#1

Review these two paper, my view as an alternative to NAD and or assisting in manufacturing/processing NAD in your system.

Second paper;

“Boosting NAD+ with a small molecule that activates NAMPT”

https://www.nature.com/articles/s41467-019-11078-z

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#2

It has been reported that NAD+ affects both Sirt1 activity and its expression level (Hayashida et al., 2010; Revollo and Li, 2013). In our study, TMZ increased NAD+ content in DN. In order to investigate how TMZ affects NAD+ content, we conducted a study on Nampt and p-Ampk. The generation of NAD+ depends on de novo synthesis and salvage pathway, and the latter is its main source. Nampt is the rate-limiting enzyme of the salvage pathway (Belenky et al., 2007). Previous literature reported that Ampk increased NAD+ content by increasing mitochondrial β-oxidation (Canto et al., 2009). In our study, only the effect of Nampt on Sirt1 expression was observed. Probably because Ampk reduced NAD+/NADH ( Figure 7D ), or because of TMZ inhibition of β-oxidation. In previous studies, although inhibition of Nampt showed deleterious effects, the expression of Nampt was elevated in DN (Yilmaz et al., 2008; Benito-Martin et al., 2014). However, in our study, the expression of Nampt was decreased in DN ( Figures 7B, C ). This may be due to the decreased expression of Nampt in the later stages of DN. The study by Muraoka et al. explained this phenomenon (Muraoka et al., 2019).

In our study, TMZ showed a deacetylation effect by promoting Sirt1 expression. In order to observe whether the combination of TMZ and Sirt1 agonist has a synergistic effect, we administrated both TMZ and RSV in diabetic rats. The results showed both TMZ and RSV could relieve renal insufficiency, ROS, and EMT. However, the combination of the two showed no obvious synergistic effect ( Supplementary Figure 2 ). The possible explanation is that, because they have the same mechanism of action, and the dosage of TMZ and RSV has reached the highest concentration of their effect in our experimental design, therefore, the combination of the two does not see a stronger anti-EMT effect.

Currently, the treatment of DN mainly consists of four parts: glycemic control, blood pressure control, inhibition of the renin-angiotensin system, and cardiovascular risk reduction (Umanath and Lewis, 2018). To date, no therapy specifically targeted at renal fibrosis is known. Although new hypoglycemic drugs with additional mechanisms are being tested for DN, such as SGLT2 inhibitor and GLP-1 activator (Warren et al., 2019), drugs targeting at renal fibrosis are needed to be used as adjuvant treatments to prevent the development and progression of DN. Our study demonstrates the renal protective effect of TMZ in relieving tubulointerstitial fibrosis in diabetic rats. Moreover, TMZ rarely has side effects in clinical practice in the past years. Therefore, TMZ is promising as a new adjuvant therapy for DN in the future. In our study, we found that TMZ was a potential Sirt1 agonist. Sirt1 has a protective effect on multiple organs, especially the heart (Gomes et al., 2019). Most patients with chronic renal failure are accompanied by cardiac insufficiency. Therefore, long-term use of TMZ in patients with DN may benefit from multiple organs and display a better result.

In conclusion, our study provides experimental evidences suggesting that TMZ can attenuate the development and the progression of renal dysfunction in DN. The underlying mechanism comes from TMZ’s inhibition of tubulointerstitial fibrosis by blunting EMT. In detail, TMZ inhibits ROS pathway and TGFβ/Smad pathway to relieve EMT in a diabetic environment by upregulating Sirt1. Further clinical research will be needed to verify if TMZ is an effective adjuvant drug, in combination with hypoglycemic agents and other treatments, against DN.

#3

Poor muscle function is increasingly obvious with aging and needs effective and safe medicine for treatment. Trimetazidine (TMZ) has potential benefits for the condition but has not yet been fully recognized. In the randomized-control pilot study part, fifty-three old patients were assigned to the TMZ group or control group. For the TMZ group, a dose of 35 mg of oral TMZ was administered with a meal twice a day for 3 months. Only conventional treatments were administrated in the control group. Muscle strength, gait speed, muscle endurance, and balance maintenance were measured during the visits. In the experiments part, thirty mice were screened and randomly assigned to three groups: model group received a D-gal (500 mg/kg) intraperitoneal injection every two days for six weeks, the control group received saline at the same condition, and the intervention group received 5 mg/kg TMZ solution every two days by gavage for two weeks.

Swimming tests and forelimb grip strength measurements were also performed. Furthermore, significantly clustered profiles from differentially expressed genes were found by RNA-seq and verified by qRT-PCR and WB. Myofiber analyses were done by H&E staining. Here, we found the improvement of skeletal performance in aged individuals and aged mouse. The dominant handgrip strength (HS) was increased by 24.4% and dominant pinch strength (PS) by 12.4% in participants with TMZ modified-release tablets consumption. Exhaustive time was increased by 23.6% and upper limb grip strength by 44.1% in aged mouse with TMZ-treated. Besides, we also identified some newly discovered molecules associated with TMZ on muscle function improvement during aging. To aged C2C12 cells and aged mouse muscle, TMZ-treated was related to a statistically significant decrease in the expressions of NOS3 and MMP-9, but a statistically significant increase in the expressions of OMD and MyoG. In summary, TMZ modified-release tablets can improve the muscle strength of elderly patients. Besides, the improvement of skeletal muscle function affected by TMZ was associated with reducing NOS3 expression in senescent myoblasts.

Bipolar depression is different from major depressive disorder in its ontogeny and clinical characteristics [11, 186]. Their biological differences are highlighted by the fact that antidepressant monotherapy is not recommended to treat bipolar depression [7, 13]. In this review, three major biological processes associated with bipolar depression were highlighted. Overall, evidence for mitochondrial dysfunction, inflammation and oxidative stress in bipolar depression is consistent with many replicated findings across tissue types, molecular assays, and ethnicities [187, 188]. A particularly compelling hypothesis is that bipolar depression is a state of decreased mitochondrial energy generation, which may be overcompensated by increased mitochondrial energy generation in mania [20–25]. Trimetazidine’s main activity in boosting mitochondrial energy generation only when mitochondrial function is reduced, while also targeting inflammation and oxidative stress that occurs in both depression and mania in bipolar disorder makes it a promising novel pharmacotherapy candidate to be tested in clinical trials. Should such trials yield positive outcomes, it can be rapidly translated into clinical care to treat bipolar depression due to its availability, low cost, safety, and tolerability.

Trimetazidine is a selective inhibitor of 3-ketoacyl-CoA thiolase.
Hence trimetazidine modulates mitochondrial energy production by inhibiting fatty acid oxidation to engage efficient glucose oxidation, which increases adenosine triphosphate (ATP) conversion compared to oxygen consumed. Trimetazidine also increases pyruvate dehydrogenase activity to decrease lactate accumulation. These effects ultimately reduces intracellular calcium ion accumulation and reactive oxygen species (ROS) to reduce apoptosis, inflammation and oxidative stress indicated by reduced level of biomarkers such as tumor necrosis factor alpha (TNF-α) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2. Trimetazidine has also been shown to increase antioxidant activity measured by increased glutathione, glutathione peroxidase, superoxide dismutase (SOD), and catalase. Taken together, accumulating preclinical and clinical evidence of trimetazidine’s regulation of mitochondrial function, anti-inflammatory and antioxidant properties strongly support its potential efficacy to reduce bipolar depression. Figure created with Biorender.com.

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It’s available in :fr:

Last, trimetazidine was not associated with any safety issues. There were no statistically significant differences between the treatment groups in the primary safety endpoint. The incidence of adjudicated adverse events was low and well balanced between treatment groups. Notably, a possible association between trimetazidine and Parkinsonism has been previously described. In our study, the occurrence of neurological symptoms such as Parkinson’s disease, atypical Parkinsonism, or drug-induced Parkinsonism, were similar in the placebo and trimetazidine arms.

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31790-6/abstract

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#4

Obesity induces skeletal muscle dysfunction. The pathogenesis of which appears to substantially involve mitochondrial dysfunction, arising from impaired quality control. Exercise is a major therapeutic strategy against muscle dysfunction. Trimetazidine, a partial inhibitor of lipid oxidation, has been proposed as a metabolic modulator for several cardiovascular pathologies. However, the effects of Trimetazidine on regulating skeletal muscle function are largely unknown. Our present study used cell culture and obese mice models to test a novel hypothesis that Trimetazidine could improve muscle atrophy with similar results to exercise. In C2C12 cells, high palmitic acid-induced atrophy and mitochondrial dysfunction, which could be reversed by the treatment of Trimetazidine. In our animal models, with high-fat diet-induced obesity associated with skeletal muscle atrophy, Trimetazidine prevented muscle dysfunction, corrected metabolic abnormalities, and improved mitochondrial quality control and mitochondrial functions similarly to exercise. Thus, our study suggests that Trimetazidine successfully mimics exercise to enhance mitochondrial quality control leading to improved high-fat diet-induced muscle dysfunction.

Human hallmarks of sarcopenia include muscle weakness and a blunted response to exercise. Nicotinamide N-methyltransferase inhibitors (NNMTis) increase strength and promote the regenerative capacity of aged muscle, thus offering a promising treatment for sarcopenia. Since human hallmarks of sarcopenia are recapitulated in aged (24-month-old) mice, we treated mice from 22 to 24 months of age with NNMTi, intensive exercise, or a combination of both, and compared skeletal muscle adaptations, including grip strength, longitudinal running capacity, plantarflexor peak torque, fatigue, and muscle mass, fiber type, cross-sectional area, and intramyocellular lipid (IMCL) content. Exhaustive proteome and metabolome analyses were completed to identify the molecular mechanisms underlying the measured changes in skeletal muscle pathophysiology. Remarkably, NNMTi-treated aged sedentary mice showed ~ 40% greater grip strength than sedentary controls, while aged exercised mice only showed a 20% increase relative to controls. Importantly, the grip strength improvements resulting from NNMTi treatment and exercise were additive, with NNMTi-treated exercised mice developing a 60% increase in grip strength relative to sedentary controls. NNMTi treatment also promoted quantifiable improvements in IMCL content and, in combination with exercise, significantly increased gastrocnemius fiber CSA. Detailed skeletal muscle proteome and metabolome analyses revealed unique molecular mechanisms associated with NNMTi treatment and distinct molecular mechanisms and cellular processes arising from a combination of NNMTi and exercise relative to those given a single intervention. These studies suggest that NNMTi-based drugs, either alone or combined with exercise, will be beneficial in treating sarcopenia and a wide range of age-related myopathies.