Dr. Ron’s Research Review – August 20, 2014

© 2014

This week’s research review focuses on the anti-aging aspects of berberine.

AMP-activated protein kinase (AMPK)

AMPK controls energy metabolism, autophagic degradation and stress resistance and ultimately the aging process. (Salminen and Kaarniranta, 2012)
Dietary restriction can extend life span in most organisms tested to date. AMPK has emerged as a key energy with the ability to transcriptionally reprogram the cell and metabolically adapt to external cues. (Canto and Auwerx, 2011)

Berberine

Berberine improves insulin resistance in cardiomyocytes via activation of 5'-AMPK. (Chang et al., 2013)
Berberine may have an indirect mechanism for AMPK activation. Berberine stimulates glycolysis for ATP production that offsets the cell toxicity after mitochondria inhibition. (Zhang and Ye, 2012)
Berberine suppresses gero-conversion from cell cycle arrest to senescence. (Zhao et al., 2013)

Dr. Ron


 

Articles

Calorie restriction: is AMPK a key sensor and effector?
            (Canto and Auwerx, 2011) Download
Dietary restriction can extend life span in most organisms tested to date, suggesting that mechanisms sensing nutrient and energy availability might regulate longevity. The AMP-activated protein kinase (AMPK) has emerged as a key energy sensor with the ability to transcriptionally reprogram the cell and metabolically adapt to external cues. In this review, we will discuss the possible role of AMPK in the beneficial effects of calorie restriction on health and life span.

Berberine improves insulin resistance in cardiomyocytes via activation of 5'-adenosine monophosphate-activated protein kinase.
            (Chang et al., 2013) Download
OBJECTIVE: Insulin resistance plays an important role in the pathogenesis of diabetic cardiomyopathy. Berberine (BBR) is a plant alkaloid which promotes hypoglycemia via increasing insulin sensitivity in peripheral tissues. Little is known of BBR's role in regulating glucose metabolism in heart. MATERIALS/METHODS: We examined the effect and mechanism of BBR on glucose consumption and glucose uptake in insulin sensitive or insulin resistant rat H9c2 cardiomyocyte cells. H9c2 myoblast cells were differentiated into cardiomyocytes and incubated with insulin for 24h to induce insulin resistance. RESULTS: BBR-treatment of H9c2 cells increased glucose consumption and glucose uptake compared to controls. In addition, BBR-treatment attenuated the reduction in glucose consumption and glucose uptake in insulin resistant H9c2 cells. Compound C, an inhibitor of AMP-activated protein kinase (AMPK), abolished the enhancement of glucose consumption and glucose uptake mediated by BBR in both insulin sensitive and insulin resistant H9c2 cells compared to controls. CONCLUSION: BBR significantly increased AMPK activity, but had little effect on the activity of protein kinase B (AKT) in insulin resistant H9c2 cells, suggesting that berberine improves insulin resistance in H9c2 cardiomyocytes at least in part via stimulation of AMPK activity.


AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network.
            (Salminen and Kaarniranta, 2012) Download
Efficient control of energy metabolic homeostasis, enhanced stress resistance, and qualified cellular housekeeping are the hallmarks of improved healthspan and extended lifespan. AMPK signaling is involved in the regulation of all these characteristics via an integrated signaling network. Many studies with lower organisms have revealed that increased AMPK activity can extend the lifespan. Experiments in mammals have demonstrated that AMPK controls autophagy through mTOR and ULK1 signaling which augment the quality of cellular housekeeping. Moreover, AMPK-induced stimulation of FoxO/DAF-16, Nrf2/SKN-1, and SIRT1 signaling pathways improves cellular stress resistance. Furthermore, inhibition of NF-kappaB signaling by AMPK suppresses inflammatory responses. Emerging studies indicate that the responsiveness of AMPK signaling clearly declines with aging. The loss of sensitivity of AMPK activation to cellular stress impairs metabolic regulation, increases oxidative stress and reduces autophagic clearance. These age-related changes activate innate immunity defence, triggering a low-grade inflammation and metabolic disorders. We will review in detail the signaling pathways of this integrated network through which AMPK controls energy metabolism, autophagic degradation and stress resistance and ultimately the aging process.

Mitochondrial inhibitor as a new class of insulin sensitizer.
            (Zhang and Ye, 2012) Download
Insulin resistance is a major risk factor for type 2 diabetes. AMP-activated protein kinase (AMPK) is a drug target in the improvement of insulin sensitivity. Several insulin-sensitizing medicines are able to activate AMPK through inhibition of mitochondrial functions. These drugs, such as metformin and STZ, inhibit ATP synthesis in mitochondria to raise AMP/ATP ratio in the process of AMPK activation. However, chemicals that activate AMPK directly or by activating its upstream kinases have not been approved for treatment of type 2 diabetes in humans. In an early study, we reported that berberine inhibited oxygen consumption in mitochondria, and increased AMP/ATP ratio in cells. The observation suggests an indirect mechanism for AMPK activation by berberine. Berberine stimulates glycolysis for ATP production that offsets the cell toxicity after mitochondria inhibition. The study suggests that mitochondrial inhibition is an approach for AMPK activation. In this review article, literature is critically reviewed to interpret the role of mitochondria function in the mechanism of insulin resistance, which supports that mitochondria inhibitors represent a new class of AMPK activator. The inhibitors are promising candidates for insulin sensitizers. This review provides a guideline in search for small molecule AMPK activators in the drug discovery for type 2 diabetes.

 

Berberine protects against palmitate-induced endothelial dysfunction: involvements of upregulation of AMPK and eNOS and downregulation of NOX4.
            (Zhang et al., 2013) Download
Endothelial dysfunction is a critical factor during the initiation of cardiovascular complications in diabetes. Berberine can ameliorate endothelial dysfunction induced by diabetes. However, the underlying mechanisms remain unclear. The aim of this study was to investigate the protective effect and mechanism of berberine on palmitate-induced endothelial dysfunction in human umbilical vein endothelial cells (HUVECs). The cell viability of HUVECs was determined by MTT assays. Nitric oxide (NO) level and production of reactive oxygen species (ROS) were determined in supernatants or in the cultured HUVECs. The mRNA level of endothelial nitric oxide synthase (eNOS) was measured by RT-PCR, and the protein levels of eNOS, p-eNOS, Akt, p-Akt, AMPK, p-AMPK, and NADPH oxidase (NOX4) were analyzed. The results demonstrated that berberine significantly elevated NO levels and reduced the production of ROS. The expressions of eNOS were significantly increased, while NOX4 protein expression was decreased in berberine-treated HUVECs. Moreover, berberine upregulated the protein expression of AMPK and p-AMPK in palmitate-treated HUVECs, but had no effect on the levels of Akt. Therefore, berberine ameliorates palmitate-induced endothelial dysfunction by upregulating eNOS expression and downregulating expression of NOX4. This regulatory effect of berberine may be related to the activation of AMPK.

Berberine suppresses gero-conversion from cell cycle arrest to senescence.
            (Zhao et al., 2013) Download
Berberine (BRB), a natural alkaloid, has a long history of medicinal use in both Ayurvedic and old Chinese medicine. Recently, available as a dietary supplement, Berberine is reported to have application in treatment of variety diseases. Previously we observed that BRB inhibited mTOR/S6 signaling concurrently with reduction of the level of endogenous oxidants and constitutive DNA damage response. We currently tested whether Berberine can affect premature, stress-induced cellular senescence caused by mitoxantrone. The depth of senescence was quantitatively measured by morphometric parameters, senescence-associated beta-galactosidase, induction of p21WAF1, replication stress (gammaH2AX expression), and mTOR signaling; the latter revealed by ribosomal S6 protein (rpS6) phosphorylation. All these markers of senescence were distinctly diminished, in a concentration-dependent manner, by Berberine. In view of the evidence that BRB localizes in mitochondria, inhibits respiratory electron chain and activates AMPK, the observed attenuation of the replication stress-induced cellular senescence most likely is mediated by AMPK that leads to inhibition of mTOR signaling. In support of this mechanism is the observation that rhodamine123, the cationic probe targeting mitochondrial electron chain, also suppressed rpS6 phosphorylation. The present findings reveal that: (a) in cells induced to senescence BRB exhibits gero-suppressive properties by means of mTOR/S6 inhibition; (b) in parallel, BRB reduces the level of constitutive DNA damage response, previously shown to report oxidative DNA damage by endogenous ROS; (c) there appears to a causal linkage between the (a) and (b) activities; (d) the in vitro model of premature stress-induced senescence can be used to assess effectiveness of potential gero-suppressive agents targeting mTOR/S6 and ROS signaling; (e) since most of the reported beneficial effects of BRB are in age-relate diseases, it is likely that gero-suppression is the primary activity of this traditional medicine.

 


References

Canto, C and J Auwerx (2011), ‘Calorie restriction: is AMPK a key sensor and effector?’, Physiology (Bethesda), 26 (4), 214-24. PubMedID: 21841070
Chang, W, et al. (2013), ‘Berberine improves insulin resistance in cardiomyocytes via activation of 5’-adenosine monophosphate-activated protein kinase.’, Metabolism, 62 (8), 1159-67. PubMedID: 23537779
Salminen, A and K Kaarniranta (2012), ‘AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network.’, Ageing Res Rev, 11 (2), 230-41. PubMedID: 22186033
Zhang, M, et al. (2013), ‘Berberine protects against palmitate-induced endothelial dysfunction: involvements of upregulation of AMPK and eNOS and downregulation of NOX4.’, Mediators Inflamm, 2013 260464. PubMedID: 24385682
Zhang, Y and J Ye (2012), ‘Mitochondrial inhibitor as a new class of insulin sensitizer.’, Acta Pharm Sin B, 2 (4), 341-49. PubMedID: 23710432
Zhao, H, et al. (2013), ‘Berberine suppresses gero-conversion from cell cycle arrest to senescence.’, Aging (Albany NY), 5 (8), 623-36. PubMedID: 23974852