs and nutraceuticals promote browning of white adipose tissue.

Obesity is a significant public health problem worldwide that is characterized by abnormal or excessive fat accumulation. Unfortunately, the application of available weight-loss drugs has been restricted because of their serious adverse effects. Browning of white adipose tissue (WAT), which refers to the transformation of white adipocytes to beige adipocytes under certain stimulations, is regarded as a new strategy to solve the obesity problem. Numerous studies have recently evidenced that traditional Chinese medicine (TCM) could promote browning of WAT with multi-component and multi-target characteristics. This article summarizes natural constituents from TCM with stimulatory effects on browning of WAT in the past two decades. The active ingredients can be generally divided into polyphenols, saponins, alkaloids, terpenoids, phenylpropanoids and others, such as resveratrol, quercetin, curcumin, genistein, capsaicin, epigallocatechin gallate (EGCG), berberine, menthol, emodin and ginsenosides. Simultaneously, the chemical structures, source, model, efficacy and mechanism of these monomeric compounds are also described. And the mechanisms of these active ingredients are mainly involved in the regulation of PRDM16, PGC-1α, PPARγ, SIRT1, AMPK, ß3-adrenergic receptors, TRPV1 and TRPM8 channels, FGF21 and miRNAs. The present article opens opportunities for developing novel drugs or supplements from TCM with wide acceptability to prevent obesity progression and its associated metabolic disorders.

Regulatory roles of phytochemicals on circular RNAs in cancer and other chronic diseases.

As novel non-coding RNAs (ncRNAs), circular RNAs (circRNAs) play an essential role in the pathogenesis of many chronic diseases, and the regulation of these functional molecules has become a research hotspot gradually. Within the past decade, phytochemicals were reported to regulate the expression of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) in various chronic diseases, and more recently, most studies focus on the regulatory roles of phytochemicals on circRNAs. Abnormal expression of circRNAs has been identified in chronic diseases like cancer, heart failure, depression and atherosclerosis, and numerous studies have revealed the modulation of circRNAs by phytochemicals including berberine, celastrol, cinnamaldehyde, curcumin, et al. The expression of circRNAs, such as circSATB2 and circFOXM1, were modulated by phytochemicals, and these regulations further affected cell proliferation, apoptosis, migration, invasion, autophagy, chemosensitivity, radiosensitivity and other biological processes. Mechanismly, the circRNAs mainly functioned as miRNA sponge, subsequently affecting miRNA-mediated regulation of target genes and related cell signaling pathways. In this review, we summarized the impact of phytochemicals on circRNAs expression and biological function, and discussed the mechanisms underlying phytochemicals regulating circRNAs in cancer and other chronic diseases.

The antihypertensive potential of flavonoids from Chinese Herbal Medicine: A review.

With the coming of the era of the aging population, hypertension has become a global health burden to be dealt with. Although there are multiple drugs and procedures to control the symptoms of hypertension, the management of it is still a long-term process, and the side effects of conventional drugs pose a burden on patients. Flavonoids, common compounds found in fruits and vegetables as secondary metabolites, are active components in Chinese Herbal Medicine. The flavonoids are proved to have cardiovascular benefits based on a plethora of animal experiments over the last decade. Thus, the flavonoids or flavonoid-rich plant extracts endowed with anti-hypertension activities and probable mechanisms were reviewed. It has been found that flavonoids may affect blood pressure in various ways. Moreover, despite the substantial evidence of the potential for flavonoids in the control of hypertension, it is not sufficient to support the clinical application of flavonoids as an adjuvant or core drug. So the synergistic effects of flavonoids with other drugs, pharmacokinetic studies, clinical trials and the safety of flavonoids are also incorporated in the discussion. It is believed that more breakthrough studies are needed. Overall, this review may shed some new light on the explicit recognition of the mechanisms of anti-hypertension actions of flavonoids, pointing out the limitations of relevant research at the current stage and the aspects that should be strengthened in future researches.

Yin-xing-tong-mai decoction attenuates atherosclerosis via activating PPARγ-LXRα-ABCA1/ABCG1 pathway.

Atherosclerosis is now the major cause of mortality and morbidity worldwide. Formation of macrophage-derived foam cells is a hallmark of atherosclerosis, which is regulated by cholesterol uptake, intracellular metabolism, and efflux. PPARγ-LXRα-ABCA1/ABCG1 pathway plays an important part in regulating cholesterol efflux and this pathway could be a promising target for treating atherosclerosis. However, due to undesirable systemic effects, PPARγ agonist therapy for atherosclerosis remains challenging. Many traditional Chinese medicine has been well accepted and applied in atherosclerosis treatment. Yin-xing-tong-mai decoction (YXTMD) has been applied for treating atherosclerosis for decades. However, the mechanism remains to be explored. Here, we showed that YXTMD effectively attenuated atherosclerosis in ApoE-/- mice. YXTMD increased cholesterol efflux of foam cell by upregulation of ABCA1 and ABCG1 in vivo and in vitro. Through bioinformatic analysis and experimental validation, we found that PPARγ was an important downstream effector of YXTMD in macrophages. Reduction of PPARγ significantly decreased LXRα, ABCA1, and ABCG1 expression in macrophages, with reduced cholesterol efflux. In conclusion, these findings confirmed that YXTMD attenuated atherosclerosis by activating the PPARγ-LXRα- ABCA1/ABCG1 pathway to enhance cholesterol efflux.

Suppression of apoptosis in vascular endothelial cell, the promising way for natural medicines to treat atherosclerosis.

Atherosclerosis, a chronic multifactorial disease, is closely related to the development of cardiovascular diseases and is one of the predominant causes of death worldwide. Normal vascular endothelial cells play an important role in maintaining vascular homeostasis and inhibiting atherosclerosis by regulating vascular tension, preventing thrombosis and regulating inflammation. Currently, accumulating evidence has revealed that endothelial cell apoptosis is the first step of atherosclerosis. Excess apoptosis of endothelial cells induced by risk factors for atherosclerosis is a preliminary event in atherosclerosis development and might be a target for preventing and treating atherosclerosis. Interestingly, accumulating evidence shows that natural medicines have great potential to treat atherosclerosis by inhibiting endothelial cell apoptosis. Therefore, this paper reviewed current studies on the inhibitory effect of natural medicines on endothelial cell apoptosis and summarized the risk factors that may induce endothelial cell apoptosis, including oxidized low-density lipoprotein (ox-LDL), reactive oxygen species (ROS), angiotensin II (Ang II), tumor necrosis factor-α (TNF-α), homocysteine (Hcy) and lipopolysaccharide (LPS). We expect this review to highlight the importance of natural medicines, including extracts and monomers, in the treatment of atherosclerosis by inhibiting endothelial cell apoptosis and provide a foundation for the development of potential antiatherosclerotic drugs from natural medicines.

Flavonoids and hERG channels: Friends or foes?

The cardiac action potential is regulated by several ion channels. Drugs capable to block these channels, in particular the human ether-à-go-go-related gene (hERG) channel, also known as KV11.1 channel, may lead to a potentially lethal ventricular tachyarrhythmia called "Torsades de Pointes". Thus, evaluation of the hERG channel off-target activity of novel chemical entities is nowadays required to safeguard patients as well as to avoid attrition in drug development. Flavonoids, a large class of natural compounds abundantly present in food, beverages, herbal medicines, and dietary food supplements, generally escape this assessment, though consumed in consistent amounts. Continuously growing evidence indicates that these compounds may interact with the hERG channel and block it. The present review, by examining numerous studies, summarizes the state-of-the-art in this field, describing the most significant examples of direct and indirect inhibition of the hERG channel current operated by flavonoids. A description of the molecular interactions between a few of these natural molecules and the Rattus norvegicus channel protein, achieved by an in silico approach, is also presented.

Targeting gut barrier dysfunction with phytotherapies: Effective strategy against chronic diseases.

The intestinal epithelial layer serves as a physical and functional barrier between the microbe-rich lumen and immunologically active submucosa; it prevents systemic translocation of microbial pyrogenic products (e.g. endotoxin) that elicits immune activation upon translocation to the systemic circulation. Loss of barrier function has been associated with chronic 'low-grade' systemic inflammation which underlies pathogenesis of numerous no-communicable chronic inflammatory disease. Thus, targeting gut barrier dysfunction is an effective strategy for the prevention and/or treatment of chronic disease. This review intends to emphasize on the beneficial effects of herbal formulations, phytochemicals and traditional phytomedicines in attenuating intestinal barrier dysfunction. It also aims to provide a comprehensive understanding of intestinal-level events leading to a 'leaky-gut' and systemic complications mediated by endotoxemia. Additionally, a variety of detectable markers and diagnostic criteria utilized to evaluate barrier improving capacities of experimental therapeutics has been discussed. Collectively, this review provides rationale for targeting gut barrier dysfunction by phytotherapies for treating chronic diseases that are associated with endotoxemia-induced systemic inflammation.

Isolation of individual isoflavone species from soybean by solvent extraction followed by the combination of macroporous resin and aluminium oxide separation.

Growing interest in the health benefits of soy isoflavones has led to research in the isolation of individual isoflavone species for further application. Herein, we develop a new strategy to isolate daidzein, genistein, daidzin and genistin in soybean. We investigated the impact of solvents used and the extraction time on the extracted isoflavone contents from soybean. A 30-min extraction with 65% aqueous methanol gave a total isoflavone yield of 345 mg/100 g soybean, the highest value among tested conditions. Further, we proposed a two-stage adsorption/desorption chromatography comprising macroporous resin and aluminium oxide to isolate isoflavone. First, HP-20 resin was used to separate the glucosidic and aglyconic forms of isoflavone, then individual species of isoflavone could be isolated using aluminium oxide by specific retention of 5-hydroxy isoflavone. This process achieved overall high recovery (82-97%) and purity (92-95%) of the four isoflavones, which confirms a high separating efficiency for isoflavones from soybean.

Anti-cancer effects of naturally derived compounds targeting histone deacetylase 6-related pathways.

Alterations of the epigenetic machinery, affecting multiple biological functions, represent a major hallmark enabling the development of tumors. Among epigenetic regulatory proteins, histone deacetylase (HDAC)6 has emerged as an interesting potential therapeutic target towards a variety of diseases including cancer. Accordingly, this isoenzyme regulates many vital cellular regulatory processes and pathways essential to physiological homeostasis, as well as tumor multistep transformation involving initiation, promotion, progression and metastasis. In this review, we will consequently discuss the critical implications of HDAC6 in distinct mechanisms relevant to physiological and cancerous conditions, as well as the anticancer properties of synthetic, natural and natural-derived compounds through the modulation of HDAC6-related pathways.

Medicinal plants used in Lesotho for treatment of reproductive and post reproductive problems.

ETHNOPHARMACOLOGICAL RELEVANCE: Reproductive healthcare has been highlighted as a major challenge in Lesotho mainly due to the high prevalence of HIV/AIDS and sexually transmitted infections. As a result other reproductive ailments have not received much attention, particularly because healthcare facilities are already limited and many of them are inaccessible. For these reasons, medicinal plants play a major role in primary healthcare system in the country, in addition the plants are easily accessible, more affordable, and their use forms part of the cultural heritage. However, documentation of medicinal plants used for reproductive ailments is scattered, more importantly the biological and pharmacological properties, as well as toxicity of many of these plants are not yet known. AIM OF THE STUDY: To document the plants used by both male and female Basotho (residing in Lesotho) for the treatment of reproductive ailments, to explore their recorded biological and pharmacological effects as well as their toxicity, and to establish if these plants are used for similar purposes in other southern African cultures. MATERIALS AND METHODS: The results stem from published findings of recent interviews of traditional medicinal practitioners in the Maseru District of Lesotho, first author's own experiences and observations from the Qacha's Nek District as well as comprehensive literature survey including numerous books and unpublished data. Electronic databases such as Google, Google Scholar, PubMed, and ScienceDirect were also used to search for the chemical compounds, pharmacological activity, and toxicity of the plants. RESULTS: A total of 87 plant species are reported to be used for the treatment of several reproductive problems such as infertility, complications associated with pregnancy (twelve plants are used to treat conditions such as colic, heartburn, nausea, and constipation), cleansing and/ or toning of the uterus (with a purpose either to induce pregnancy or to get rid of the placenta, for example Withania somnifera and Zantedeschia albomaculata), difficult childbirth, as well treatment of breast and cervical cancer, cysts, fibroids, and testicular tumours (e.g. Hypoxis hemerocallidea). For the toning of the uterus, it is common to use a combination of plants, e.g. Gunnera perpensa, Scabiosa columbaria, and Eriospermum ornithogaloides. CONCLUSIONS: Of the 87 plants used for reproductive healthcare, the highest number (31) is used for the treatment of infertility (in both men and women). The pharmacological effects, active compounds, and toxicology of many of these plants are not yet known.

Belamcanda chinensis (L.) DC-An ethnopharmacological, phytochemical and pharmacological review.

ETHNOPHARMACOLOGICAL RELEVANCE: Belamcanda chinensis (L.) DC is the sole species in the genus Belamcanda Adans. (Iridaceae), found mainly in Northeast Asia. Bombus chinensis has long been used in traditional Chinese medicine for its multiple therapeutic uses in the form of antipyretic agents, antidote, expectorant, antiphlogistic and analgesic. AIM OF THE REVIEW: This manuscript comprehensively summarizes the various studies published in recent years on the botany, ethnopharmacology, phytochemistry, biological activity and toxicology of B. chinensis. We hope to provide a foundation for future studies on the mechanism of action and development of better therapeutic agents based on B. chinensis. MATERIAL AND METHODS: All information available on B. chinensis was collected using electronic search engines, such as PubMed, SciFinder Scholar, CNKI, TPL (www.theplantlist.org), Google Scholar and Web of Science. RESULTS: The analysis shown that ethno-medical uses of B. chinensis have been recorded in China, Japan and Korea since a long time. Based on a phytochemical investigation, this plant contains flavonoids, terpenoids, quinones, phenolic compounds, ketones, organic acids, etc. Crude extracts and pure compounds isolated from B. chinensis exhibited various biological effects. CONCLUSIONS: In light of its long traditional use and the modern phytochemical and pharmacological studies summarized here, B. chinensis is known to be a promising medicinal plant with the isolated extracts and chemical components showing a wide range of biological activities. Thus, it is imperative that the necessary programs and value assessment of B. chinensis be established for further studies. It is also important that the synergistic or antagonistic effects of this traditional herbal medicine are investigated in depth to identify more bioactive components by bioactivity-guided isolation strategies, and to illustrate the mechanisms of action targeting on ethnomedical uses. Future clinical studies can also focus on the main therapeutic aspects, toxicity and adverse effects of B. chinensis.

Simultaneous determination of phenolic compounds in sesame oil using LC-MS/MS combined with magnetic carboxylated multi-walled carbon nanotubes.

A novel magnetic carboxylated multi-walled carbon nanotubes (c-MWCNT-MNPs) was proposed for magnetic solid-phase extraction coupled with liquid chromatography-tandem mass spectrometry to determine phenolic compounds in sesame oil. In this study, c-MWCNT-MNPs were acquired by simply dispersing Fe3O4 magnetic nanoparticles into carboxylated multi-walled carbon nanotubes. The major parameters affecting extraction efficiency were optimized, including the type and volume of desorption solvents, extraction and desorption time, washing solution, and sorbent amount. The limit of quantifications and limit of detections were from 0.03µg/kg to 43.00µg/kg and from 0.01µg/kg to 13.60µg/kg, respectively. The recoveries of phenolic compounds in vegetable oils were in the range of 83.8-125.9% with inter-day and intra-day precisions of less than 13.2%. It was confirmed that this method was simple, rapid and reliable with an excellent potential for routine analysis of phenolic compounds in oil samples.

Natural products for treatment of osteoporosis: The effects and mechanisms on promoting osteoblast-mediated bone formation.

Osteoporosis is a systemic metabolic bone disease characterized by a reduction in bone mass, bone quality, and microarchitectural deterioration. An imbalance in bone remodeling that is caused by more osteoclast-mediated bone resorption than osteoblast-mediated bone formation results in such pathologic bone disorder. Traditional Chinese medicines (TCM) have long been used to prevent and treat osteoporosis and have received extensive attentions and researches at home and abroad, because they have fewer adverse reactions and are more suitable for long-term use compared with chemically synthesized medicines. Here, we put the emphasis on osteoblasts, summarized the detailed research progress on the active compounds derived from TCM with potential anti-osteoporosis effects and their molecular mechanisms on promoting osteoblast-mediated bone formation. It could be concluded that TCM with kidney-tonifying, spleen-tonifying, and stasis-removing effects all have the potential effects on treating osteoporosis. The active ingredients derived from TCM that possess effects on promoting osteoblasts proliferation and differentiation include flavonoids, glycosides, coumarins, terpenoids (sesquiterpenoids, monoterpenoids, diterpenoids), phenolic acids, phenols and others (tetrameric stilbene, anthraquinones, diarylheptanoids). And it was confirmed that the bone formation effect induced by the above natural products was regulated by the expressions of bone specific matrix proteins (ALP, BSP, OCN, OPN, COL I), transcription factor (Runx2, Cbfa1, Osx), signal pathways (MAPK, BMP), local factors (ROS, NO), OPG/RANKL system of osteoblasts and estrogen-like biological activities. All the studies provided theoretical basis for clinical application, as well as new drug research and development on treating osteoporosis.

Changes occurring in compositions and antioxidant properties of healthy soybean seeds [Glycine max (L.) Merr.] and soybean seeds diseased by Phomopsis longicolla and Cercospora kikuchii fungal pathogens.

Changes in the compositions (isoflavone, protein, oil, and fatty acid) and antioxidant properties were evaluated in healthy soybeans and soybeans diseased by Phomopsis longicolla and Cercospora kikuchii. The total isoflavone content (1491.3 µg/g) of healthy seeds was observed to be considerably different than that of diseased seeds (P. longicolla: 292.6, C. kikuchii: 727.2 µg/g), with malonlygenistin exhibiting the greatest decrease (726.1 → 57.1, 351.9 µg/g). Significantly, three isoflavones exhibited a slight increase, and their structures were confirmed as daidzein, glycitein, and genistein, based on their molecular ions at m/z 253.1, 283.0, and 269.1 using the negative mode of HPLC-DAD-ESI/MS. The remaining compositions showed slight variations. The effects against 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) radicals in healthy seeds were stronger than the diseased soybeans, depending upon the isoflavone level. Our results may be useful in evaluating the relationship between composition and antioxidant activity as a result of changes caused by soybean fungal pathogens.

Simultaneous determination of isoflavones and resveratrols for adulteration detection of soybean and peanut oils by mixed-mode SPE LC-MS/MS.

To ensure authenticity of vegetable oils, isoflavones (genistein, genistin, daidzein and daidzin) and resveratrols (cis-resveratrol and trans-resveratrol) were selected as the putative markers for adulteration of soybean and peanut oils. Firstly, mixed mode solid-phase extraction coupled with liquid chromatography tandem mass spectrometry (mixed-mode SPE LC-MS/MS) method was developed to analyze isoflavones and resveratrols in vegetable oils. The concentration of marker compounds in vegetable oils were 0.08-1.47mgkg(-1) for daidzein, ND-78.9µgkg(-1) for daidzin, 0.40-5.89mgkg(-1) for genistein, 1.2-114.9µgkg(-1) for genistin, 3.1-85.0µgkg(-1) for trans-resveratrol and 1.9-51.0µgkg(-1) for cis-resveratrol, which are compatible with the raw materials for oil press. Additionally, the applicability of this method has been successfully tested in thirteen vegetable oils from the market. Mixed-mode SPE LC-MS/MS method can simultaneously detect isoflavones and resveratrols in vegetable oils and assess adulteration and quality of soybean and peanut oils.

Isoflavone content and estrogenic activity of different batches of red clover (Trifolium pratense L.) extracts: an in vitro study in MCF-7 cells.

The estrogenicity of different batches of red clover (Trifolium pratense L., Fabaceae; RCL) extracts and its relationship with the isoflavone content were assessed by measuring MCF-7 cell proliferation by flow cytometry and propidium iodide staining. RCL extracts were compared to estradiol (E2) and to the main RCL isoflavones biochanin A, daidzein, genistein and formononetin. Isoflavone content in the extracts was assayed by HPLC. E2 and isoflavones increased MCF-7 proliferation in a concentration-dependent fashion, with the following potency order: E2>>>genistein>biochanin A=daidzein>formononetin. Extracts increased MCF-7 proliferation with different potencies, which in four out of five extracts correlated with the ratios 5,7-dihydroxyisoflavones/7-hydroxyisoflavones. The efficacy of all extracts increased with decreasing genistein contents. A solution containing the main isoflavones at the average concentration of RCL extracts increased MCF-7 proliferation with higher potency and steeper concentration-response curve. The effects of E2, of RCL extracts and of the isoflavone solution were inhibited by the estrogen receptor antagonist 4-hydroxytamoxifen. Flow cytometric analysis of MCF-7 proliferation is a suitable bioassay for the estrogenicity of RCL extracts, thus expanding the characterization of individual batches beyond assessment of chemical composition and contributing to improved standardization of quality and activity.