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1.
Neuro Endocrinol Lett ; 43(4): 208-212, 2022 Nov 30.
Article in English | MEDLINE | ID: mdl-36528882

ABSTRACT

BACKGROUND: Patients with adrenal Cushing's syndrome (ACS) typically present with central obesity, hirsutism, hypertension, or glucose intolerance, which can be easily identified by a clinical physician. However, recognizing those with subclinical CS or those with less common symptoms and signs is challenging to the subspecialist, which can lead to delayed diagnosis and treatment. We report a case who presented with repeated vertebral fractures in 6 months. Typical physical appearance of CS was not shown so that suspicions were not raised until severe osteoporosis was demonstrated from bone marrow density study. From our case report, endocrine tests and image survey should always be considered in young patients with repeat vertebral fractures. CASE PRESENTATION: A 48-year-old man presented with severe back pain for 3 months. Second and fifth lumbar spine (L2 and L5) vertebral compression fractures were noted from X-ray and magnetic resonance imaging (MRI), and vertebroplasty was performed by orthopedic surgeons. After 1 month, a newly developed compression fracture of the ninth to twelfth thoracic spine and L4-L5 were noted. Severe osteoporosis was noted from the hip bone mineral density test, and he was referred to an endocrinologist for analysis. Serial endocrine tests confirmed hypercortisolism, and subsequent abdomen MRI showed a left adrenal tumor. ACS was diagnosed. Left laparoscopic adrenalectomy was performed, and the patient received cortisol supplement for 12 months. Thereafter, no new fractures were identified. CONCLUSIONS: ACS should be considered and carefully verified in middle-aged adults who present with severe osteoporosis and repeated vertebral compression fracture.


Subject(s)
Adrenal Gland Neoplasms , Bone Diseases, Metabolic , Fractures, Compression , Osteoporosis , Osteoporotic Fractures , Spinal Fractures , Male , Middle Aged , Humans , Young Adult , Spinal Fractures/complications , Spinal Fractures/diagnostic imaging , Spinal Fractures/surgery , Fractures, Compression/diagnostic imaging , Fractures, Compression/surgery , Adrenal Gland Neoplasms/complications , Adrenal Gland Neoplasms/diagnostic imaging , Adrenal Gland Neoplasms/surgery , Osteoporotic Fractures/surgery
2.
Front Oncol ; 12: 791620, 2022.
Article in English | MEDLINE | ID: mdl-35574295

ABSTRACT

Purpose: This study aimed to compare the oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) without clinical lymph node metastasis (cN0) undergoing lymph node dissection (LND) during radical nephroureterectomy (NU). Methods: From the updated data of the Taiwan UTUC Collaboration Group, a total of 2726 UTUC patients were identified. We only include patients with ≥ pT2 stage and enrolled 658 patients. The Kaplan-Meier estimator and Cox proportional hazards model were used to analyze overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), and bladder recurrence-free survival (BRFS) in LND (+) and LND (-) groups. Results: A total of 658 patients were included and 463 patients without receiving LND and 195 patients receiving LND. From both univariate and multivariate survival analysis, there are no significant difference between LND (+) and LND (-) group in survival rate. In LND (+) group, 18.5% patients have pathological LN metastasis. After analyzing pN+ subgroup, it revealed worse CSS (p = 0.010) and DFS (p < 0.001) compared with pN0 patients. Conclusions: We found no significant survival benefit related to LND in cN0 stage, ≥ pT2 stage UTUC, irrespective of the number of LNs removed, although pN+ affected cancer prognosis. However, from the result of pN (+) subgroup of LND (+) cohort analysis, it may be reasonable to not perform LND in patients with cT2N0 stage due to low positive predictive value of pN (+). In addition, performing LND may be considered for ureter cancer, which tends to cause lymphatic and hematogenous tumor spreading. Further large prospective studies are needed to validate our findings.

3.
J Pers Med ; 12(2)2022 Feb 06.
Article in English | MEDLINE | ID: mdl-35207714

ABSTRACT

The clinical efficacy of adjuvant chemotherapy in upper tract urothelial carcinoma (UTUC) is unclear. We aimed to assess the therapeutic outcomes of adjuvant chemotherapy in patients with advanced UTUC (pT3-T4) after radical nephroureterectomy (RNU). We retrospectively reviewed the data of 2108 patients from the Taiwan UTUC Collaboration Group between 1988 and 2018. Comprehensive clinical features, pathological characteristics, and survival outcomes were recorded. Univariate and multivariate Cox proportional hazards models were used to evaluate overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS). Of the 533 patients with advanced UTUC included, 161 (30.2%) received adjuvant chemotherapy. In the multivariate analysis, adjuvant chemotherapy was significantly associated with a reduced risk of overall death (hazard ratio (HR), 0.599; 95% confidence interval (CI), 0.419-0.857; p = 0.005), cancer-specific mortality (HR, 0.598; 95% CI, 0.391-0.914; p = 0.018), and cancer recurrence (HR, 0.456; 95% CI, 0.310-0.673; p < 0.001). The Kaplan-Meier survival analysis revealed that patients receiving adjuvant chemotherapy had significantly better five-year OS (64% vs. 50%, p = 0.002), CSS (70% vs. 62%, p = 0.043), and DFS (60% vs. 48%, p = 0.002) rates compared to those who did not receive adjuvant chemotherapy. In conclusion, adjuvant chemotherapy after RNU had significant therapeutic benefits on OS, CSS, and DFS in advanced UTUC.

5.
Surg Endosc ; 36(6): 4342-4348, 2022 06.
Article in English | MEDLINE | ID: mdl-34716480

ABSTRACT

PURPOSE: Laparoscopic radical nephroureterectomy (LNU) has gradually become the new standard treatment for localized upper tract urothelial cancer (UTUC). With more blunt dissection and tactile sensation, hand-assisted LNU might shorten the operative time compared with the pure laparoscopic approach. However, whether the use of the hand-assisted or the pure laparoscopic approach has an effect on oncological outcomes remains unclear. METHODS: We retrospectively identified 629 patients with non-metastatic UTUC who underwent hand-assisted (n = 515) or pure LNU (n = 114) at 9 hospitals in Taiwan between 2004 and 2019. Overall survival, cancer-specific survival, recurrence-free survival, and bladder recurrence-free survival were compared between these two groups using inverse-probability of treatment weighting (IPTW) derived from the propensity scores for baseline covariate adjustment. RESULTS: The median follow-up period was 32.9 and 28.7 months in the hand-assisted and the pure groups, respectively. IPTW-adjusted Cox proportional hazards models showed that the laparoscopic approach (pure vs. hand-assisted) was not significantly associated with all-cause mortality (HR 0.79, 95% CI 0.49-1.24, p = 0.304), cancer-specific mortality (HR 0.88, 95% CI 0.51-1.51, p = 0.634), or extra-vesical recurrence (HR 0.65, 95% CI 0.41-1.04, p = 0.071). However, the pure laparoscopic approach was significantly associated with lower intra-vescial recurrence (HR 0.64, 95% CI 0.43-0.96, p = 0.029) for patients who underwent LNU. Kaplan-Meier curves also revealed that the pure laparoscopic approach was associated with better bladder recurrence-free survival compared with the hand-assisted laparoscopic approach in both the original cohort and the IPTW-adjusted cohort (log-rank p = 0.042 and 0.027, respectively). CONCLUSIONS: The performance of hand-assisted or pure LNU does not significantly affect the all-cause mortality, cancer-specific mortality, or extra-vesical recurrence for patients with non-metastatic UTUC. However, the hand-assisted laparoscopic approach could increase the risk of intra-vesical recurrence for patients who undergo LNU.


Subject(s)
Carcinoma, Transitional Cell , Laparoscopy , Ureteral Neoplasms , Urinary Bladder Neoplasms , Carcinoma, Transitional Cell/surgery , Female , Humans , Laparoscopy/methods , Male , Nephroureterectomy/methods , Retrospective Studies , Taiwan/epidemiology , Treatment Outcome , Ureteral Neoplasms/surgery , Urinary Bladder Neoplasms/surgery
6.
Nat Commun ; 12(1): 7041, 2021 12 06.
Article in English | MEDLINE | ID: mdl-34873175

ABSTRACT

Despite unprecedented responses of some cancers to immune checkpoint blockade (ICB) therapies, the application of checkpoint inhibitors in pancreatic cancer has been unsuccessful. Glucocorticoids and glucocorticoid receptor (GR) signaling are long thought to suppress immunity by acting on immune cells. Here we demonstrate a previously undescribed tumor cell-intrinsic role for GR in activating PD-L1 expression and repressing the major histocompatibility complex class I (MHC-I) expression in pancreatic ductal adenocarcinoma (PDAC) cells through transcriptional regulation. In mouse models of PDAC, either tumor cell-specific depletion or pharmacologic inhibition of GR leads to PD-L1 downregulation and MHC-I upregulation in tumor cells, which in turn promotes the infiltration and activity of cytotoxic T cells, enhances anti-tumor immunity, and overcomes resistance to ICB therapy. In patients with PDAC, GR expression correlates with high PD-L1 expression, low MHC-I expression, and poor survival. Our results reveal GR signaling in cancer cells as a tumor-intrinsic mechanism of immunosuppression and suggest that therapeutic targeting of GR is a promising way to sensitize pancreatic cancer to immunotherapy.


Subject(s)
B7-H1 Antigen/immunology , Carcinoma, Pancreatic Ductal/immunology , Histocompatibility Antigens Class I/immunology , Pancreatic Neoplasms/immunology , Receptors, Glucocorticoid/immunology , Tumor Escape/immunology , Animals , B7-H1 Antigen/genetics , B7-H1 Antigen/metabolism , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/therapy , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/metabolism , Humans , Immunoblotting , Immunotherapy/methods , Kaplan-Meier Estimate , Mice, Inbred C57BL , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/therapy , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tumor Escape/genetics
7.
Front Oncol ; 11: 731460, 2021.
Article in English | MEDLINE | ID: mdl-34671556

ABSTRACT

PURPOSE: This study aimed to compare the oncological outcomes and surgical complications of patients with upper tract urothelial carcinoma (UTUC) treated with different minimally invasive techniques for nephroureterectomy. METHODS: From the updated data of the Taiwan UTUC Collaboration Group, a total of 3,333 UTUC patients were identified. After excluding ineligible cases, we retrospectively included 1,340 patients from 15 institutions who received hand-assisted laparoscopic nephroureterectomy (HALNU), laparoscopic nephroureterectomy (LNU) or robotic nephroureterectomy (RNU) between 2001 and 2021. Kaplan-Meier estimator and Cox proportional hazards model were used to analyze the survival outcomes, and binary logistic regression model was selected to compare the risks of postoperative complications of different surgical approaches. RESULTS: Among the enrolled patients, 741, 458 and 141 patients received HALNU, LNU and RNU, respectively. Compared with RNU (41.1%) and LNU (32.5%), the rate of lymph node dissection in HALNU was the lowest (17.4%). In both Kaplan-Meier and univariate analysis, the type of surgery was significantly associated with overall and cancer-specific survival. The statistical significance of surgical methods on survival outcomes remained in multivariate analysis, where patients undergoing HALNU appeared to have the worst overall (p = 0.007) and cancer-specific (p = 0.047) survival rates among the three groups. In all analyses, the surgical approach was not related to bladder recurrence. In addition, HALNU was significantly associated with longer hospital stay (p = 0.002), and had the highest risk of major Clavien-Dindo complications (p = 0.011), paralytic ileus (p = 0.012), and postoperative end-stage renal disease (p <0.001). CONCLUSIONS: Minimally invasive surgery can be safe and feasible. We proved that compared with the HALNU group, the LNU and RNU groups have better survival rates and fewer surgical complications. It is crucial to uphold strict oncological principles with sophisticated technique to improve outcomes. Further prospective studies are needed to validate our findings.

8.
Front Oncol ; 11: 766576, 2021.
Article in English | MEDLINE | ID: mdl-35096575

ABSTRACT

BACKGROUND: Taiwan is one of the endemic regions where upper tract urothelial carcinoma (UTUC) accounts for approximately a third of all urothelial tumors. Owing to its high prevalence, extensive experience has been accumulated in minimally invasive radical nephroureterectomy (RNU). Although a variety of predictive factors have been explored in numerous studies, most of them were on a single-center or limited institutional basis and data from a domestic cohort are lacking. OBJECTIVE: This study aims to identify significant predicting factors of oncological outcomes, including overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), and intravesical recurrence-free survival (IVRFS), following RNU for UTUC in Taiwan. METHODS: A multicenter registry database, Taiwan UTUC Collaboration Group, was utilized to analyze oncological outcomes of 3,333 patients undergoing RNU from 1988 to 2021 among various hospitals in Taiwan. Clinicopathological parameters were recorded according to the principles established by consensus meetings. The Kaplan-Meier estimator was utilized to estimate the survival rates, and the curves were compared using the stratified log-rank test. Univariate and multivariate analyses were performed with the Cox proportional hazard model to explore potential predicting factors. RESULTS: With a median follow-up of 41.8 months in 1,808 patients with complete information, the 5-year IVRFS, DFS, CSS, and OS probabilities were 66%, 72%, 81%, and 70%, respectively. In total, 482 patients experienced intravesical recurrence, 307 died of UTUC, and 583 died of any cause. Gender predominance was female (57%). A total of 1,531 patients (84.7%) had high-grade tumors; preoperative hydronephrosis presented in 1,094 patients (60.5%). Synchronous bladder UC was identified in 292 patients (16.2%). Minimally invasive procedures accounted for 78.8% of all surgeries, including 768 hand-assisted laparoscopic (42.5%) and 494 laparoscopic (27.3%) approaches. Synchronous bladder UC was the dominant adverse predicting factor for all survival outcomes. Other independent predicting factors for OS, CSS, and DFS included age ≧70, presence of preoperative hydronephrosis, positive surgical margin, LVI, pathological T and N staging, and laparoscopic RNU. CONCLUSION: Synchronous UC of the urinary bladder is an independent adverse prognostic factor for survival in UTUC. The presence of preoperative hydronephrosis was also corroborated as a disadvantageous prognostic factor. Our multivariate analysis suggested that laparoscopic RNU might provide better oncological control.

9.
FASEB J ; 34(4): 4852-4869, 2020 04.
Article in English | MEDLINE | ID: mdl-32048347

ABSTRACT

Cellular long-chain fatty acids' (LCFAs) uptake is a crucial physiological process that regulates cellular energy homeostasis. AMPK has been shown to modulate LCFAs uptake in several kinds of cells, but whether it exerts an impact on intestinal LCFAs uptake is not quite clear. In the current study, we found that AMPK reinforced LCFAs uptake in intestinal epithelial cells (IECs). Moreover, intestinal epithelium-specific AMPK deletion impaired intestinal LCFAs absorption and protected mice from high-fat diet-induced obesity. Mechanistically, we discovered that AMPK deletion reduced the CD36 protein level by upregulating Parkin-mediated polyubiquitination of CD36 in IECs. Furthermore, our results revealed that AMPK affected PARK2 (gene name of Parkin) mRNA stability in a YTHDF2-dependent manner through FTO-dependent demethylation of N6 -methyladenosine (m6 A). Besides, AMPK promoted the translocation of CD36 to the plasma membrane in IECs, but the inhibition of AKT signaling suppressed this effect, which also halted the accelerated fatty acid uptake induced by AMPK. These results suggest that AMPK facilitates the intestinal LCFAs uptake by upregulating CD36 protein abundance and promoting its membrane translocation simultaneously. Such findings shed light on the role of AMPK in the regulation of intestinal LCFAs uptake.


Subject(s)
CD36 Antigens/metabolism , Fatty Acids/metabolism , Intestinal Absorption , Intestinal Mucosa/metabolism , Protein Kinases/metabolism , AMP-Activated Protein Kinase Kinases , Animals , CD36 Antigens/genetics , Caco-2 Cells , Female , HEK293 Cells , Humans , Male , Mice , Mice, Inbred C57BL , Protein Kinases/genetics , Proto-Oncogene Proteins c-akt/metabolism , RNA Stability , RNA, Messenger/metabolism , RNA-Binding Proteins/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism
10.
Free Radic Biol Med ; 129: 338-353, 2018 12.
Article in English | MEDLINE | ID: mdl-30273672

ABSTRACT

Dysregulated activation of inflammation is associated with the development and progression of many diseases. Generation of reactive oxygen species (ROS) has been shown to promote an inflammatory response. Cathelicidin peptides not only defend against the invasion of various microbes but also play an important role in regulating immune responses. The objective of this study was to investigate the effects and mechanisms of Cathelicidin-WA (CWA) on the inflammatory response and oxidative stress in macrophages. Our results showed that CWA efficiently attenuated lipopolysaccharide (LPS)-stimulated inflammation and oxidative stress both in vivo and in vitro. Mechanistically, we found that CWA significantly reduced the LPS-induced nuclear translocation of NF-κB, thus decreasing the production of the pro-inflammatory cytokines TNF-α and IL-6 in macrophages. On the other hand, CWA markedly promoted the nuclear translocation of Nrf2 via the AKT pathway and p38 signaling. This resulted in increased expression of the anti-oxidative genes NQO-1 and HO-1 and alleviated oxidative stress in LPS-stimulated macrophages. Interestingly, the effects of CWA were diminished when AMPK was knocked down. Consistently, we noticed that CWA failed to ameliorate the LPS-induced inflammatory response and oxidative stress in AMPK knockout mice. Furthermore, we discovered that LKB1 was essential for AMPK activation by CWA. These data demonstrated for the first time that CWA attenuated LPS-stimulated inflammation and redox imbalance through regulating LKB1-AMPK signaling. Such knowledge provides new insights into the mechanisms through which Cathelicidin peptides modulate immune responses.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Cathelicidins/pharmacology , Gene Expression Regulation/drug effects , Reactive Oxygen Species/antagonists & inhibitors , Signal Transduction/drug effects , p38 Mitogen-Activated Protein Kinases/genetics , AMP-Activated Protein Kinases , Animals , Heme Oxygenase-1/genetics , Heme Oxygenase-1/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Lipopolysaccharides/administration & dosage , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , NAD(P)H Dehydrogenase (Quinone)/genetics , NAD(P)H Dehydrogenase (Quinone)/metabolism , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , NF-kappa B/genetics , NF-kappa B/metabolism , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , RAW 264.7 Cells , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Reactive Oxygen Species/metabolism , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/metabolism
11.
Mol Pharm ; 15(8): 3272-3284, 2018 08 06.
Article in English | MEDLINE | ID: mdl-29969038

ABSTRACT

Metformin not only regulates energy metabolism but also participates in many cellular processes. In this study, we investigated the effect of metformin on lipopolysaccharide (LPS)-induced intestinal barrier damage. We found that LPS treatment decreased the expression of tight junction proteins and caused a proinflammatory response and oxidative stress in the intestine. Interestingly, metformin treatments attenuated LPS-induced intestinal barrier damage, inflammation, and oxidative stress. We found that metformin improved the expression of intestinal tight junction proteins (ZO1, occludin, and Claudin1) that were reduced by LPS stimulation. Moreover, metformin alleviated LPS-induced NF-κB phosphorylation, promoted Nrf2 nuclear translocation, and increased the expression of the antioxidative genes (HO-1 and NQO-1), leading to reduced intestinal ROS content. Mechanistically, we found that metformin protects against LPS-induced intestinal barrier dysfunction by activating AMPK. These results reveal the potential of metformin as an effective therapy for treating intestinal diseases.


Subject(s)
Inflammatory Bowel Diseases/drug therapy , Intestinal Mucosa/drug effects , Metformin/pharmacology , Protective Agents/pharmacology , AMP-Activated Protein Kinases/metabolism , Administration, Oral , Animals , Disease Models, Animal , Humans , Inflammation , Inflammatory Bowel Diseases/immunology , Inflammatory Bowel Diseases/pathology , Intestinal Mucosa/immunology , Intestinal Mucosa/pathology , Lipopolysaccharides/immunology , Male , Metformin/therapeutic use , Mice , Mice, Inbred C57BL , Protective Agents/therapeutic use , Signal Transduction/drug effects , Tight Junction Proteins/metabolism
12.
J. physiol. biochem ; 74(2): 195-205, mayo 2018. tab, graf
Article in English | IBECS | ID: ibc-178977

ABSTRACT

Excessive intramyocellular triacylglycerols (IMTGs, muscle lipids) are associated with the abnormal energy metabolism and insulin resistance of skeletal muscle. AMP-activated protein kinase (AMPK), a crucial cellular energy sensor, consists of α, β and γ subunits. Researchers have not clearly determined whether Prkaa1 (also known as AMPKα1) affects IMTG accumulation in skeletal muscle. Here, we show an important role of Prkaa1 in skeletal muscle lipid metabolism. Deletion of muscle Prkaa1 leads to the delayed development of skeletal muscles but does not affect glucose tolerance or insulin sensitivity in animals fed a normal diet. Notably, when animals are fed a high-fat diet, the skeletal muscle of muscle-specific Prkaa1 knockout mice accumulates more lipids than the skeletal muscle of wild-type (WT) mice, with concomitant upregulation of adipogenic gene expressions and downregulation of the expression of genes associated with mitochondrial oxidation. Muscle-specific Prkaa1 ablation also results in hyperlipidemia, which may contribute to the increased IMTG levels. Furthermore, Prkaa1 deletion activates skeletal muscle mTOR signalling, which has a central role in lipid metabolism and mitochondrial oxidation. Collectively, our study provides new insights into the role of Prkaa1 in skeletal muscle. This knowledge may contribute to the treatment of related metabolic diseases


Subject(s)
Animals , Male , Mice , Diet, High-Fat , Lipid Metabolism , Muscle, Skeletal/metabolism , Cell Line , Energy Metabolism , Gene Deletion , Insulin Resistance , Mice, Knockout , Real-Time Polymerase Chain Reaction , Signal Transduction , TOR Serine-Threonine Kinases , Up-Regulation
13.
Mol Cell Biochem ; 447(1-2): 137-149, 2018 Oct.
Article in English | MEDLINE | ID: mdl-29383561

ABSTRACT

Betaine, a neutral zwitterionic compound, could regulate intramuscular fat (IMF) deposition and meat quality. However, the efficacy is controversial. Moreover, the regulatory mechanism of betaine on lipid metabolism in skeletal muscle cells remains unclear. Therefore, in this study, we examined the effects and regulatory mechanism of betaine on lipid accumulation in adipogenic-differentiated C2C12 cells. We found that adipogenic-induced C2C12 cells treated with 10 mM betaine for 24 and 48 h had more lipid accumulation than the control group. Real-time PCR and Western blot results revealed that betaine treatment did not alter the expression of lipolysis and lipid oxidation-related genes, but dramatically increased the expression of peroxisome proliferator-activated receptor γ (PPARγ) and its target genes such as fatty acid binding protein 4 (aP2), fatty acid synthase (FAS) and lipoprteinlipase (LPL). Furthermore, betaine combined with PPARγ inhibitor GW9662 treatment showed that betaine elevated C2C12 lipid accumulation through upregulation of PPARγ. Mechanistically, we found that betaine promoted PPARγ expression and lipid accumulation through inhibition of extracellular regulated protein kinases1/2 (ERK1/2) signalling pathway. These results demonstrate that betaine acts through ERK1/2-PPARγ signalling pathway to regulate lipid metabolism in adipogenic-differentiated skeletal muscle cells, which could provide some useful information for controlling muscle lipid accumulation by manipulating ERK1/2 and PPARγ signalling pathway.


Subject(s)
Adipogenesis/drug effects , Betaine/pharmacology , Cell Differentiation/drug effects , Lipid Metabolism/drug effects , MAP Kinase Signaling System/drug effects , Muscle, Skeletal/metabolism , PPAR gamma/metabolism , Cell Line , Dose-Response Relationship, Drug , Humans , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Muscle, Skeletal/cytology
14.
J Physiol Biochem ; 74(2): 195-205, 2018 May.
Article in English | MEDLINE | ID: mdl-29288408

ABSTRACT

Excessive intramyocellular triacylglycerols (IMTGs, muscle lipids) are associated with the abnormal energy metabolism and insulin resistance of skeletal muscle. AMP-activated protein kinase (AMPK), a crucial cellular energy sensor, consists of α, ß and γ subunits. Researchers have not clearly determined whether Prkaa1 (also known as AMPKα1) affects IMTG accumulation in skeletal muscle. Here, we show an important role of Prkaa1 in skeletal muscle lipid metabolism. Deletion of muscle Prkaa1 leads to the delayed development of skeletal muscles but does not affect glucose tolerance or insulin sensitivity in animals fed a normal diet. Notably, when animals are fed a high-fat diet, the skeletal muscle of muscle-specific Prkaa1 knockout mice accumulates more lipids than the skeletal muscle of wild-type (WT) mice, with concomitant upregulation of adipogenic gene expressions and downregulation of the expression of genes associated with mitochondrial oxidation. Muscle-specific Prkaa1 ablation also results in hyperlipidemia, which may contribute to the increased IMTG levels. Furthermore, Prkaa1 deletion activates skeletal muscle mTOR signalling, which has a central role in lipid metabolism and mitochondrial oxidation. Collectively, our study provides new insights into the role of Prkaa1 in skeletal muscle. This knowledge may contribute to the treatment of related metabolic diseases.


Subject(s)
AMP-Activated Protein Kinases/genetics , Diet, High-Fat , Lipid Metabolism , Muscle, Skeletal/metabolism , Animals , Cell Line , Energy Metabolism , Gene Deletion , Insulin Resistance , Male , Mice, Knockout , Real-Time Polymerase Chain Reaction , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , Up-Regulation
15.
J Cell Physiol ; 233(2): 818-821, 2018 Feb.
Article in English | MEDLINE | ID: mdl-28322447

ABSTRACT

The cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling pathway plays important role in regulating energy homeostasis. Many of the effects of the cAMP-PKA signaling is mediated through the cAMP responsive element binding protein (CREB) and its coactivator CREB-regulated transcription coactivators (CRTCs). CRTC3 is a member of CRTCs family proteins and plays important roles in glucose and energy metabolism. Previous studies show that global knockout of CRTC3 enhances oxygen consumption and energy expenditure and subsequently protects the knockout animal against obesity. In skeletal muscle, CRTC3 affects lipid and glycogen metabolism and mitochondrial biogenesis. In white adipocytes, CRTC3 regulates GLUT4 expression and glucose uptake. More recently, the localization and function of CRTC3 in brown fat have been reported. In this review, we mainly discuss the regulatory role of CRTC3 in skeletal muscle and adipose tissues.


Subject(s)
Adipose Tissue/metabolism , Energy Metabolism , Muscle, Skeletal/metabolism , Signal Transduction , Transcription Factors/metabolism , AMP-Activated Protein Kinases/metabolism , Animals , Cyclic AMP/metabolism , Cyclic AMP-Dependent Protein Kinases/metabolism , Glucose/metabolism , Humans , Phosphorylation
16.
Sci Rep ; 7: 41606, 2017 02 08.
Article in English | MEDLINE | ID: mdl-28176824

ABSTRACT

Skeletal muscle plays important roles in whole-body energy homeostasis. Excessive skeletal muscle lipid accumulation is associated with some metabolic diseases such as obesity and Type 2 Diabetes. The energy sensor AMPK (AMP-activated protein kinase) is a key regulator of skeletal muscle lipid metabolism, but the precise regulatory mechanism remains to be elucidated. Here, we provide a novel mechanism by which AMPK regulates skeletal muscle lipid accumulation through fat mass and obesity-associated protein (FTO)-dependent demethylation of N6-methyladenosine (m6A). We confirmed an inverse correlation between AMPK and skeletal muscle lipid content. Moreover, inhibition of AMPK enhanced lipid accumulation, while activation of AMPK reduced lipid accumulation in skeletal muscle cells. Notably, we found that mRNA m6A methylation levels were inversely correlated with lipid content in skeletal muscle. Furthermore, AMPK positively regulated the m6A methylation levels of mRNA, which could negatively regulate lipid accumulation in C2C12. At the molecular level, we demonstrated that AMPK regulated lipid accumulation in skeletal muscle cells by regulating FTO expression and FTO-dependent demethylation of m6A. Together, these results provide a novel regulatory mechanism of AMPK on lipid metabolism in skeletal muscle cells and suggest the possibility of controlling skeletal muscle lipid deposition by targeting AMPK or using m6A related drugs.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Adenosine/analogs & derivatives , Alpha-Ketoglutarate-Dependent Dioxygenase FTO/metabolism , Lipid Metabolism , Muscle Fibers, Skeletal/metabolism , Adenosine/genetics , Adenosine/metabolism , Animals , Cell Line , Demethylation , Gene Expression , Male , Mice , Mice, Knockout , Models, Biological , Phosphorylation , RNA, Messenger/genetics , RNA, Messenger/metabolism
17.
J Cell Physiol ; 232(10): 2653-2656, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28067405

ABSTRACT

Liver kinase B1 (Lkb1), also named as Serine/Threonine protein kinase 11 (STK11), is a serine/threonine kinase that plays crucial roles in various cellular processes including cell survival, cell division, cellular polarity, cell growth, cell differentiation, and cell metabolism. In metabolic tissues, Lkb1 regulates glucose homeostasis and energy metabolism through phosphorylating and activating the AMPK subfamily proteins. In skeletal muscle, Lkb1 affects muscle development and postnatal growth, lipid and fatty acid oxidation, glucose metabolism, and insulin sensitivity. Recently, the regulatory roles of Lkb1 in regulating division, self-renew, proliferation, and differentiation of skeletal muscle progenitor cells have been reported. In this review, we discuss the roles of Lkb1 in regulating skeletal muscle progenitor cell homeostasis and skeletal muscle development and metabolism.


Subject(s)
Cell Differentiation , Cell Proliferation , Energy Metabolism , Muscle Development , Muscle, Skeletal/enzymology , Protein Serine-Threonine Kinases/metabolism , Stem Cells/enzymology , AMP-Activated Protein Kinase Kinases , Animals , Homeostasis , Humans , Muscle, Skeletal/growth & development , Signal Transduction
18.
J Cell Physiol ; 232(11): 2964-2967, 2017 Nov.
Article in English | MEDLINE | ID: mdl-27943289

ABSTRACT

Adult skeletal muscle stem cells, also called satellite cells, are indispensable for the growth, maintenance, and regeneration of the postnatal skeletal muscle. Satellite cells, predominantly quiescent in mature resting muscles, are activated after skeletal muscle injury or degeneration. Notch1 signaling is an evolutionarily conserved pathway that plays crucial roles in satellite cells homeostasis and postnatal skeletal myogenesis and regeneration. Activation of Notch1 signaling promotes the muscle satellite cells quiescence and proliferation, but inhibits differentiation of muscle satellite cells. Notably, the new roles of Notch1 signaling during late-stage of skeletal myogenesis including in post-differentiation myocytes and post-fusion myotubes have been recently reported. Here, we mainly review and discuss the regulatory roles of Notch1 in regulating satellite cell fates choices and skeletal myogenesis. J. Cell. Physiol. 232: 2964-2967, 2017. © 2016 Wiley Periodicals, Inc.


Subject(s)
Cell Differentiation , Cell Lineage , Muscle Development , Muscle Fibers, Skeletal/metabolism , Receptor, Notch1/metabolism , Satellite Cells, Skeletal Muscle/metabolism , Signal Transduction , Animals , Humans , Ligands , Phenotype
19.
J Cell Physiol ; 232(10): 2698-2703, 2017 Oct.
Article in English | MEDLINE | ID: mdl-27808422

ABSTRACT

Adipose tissues play important roles in whole body energy homeostasis and lifer span. Understanding the mechanisms of controlling adipose tissues development is significant for providing useful information to treat the worldwide epidemic of obesity and its associated metabolic diseases. Several different Cre transgenes have been generated and used for determining the origin of adipose tissues and the function of individual gene in regulating adipose growth and development. Here, we mainly review and discuss the efficiency and specific of those Cre recombinase mouse strains used for the study of adipose tissues and adipocyte progenitors. J. Cell. Physiol. 232: 2698-2703, 2017. © 2016 Wiley Periodicals, Inc.


Subject(s)
Adipocytes/physiology , Adipogenesis , Adipose Tissue/cytology , Cell Lineage , Integrases/genetics , Stem Cells/physiology , Transgenes , Adipocytes/metabolism , Animals , Gene Expression Regulation, Developmental , Genetic Markers , Humans , Integrases/metabolism , Mice, Transgenic , Phenotype , Stem Cells/metabolism
20.
J Cell Physiol ; 232(6): 1258-1261, 2017 Jun.
Article in English | MEDLINE | ID: mdl-27869309

ABSTRACT

Adipose tissues, composed with mature adipocytes and preadipocytic stromal/stem cells, play crucial roles in whole body energy metabolism and regenerative medicine. Mature adipocytes are derived and differentiated from mesenchymal stem cells (MSCs) or preadipocytes. This differentiation process, also called adipogenesis, is regulated by several signaling pathways and transcription factors. Notch1 signaling is a highly conserved pathway that is indispensable for stem cell hemostasis and tissue development. In adipocyte progenitor cells, Notch1 signaling regulates the adipogenesis process including proliferation and differentiation of the adipocyte progenitor cells in vitro. Notably, the roles of Notch1 signaling in beige adipocytes formation, adipose development, and function, and the whole body energy metabolism have been recently reported. Here, we mainly review and discuss the roles of Notch1 signaling in adipogenesis in vitro as well as in beige adipocytes formation, adipocytes dedifferentiation, and function in vivo. J. Cell. Physiol. 232: 1258-1261, 2017. © 2016 Wiley Periodicals, Inc.


Subject(s)
Adipocytes/cytology , Cell Differentiation , Receptors, Notch/metabolism , Signal Transduction , Stem Cells/metabolism , Animals , Humans , Models, Biological
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