Mitochondrial Function as a Potential Tool for Assessing Function, Quality and Adulteration in Medicinal Herbal Teas

Quality control has been a significant issue in herbal medicine since herbs became widely used to heal. With the advent of modern technologies, evaluating the quality of medicinal herbs has become more sophisticated but so have the methods of adulterating them. In this paper we undertook a comprehensive literature search to identify the key analytical techniques used in the quality assurance of herbal medicine, reviewing their uses and limitations. We also present a new tool, based on mitochondrial profiling, that can be used to measure medicinal herbal quality. Besides being fundamental to the energy metabolism required for most cellular activities, mitochondria play a direct role in cellular signalling, apoptosis, stress responses, inflammation, cancer, ageing, and neurological function, mirroring some of the most common reasons people take herbal medicines. A fingerprint of the specific mitochondrial effects of medicinal herbs can be documented in order to assess their potential efficacy, detect adulterations that modulate these effects and determine the relative potency of batches. Furthermore, through this method it will be possible to assess whole herbs or complex formulas thus avoiding the issues inherent in identifying active ingredients which may be complex or unknown. Thus, while current analytical methods focus on determining the chemical quality of herbal medicines, including adulteration and contamination, mitochondrial functional analysis offers a new way of determining the quality of plant derived products that is more closely linked to the biological activity of a product and its potential clinical effectiveness

Metabolic dysfunction following weight cycling in male mice

Background: Combatting over-weight or obesity can lead to large fluctuations in an individual‟s body weight, often referred to as weight cycling or “yo-yo” dieting. Current evidence regarding the potentially damaging effects of these changes is conflicting. Methods: Here, we assess the metabolic effects of weight cycling in a murine model, comprising three dietary switches to normal or high fat diets at 6 week intervals; male C57BL/6 mice were fed either a control (C) or high fat (F) diet for 6 weeks (n=140/group). C and F groups were then either maintained on their initial diet (CC and FF respectively) or switched to a high fat (CF) or control (FC) diet (n=35/group). For the final 6 week interval, CC and CF groups were returned to the control diet (CCC and CFC groups) while FC and FF groups were placed on a high fat diet (FCF and FFF) (n=28/group). Results: For the majority of metabolic outcomes changes aligned with dietary switches; however assessment of neuropeptides and receptors involved in appetite regulation and reward signalling pathways reveal variable patterns of expression. Furthermore, we demonstrate that multiple cycling events leads to a significant increase in internal fat deposition, even when compared to animals maintained on a high fat diet (Internal Fat: FCF: 7.4 ± 0.2g vs. FFF: 5.6 ± 0.2g; p<0.01). Conclusions: Increased internal adipose tissue is strongly linked to the development of metabolic syndrome associated conditions such as type 2 diabetes, cardiovascular disease and hypertension. While further work will be required to elucidate the mechanisms underlying the neuronal control of energy homeostasis, these studies provide a causative link between weight cycling and adverse health

Mitochondrial Function as a Potential Tool for Assessing Function, Quality and Adulteration in Medicinal Herbal Teas

Quality control has been a significant issue in herbal medicine since herbs became widely used to heal. Modern technologies have improved the methods of evaluating the quality of medicinal herbs but the methods of adulterating them have also grown in sophistication. In this paper we undertook a comprehensive literature search to identify the key analytical techniques used in the quality control of herbal medicine, reviewing their uses and limitations. We also present a new tool, based on mitochondrial profiling, that can be used to measure medicinal herbal quality. Besides being fundamental to the energy metabolism required for most cellular activities, mitochondria play a direct role in cellular signalling, apoptosis, stress responses, inflammation, cancer, ageing, and neurological function, mirroring some of the most common reasons people take herbal medicines. A fingerprint of the specific mitochondrial effects of medicinal herbs can be documented in order to assess their potential efficacy, detect adulterations that modulate these effects and determine the relative potency of batches. Furthermore, through this method it will be possible to assess whole herbs or complex formulas thus avoiding the issues inherent in identifying active ingredients which may be complex or unknown. Thus, while current analytical methods focus on determining the chemical quality of herbal medicines, including adulteration and contamination, mitochondrial functional analysis offers a new way of determining the quality of plant derived products that is more closely linked to the biological activity of a product and its potential clinical effectiveness

Acetate induces growth arrest in colon cancer cells through modulation of mitochondrial function

Acetate is one of the main short chain fatty acids produced in the colon when fermentable carbohydrates are digested. It has been shown to affect normal metabolism, modulating mitochondrial function and fatty acid oxidation. Currently, there is no clear consensus regarding the effects of acetate on tumorigenesis and cancer metabolism. Here, we investigate the metabolic effects of acetate on colon cancer. HT29 and HCT116 colon cancer cell lines were treated with acetate and its effect on mitochondrial proliferation, reactive oxygen species, density, permeability transition pore, cellular bioenergetics, gene expression of acetyl-CoA synthetase 1 (ACSS1) and 2 (ACSS2) and lipid levels were investigated. Acetate was found to reduce proliferation of both cell lines under normoxia as well as reducing glycolysis; it was also found to increase both oxygen consumption and ROS levels. Cell death observed was independent of ACSS1/2 expression. Under hypoxic conditions, reduced proliferation was maintained in the HT29 cell line but no longer observed in the HCT116 cell line. ACSS2 expression together with cellular lipid levels was increased in both cell lines under hypoxia which may partly protect cells from the anti-proliferative effects of reversed Warburg effect caused by acetate. The findings from this study suggest that effect of acetate on proliferation is a consequence of its impact on mitochondrial metabolism and during normoxia is independent of ACCS1/2 expression

Intraperitoneal Delivery of Acetate-Encapsulated Liposomal Nanoparticles for Neuroprotection of the Penumbra in a Rat Model of Ischemic Stroke

Background: Ischemic stroke is a devastating condition, with metabolic derangement and persistent inflammation enhancing the initial insult of ischaemia. Recombinant tissue plasminogen remains the only effective treatment but limited as therapy must commence soon after the onset of symptoms. Purpose: We investigated whether acetate, which modulates many pathways including inflammation, may attenuate brain injury in stroke. As acetate has a short blood half-life and high amounts irritate the gastrointestinal tract, acetate was administered encapsulated in a liposomal nanoparticle (liposomal-encapsulated acetate, LITA). Methods: Transient ischemia was induced by 90 mins middle-cerebral artery occlusion (MCAO) in Sprague-Dawley rats, and LITA or control liposomes given intraperitoneally at occlusion and daily for up to two weeks post-MCAO. Magnetic resonance imaging (MRI) was used to estimate lesion volume at 24 h, 1 and 2 weeks post-MCAO and anterior lateral ventricular volume (ALVv) at 2 weeks post-MCAO. Locomotive behaviour was tested prior to the final MRI scan. After the final scan, brains were collected, and immunohistochemistry was performed. Results: Lesion volumes were decreased by ~80% from 24 h to one-week post-MCAO, in both control and LITA groups (P<0.05). However, the lesion was increased by ~50% over the subsequent 1 to 2 weeks after MCAO in the control group (from 24.1±10.0 to 58.7±28.6 mm3; P<0.05) but remained unchanged in the LITA group. ALVv were also attenuated by LITA treatment at 2 weeks post-MCAO (177.2±11.9% and 135.3±10.9% of contralateral ALVv for control and LITA groups, respectively; P<0.05). LITA-treated animals also appeared to have improved motor activity, moving with greater average velocity than control animals. Microglial immunoreactivity was ~40% lower in the LITA group compared to the control group (P<0.05), but LITA did not modulate neurogenesis, apoptosis, histone acetylation and lipid peroxidation. Conclusion: LITA appears to attenuate the harmful chronic neuroinflammation observed during brain remodeling after a focal ischemic insult

Cationic lipid-based nanoparticles mediate functional delivery of acetate to tumor cells in vivo leading to significant anticancer effects

Metabolic reengineering using nanoparticle delivery represents an innovative therapeutic approach to normalizing the deregulation of cellular metabolism underlying many diseases, including cancer. Here, we demonstrated a unique and novel application to the treatment of malignancy using a short-chain fatty acid (SCFA)-encapsulated lipid-based delivery system – liposome-encapsulated acetate nanoparticles for cancer applications (LITA-CAN). We assessed chronic in vivo administration of our nanoparticle in three separate murine models of colorectal cancer. We demonstrated a substantial reduction in tumor growth in the xenograft model of colorectal cancer cell lines HT-29, HCT-116 p53+/+ and HCT-116 p53-/-. Nanoparticle-induced reductions in histone deacetylase gene expression indicated a potential mechanism for these anti-proliferative effects. Together, these results indicated that LITA-CAN could be used as an effective direct or adjunct therapy to treat malignant transformation in vivo

Reprogramming of hepatic fat accumulation and 'browning' of adipose tissue by the short-chain fatty acid acetate

Background/Objectives: Short-chain fatty acids, produced by microbiome fermentation of carbohydrates, have been linked to a reduction in appetite, body weight and adiposity. However, determining the contribution of central and peripheral mechanisms to these effects has not been possible. Subjects/Methods:C57BL/6 mice fed with either normal or high-fat diet were treated with nanoparticle-delivered acetate, and the effects on metabolism were investigated. Results:In the liver, acetate decreased lipid accumulation and improved hepatic function, as well as increasing mitochondrial efficiency. In white adipose tissue, it inhibited lipolysis and induced 'browning', increasing thermogenic capacity that led to a reduction in body adiposity. Conclusions:This study provides novel insights into the peripheral mechanism of action of acetate, independent of central action, including ‘browning’ and enhancement of hepatic mitochondrial function

Withania somnifera Root Extract Enhances Chemotherapy through ‘Priming’

Withania somnifera extracts are known for their anti-cancerous, anti-inflammatory and antioxidative properties. One of their mechanisms of actions is to modulate mitochondrial function through increasing oxidative stress. Recently ‘priming’ has been suggested as a potential mechanism for enhancing cancer cell death. In this study we demonstrate that ‘priming’, in HT-29 colon cells, with W. somnifera root extract increased the potency of the chemotherapeutic agent cisplatin. We have also showed the W. somnifera root extract enhanced mitochondrial dysfunction and that the underlying mechanism of ‘priming’ was selectively through increased ROS. Moreover, we showed that this effect was not seen in non-cancerous cells