VEGF-B is involved in diabetic peripheral neuropathy in patients with type 2 diabetes.

Aims: This study aims to explore the potential role of vascular endothelial growth factor-B (VEGF-B) in the pathogenesis of diabetic peripheral neuropathy (DPN). The expression of VEGFRs were reanalysed by using gene arrays of peripheral nerve samples from mouse models of DPN retrieved from the GEO database. 213 T2D patients as well as 31 healthy individuals were recruited. The serum VEGF-B was detected and its relationship with DPN was analysed. The elevated VEGFR1 was the only change of VEGFR gene expression in the peripheral nerve from mouse models of DPN. The level of serum VEGF-B in T2D patients with DPN was higher than that in T2D patients without DPN and healthy people. Analysis of correlation and binary logistic regression confirmed that the increased serum VEGF-B level was an independent risk factor of DPN in T2D patients. VEGF-B-VEGFR1 signaling pathway may be involved in the development of DPN.

Acetylation of p65Lys310 by p300 in macrophages mediates anti-inflammatory property of berberine.

Nuclear factor (NF)-κB plays a pivotal role in the regulation of inflammatory response in macrophages. Berberine (BBR), which is an active constituent isolated from Coptis rhizome, possesses a prominent anti-inflammatory activity. Here we show that BBR changes the global acetylation landscape in LPS-induced protein acetylation of macrophages and reduces the acetylation of NF-κB subunit p65 at site Lys310(p65Lys310), leading to the inhibition of NF-κB translocation and transcriptional activity to suppress the expressions of inflammatory factors. BBR resists the inflammatory response in acute LPS-stimulated mice through downregulation of p65Lys310 acetylation in peritoneal macrophages. In obese mice, BBR alleviates the metabolic disorder and inflammation with the reduced acetylation of p65Lys310 in white adipose tissue. Furthermore, we demonstrate that BBR acts as a regulator of p65Lys310 by inhibiting the expression of p300 in macrophages. Our findings elucidate a new molecular mechanism for the anti-inflammatory effect of BBR via the p300/p65Lys310 axis.

Upregulation of adiponectin by Ginsenoside Rb1 contributes to amelioration of hepatic steatosis induced by high fat diet.

Background: Ginsenoside Rb1 (GRb1) is capable of regulating lipid and glucose metabolism through its action on adipocytes. However, the beneficial role of GRb1-induced up-regulation of adiponectin in liver steatosis remains unelucidated. Thus, we tested whether GRb1 ameliorates liver steatosis and insulin resistance by promoting the expression of adiponectin. Methods: 3T3-L1 adipocytes and hepatocytes were used to investigate GRb1's action on adiponectin expression and triglyceride (TG) accumulation. Wild type (WT) mice and adiponectin knockout (KO) mice fed high fat diet were treated with GRb1 for 2 weeks. Hepatic fat accumulation and function as well as insulin sensitivity was measured. The activation of AMPK was also detected in the liver and hepatocytes. Results: GRb1 reversed the reduction of adiponectin secretion in adipocytes. The conditioned medium (CM) from adipocytes treated with GRb1 reduced TG accumulation in hepatocytes, which was partly attenuated by the adiponectin antibody. In the KO mice, the GRb1-induced significant decrease of TG content, ALT and AST was blocked by the deletion of adiponectin. The elevations of GRb1-induced insulin sensitivity indicated by OGTT, ITT and HOMA-IR were also weakened in the KO mice. The CM treatment significantly enhanced the phosphorylation of AMPK in hepatocytes, but not GRb1 treatment. Likewise, the phosphorylation of AMPK in liver of the WT mice was increased by GRb1, but not in the KO mice. Conclusions: The up-regulation of adiponectin by GRb1 contributes to the amelioration of liver steatosis and insulin resistance, which further elucidates a new mechanism underlying the beneficial effects of GRb1 on obesity.

Increased Serum VEGF-B Level Is Associated With Renal Function Impairment in Patients With Type 2 Diabetes.

Aims/Introduction: Renal function impairment related to type 2 diabetes (T2DM) presents serious threat to public health. Previous studies suggest that vascular endothelial growth factor-B (VEGF-B) might contribute to renal injury. Therefore, this study investigated the association of serum VEGF-B level with the risk of renal function impairment in T2DM patients. Materials and Methods: Serum VEGF-B levels were measured in 213 patients with type 2 diabetes and 31 healthy participants. Participants with type 2 diabetes were further divided into a group of 112 participants with eGFR<90 mL/min/1.73m2 and 101 participants with eGFR≥ 90 mL/min/1.73m2. Clinical data were collected, and a binary logistic regression model was employed to test the association between potential predictors and eGFR. Results: Serum VEGF-B levels evaluated in type 2 diabetes patients compared with healthy controls. In patients with type 2 diabetes, serum VEGF-B level was positively correlated with triglyceride, serum creatinine and cystatin C while negatively correlated with HDL-C and eGFR. Binary logistic regression showed that serum VEGF-B level was an independent risk factor of eGFR<90 mL/min/1.73m2. Conclusions: Serum VEGF-B level is associated with renal function impairment in patients with type 2 diabetes and may be a potential drug target for diabetic kidney disease.

Spexin ameliorates skeletal muscle insulin resistance through activation of GAL2 receptor.

Skeletal muscle is a principal tissue involved in energy expenditure and glucose metabolism. Although the results of our and other studies show that spexin could decrease food intake and obesity, the specific metabolic effect of spexin on glucose metabolism of skeletal muscle is still unclear. The aim of this study is to investigate whether spexin might mitigate obesity-induced insulin resistance in skeletal muscles and to explore its underlying mechanisms. The high fat diet-fed mice were treated with 50 µg/kg/d spexin for 21 consecutive days, and the differentiated myotubes of L6 were treated with spexin (200, 400, 800 nM) in the absence or presence of M871 (800 nM) for 12 h respectively. Besides, the galanin type 2 (GAL2) receptor knockdown myotubes were treated with 800 nM spexin for 12 h in this study. The present findings showed that spexin reversed hyperglycemia and glucose intolerance as well as insulin intolerance and insulin resistance in the mice fed with high fat diet. Furthermore, spexin markedly augmented the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) expression and deacetylation, and further triggered glucose transporter 4 (GLUT4) expression and trafficking in myotubes through p38 mitogen-activated protein kinase (P38MAPK) and protein kinase B (AKT) activation. More importantly, the elevation of glucose consumption related genes by spexin were abolished by GAL2 receptor antagonist or silencing of GAL2 receptor in myotubes. In conclusion, our findings provide a novel insight that spexin can protect against insulin resistance and increase glucose consumption in skeletal muscles mainly through activation of GAL2/GLUT4 signal pathway. Spexin might therefore be a novel therapeutic target for hyperglycemia and insulin resistance in clinic.

Adipose tissue spexin in physical exercise and age-associated diseases.

It is known that a strong association exists between a suboptimal lifestyle (physical inactivity and sedentary behavior and/or high calorie diet) and increased propensity of developing age-associated diseases, such as obesity and T2DM. Physical exercise can alleviate obesity-induced insulin resistance and T2DM, however, the precise mechanism for this outcome is not fully understood. The endocrine disorder of adipose tissue in obesity plays a critical role in the development of insulin resistance. In this regard, spexin has been recently described as an adipokine that plays an important role in the pathophysiology of obesity-induced insulin resistance and T2DM. In obese states, expression of adipose tissue spexin is reduced, inducing the adipose tissue and skeletal muscle more susceptible to insulin resistance. Emerging evidences point out that exercise can increase spexin expression. In return, spexin could exert the exercise-protective roles to ameliorate insulin resistance, suggesting that spexin is a potential mediator for exercise to ameliorate obesity-induced insulin resistance and T2DM, namely, the beneficial effect of exercise on insulin sensitivity is at least partly mediated by spexin. This review summarizes our and others' recent studies regarding the effects of obesity on adipose tissue spexin induction, along with the potential effect of exercise on this response in obese context, and provides a new insight into the multivariate relationship among exercise, spexin and T2DM. It should be therefore taken into account that a combination of spexin and exercise training is an effective therapeutic strategy for age-associated diseases.

Emerging roles of kisspeptin/galanin in age-related metabolic disease.

Age is a major risk factor for developing metabolic diseases such as obesity and diabetes. There is an unprecedented rise in obesity and type 2 diabetes in recent decades. A convincing majority of brain-gut peptides are associated with a higher risk to develop metabolic disorders, and may contribute to the pathophysiology of age-related metabolic diseases. Accumulating basic studies revealed an intriguing role of kisspeptin and galanin involved in the amelioration of insulin resistance in different ways. In patients suffered from obesity and diabetes a significant, sex-related changes in the plasma kisspeptin and galanin levels occurred. Kisspeptin is anorexigenic to prevent obesity, its level is negatively correlative with obesity and insulin resistance. While galanin is appetitive to stimulate food intake and body weight, its level is positively correlative with obesity, HOMA-IR and glucose/triglyceride concentration. In turn, kisspeptin and galanin also distinctly increase glucose uptake and utilization as well as energy expenditure. This article reviews recent evidence dealing with the role of kisspeptin and galanin in the pathophysiology of age-related metabolic diseases. It should be therefore taken into account that the targeted modulation of those peptidergic signaling may be potentially helpful in the future treatment of age-related metabolic diseases.

Sn-based metal-organic framework for highly selective capture of monophosphopeptides.

Sn-based metal-organic framework (MOF) was utilized to effectively capture monophosphopeptides due to the unique affinity. The Sn-based MOF demonstrated the good sensitivity and selectivity in the model phosphoproteins enrichment and was successfully applied in the biological fluids.

A hydrophilic two-dimensional titanium-based metal-organic framework nanosheets for specific enrichment of glycopeptides.

A hydrophilic two-dimensional titanium-based metal-organic framework (MOF) nanosheets were prepared and applied to improve the glycopeptides enrichment efficiency. Seventeen N-linked glycopeptides from horseradish peroxidase (HRP) tryptic digests were readily identified and the results showed highly improved signal intensities. As the molar ratio of the mixture of tryptic digests of HRP, glycoprotein (HRP), and nonglycoprotein (BSA) reached 1:800:800, good selectivity of the Ti-MOF nanosheets were still clearly observed. As to human serum samples, 41 glycoproteins and 66 glycopeptides corresponding to 68 N-glycosylation sites were finally detected, which showed the good ability of the nanosheets material to enrich N-linked glycopeptides from complex human serum samples. Moreover, the Ti-MOF nanosheets exhibited unique stability and reusability even after being regenerated and reused for five times. It also performed a high sensitivity (1 × 10-10 M HRP), a good enrichment capacity (250 mg/g) for glycopeptides enrichment and a high enrichment recovery of 78%, suggesting a great application prospect for the enrichment of N-linked glycopeptides and the analysis glycoproteomic research.

Highly efficient enrichment of N-glycopeptides by two-dimensional Hf-based metal-organic framework nanosheets.

Highly efficient enrichment of target glycopeptides plays a crucial role in glycoproteome research. Owing to their large surface area and excellent hydrophilicity, 2-D Hf-BTB nanosheets showed effective and selective enrichment of 78 glycopeptides derived from 29 glycoproteins with 90 N-glycosylation sites from just 2 µL of human serum.

Adipose Tissue SIRT1 Regulates Insulin Sensitizing and Anti-Inflammatory Effects of Berberine.

Berberine (BBR), which is an active component of Coptis chinensis Franch, has been reported to improve glucose metabolism and insulin resistance in animal and human studies, predominantly via activation of the 5'-adenosine monophosphate kinase (AMPK) pathway and suppression of the inflammation response. However, the mechanisms underlying the effects of BBR on AMPK and inflammation remain unclear. In this present study, we found that BBR upregulated SIRT1 expression in 3T3L-1 adipocytes and adipose tissue. Inhibition of SIRT1 blunted the BBR-induced increase in glucose consumption and uptake in adipocytes. The BBR-induced activation of the AMPK pathway and AKT phosphorylation in adipocytes and adipose tissue were also attenuated by inhibition or knockout of Sirt1. The BBR-induced improvement of systemic insulin sensitivity was impaired by Sirt1 knockout in HFD-induced obese mice. The suppressing effects of BBR on systemic and local inflammatory responses, such as serum concentrations and expression of inflammatory cytokines, phosphorylation of c-Jun N-terminal kinase (JNK) and IKKß, and the accumulation of F4/80-positive macrophages in adipose tissue were also attenuated in Sirt1 knockout mice. The BBR-induced decrease in PGC-1α acetylation was reversed by inhibition or knockout of Sirt1 in adipocytes and adipose tissue. Together, these results indicate that adipose tissue SIRT1 is a key regulator of the insulin sensitizing and anti-inflammatory effects of BBR, which contributes to the improvement of metabolic dysregulation.

Solvothermal Synthesis of Novel Magnetic Nickel Based Iron Oxide Nanocomposites for Selective Capture of Global- and Mono-Phosphopeptides.

A facile solvothermal method was developed for synthesis of magnetic nickel-based iron oxide nanocomposites (MNFOs) with different ratios of Ni2+ to Fe3+ for different reaction time. Two factors including dosage of Ni source and length of reaction were investigated for influence on the morphology and composition of MNFOs, as well as their distinct selectivity for different phosphopeptides. After thorough characterization, the possible formation mechanism of MNFOs was proposed. Very interestingly, MNFOs with Ni2+/Fe3+ ratios of 4:5 prepared for 8 h (MNFO-S) and for 24 h (MNFO-L) can selectively capture global- and monophosphopeptides at the fmol level with excellent enrichment performance. These two affinity probes have been exploited to isolate and enrich the phosphopeptides from human normal hepatic cells HL 7702 after exposure to atmospheric fine particulates (PM2.1), which revealed that the protein phosphorylation level was increased significantly in cells after stimulation by fine particulate matters. The findings could provide a new insight for the nickel-based affinity protocol to analyze the mutation of phosphopeptides during cellular signaling pathways in response to exogenous environment stimulation. Consequently, this present work proposed a promising strategy to isolate monophosphopeptides from global phosphopeptides for phosphoproteome research.

Highly Selective Capture of Monophosphopeptides by Two-Dimensional Metal-Organic Framework Nanosheets.

Separation of monophosphopeptides from multi-phosphopeptides in complex biological samples is significant in the study of protein kinase signal transduction pathways. To the best of our knowledge, very few materials have been reported that could selectively enrich monophosphopeptides because of the chemical difficulty in retaining the intermediate monophosphopeptides and excluding both non-phosphopeptides and multi-phosphopeptides in acidic conditions, which requires unique interactions to balance the metallic affinity and the hydrophobicity. With the large surface area, abundant accessible active sites, and ultrathin structures, two-dimensional (2-D) metal-organic framework (MOF) Hf-1,3,5-tris(4-carboxyphenyl)benzene (BTB) nanosheets were rationally selected. Due to the elongated organic ligands and the balance between metallic affinity of clusters and hydrophobicity from ligands, the 2-D Hf-BTB nanosheets exhibited unique enrichment selectivity toward monophosphopeptides. The 2-D MOF nanosheets demonstrated excellent sensitivity (detection limit of 0.4 fmol µL-1) and selectivity [1:1000 molar ratios of ß-casein/BSA (bovine serum albumin)] in model phosphopeptides enrichment. The nanosheets were implemented for the analysis of nonfat milk and human saliva samples as well as in situ isotope labeling for dysregulated phosphopeptides from patients' serum with anal canal inflammation, exhibiting 6.6-fold upregulation of serum phosphopeptide HS4 (ADpSGEGDFLAEGGGVR) compared to the control healthy serum. The proteomics analysis of mouse brain cortical samples associated with Alzheimer's disease, which were from Akt (protein kinase B) conditional knockout mouse and littermate control mouse, was further established with 2-D Hf-BTB nanosheets. With high capture efficiency for monophosphopeptides, this method was capable of distinguishing the difference of monophosphopeptides from microtubule-associated protein τ (MAPT/τ) between the Akt knockout sample and control sample.

Enrichment of Phosphorylated Peptides with Metal-Organic Framework Nanosheets for Serum Profiling of Diabetes and Phosphoproteomics Analysis.

Capturing phosphopeptides from complicated biological samples is essential for the discovery of new post-translational modification sites and disease diagnostics. Although several two-dimensional (2-D) materials have been used for phosphopeptides capturing, metal-organic framework (MOF) nanosheets have not been reported. The Ti-based MOF nanosheets have well-defined 2-D morphology, high density of active sites, large surface area, and an ultrathin structure. Phosphopeptides can be efficiently extracted and superior detection limits of 0.1 fmol µL-1 can be achieved even for an extremely low molar ratio of phosphoprotein/nonphosphoprotein (1:10000) mixtures. The selectivity over nonphosphopeptides can be enhanced further by pretreatment with a 10 mM salt solution (ß-glycerophosphate disodium, NaCl, or KCl). The performance of 2-D Ti-based MOF nanosheets is much better than Zr-based MOF (Zr-BTB) nanosheets or any other Ti-based 3-D MOF counterpart, such as MIL-125 and NH2-MIL-125. The nanosheets were used for in situ isotope labeling for abnormally regulated phosphopeptides analysis from serum samples of type 2 diabetes patients. The relative quantitative results showed that three of the phosphorylated fibrinogen peptides A (FPA, DpSGEGDFLAEGGGV, DpSGEGDFLAEGGGVR, and ADpSGEGDFLAEGGGVR) were down-regulated, while the other isoform (ADpSGEGDFLAEGGGV) was up-regulated in the serum samples of type 2 diabetes patients compared with those of healthy volunteers. Finally, proteomics analysis showed selective enrichment of phosphopeptides with 2-D Ti-based MOF nanosheets from real samples, including tryptic digests of mouse brain neocortex lysate, mouse spinal cord lysate, and mouse testis lysate, followed by LC-MS/MS analysis. Total numbers of 2601, 3208, and 2866 phosphopeptides were successfully identified from the three samples, respectively. The 2-D Ti-based MOF nanosheets significantly improved sample preparation for mass spectrometric analysis in phosphopeptides and phosphoproteomics research.

Ultrahigh efficient laser desorption ionization of saccharides by Ti-based metal-organic frameworks nanosheets.

We proposed some exfoliated Ti-based metal-organic frameworks (MOFs) nanosheets as matrices with ultrahigh ionization efficiency, free matrix background, significant dispersibility and acidic resistance. Combining the features between MOFs and 2-D nanomaterials, the NTU-9 nanosheets matrix also demonstrated suitable band gap energy and superior photoabsorption properties, much better than other representative MOFs. A wide range of small molecules that involving low mass region were also analyzed with NTU-9 nanosheets as the matrices in both positive-ion and negative-ion reflector modes. The ultra-efficient NTU-9 nanosheets matrix was successfully applied to serum for quantitative determination of glucose as a clinical diagnosis indicator of diabetes mellitus.

An Exfoliated 2D Egyptian Blue Nanosheet for Highly Selective Enrichment of Multi-phosphorylated Peptides in Mass Spectrometric Analysis.

Phosphopeptide enrichment is essential for the phosphoprotein profiling, due to the low abundance in complex biological samples. Moreover, selective binding of multi-phosphopeptides over mono-phosphopeptides is rarely established, but strongly needed in real sample analysis, especially for the investigation of cell behaviors with the multisite phosphorylation cascades. Here two-dimensional (2D) nanosheets were synthesized of Egyptian blue (CaCuSi4 O10 ), the well-known ancient pigment, and its analogues (SrCuSi4 O10 and BaCuSi4 O10 ), which were employed in the enrichment of phosphopeptides for the first time. Surprisingly, the 2D CaCuSi4 O10 nanosheet was highly selective towards multi-phosphopeptides without enriching the mono-phosphorylated peptides in a wide range of acidic conditions or buffer compositions. Meanwhile, the SrCuSi4 O10 and BaCuSi4 O10 nanosheet analogues do not exhibit this unique selectivity. Moreover, the ultrathin and well-defined 2D morphology, with abundant CaII , of Egyptian blue nanosheet was applied in cortical samples of forebrain specific PDK1 conditional knockout mice and their age-matched littermate controls, that are associated with Alzheimer's disease. The as-prepared 2D CaCuSi4 O10 nanosheet not only showed specific selectivity, but also exhibited high sensitivity (detection limit of 4×10-7 m).

[Research progress on therapeutic targets of active components in Chinese herbs for treatment of nonalcoholic fatty liver disease].

Nonalcoholic fatty liver disease(NAFLD) is a kind of metabolic liver injury, which is closely associated with insulin resistance and genetic susceptibility. Traditional Chinese herbs used in the treatment of nonalcoholic fatty liver disease are widely investigated in recent years. A series of recent studies show that the effects of the active components in traditional Chinese herbs on NAFLD are associated with activating AMPK signaling pathway, improving insulin resistance, modulating the activity and expression of peroxisome proliferator-activated receptor γ, antioxidant and anti-inflammatory activities and regulating intestinal flora. In this review, the potential therapeutic targets of the active components from traditional Chinese herbs for NAFLD would be summarized to provide a new thought for further research and clinical treatment of nonalcoholic fatty liver disease.

Atractylodin Induces Myosin Light Chain Phosphorylation and Promotes Gastric Emptying through Ghrelin Receptor.

Atractylodin is one of the main constituents in the rhizomes of Atractylodes lancea Thunb., being capable of treating cancer cachexia-anorexia and age-related diseases as an agonist of growth hormone secretagogue receptor (GHSR). GHSR was herein expressed in human gastric smooth muscle cells (HGSMCs) and activated by ghrelin receptor agonist L-692,585. Like L-692,585, atractylodin also increased Ca2+ and enhanced the phosphorylation of myosin light chain (MLC) through GHSR in HGSMCs. In addition, atractylodin promoted gastric emptying and MLC phosphorylation in the gastric antrum of mice also through GHSR. Collectively, atractylodin can activate GHSR in gastric smooth muscle, as a potential target in clinical practice.

Berberine suppresses LPS-induced inflammation through modulating Sirt1/NF-κB signaling pathway in RAW264.7 cells.

Chronic inflammation is a major contributing factor in the pathogenesis of many diseases. Natural product berberine (BBR) exhibits potent anti-inflammatory effect in vitro and in vivo, while the underlying mechanisms remain elusive. Sirt1, a NAD+-dependent protein deacetylase, was recently found to play an important role in modulating the development and progression of inflammation. Thus, we speculate that Sirt1 might mediate the inhibitory effect of BBR on inflammation. In LPS-stimulated RAW264.7 macrophages, BBR treatment significantly downregulated the expression of proinflammatory cytokines such as MCP-1, IL-6 and TNF-α. Importantly, BBR potently reversed LPS-induced down-regulation of Sirt1. Consistently, the inhibitory effects of BBR on proinflammatory cytokines expression was largely abrogated by Sirt1 inhibition either by EX527, a Sirt1 inhibitor or Sirt1 siRNA. Further mechanistic studies revealed that BBR-induced inhibition of NF-κB is Sirt1-dependent, as either pharmacologically or genetically inactivating Sirt1 enhanced the IκΒα degradation, IKK phosphorylation, NF-κB p65 acetylation and DNA-binding activity. Taken together, our results provide the first evidence that BBR potently suppressed inflammatory responses in macrophages through inhibition of NF-κB signaling via Sirt1-dependent mechanisms.

Anamorelin for cancer anorexia-cachexia syndrome: a systematic review and meta-analysis.

PURPOSE: The aim of this study was to evaluate the therapeutic effects of Anamorelin on patients with cancer anorexia-cachexia syndrome (CACS) based on a meta-analysis of published randomized trials. METHODS: We searched PubMed, Embase, Medline, and the Cochrane Central Register of Controlled Trials databases. Data from each selected study were evaluated individually. All continuous outcomes were calculated by the mean difference or standardized mean difference with 95% confidence interval for each study. Heterogeneity was assessed by using the Chi2 test at a significance level of P < 0.1, in addition to the I 2 statistic (I 2 > 50% indicated substantial heterogeneity). RESULT: At last, four studies were included from 284 records. In three studies, lean body mass was reported and there was a significant difference between placebo and Anamorelin groups (P < 0.00001), without significant heterogeneity (I 2 = 0%). All the four studies reported the body weight change from baseline, and there was significant difference between placebo and Anamorelin groups (P = 0.007), but with high heterogeneity (I 2 = 97%). Two studies reported Anderson Symptom Assessment Scale (ASAS) score, and Anamorelin significantly increased the total ASAS score of CACS patients (P < 0.00001), without any heterogeneity (I 2 = 0%). Three studies reported non-dominant handgrip strength, and there was no significant difference between Anamorelin and placebo groups (P = 0.16). Three studies reported insulin-like growth factor-1 level, and there was significant difference between Anamorelin and placebo groups (P = 0.02), but with high heterogeneity (I 2 = 96%). Three studies reported IGF binding protein-3 concentration. Anamorelin significantly increased such concentration compared with placebo did (P < 0.00001). However, there was still higher heterogeneity (I 2 = 59%). All the included studies reported adverse events. Compared with placebo, Anamorelin induced fewer adverse events, but there was no significant difference between the two groups (RR = 0.07, P = 0.35). CONCLUSION: In the included studies, Anamorelin had some positive effects to relieve the symptoms and improved the quality of life. However, the heterogeneity was apparent, so the clinical effects of Anamorelin should be further validated by increasing the sample size, varying the range of doses during treatment, and observing other outcomes. We are still confident for the future application of Anamorelin in phase III clinical trials.