Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus : a randomized prospective 6-year study

Evidence is growing that the gut microbiota modulates the host response to chemotherapeutic drugs, with three main clinical outcomes: facilitation of drug efficacy; abrogation and compromise of anticancer effects; and mediation of toxicity. The implication is that gut microbiota are critical to the development of personalized cancer treatment strategies and, therefore, a greater insight into prokaryotic co-metabolism of chemotherapeutic drugs is now required. This thinking is based on evidence from human, animal and in vitro studies that gut bacteria are intimately linked to the pharmacological effects of chemotherapies (5-fluorouracil, cyclophosphamide, irinotecan, oxaliplatin, gemcitabine, methotrexate) and novel targeted immunotherapies such as anti-PD-L1 and anti-CLTA-4 therapies. The gut microbiota modulate these agents through key mechanisms, structured as the 'TIMER' mechanistic framework: Translocation, Immunomodulation, Metabolism, Enzymatic degradation, and Reduced diversity and ecological variation. The gut microbiota can now, therefore, be targeted to improve efficacy and reduce the toxicity of current chemotherapy agents. In this Review, we outline the implications of pharmacomicrobiomics in cancer therapeutics and define how the microbiota might be modified in clinical practice to improve efficacy and reduce the toxic burden of these compounds.

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Gut microbiota modulation of chemotherapy efficacy and toxicity

Ginsenosides are a special group of triterpenoid saponins that can be classified into two groups by the skeleton of their aglycones, namely dammarane‐ and oleanane‐type. Ginsenosides are found nearly exclusively in Panax species (ginseng) and up to now more than 150 naturally occurring ginsenosides have been isolated from roots, leaves/stems, fruits, and/or flower heads of ginseng. Ginsenosides have been the target of a lot of research as they are believed to be the main active principles behind the claims of ginsengs efficacy. The potential health effects of ginsenosides that are discussed in this chapter include anticarcinogenic, immunomodulatory, anti‐inflammatory, antiallergic, antiatherosclerotic, antihypertensive, and antidiabetic effects as well as antistress activity and effects on the central nervous system. Ginsensoides can be metabolized in the stomach (acid hydrolysis) and in the gastrointestinal tract (bacterial hydrolysis) or transformed to other ginsenosides by drying and steaming of ginseng to more bioavailable and bioactive ginsenosides. The metabolization and transformation of intact ginsenosides, which seems to play an important role for their potential health effects, are discussed. Qualitative and quantitative analytical techniques for the analysis of ginsenosides are important in relation to quality control of ginseng products and plant material and for the determination of the effects of processing of plant material as well as for the determination of the metabolism and bioavailability of ginsenosides. Analytical techniques for the analysis of ginsenosides that are described in this chapter are thin‐layer chromatography (TLC), high‐performance liquid chromatography (HPLC) combined with various detectors, gas chromatography (GC), colorimetry, enzyme immunoassays (EIA), capillary electrophoresis (CE), nuclear magnetic resonance (NMR) spectroscopy, and spectrophotometric methods.

Ginsenosides: Chemistry, biosynthesis, analysis and potential health effects

Herbs are often administered in combination with therapeutic drugs, raising the potential of herb-drug interactions. An extensive review of the literature identified reported herb-drug interactions with clinical significance, many of which are from case reports and limited clinical observations. Cases have been published reporting enhanced anticoagulation and bleeding when patients on long-term warfarin therapy also took Salvia miltiorrhiza (danshen). Allium sativum (garlic) decreased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration of saquinavir, but not ritonavir and paracetamol (acetaminophen), in volunteers. A. sativum increased the clotting time and international normalised ratio of warfarin and caused hypoglycaemia when taken with chlorpropamide. Ginkgo biloba (ginkgo) caused bleeding when combined with warfarin or aspirin (acetylsalicylic acid), raised blood pressure when combined with a thiazide diuretic and even caused coma when combined with trazodone in patients. Panax ginseng (ginseng) reduced the blood concentrations of alcohol (ethanol) and warfarin, and induced mania when used concomitantly with phenelzine, but ginseng increased the efficacy of influenza vaccination. Scutellaria baicalensis (huangqin) ameliorated irinotecan-induced gastrointestinal toxicity in cancer patients. Piper methysticum (kava) increased the ‘off’ periods in patients with parkinsonism taking levodopa and induced a semicomatose state when given concomitantly with alprazolam. Kava enhanced the hypnotic effect of alcohol in mice, but this was not observed in humans. Silybum marianum (milk thistle) decreased the trough concentrations of indinavir in humans. Piperine from black (Piper nigrum Linn) and long (P. longum Linn) peppers increased the AUC of phenytoin, propranolol and theophylline in healthy volunteers and plasma concentrations of rifamipicin (rifampin) in patients with pulmonary tuberculosis. Eleutheroccus senticosus (Siberian ginseng) increased the serum concentration of digoxin, but did not alter the pharmacokinetics of dextromethorphan and alprazolam in humans. Hypericum perforatum (hypericum; St John’s wort) decreased the blood concentrations of ciclosporin (cyclosporin), midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline, but did not alter the pharmacokinetics of carbamazepine, pravastatin, mycophenolate mofetil and dextromethorphan. Cases have been reported where decreased ciclosporin concentrations led to organ rejection. Hypericum also caused breakthrough bleeding and unplanned pregnancies when used concomitantly with oral contraceptives. It also caused serotonin syndrome when used in combination with selective serotonin reuptake inhibitors (e.g. sertraline and paroxetine). In conclusion, interactions between herbal medicines and prescribed drugs can occur and may lead to serious clinical consequences. There are other theoretical interactions indicated by preclinical data. Both pharmacokinetic and/or pharmacodynamic mechanisms have been considered to play a role in these interactions, although the underlying mechanisms for the altered drug effects and/or concentrations by concomitant herbal medicines are yet to be determined. The clinical importance of herb-drug interactions depends on many factors associated with the particular herb, drug and patient. Herbs should be appropriately labeled to alert consumers to potential interactions when concomitantly used with drugs, and to recommend a consultation with their general practitioners and other medical carers.

Herb-drug interactions: a literature review.

Anti-diabetic effect of cinnamon extract on blood glucose in db/db mice.

Colorectal cancer is the second leading cause of cancer related-death and the third most commonly diagnosed cancer in the United States, with approximately 100,000 new cases diagnosed per year [1, 2]. If detected very early in the course of the disease, surgical resection may be adequate, but many patients still need supplemental chemotherapy or radiotherapy. In most cases, commonly used chemotherapies are limited by severe side effects and dose-limiting toxicity. Adding more drugs or increasing the dosages increases the probability of adverse effects. The drug-related adverse events not only worsen patients' quality of life, but can also lead to their refusal to continue the potentially curative chemotherapy [3]. Newer therapies involving targeted chemotherapy of metastatic colorectal cancer are also associated with undesirable adverse effects [4]. Considering these facts, significant improvement in treating patients with colorectal cancer is required.

In the last two decades, botanicals with effective anti-cancer activity have been researched. The use of herbal medicines is also on the rise in cancer patients [5, 6]. Long-term consumption of certain botanicals could be associated with reduced cancer incidence and thus has an epidemiological basis for further investigation. Research that explores new botanical candidates with potential anti-cancer effects is imperative, and allows for the development of safe and efficacious anti-cancer therapies [7, 8].

Crocus sativus is a plant of the iris family (Iridaceae) and its flower contains various chemical constituents [9]. Stigmas of the flower (saffron) contain crocin, anthocyanin, carotene and lycopene [10], and these constituents have various pharmacological effects on different illness, including anti-tumor effects by inhibition of cell growth [11]. Recently, Crocus sativus extract (CSE) was found to have anti-cancer activities against leukaemia, osteosarcoma, fibrosarcoma and ovarian carcinoma cells [9]. Crocin (Fig. 1) is a main constituent the CSE. However, effects of CSE and crocin on human colorectal cancer have not been evaluated.



Fig. 1

Chemical structure of crocin (MW: 977)



In this study, using high performance liquid chromatography (HPLC), we analyzed CSE and its content of crocin. The anti-proliferation effects of CSE and crocin were evaluated in three human colorectal cancer cell lines, i. e., HT-29, SW-480 and HCT-116. The inhibitory effects on colorectal cancer cell growth were also compared to a different cancer, non-small cell lung cancer (NSCLC) cells. Additionally, we also tested if CSE's anti-proliferative effects can bee seen in non-cancer young adult mouse colon (YAMC) cells.

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Crocin from Crocus sativus possesses significant anti-proliferation effects on human colorectal cancer cells.

Red Asian ginseng ( Panax ginseng C. A. Meyer, Araliaceae) is used in many Oriental countries. In this study, the saponin constituents and anticancer activities of steamed American ginseng ( Panax quinquefolius L.) roots were evaluated. The contents of 12 ginsenosides in the roots were determined using high performance liquid chromatography (HPLC). After the steaming treatment (100 - 120 degrees C for 1 h and 120 degrees C for 0.5 - 4 h), the quantity of 7 ginsenosides decreased and that of 5 others increased. The content of ginsenoside Rg3, a previously recognized anticancer compound, increased significantly when the root was steamed at 120 degrees C for 0.5 - 3 h. The antiproliferative effects of unsteamed and steamed (120 degrees C for 1 h and 2 h) American ginseng root extracts were assayed by the modified trichrome stain (MTS) method using three cancer cell lines (SW-480, HT-29, NSCLC). Heat-processing increased the antiproliferative effect of American ginseng significantly, and the activity of the extract from roots steamed for 2 h was greater than that of roots steamed for 1 h. Chemical constituents and antiproliferative activities of white and red Asian ginseng have also been evaluated. Five representative ginsenosides, Rb1, Rd, Re, Rg2 and Rg3, were studied. Ginsenoside Rg3 had the most potent effect. The antiproliferative activities of red American ginseng are augmented when ginsenoside Rg3 is increased.

Red American Ginseng: Ginsenoside Constituents and Antiproliferative Activities of Heat-Processed Panax quinquefolius Roots

This study was designed to determine the changes in saponin content in American ginseng berries after treatment by heating and to assess the anticancer effects of the extracts. After steaming treatment (100−120 °C for 1 h, and 120 °C for 0.5−4 h), the content of seven ginsenosides, Rg1, Re, Rb1, Rc, Rb2, Rb3, and Rd, decreased; the content of five ginsenosides, Rh1, Rg2, 20R-Rg2, Rg3, and Rh2, increased. Rg3, a previously identified anticancer ginsenoside, increased significantly. Two hours of steaming at 120 °C increased the content of ginsenoside Rg3 to a greater degree than other tested ginsenosides. When human colorectal cancer cells were treated with 0.5 mg/mL steamed berry extract (120 °C 2 h), the antiproliferation effects were 97.8% for HCT-116 and 99.6% for SW-480 cells. At the same treatment concentration, the effects of unsteamed berry extract were 34.1% for HCT-116 and 4.9% for SW-480 cells. After staining with Hoechst 33258, apoptotic cells increased significantly by treatment with steamed be...

Steamed American Ginseng Berry: Ginsenoside Analyses and Anticancer Activities

Anti-diabetic effect of ginsenoside Re in ob/ob mice.

Sexual dysfunction is prevalent in both men and women. Although new pharmaceutical agents have been identified for male erectile problems, sexual desire and orgasm disorders, individuals with sexual dysfunction often seek alternative therapies, including traditional Chinese medicine. This article reviews currently used alternative therapies, such as herbal medications, L-arginine, acupuncture, biofeedback and others. Potential herb-drug interactions are also presented.

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Han H. Aung

Papers

Crocin from Crocus sativus possesses significant anti-proliferation effects on human colorectal cancer cells.

Red American Ginseng: Ginsenoside Constituents and Antiproliferative Activities of Heat-Processed Panax quinquefolius Roots

Steamed American Ginseng Berry: Ginsenoside Analyses and Anticancer Activities

Anti-diabetic effect of ginsenoside Re in ob/ob mice.

Alternative therapies for male and female sexual dysfunction.