Non-alcoholic fatty liver disease (NAFLD), or metabolic (dysfunction)-associated fatty liver disease (MAFLD), is characterized by high global incidence and prevalence, a tight association with common metabolic comorbidities, and a substantial risk of progression and associated mortality. Despite the increasingly high medical and socioeconomic burden of NAFLD, the lack of approved pharmacotherapy regimens remains an unsolved issue. In this paper, we aimed to provide an update on the rapidly changing therapeutic landscape and highlight the major novel approaches to the treatment of this disease. In addition to describing the biomolecules and pathways identified as upcoming pharmacological targets for NAFLD, we reviewed the current status of drug discovery and development pipeline with a special focus on recent evidence from clinical trials.

https://www.mdpi.com/2227-9059/10/2/274/pdf

Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates

Background: Galectins, a family of β-galactoside-binding proteins, are related to the development and progression of various human diseases such as cancer, heart failure, and chronic kidney disease. However, its role in liver diseases is unclear. Methods: The PubMed, Embase, and Cochrane Library databases were searched. Hazard ratios (HRs), odds ratios (ORs), and mean differences (MDs) with 95% CIs were pooled to evaluate the association of the galectins with the outcomes and risk of liver diseases by a random effects model. Results: Thirty three studies involving 43 cohorts and 4,168 patients with liver diseases were included. In the patients with hepatocellular carcinoma (HCC), high expression of galectin-1 and -3 in the tissues was significantly associated with worse overall survival (galectin-1: HR = 1.94, 95% CI = 1.61-2.34, p < 0.001; galectin-3: HR = 3.29, 95% CI = 1.62-6.68, p < 0.001) and positive vascular invasion (galectin-1: OR = 1.74, 95% CI = 1.18-2.58, p = 0.005; galectin-3: OR = 2.98, 95% CI = 1.58-5.60, p = 0.001); but, high expression of galectin-4 and -9 in the tissues was significantly associated with better overall survival (galectin-4: HR = 0.53, 95% CI = 0.36-0.79, p = 0.002; galectin-9: HR = 0.56, 95% CI = 0.44-0.71, p < 0.001) and negative vascular invasion (galectin-4: OR = 0.36, 95% CI = 0.19-0.72, p = 0.003; galectin-9: OR = 0.60, 95% CI = 0.37-0.97, p = 0.037). Serum galectin-3 level was significantly higher in HCC (MD = 3.06, 95% CI = 1.79-4.32, p < 0.001), liver failure (MD = 0.44, 95% CI = 0.23-0.66, p < 0.001), liver cirrhosis (MD = 1.83, 95% CI = 1.15-2.51, p < 0.001), and chronic active hepatitis B (MD = 18.95, 95% CI = 10.91-27.00, p < 0.001); serum galectin-9 level was significantly higher in HCC (MD = 3.74, 95% CI = 2.57-4.91, p < 0.001) and autoimmune hepatitis (MD = 8.80, 95% CI = 7.61-9.99, p < 0.001). Conclusion: High galectin-1 and -3 and low galectin-4 and -9 expression indicate worse outcomes of patients with HCC. Serum galectin-3 and -9 levels are positively associated with the risk of chronic liver diseases.

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Role of Galectins in the Liver Diseases: A Systematic Review and Meta-Analysis.

Current data indicates that anti-tumor T cell-mediated immunity correlates with a better prognosis in cancer patients. However, it has widely been demonstrated that tumor cells negatively manage immune attack by activating several immune-suppressive mechanisms. It is, therefore, essential to fully understand how lymphocytes are activated in a tumor microenvironment and, above all, how to prevent these cells from becoming dysfunctional. Tumors produce galectins-1, -3, -7, -8, and -9 as one of the major molecular mechanisms to evade immune control of tumor development. These galectins impact different steps in the establishment of the anti-tumor immune responses. Here, we carry out a critical dissection on the mechanisms through which tumor-derived galectins can influence the production and the functionality of anti-tumor T lymphocytes. This knowledge may help us design more effective immunotherapies to treat human cancers.

Unraveling How Tumor-Derived Galectins Contribute to Anti-Cancer Immunity Failure.

Objectives: Obstructive sleep apnea (OSA) is an independent risk factor for metabolic syndrome (MetS). Recent studies have indicated that circadian clock genes were dysregulated in OSA. In addition, it is clear that the impairment of circadian clocks drives the progression of MetS. Therefore, we hypothesized that circadian rhythm disruption links OSA with MetS. Methods: A total of 118 participants, who underwent polysomnography (PSG) and were diagnosed as healthy snorers (control, n = 29) or OSA (n = 89) patients based on the apnea–hypopnea index (AHI), were enrolled in the present study. General information, anthropometric data, blood biochemical indicators, clock gene expressions, and levels of oxidative and inflammatory indicators were collected, determined, and compared in all the participants. Results: We found that Brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1) and Differentiated embryo chondrocyte 1 (Dec1) were upregulated, while Period 1 (Per1) was reduced in OSA patients. In addition, these changing trends were closely associated with the hypoxia indicator of AHI and have a significant impact on the presence of MetS components, such as hyperglycemia (Dec1 and Per1, p < 0.05 and 0.001, respectively), hypertension (Bmal1 and Dec1, p < 0.001 and 0.01, respectively), hyperlipidemia (Dec1, p < 0.01), and obesity (Dec1, p < 0.05). Notably, expressions of Dec1 correlated with IR and predicted the presence of MetS in OSA patients. Finally, we also observed that Dec1 expression was interrelated with levels of both oxidative indicators and inflammatory biomarkers (IL-6) in OSA. Conclusion: This study concluded that circadian clock disruptions, especially Dec1, link OSA with MetS in an oxidative and inflammatory-related manner. Circadian clock Dec1 can be used as a specific biomarker (p < 0.001) and therapeutic target in OSA combined with Mets patients.

Circadian clock disruptions link oxidative stress and systemic inflammation to metabolic syndrome in obstructive sleep apnea patients

Introduction to Comprehensive Glycoscience: The Good, the Better and What's to Come

Hepatic diseases include all diseases that occur in the liver, including hepatitis, cirrhosis, hepatocellular carcinoma, etc. Hepatic diseases worldwide are characterized by high incidences of digestive system diseases, which present with subtle symptoms, are difficult to treat and have high mortality. Galectins are β-galactoside-binding proteins that have been found to be aberrantly expressed during hepatic disease progression. An increasing number of studies have shown that abnormal expression of galectins is extensively involved in hepatic diseases, such as hepatocellular carcinoma (HCC), liver cirrhosis, hepatitis and liver fibrosis. Galectins function as intracellular and extracellular hepatic disease regulators mainly through the binding of their carbohydrate recognition domain to glycoconjugates expressed in hepatocytes. In this review, we summarize current research on the various roles of galectins in cirrhosis, hepatitis, liver fibrosis and HCC, which may provide a preliminary theoretical basis for the exploration of new targets for the treatment of hepatic diseases.

The roles of galectins in hepatic diseases

Serum biomarkers for liver fibrosis.

Background Obstructive sleep apnea-hypopnea syndrome (OSA) may cause liver fibrosis, and liver fibrosis serum biomarkers plays an important role on the diagnosis of liver fibrosis. In addition, this study aimed to observe the changes of 4 serum markers and Chitinase 3-like protein 1 (CHII3L1) levels in OSA patients with different disease severity and explore their interactions. And then, we examined whether intermittent hypoxia (IH) exposure can activate hepatic stellate cell. Methods 74 OSA patients in Second Xiangya hospital from January 2021 to October 2021 was selected and categorized into mild, moderate, and severe groups according to AHI. In addition, 20 subjects were selected as the control group. Serum levels of liver fibrosis markers were determined by electrochemiluminescence immunoassay. Hepatic stellate cells were exposed to intermittent IH or normoxia (RA). Results were analyzed using the SPSS software. Results There was a significant increase in serum hyaluronic acid (HA), collagen type IV (CIV) and CHI3L1 levels in OSA patients compared with control group. Specifically, serum liver fibrosis markers HA, CIV and CHI3L1 levels were positively correlated with apnea-hypopnea index (AHI), but negatively correlated with the lowest saturation oxygen (LSaO2) respectively. The LX-2 cells (human hepatic stellate cell line) exposed to IH showed significant increases in fibrotic protein expression. Conclusion OSA might either directly or indirectly trigger or exacerbate liver fibrosis, possibly via IH-related pathways.

Increased Levels of CHI3L1 and HA Are Associated With Higher Occurrence of Liver Damage in Patients With Obstructive Sleep Apnea

OBJECTIVE
To investigate the difference in serum sphingosine-1 phosphate (S1P) concentration between the HBV hepatitis patients and healthy controls, and its relevant association with serum liver fibrosis indicators.


METHODS
A total of 28 HBsAg (+) HBeAg (+) Anti-HBc (+) hepatitis B patients, 42 HBsAg (+) Anti-HBe (+) Anti-HBc (+) hepatitis B patients, and 21 healthy subjects with normal liver function were included. Liquid chromatography-tandem mass method was used to detect the level of serum S1P.


RESULTS
SerumS1P concentration of Anti-HBe (+) hepatitis B patients was higher than that of the control group (P=0.017) and HBeAg (+) patients (P=0.007). At the same time, there was no significant difference in the serum S1P concentration between HBeAg (+) hepatitis B patients and the control group (P>0.05). Moreover, serum S1P concentration was positively correlated with liver fibrosis indices, Collage Type IV Protein (r=0.264; P=0.011), and Chitosanase 3-like protein 1 (r=0.295; P=0.004).


CONCLUSIONS
Serum S1P level is increased in patients with hepatitis B and displays a positive association with liver fibrosis.

Serum sphingosine-1 phosphate level is increased in patients with hepatitis B and displays a positive association with liver fibrosis.

Introduction This systematic review and meta-analysis evaluates the overall effects of lifestyle interventions upon hepatic fat content and metabolism-related indicators among adults with metabolic associated fatty liver disease. Methods It was registered under PROSPERO (CRD42021251527). We searched PubMed, EMBASE, MEDLINE, Cochrane, CINAHL, Scopus, CNKI, Wan-fang, VIP, and CBM from the inception of each database to May 2021 for RCT studies of lifestyle interventions on hepatic fat content and metabolism-related indicators. We used Review Manager 5.3 for meta-analysis and used text and detailed tabular summaries when heterogeneity existed. Results Thirty-four RCT studies with 2652 participants were included. All participants were obesity, 8% of whom also had diabetes, and none was lean or normal weight. Through subgroup analysis, we found low carbohydrate diet, aerobic training and resistance training significantly improved the level of HFC, TG, HDL, HbA1c, and HOMA-IR. Moreover, low carbohydrate diet is more effective in improving HFC than low fat diet and resistance training is better than aerobic training in reduction in HFC and TG (SMD, -0.25, 95% CI, -0.45 to -0.06; SMD, 0.24, 95% CI, 0.03 to 0.44, respectively). Discussion Overall, this is the first review that systematically synthesizes studies focused on the effects of various lifestyle on adults with MAFLD. The data generated in this systematic review were more applicable to obesity MAFLD rather than lean or normal weight MAFLD. Systematic Review Registration https://www.crd.york.ac.uk/prospero/, identifier (CRD42021251527).

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Mei-Juan Sun

Papers

The roles of galectins in hepatic diseases

Serum biomarkers for liver fibrosis.

Increased Levels of CHI3L1 and HA Are Associated With Higher Occurrence of Liver Damage in Patients With Obstructive Sleep Apnea

Serum sphingosine-1 phosphate level is increased in patients with hepatitis B and displays a positive association with liver fibrosis.

Effects of lifestyle intervention on adults with metabolic associated fatty liver disease: A systematic review and meta-analysis