<p>Ninjin’yoeito Ameliorates Skeletal Muscle Complications in COPD Model Mice by Upregulating Peroxisome Proliferator-Activated Receptor γ Coactivator-1α Expression</p>

Abstract

Purpose: Sarcopenia, the loss of skeletal muscle mass and strength, is a common systemic consequence of chronic obstructive pulmonary disease (COPD) and is correlated with higher mortality. Ninjin'yoeito (NYT) is a Japanese herbal medicine used to treat athrepsia and anorexia and is reported to ameliorate weight loss and muscular dysfunction. Recent studies have shown that its crude components upregulate the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)-related pathway, which is involved in skeletal muscle functions. Here, we examined whether NYT improves skeletal muscle complications by upregulating PGC-1α in COPD model mice. Materials and Methods: Mice were divided into four groups: control, NYT, smoking, and smoking + NYT. The smoking and smoking + NYT groups were exposed to cigarette smoke for 60 min once daily. The mice in the NYT and smoking + NYT groups were fed an NYT-containing diet (3% w/w). We performed cellular analysis of bronchoalveolar lavage fluid, assessed pulmonary morphological changes, examined the expression of PGC-1α mRNA and protein in the gastrocnemius and soleus muscle, measured the hindlimb muscle volume with micro-computed tomography, and determined the myofiber proportion in soleus muscle after 12 weeks. Results: Cigarette smoke exposure resulted in reduced skeletal muscle volume and slowtwitch muscle fibers and development of pulmonary emphysema. NYT feeding induced partial recovery of the damaged alveolar wall; however, NYT did not ameliorate smokeinduced alveolar enlargement. These findings revealed that NYT did not have sufficient efficacy in suppressing pulmonary emphysema. On the other hand, PGC-1α expression in muscle tissue of the NYT-fed mice increased significantly, resulting in suppression of smokeinduced loss of muscle mass and alteration in the muscle fiber distribution. Conclusion: NYT increases PGC-1α expression in the muscle of COPD model mice and is involved in suppressing cigarette smoke-induced muscle complications. NYT may be a novel preventive and therapeutic medication for muscular dysfunctions in COPD.

Ninjinyoeito ameliorated cigarette smoke extract-induced apoptosis and inflammation through JNK signaling inhibition in human lung fibroblasts

“…NYT reportedly ameliorates cigarette smoke-induced alveolar damage as indicated by the destructive index; however, it does not affect the air space enlargement, as indicated by the mean linear intercept in a cigarette smoke-induced COPD mice model [8]. This report suggests that NYT has some favorable effects on the localized damage to the alveolar wall, including that on fibroblasts, and that NYT has no effects on other connective structures, such as elastic fibers [8]. However, this report did not investigate the type of cells and the mechanism by which NYT treatment ameliorates cigarette smoke-induced injury.…”

“…In an in vivo study, NYT could ameliorate cigarette smokeinduced alveolar damage, as indicated by the destructive index in a mouse model of cigarette smoke-induced COPD. Although this previous report did not investigate the mechanism of action of NYT on lung damage, the authors suggested that NYT has some favorable effects on localized damage to the alveolar wall, including that on fibroblasts [8]. In addition, NYT has also been reported to have radical scavenging activity in hepatocytes [9] and can ameliorate nitric oxide-mediated lung injury in a murine cytomegalovirus (MCMV)-infected model [10].…”

Ninjinyoeito Ameliorated Cigarette Smoke Extract-induced Apoptosis and Inflammation Through JNK Signaling Inhibition in Human Lung Fibroblasts

“…NYT reportedly ameliorates cigarette smoke-induced alveolar damage as indicated by the destructive index; however, it does not affect the air space enlargement, as indicated by the mean linear intercept in a cigarette smoke-induced COPD mice model. This report suggests that NYT has some favorable effects on the localized damage to the alveolar wall, including that on broblasts, and that NYT has no effects on other connective structures, such as elastic bers [8]. However, this report did not investigate the type of cells and the mechanism by which NYT treatment ameliorates cigarette smoke-induced lung injury.…”

“…In an in vivo study, NYT could ameliorate cigarette smoke-induced alveolar damage, as indicated by the destructive index in a mouse model of cigarette smoke-induced COPD. Although this previous report did not investigate the mechanism of action of NYT on lung damage, the authors suggested that NYT has some favorable effects on localized damage to the alveolar wall, including that on broblasts [8]. In addition, NYT has also been reported to have radical scavenging activity in hepatocytes [9] and can ameliorate nitric oxidemediated lung injury in a murine cytomegalovirus (MCMV)-infected model [10].…”

The Protective Role of Hydrogen Sulfide and Its Impact on Gene Expression Profiling in Rat Model of COPD

“…Our study has found some DE genes between NaHS treatment group and CS + LPS group, such as Psen1 , Ptgs2 , Mpo , and Slc23a2 , were involved in oxidative stress pathway, and Ppargc1a was upregulated by NaHS treatment. The protein encoded by Ppargc1a gene (also known as PGC-1 α in human) is peroxisome proliferator-activated receptor gamma coactivator 1 α (PGC-1 α ), as a transcriptional coactivator, it is an important regulator of energy metabolism [ 34 ], overexpressed PGC-1 α alleviates oxidative stress and decreases apoptotic cell death in endothelial cells [ 34 ], and upregulation of PGC-1 α is associated with reduction of oxidative stress and inflammation in diabetic myocardium [ 35 ] and attenuation of COPD in mice [ 36 ]. PGC-1 α is essential for the induction of ROS-detoxifying enzymes such as glutathione peroxidase and SOD2 under oxidative stress, PGC-1 α null mice were sensitive to oxidative stress [ 37 ]; PGC-1 α inhibited mitochondrial oxidative stress by facilitating Nrf2 binding to antioxidant response element promoter site and inducing SOD2 expression in sepsis [ 38 ].…”