scholarly journals Sirt3 mediated by lentiviral vector in the periaqueductal gray suppresses morphine withdrawal in rats: A preliminary study

2019 ◽  
Author(s):  
Shue Liu ◽  
Hyun Yi ◽  
Jun Gu ◽  
Daigo Ikegami ◽  
Kentaro Hayashi ◽  
...  
Keyword(s):  
Behavioral Response ◽  
Molecular Mechanisms ◽  
Lentiviral Vector ◽  
Morphine Withdrawal ◽  
Withdrawal Symptoms ◽  
Opioid Use ◽  
Chronic Morphine ◽  
Mitochondrial Energy Metabolism ◽  
Preliminary Study ◽  
Novel Therapeutic

AbstractOpioid use disorder (OUD) is a significant clinical and social problem, inducing dependence/addiction and over-dose death. Opioid dependence/withdrawal contributes to the addiction vulnerability. Limited understanding of the exact mechanisms of morphine withdrawal leads to failure to adequately manage opioid withdrawal symptoms. Determining new molecular mechanisms of morphine withdrawal (MW) may allow development of novel therapeutic strategies for treating this disorder. Chronic morphine with naloxone precipitation induces MW behavioral response. Sirt3 (one member of sirtuins family) as a mitochondrial fidelity, plays an important role in mitochondrial homeostasis through the direct regulation of mitochondrial energy metabolism, ATP synthesis, detoxification of mitochondrial ROS, etc. In the pilot study, we found that (1) cultured neurons infected with lentiviral vector expressing Sirt3 induced over-expression of Sirt3, (2) microinjection of LV-Sirt3 into the vlPAG increased Sirt3 protein expression in rats, (3) MW lowered the expression of Sirt3 in the vlPAG, and (4) microinjection of LV-Sirt3 into the vlPAG decreased the MW behavioral response. Current preliminary study demonstrates that complement of Sirt3 in the PAG suppressed MW, providing a novel therapeutic approach to morphine physical withdrawal symptoms. The exact up-and/or down-stream factors of Sirt3 in the model are under the investigation.

scholarly journals The Senescence-Associated Secretory Phenotype (SASP) in the Challenging Future of Cancer Therapy and Age-Related Diseases

Biology ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 485
Author(s):  
Lorenzo Cuollo ◽  
Fabrizio Antonangeli ◽  
Angela Santoni ◽  
Alessandra Soriani
Keyword(s):  
Cancer Therapy ◽  
Molecular Mechanisms ◽  
Therapeutic Strategies ◽  
Senescent Cell ◽  
Pharmacological Intervention ◽  
Tissue Microenvironment ◽  
Age Related ◽  
Secretory Phenotype ◽  
Novel Therapeutic Strategies ◽  
Novel Therapeutic

Cellular senescence represents a robust tumor-protecting mechanism that halts the proliferation of stressed or premalignant cells. However, this state of stable proliferative arrest is accompanied by the Senescence-Associated Secretory Phenotype (SASP), which entails the copious secretion of proinflammatory signals in the tissue microenvironment and contributes to age-related conditions, including, paradoxically, cancer. Novel therapeutic strategies aim at eliminating senescent cells with the use of senolytics or abolishing the SASP without killing the senescent cell with the use of the so-called “senomorphics”. In addition, recent works demonstrate the possibility of modifying the composition of the secretome by genetic or pharmacological intervention. The purpose is not to renounce the potent immunostimulatory nature of SASP, but rather learning to modulate it for combating cancer and other age-related diseases. This review describes the main molecular mechanisms regulating the SASP and reports the evidence of the feasibility of abrogating or modulating the SASP, discussing the possible implications of both strategies.

scholarly journals Cytoprotective Effects of N-Acetylcysteine on Streptozotocin- Induced Oxidative Stress and Apoptosis in RIN-5F Pancreatic β-Cells

2018 ◽  
Vol 51 (1) ◽  
pp. 201-216 ◽  
Author(s):  
Arwa M.T. Al-Nahdi ◽  
Annie John ◽  
Haider  Raza
Keyword(s):  
Oxidative Stress ◽  
Insulin Secretion ◽  
Molecular Mechanisms ◽  
Protective Action ◽  
Mitochondrial Enzymes ◽  
Partial Recovery ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Mitochondrial Energy Metabolism ◽  
Mitochondrial Functions

Background/Aims: Numerous studies have reported overproduction of reactive oxygen species (ROS) and alterations in mitochondrial energy metabolism in the development of diabetes and its complications. The potential protective effects of N-acetylcysteine (NAC) in diabetes have been reported in many therapeutic studies. NAC has been shown to reduce oxidative stress and enhance redox potential in tissues protecting them against oxidative stress associated complications in diabetes. In the current study, we aimed to investigate the molecular mechanisms of the protective action of NAC on STZ-induced toxicity in insulin secreting Rin-5F pancreatic β-cells. Methods: Rin-5F cells were grown to 80% confluence and then treated with 10mM STZ for 24h in the presence or absence of 10mM NAC. After sub-cellular fractionation, oxidative stress, GSH-dependent metabolism and mitochondrial respiratory functions were studied using spectrophotometric, flow cytometric and Western blotting techniques. Results: Our results showed that STZ-induced oxidative stress and apoptosis caused inhibition in insulin secretion while NAC treatment restored the redox homeostasis, enhanced insulin secretion in control cells and prevented apoptosis in STZ-treated cells. Moreover, NAC attenuated the inhibition of mitochondrial functions induced by STZ through partial recovery of the mitochondrial enzymes and restoration of membrane potential. STZ-induced DNA damage and expression of apoptotic proteins were significantly inhibited in NAC-treated cells. Conclusion: Our results suggest that the cytoprotective action of NAC is mediated via suppression of oxidative stress and apoptosis and restoration of GSH homeostasis and mitochondrial bioenergetics. This study may, thus, help in better understanding the cellular defense mechanisms of pancreatic β-cells against STZ-induced cytotoxicity.

scholarly journals Prolonged Withdrawal from Escalated Oxycodone is Associated with Increased Expression of Glutamate Receptors in the Rat Hippocampus

2020 ◽  
Author(s):  
Aaron J Salisbury ◽  
Christopher A Blackwood ◽  
Jean Lud Cadet
Keyword(s):  
Glutamate Receptors ◽  
Molecular Mechanisms ◽  
Quantitative Polymerase Chain Reaction ◽  
Opioid Use Disorder ◽  
Mrna Levels ◽  
Opioid Use ◽  
Self Administration ◽  
Lever Pressing ◽  
Polymerase Chain ◽  
Long Access

People suffering from opioid use disorder (OUD) exhibit cognitive dysfunctions. Here, we investigated potential changes in the expression of glutamate receptors in rat hippocampi at 2 hours and 31 days after the last session of oxycodone self-administration (SA). RNA extracted from the hippocampus was used in quantitative polymerase chain reaction (qPCR) analyses. Rats, given long-access (9 hours per day) to oxycodone (LgA), took significantly more drug than rats exposed to short-access (3 hours per day) (ShA). In addition, LgA rats could be further divided into higher oxycodone taking (LgA-H) or lower oxycodone taking (LgA-L) groups, based on a cut-off of 50 infusions per day. LgA rats, but not ShA, rats exhibited incubation of oxycodone craving. In addition, LgA rats showed increased mRNA expression of GluA1-3 and GluN2a-c subunits as well as Grm3, Grm5, Grm6 and Grm8 subtypes of glutamate receptors after 31 days but not after 2 hours of stopping the SA experiment. Changes in GluA1-3, Grm6, and Grm8 mRNA levels also correlated with increased lever pressing (incubation) after long periods of withdrawal from oxycodone. More studies are needed to elucidate the molecular mechanisms involved in altering the expression of these receptors during withdrawal from oxycodone and/or incubation of drug seeking.

scholarly journals The Expression and Function of Circadian Rhythm Genes in Hepatocellular Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Yanan Jiang ◽  
Xiuyun Shen ◽  
Moyondafoluwa Blessing Fasae ◽  
Fengnan Zhi ◽  
Lu Chai ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Circadian Rhythm ◽  
Circadian Rhythms ◽  
Molecular Mechanisms ◽  
Therapeutic Targets ◽  
Pathogenic Mechanism ◽  
Research Progress ◽  
Biological Processes ◽  
And Function ◽  
Novel Therapeutic

Hepatocellular carcinoma (HCC) is among the most common and lethal form of cancer worldwide. However, its diagnosis and treatment are still dissatisfactory, due to limitations in the understanding of its pathogenic mechanism. Therefore, it is important to elucidate the molecular mechanisms and identify novel therapeutic targets for HCC. Circadian rhythm-related genes control a variety of biological processes. These genes play pivotal roles in the initiation and progression of HCC and are potential diagnostic markers and therapeutic targets. This review gives an update on the research progress of circadian rhythms, their effects on the initiation, progression, and prognosis of HCC, in a bid to provide new insights for the research and treatment of HCC.

scholarly journals Mice with High FGF21 Serum Levels Had a Reduced Preference for Morphine and an Attenuated Development of Acute Antinociceptive Tolerance and Physical Dependence

2021 ◽  
Author(s):  
Louben Dorval ◽  
Brian I. Knapp ◽  
Olufolake A. Majekodunmi ◽  
Sophia Eliseeva ◽  
Jean M Bidlack
Keyword(s):  
Pain Treatment ◽  
Therapeutic Potential ◽  
Physical Dependence ◽  
Serum Levels ◽  
Opioid Use Disorder ◽  
Fibroblast Growth Factor 21 ◽  
Opioid Use ◽  
Chronic Morphine ◽  
Hot Plate ◽  
Antinociceptive Tolerance

As a result of the opioid epidemic, there is a desire to identify new targets for treating opioid use disorder. Previous studies showed that fibroblast growth factor 21 (FGF21) decreased alcohol and sweet preference in mice. In this study, FGF21-transgenic (FGF21-Tg) mice, expressing high FGF21 serum levels, and wildtype (WT) C57BL/6J littermates were treated with morphine and saline to determine if differences exist in their physiological and behavioral responses to opioids. FGF21-Tg mice displayed reduced preference for morphine in the conditioned place preference assay compared to WT littermates. Similarly, FGF21-Tg mice had an attenuation of the magnitude and rate of acute morphine antinociceptive tolerance development, and acute and chronic morphine physical dependence, but exhibited no change in chronic morphine antinociceptive tolerance. The ED50 values for morphine-induced antinociception in the 55-degree C hot plate and the 55-degree C warm-water tail withdrawal assays were similar in both strains of mice. Likewise, FGF21-Tg and WT littermates had comparable responses to morphine-induced respiratory depression. Overall, FGF21-Tg mice had an attenuated preference for morphine, a reduced development of morphine-induced dependence, and a reduction in the development of acute morphine antinociceptive tolerance. FGF21 and its receptor have therapeutic potential for reducing opioid withdrawal symptoms and craving, and augmenting opioid therapeutics for acute pain treatment.

scholarly journals Lofexidine for acute opioid withdrawal: A clinical case series

2020 ◽  
Vol 10 (5) ◽  
pp. 259-263
Author(s):  
Mandy L. Renfro ◽  
Lindsey J. Loera ◽  
Carlos F. Tirado ◽  
Lucas G. Hill
Keyword(s):  
Addiction Treatment ◽  
Case Series ◽  
Retrospective Chart Review ◽  
The United States ◽  
Opioid Withdrawal ◽  
Withdrawal Symptoms ◽  
Total Daily Dose ◽  
Opioid Use ◽  
Management Protocol ◽  
Patient Reported

Abstract Introduction Maintaining abstinence through the opioid withdrawal period is a substantial barrier to treatment for patients with opioid use disorder. The alpha-2 agonist lofexidine has demonstrated efficacy and safety in clinical trials, but pragmatic studies describing its use in clinical practice are lacking. This case series describes the use of lofexidine for opioid withdrawal symptoms in an inpatient addiction treatment facility. Methods Seventeen patients receiving at least 1 dose of lofexidine during inpatient treatment for opioid withdrawal were included in this study. A retrospective chart review was conducted for clinical, subjective, and objective data. Adverse events, total daily dose, clinical opioid withdrawal scale (COWS) scores, vital signs, and reasons for early discontinuation of lofexidine are reported. Results Patients treated with lofexidine experienced mild withdrawal symptoms throughout treatment. Most patients (65%) experienced a decrease in their average daily COWS scores from intake to discharge. Two patients (12%) left treatment against medical advice, and 5 patients (29%) discontinued treatment prior to day 7 due to resolution of symptoms. Average daily blood pressure readings remained stable, and daily average heart rate decreased over time. Discussion Lofexidine can be successfully incorporated into a conventional withdrawal management protocol. The cost of lofexidine and its recent introduction to the market remain barriers to accessibility in the United States. Studies evaluating patient-reported outcomes as well as direct comparisons with other alpha-2 agonists are needed to inform optimal clinical use of lofexidine.

Abstract 533: Crucial Role of Rho-Kinase in Pressure Overload--Induced Right Ventricular Hypertrophy and Dysfunction in Mice: A Possible Novel Therapeutic Target of Right Ventricular Failure

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Shohei Ikeda ◽  
Kimio Satoh ◽  
Nobuhiro Kikuchi ◽  
Satoshi Miyata ◽  
Kota Suzuki ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Right Ventricular ◽  
Therapeutic Target ◽  
Crucial Role ◽  
Molecular Mechanisms ◽  
Rho Kinase ◽  
Pressure Overload ◽  
Dominant Negative ◽  
Term Survival ◽  
Novel Therapeutic

Rationale: Right ventricular (RV) failure is the leading cause of death in various cardiopulmonary diseases, including pulmonary hypertension. It is generally considered that the RV is vulnerable to pressure-overload as compared with the left ventricle (LV). However, as compared with LV failure, the molecular mechanisms of RV failure are poorly understood. Objective: We aimed to identify molecular therapeutic targets for RV failure in a mouse model of pressure-overload. Methods and Results: To induce pressure-overload to respective ventricles, we performed pulmonary artery constriction (PAC) or transverse aortic constriction (TAC) in mice. We first performed microarray analysis and found that the molecules related to RhoA/Rho-kinase and integrin pathways were significantly up-regulated in the RV with PAC compared with the LV with TAC. Then, we examined the responses of both ventricles to chronic pressure-overload in vivo. We demonstrated that compared with TAC, PAC caused greater extents of mortality, Rho-kinase expression (especially ROCK2 isoform) and oxidative stress in pressure-overloaded RV, reflecting the weakness of the RV in response to pressure-overload. Additionally, mechanical stretch of RV cardiomyocytes from rats immediately up-regulated ROCK2 expression (not ROCK1), suggesting the specific importance of ROCK2 in stretch-induced responses of RV tissues. Furthermore, mice with myocardial-specific overexpression of dominant-negative Rho-kinase (DN-RhoK) showed resistance to pressure-overload-induced hypertrophy and dysfunction associated with reduced oxidative stress. Finally, DN-RhoK mice showed a significantly improved long-term survival in both PAC and TAC as compared with littermate controls. Conclusions: These results indicate that the Rho-kinase pathway plays a crucial role in RV hypertrophy and dysfunction, suggesting that the pathway is a novel therapeutic target of RV failure in humans.

A new way to treat morphinism

1930 ◽  
Vol 26 (10) ◽  
pp. 1056-1056
Author(s):  
M. Sokel
Keyword(s):  
Morphine Withdrawal ◽  
Withdrawal Symptoms ◽  
New Treatment

Abstracts. Neuropathology and Psychiatry. Dr. M. Sokel describes (D. m. W. 1930, no. 42) a new treatment for morphinism. With the sudden withdrawal of morphine to avoid the phenomena of morphine withdrawal a. in the first 6-8 days he injected a large amount of insulin (up to 80 units of insulin "Leo" in 24 hours) without wine. Sahara. The amount of insulin depended on the severity of the withdrawal symptoms. A total of 15 patients were treated.

scholarly journals Ileal Transcriptome Profiles of Japanese Quail Divergent in Phosphorus Utilization

2020 ◽  
Vol 21 (8) ◽  
pp. 2762 ◽  
Author(s):  
Michael Oster ◽  
Henry Reyer ◽  
Nares Trakooljul ◽  
Frank M. Weber ◽  
Lu Xi ◽  
...  
Keyword(s):  
Japanese Quail ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Animal Husbandry ◽  
Coturnix Japonica ◽  
P Efficiency ◽  
Mitochondrial Energy Metabolism ◽  
False Discovery ◽  
P Utilization ◽  
Total P

Phosphorus (P) is an essential component for all living beings. Low P diets prompt phenotypic and molecular adaptations to maintain P homeostasis and increase P utilization (PU). Knowledge of the molecular mechanisms of PU is needed to enable targeted approaches to improve PU efficiency and thus lower P excretion in animal husbandry. In a previous population study, Japanese quail were subjected to a low P diet lacking mineral P and exogenous phytase. Individual PU was determined based on total P intake and excretion. A subset of 20 extreme siblings discordant for PU was selected to retrieve gene expression patterns of ileum (n = 10 per PU group). Sequencing reads have been successfully mapped to the current Coturnix japonica reference genome with an average mapping rate of 86%. In total, 640 genes were found to be differentially abundant between the low and high PU groups (false discovery rate ≤ 0.05). Transcriptional patterns suggest a link between improved PU and mitochondrial energy metabolism, accelerated cell proliferation of enterocytes, and gut integrity. In assessing indicators of the efficient use of macro- and micronutrients, further research on turnover and proliferation rates of intestinal cells could provide an approach to improve P efficiency in poultry species.

Molecular Interactions of α-Synuclein, Mitochondria, and Cellular Degradation Pathways in Parkinson's Disease

2020 ◽  
pp. 212-234
Author(s):  
Mansi Verma ◽  
Sujata Basu ◽  
Manisha Singh ◽  
Rachana R. ◽  
Simrat Kaur ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Interactions ◽  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Degradation Pathways ◽  
Functional Changes ◽  
The World ◽  
Novel Therapeutic

Parkinson's disease (PD) has been reported to be the most common neurodegenerative diseases all over the world. Several proteins are associated and responsible for causing PD. One such protein is α-synuclein. This chapter discusses the role of α-synuclein in PD. Various genetic and epigenetic factors, which cause structural and functional changes for α-synuclein, have been described. Several molecular mechanisms, which are involved in regulating mitochondrial and lysosomal related pathways and are linked to α-synuclein, have been discussed in detail. The knowledge gathered is further discussed in terms of using α-synuclein as a diagnostic marker for PD and as a novel therapeutic target for the same.

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