Ginsenoside Rb1 Ameliorates Age-Related Myocardial Dysfunction by Regulating the NF-κB Signaling Pathway

2020 ◽  
Vol 48 (06) ◽  
pp. 1369-1383
Author(s):  
Shi-Ye Ke ◽  
Ding-Hui Liu ◽  
Lin Wu ◽  
Xian-Guan Yu ◽  
Min Wang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Myocardial Dysfunction ◽  
Internal Diameter ◽  
Ginsenoside Rb1 ◽  
Aged Mice ◽  
Age Related ◽  
Collagen Iii ◽  
Related Proteins ◽  
Molecular Expression

Age-related myocardial dysfunction is a very large healthcare burden. Here, we aimed to investigate whether ginsenoside Rb1 (Rb1) improves age-related myocardial dysfunction and to identify the relevant molecular mechanism. Young mice and aged mice were injected with Rb1 or vehicle for 3 months. Then, their cardiac function was inspected by transthoracic echocardiography. Serum and myocardium tissue were collected from all mice for histological or molecular expression analyses, including aging-related proteins, markers relevant to fibrosis and inflammation, and markers indicating the activation of the nuclear factor-kappa B (NF-[Formula: see text]B) pathway. Compared with the control condition, Rb1 treatment significantly increased the ejection fraction percentage and significantly decreased the internal diameter and volume of the left ventricle at the end-systolic and end-diastolic phases in aged mice. Rb1 treatment reduced collagen deposition and collagen I, collagen III, and transforming growth factor-[Formula: see text]1 protein expression levels in aged hearts. Rb1 also decreased the aging-induced myocardial inflammatory response, as measured by serum or myocardial interleukin-6 and tumor necrosis factor-[Formula: see text] levels. Furthermore, Rb1 treatment in aged mice increased cytoplasmic NF-[Formula: see text]B but decreased nuclear NF-[Formula: see text]B, which indicated the suppression of the NF-[Formula: see text]B signaling pathway by regulating the translocation of NF-[Formula: see text]B. Rb1 could alleviate aging-related myocardial dysfunction by suppressing fibrosis and inflammation, which is potentially associated with regulation of the NF-[Formula: see text]B signaling pathway.

scholarly journals Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway

2021 ◽  
Vol 22 (4) ◽  
pp. 1985
Author(s):  
Xiaohe Li ◽  
Ling Ma ◽  
Kai Huang ◽  
Yuli Wei ◽  
Shida Long ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
In Vivo Experiments ◽  
Age Related ◽  
And Migration ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-β1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-β1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway.

Abstract 65: Restoration of Growth Differentiation Factor 11 Protects Against Stroke in Mice

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Anjali Chauhan ◽  
Jacob Hudobenko ◽  
Anthony Patrizz ◽  
Louise D McCullough
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
The Elderly ◽  
Vehicle Group ◽  
Peripheral Tissues ◽  
Delayed Treatment ◽  
Aged Mice ◽  
Infarct Area ◽  
Age Related

Introduction: GDF 11 is a member of the transforming growth factor β superfamily. Loss of GDF11 occurs with aging and declining levels correlate with several detrimental age-associated phenotypes in both peripheral tissues and brain. Restoration of GDF11 enhances neurogenesis and cognitive function in aged mice. Brain expression of GDF11 has not been investigated after stroke. Stroke differentially affects the elderly. In this work we examined the role of GDF11 in aging, stroke and its potential utility as a neuroprotective agent. Methods: Male C57/BL6NCrl young (2-3 months) and aged (19-21) mice were used. Brain GDF11 expression was evaluated in young and aged mice by western blot. Focal ischemia was induced with a transient middle cerebral artery occlusion (MCAO). Mice were randomly assigned into two groups and were subjected to 90 min MCAO. Group 1 received vehicle (phosphate buffered saline) and group 2 was administered rGDF11 (100 ug/kg., ip) at the onset of ischemia. In additional experiments, the efficacy of delayed treatment (3 h after ischemia) with rGDF11 was tested. These mice were subjected to a 60 min MCAO. Mice were euthanized after 24 hours and 7 days respectively and brains were harvested to estimate infarct area. Results: A significant decrease in brain GDF11 levels was observed in aged mice as compared to young (p<0.05). Additionally, a significant decline in brain GDF11 expression was observed after stroke at 24 hours vs. sham groups (p<0.05). A significant decrease in cortical and hemispheric infarct area was observed in the rGDF11 group (cortical 48.73±1.05; hemisphere 49.68±3.58) as compared to vehicle group (60.54±4.88; 61.35±6.03), when GDF was administered at the time of ischemia. Delayed treatment with rGDF11 also reduced infarct at 7 days. Conclusions: Brain GDF11 levels decline with age and after stroke. Supplementation with rGDF11 ameliorates stroke induced injury in young mice at 24h and 7 days. These finding suggest potential role of GDF11 in age and stroke. Restoration of age-related loss of GDF may be a viable therapy for stroke.

scholarly journals Improvement of muscular atrophy by AAV–SaCas9-mediated myostatin gene editing in aged mice

2020 ◽  
Vol 27 (12) ◽  
pp. 960-975
Author(s):  
Shaoting Weng ◽  
Feng Gao ◽  
Juan Wang ◽  
Xingyu Li ◽  
Beibei Chu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Gene Editing ◽  
Therapeutic Potential ◽  
Muscular Atrophy ◽  
Muscle Cells ◽  
Physiological Status ◽  
Myostatin Gene ◽  
Aged Mice ◽  
Protein Levels ◽  
Age Related

AbstractMuscle mass and area usually decrease with age, and this phenomenon is known as sarcopenia. This age-related atrophy correlates with insufficient levels of muscle cells differentiate and proliferate regulated by the TGF-β signaling pathway and the expression of E3s ubiquitin-protein ligase by the aged. Sarcopenia makes a huge impact on the aging society, because it has the characteristic of high incidence, extensive adverse effects and disease aggravation gradually. Guided by a single-guide RNA (sgRNA), Cas9 nuclease has been widely used in genome editing, opening up a new pathway for sarcopenia treatment. Here, we present two rAAV9 systems, pX601-AAV-CMV:SaCas9-U6:sgRNA and pX601-AAV-EF1α:SaCas9-tRNAGLN: sgRNA, which edited myostatin efficiently. By delivering the two rAAV–SaCas9 targets to myostatin via intramuscular injection of aged mice, an increase in body weight and an increase in the number and area of myofibers were observed. Knockout of myostatin led to TGF-β signaling pathway changes, and increased MyoD, Pax7 and MyoG protein levels and increased the number of satellite cells to improve muscle cells differentiation. Moreover, knockout of myostatin prevented the atrophy of muscle cells through reduced Murf1 and MAFbx protein levels. We found that both rAAV–SaCas9 systems had gene editing efficiency, reducing the expression of myostatin by affecting the relevant signaling pathways, thereby altering the physiological status. We showed that myostatin has an important role in activating skeletal muscle proliferation and inhibiting muscular atrophy during aging. Thus, we propose that knockout of myostatin using the rAAV9–SaCas9 system has significant therapeutic potential in sarcopenia.

Reduced Levels of mTOR and TGF- β Signaling Pathway-Associated Proteins in Patients with High Risk MDSsamia AL-Shouli. , Pilar Perezabellan, Frederic Toulza. Shahram Kordasti, Ghulam Mufti

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5501-5501
Author(s):  
Samia Towfeek Al-Shouli ◽  
Ghulam J Mufti
Keyword(s):  
T Cells ◽  
High Risk ◽  
Signaling Pathway ◽  
Transforming Growth Factor Beta ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Conflicts Of Interest ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Related Proteins

Abstract Background: T cell mediated immune dysregulation is an important feature of MDS. The expansion of regulatory T cells (Tregs) is one of the important factors in the progression of intermediate/high risk myelodysplastic syndrome (MDS) to acute myeloid leukemia. However, the exact mechanism for the expansion of Tregs in MDS is not known. Intracellular complements (particularly C3a and C5a) play a crucial role in the polarization of CD4+ T cells toward regulatory or effector phenotypes through Transforming growth factor-beta (TGF-β) pathway (C5aR2 mediated) or Mammalian Target of Rapamycin (mTOR)(C5aR mediated) respectively. The aim of this study was to investigate the potential role of mTOR and Akt as important proteins in complement related polarization of CD4+ T cells toward pro-inflammatory T helper cells in MDS. We have also studied the TGF-β signaling pathway related proteins, which are crucial for the expansion of Tregs. We investigated the level of TGF- β related proteins (phosphorylated (p) SMADs), as well as mTORc and Akt (Ser473) in high risk MDS and healthy donors (HD) before and after stimulation with CD3 and CD46 as a complement related co-stimulatory molecule. Methods: Peripheral blood mononuclear cell (PBMCs) from healthy controls and high-risk MDS patients were used for this study. Anti-CD3 (2.0 µg/mL), anti-CD28 (3.0 µg/mL) and/or anti-CD46 (2.0 µg/mL) antibodies were used to stimulate cells. The total protein was extracted by Bicinchoninic Acid (BCA) assay and quantified by nano-drop. The MILLIPLEX MAP Human TGF-β Signaling Magnetic Bead Panel 6-plex was used to detect the signaling changes in cell lysates using the Luminex® system following the manufacturer's instructions. Data were analysed using Microsoft Excel and expressed in means and standards deviation. The students T-test were used to assess the difference in means between groups. Results: TGF-β signaling pathway proteins pSMAD2, pSMAD3 and pSMAD4 as well as mTORc were evaluated. Unstimulated PBMCs from high-risk MDS patients showed a significantly lower level of m-TOR (p=0.01), pSMAD2 (p=0.01), pSMAD3 (p=0.02) and pSMAD4 (p=0.044) as compared to healthy donors. Following stimulation with anti-CD3±CD46 for 24 hours, there was no significant increase in protein levels of mTORc or Akt. However, in high-risk MDS patients the level of pSMAD2 (p=0.02) and pSMAD4 (p=0.006) remain significantly lower than healthy donors after 24 hours of stimulation with anti-CD3 and CD46. An aliquot of cells were used for flowcytometry following stimulation. Interestingly Tregs phenotype CD4+CD25highCD127lowexpressed higher level of intracellular C5aR2 in MDS (n=5) compared to HD (n=5). Conclusion: mTORc protein level in MDS is reduced and does not change in response to complement receptor stimulation neither does the level of Akt. This may prevent T cells to polarize toward pro-inflammatory T cells (Th1 or Th17) therefore avert an effective immune-surveillance against malignant clone. Lack of response to complement related co-stimulation and increase in C5aR2 expression suggest a potential mechanism for Treg expansion in MDS. These findings may lead to identification of new therapeutic targets in MDS, although need further studies on larger cohort of patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Mice overexpressing latent TGF-β1 are protected against renal fibrosis in obstructive kidney disease

2008 ◽  
Vol 295 (1) ◽  
pp. F118-F127 ◽  
Author(s):  
Xiao R. Huang ◽  
Arthur C. K. Chung ◽  
Xiao J. Wang ◽  
Kar Neng Lai ◽  
Hui Y. Lan
Keyword(s):  
Kidney Disease ◽  
Signaling Pathway ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Critical Factor ◽  
Collagen I ◽  
Collagen Iii ◽  
Renal Histology ◽  
Tgf Β1

Transforming growth factor (TGF)-β1, once activated, binds to its receptors and mediates renal fibrosis via the downstream Smad signaling pathway. We reported here that mice overexpressing latent TGF-β1 in keratinocytes were protected against renal fibrosis in a model of obstructive kidney disease. In normal mice, both transgenic (Tg) and wild-type (WT) mice had normal renal histology and function, despite a 10-fold increase in plasma latent TGF-β1 in Tg mice. A severe renal fibrosis was developed in WT mice at 7 days after urinary obstruction. Unexpectedly, renal fibrosis was prevented in Tg mice, although levels of latent TGF-β1 in both circulation and renal tissues remained high. Compared with the WT mice, quantitative real-time PCR showed that upregulation of renal α-smooth muscle actin (SMA), collagen I, and collagen III mRNA was inhibited in Tg mice (60–70% reduced, all P < 0.01). These were further confirmed by immunohistochemistry with a marked inhibition of tubulointerstitial accumulation of α-SMA+ fibroblasts, collagen I, and collagen III matrix in Tg mice (all P < 0.001). Further studies showed that inhibition of renal fibrosis in Tg mice was associated with a significant reduction in renal TGF-β1 and CTGF (60% reduced, P < 0.05), an increase in renal Smad7, a suppression of TSP-1 (a critical factor for TGF-β1 activation), and an inhibition of Smad2/3 activation (all P < 0.001). In conclusion, latent TGF-β may play a protective role in renal fibrosis. Inhibition of renal TGF-β1 expression and activation, thereby blocking the downstream TGF-β signaling pathway, may be a critical mechanism by which latent TGF-β1 protects against renal fibrosis.

scholarly journals Pirfenidone Alleviates Choroidal Neovascular Fibrosis through TGF-β/Smad Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Chuang Gao ◽  
Xin Cao ◽  
Lili Huang ◽  
Yueqi Bao ◽  
Tao Li ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Age Related Macular Degeneration ◽  
Type I ◽  
Fundus Fluorescein Angiography ◽  
Smad Signaling ◽  
Age Related ◽  
Smad Signaling Pathway

Background. Transforming growth factor-β (TGF-β) plays a major role in CNV. However, the mechanism is unclear. This study investigates the effect of Pirfenidone (PFD) on TGF-β/Smad signaling pathway on the development of choroidal neovascular fibrosis in choroidal neovascularization (CNV) mouse model. C57BL/6J male mice (aged from 6 to 8 weeks) received intravitreal injections of phosphate-buffered saline (PBS)/PFD solution on 14 days after laser injury. Mice were anesthetized by intraperitoneal injection of 4% pentobarbital (0.05 mg/g body weight). Optical Coherence Tomography (OCT), Fundus Fluorescein angiography (FFA), and hematoxylin-eosin (HE) were used to assess CNV formation. The fibrosis area was monitored by staining the collagen type I (Col-I). Western blotting was used to analyze the expression of TGF-β2, Smad 2/3, phosphorylated Smad 2/3 (p-Smad 2/3), and α-smooth muscle actin (α-SMA). Terminal deoxynucleotidy1 transferase dUTP nick-end labelling (TUNEL) assay was performed on cryosections of mouse eyes to detect apoptosis. Our data showed PFD inhibited areas of fibrosis during day 21 to day 28. We also found that the levels of TGF-β2 protein expressions increasingly reached the peak till the 3rd week during the CNV development. The protein levels of Smad 2/3, p-Smad 2/3, and α-SMA also increased significantly in CNV mice, but this response was profoundly suppressed by the TGF-β inhibitor PFD. The results of this study suggest that TGF-β2 represents a target to prevent or treat choroidal neovascular fibrosis, and PFD may provide an alternative to traditional methods for Wet Age-related macular degeneration (wAMD) treatment.

scholarly journals Reduced TGF-β Expression and CD206-Positive Resident Macrophages in the Intervertebral Discs of Aged Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Yuji Yokozeki ◽  
Ayumu Kawakubo ◽  
Masayuki Miyagi ◽  
Akiyoshi Kuroda ◽  
Hiroyuki Sekiguchi ◽  
...  
Keyword(s):  
Real Time ◽  
Real Time Pcr ◽  
Transforming Growth Factor ◽  
Intervertebral Discs ◽  
M2 Macrophage ◽  
Aged Mice ◽  
Age Related ◽  
Key Factor ◽  
Time Point

Age is a key factor in intervertebral disc (IVD) degeneration; however, the changes that occur in IVDs with age are not fully understood. Tissue-resident macrophages are critical for tissue homeostasis and are regulated by transforming growth factor- (TGF-) β. We examined changes in the proportion of resident macrophages in young versus aged mice and the role of TGF-β in regulating resident macrophages in IVDs. IVDs were harvested from 4-month (young) and 18-month-old (aged) C57BL/6J mice. The proportion of macrophages in IVDs was determined using flow cytometry ( n = 5 for each time point) and the expression of Cd11b, Cd206, and Tgfb genes, which encode CD11b, CD206, and TGF-β protein, respectively, using real-time PCR. To study the role of TGF-β in the polarization of resident macrophages, resident macrophages isolated from IVDs from young and aged mice were treated with recombinant TGF-β with and without a TGF-β inhibitor (SB431542). Additionally, SB431542 was intraperitoneally injected into young and aged mice, and Cd206 expression was examined using real-time PCR ( n = 10 for each time point). The proportion of CD11b+ and CD11b+ CD206+ cells was significantly reduced in aged versus young mice, as was Cd11b, Cd206, and Tgfb expression. TGF-β/IL10 stimulation significantly increased the expression of Cd206, an M2 macrophage marker, in disc macrophages from both young and aged mice. Meanwhile, administration of a TGF-β inhibitor significantly reduced Cd206 expression compared to vehicle control in both groups. Conclusion. Resident macrophages decrease with age in IVDs, which may be associated with the concomitant decrease in TGF-β. Our findings provide new insight into the mechanisms of age-related IVD pathology.

scholarly journals Preservation of Cognitive Function byLepidium meyenii(Maca) Is Associated with Improvement of Mitochondrial Activity and Upregulation of Autophagy-Related Proteins in Middle-Aged Mouse Cortex

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Shan-Shan Guo ◽  
Xiao-Fang Gao ◽  
Yan-Rong Gu ◽  
Zhong-Xiao Wan ◽  
A-Ming Lu ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Cognitive Decline ◽  
Mitochondrial Function ◽  
Mitochondrial Activity ◽  
Middle Aged ◽  
Aged Mice ◽  
Age Related ◽  
Mouse Cortex ◽  
Related Proteins ◽  
Age Related Cognitive Decline

Maca has been used as a foodstuff and a traditional medicine in the Andean region for over 2,000 years. Recently the neuroprotective effects of maca also arouse interest of researchers. Decrease in mitochondrial function and decline in autophagy signaling may participate in the process of age-related cognitive decline. This study aimed to investigate if maca could improve cognitive function of middle-aged mice and if this effect was associated with improvement of mitochondrial activity and modulation of autophagy signaling in mouse cortex. Fourteen-month-old male ICR mice received maca powder administered by gavage for five weeks. Maca improved cognitive function, motor coordination, and endurance capacity in middle-aged mice, accompanied by increased mitochondrial respiratory function and upregulation of autophagy-related proteins in cortex. Our findings suggest that maca is a newly defined nutritional plant which can improve mitochondrial function and upregulate autophagy-related proteins and may be an effective functional food for slowing down age-related cognitive decline.

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