Chronic neuropathic pain can significantly reduce quality of life and place an economic burden on individuals and society. Spinal cord stimulation (SCS) is an alternative approach to the treatment of ...neuropathic pain when standard pharmacological agents have failed. However, an improved understanding of the mechanisms by which SCS inhibits pain is needed to enhance its clinical utility. This review summarizes important findings from recent studies of SCS in animal models of neuropathic pain, highlights current understanding of the spinal neurophysiological and neurochemical mechanisms by which SCS produces an analgesic effect, and discusses the potential clinical applicability of these findings and future directions for research.
Isorhamnetin: A review of pharmacological effects Gong, Gang; Guan, Ying-Yun; Zhang, Zhong-Lin ...
Biomedicine & pharmacotherapy,
August 2020, 2020-Aug, 2020-08-00, 2020-08-01, Letnik:
128
Journal Article
Recenzirano
Odprti dostop
Display omitted
•The pharmacological effects of isorhamnetin are reviewed comprehensively.•Isorhamnetin is mainly contained in Hippophae rhamnoides and Ginkgo biloba.•Isorhamnetin protects ...cardio-cerebral vessels and nerves.•Investigations on the mechanism of action of isorhamnetin are limited.•The research on the target of isorhamnetin is missing.
Isorhamnetin is one of the most important active ingredients in the fruits of Hippophae rhamnoides L. and the leaves of Ginkgo biloba L., which possesses extensive pharmacological activities. At present, there have been numerous investigations on isorhamnetin, which has the effects of cardiovascular and cerebrovascular protection, anti-tumor, anti-inflammatory, anti-oxidation, organ protection, prevention of obesity, etc. The related mechanisms involve the regulation of PI3K/AKT/PKB, NF-κB, MAPK and other signaling pathways as well as the expression of related cytokines and kinases. Isorhamnetin has a high value of development and application. However, the investigations on its mechanism of action are limited and lack of detailed scientific validation. The manuscript reviewed the pharmacological effects of isorhamnetin and related mechanisms of action for the development of its medicinal properties further.
Whether sensory nerve can sense bone density or metabolic activity to control bone homeostasis is unknown. Here we found prostaglandin E2 (PGE2) secreted by osteoblastic cells activates PGE2 receptor ...4 (EP4) in sensory nerves to regulate bone formation by inhibiting sympathetic activity through the central nervous system. PGE2 secreted by osteoblasts increases when bone density decreases as demonstrated in osteoporotic animal models. Ablation of sensory nerves erodes the skeletal integrity. Specifically, knockout of the EP4 gene in the sensory nerves or cyclooxygenase-2 (COX2) in the osteoblastic cells significantly reduces bone volume in adult mice. Sympathetic tone is increased in sensory denervation models, and propranolol, a β2-adrenergic antagonist, rescues bone loss. Furthermore, injection of SW033291, a small molecule to increase PGE2 level locally, significantly boostes bone formation, whereas the effect is obstructed in EP4 knockout mice. Thus, we show that PGE2 mediates sensory nerve to control bone homeostasis and promote regeneration.
Objective:
Stroke is a leading cause of mortality and disability. Nicotinamide phosphoribosyltransferase (Nampt) is the rate‐limiting enzyme in mammalian nicotinamide adenine dinucleotide (NAD)+ ...biosynthesis and contributes to cell fate decisions. However, the role of Nampt in brain and stroke remains to be investigated.
Methods:
We used lentivirus‐mediated Nampt overexpression and knockdown to manipulate Nampt expression and explore the effects of Nampt in neuronal survival on ischemic stress both in vivo and in vitro. We also used adenosine monophosphate (AMP)‐activated kinase‐α2 (AMPKα2) and silent mating type information regulation 2 homolog 1 (SIRT1) knockout mice to investigate the underlying mechanisms of Nampt neuroprotection.
Results:
Nampt inhibition by a highly‐specific Nampt inhibitor, FK866, aggravated brain infarction in experimentally cerebral ischemia rats, whereas Nampt overexpression in local brain and Nampt enzymatic product nicotinamide mononucleotide (NMN) reduced ischemia‐induced cerebral injuries. Nampt overexpression and knockdown regulated neuron survival via the AMPK pathway. Neuroprotection of Nampt was abolished in AMPKα2−/− neurons. In neurons, Nampt positively modulated NAD+ levels and thereby controlled SIRT1 activity. SIRT1 coprecipitated with serine/threonine kinase 11 (LKB1), an upstream kinase of AMPK, and promoted LKB1 deacetylation in neurons. Nampt‐induced LKB1 deacetylation and AMPK activation disappeared in SIRT1−/− neurons. In contrast, Ca2+/calmodulin‐dependent protein kinase kinase‐β (CaMKK‐β), another upstream kinase of AMPK, was not involved in the neuroprotection of Nampt. More important, Nampt overexpression‐induced neuroprotection was abolished in SIRT1+/− and AMPKα2−/− mice.
Interpretation:
Our findings reveal that Nampt protects against ischemic stroke through rescuing neurons from death via the SIRT1‐dependent AMPK pathway and indicate that Nampt is a new therapeutic target for stroke. Ann Neurol 2011.
Energy consumption is a major concern in today's wireless communications due to the consensus for a greener world. LTE-Advanced (LTE-A) has been standardized for the fourth-generation mobile ...communications to meet the growing demands for high-speed wireless communications. However, high-speed signal processing on LTE/LTE-A user equipment (UE) causes excessive power consumption. The discontinuous reception (DRX) mechanism is a critical technique for tackling this issue. Delay constraint and power savings are two contradictory performance metrics associated with the DRX mechanism. Using recursive deduction and Markov model, this paper provides an in-depth analysis on the average delay and average power consumption of the DRX mechanism. Two performance metrics, namely, power-saving factor and relative power saving, are devised to assess the power-saving performance of the DRX mechanism. The accuracy of theoretical analysis is validated by computer simulations using the parameters in compliance with LTE specifications. The performance of the DRX mechanism is governed by a set of parameters that interact with one another in an intricate manner. Therefore, the values of key parameters are tested to assess their impacts on the performance of the DRX mechanism. The results shown in this paper give an insight into the operation and further improvement of the DRX mechanism.
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Orphan nuclear receptor Nur77, which is low expressed in HCC, functions as a tumor suppressor to ...suppress HCC. However, the detailed mechanism is still not well understood. Here, we demonstrate that Nur77 could inhibit HCC development via transcriptional activation of the lncRNA WAP four-disulfide core domain 21 pseudogene (WFDC21P). Nur77 binds to its response elements on the WFDC21P promoter to directly induce WFDC21P transcription, which inhibits HCC cell proliferation, tumor growth, and tumor metastasis both in vitro and in vivo. In clinical HCC samples, WFDC21P expression positively correlated with that of Nur77, and the loss of WFDC21P is associated with worse prognosis. Mechanistically, WFDC21P could inhibit glycolysis by simultaneously interacting with PFKP and PKM2, two key enzymes in glycolysis. These interactions not only abrogate the tetramer formation of PFKP to impede its catalytic activity but also prevent the nuclear translocation of PKM2 to suppress its function as a transcriptional coactivator. Cytosporone-B (Csn-B), an agonist for Nur77, could stimulate WFDC21P expression and suppress HCC in a WFDC21P-dependent manner. Therefore, our study reveals a new HCC suppressor and connects the glycolytic remodeling of HCC with the Nur77-WFDC21P-PFKP/PKM2 axis.
Tetracycline (C22H24N2O8) is a well-known emerging contaminant that is generally used in pharmaceuticals and personal-care products. Traditional biological treatment technologies are inadequate for ...quickly and completely removing tetracycline from wastewater; hence, the ozonation investigated in this study is preferable. The effects of several reaction parameters, such as tetracycline concentration, pH, temperature, addition of ·OH radical scavengers, gas type, and bubble size, were investigated. Experimental results indicated that the connection of air or pure oxygen gas with a millibubble or ultrafine-bubble compressor could not remove tetracycline. As the ozonation was carried out, the degradation of tetracycline exceeded 99.5 %, followed by approximately 40 % mineralization with 60-min treatment. A lower pH level or a higher reaction temperature was practical to increase the degradation of tetracycline; also, the increase in the formation of ·OH radicals was impressive to mineralize further the organic compound. According to the experimental results shown in this study, ultrafine-bubble ozonation is a feasible way to degrade the antibiotics effectively and decrease the toxicity in water within a short treatment duration, and with low ozone gas consumption.
Spinal cord stimulation (SCS) is a minimally invasive therapy used for the treatment of chronic neuropathic pain. SCS is a safe and effective alternative to medications such as opioids, and multiple ...randomized controlled studies have demonstrated efficacy for difficult‐to‐treat neuropathic conditions such as failed back surgery syndrome. Conventional SCS is believed mediate pain relief via activation of dorsal column Aβ fibers, resulting in variable effects on sensory and pain thresholds, and measurable alterations in higher order cortical processing. Although potentiation of inhibition, as suggested by Wall and Melzack's gate control theory, continues to be the leading explanatory model, other segmental and supraspinal mechanisms have been described. Novel, non‐standard, stimulation waveforms such as high‐frequency and burst have been shown in some studies to be clinically superior to conventional SCS, however their mechanisms of action remain to be determined. Additional studies are needed, both mechanistic and clinical, to better understand optimal stimulation strategies for different neuropathic conditions, improve patient selection and optimize efficacy.
During neuropathic pain, glial cells (mainly astrocytes and microglia) become activated and initiate a series of signaling cascades that modulate pain processing at both spinal and supraspinal ...levels. It has been generally accepted that glial cell activation contributes to neuropathic pain because glia release proinflammatory cytokines, chemokines, and factors such as calcitonin gene-related peptide, substance P, and glutamate, which are known to facilitate pain signaling. However, recent research has shown that activation of glia also leads to some beneficial outcomes. Glia release anti-inflammatory factors that protect against neurotoxicity and restore normal pain. Accordingly, use of glial inhibitors might compromise the protective functions of glia in addition to suppressing their detrimental effects. With a better understanding of how different conditions affect glial cell activation, we may be able to promote the protective function of glia and pave the way for future development of novel, safe, and effective treatments of neuropathic pain.
Pain is a serious clinical challenge, and is associated with a significant reduction in quality of life and high financial costs for affected patients. Research efforts have been made to explore the ...etiological basis of pain to guide the future treatment of patients suffering from pain conditions. Findings from studies using KA (kainate) receptor agonist, antagonists and receptor knockout mice suggested that KA receptor dysregulation and dysfunction may govern both peripheral and central sensitization in the context of pain. Additional evidence showed that KA receptor dysfunction may disrupt the finely-tuned process of glutamic acid transmission, thereby contributing to the onset of a range of pathological contexts. In the present review, we summarized major findings in recent studies which examined the roles of KA receptor dysregulation in nociceptive transmission and in pain. This timely overview of current knowledge will help to provide a framework for future developing novel therapeutic strategies to manage pain.
PDF
