Search Results (410)

Type 2 diabetes mellitus (T2DM) involves progressive muscle wasting, metabolic dysregulation in peripheral tissues, chronic hyperglycemia, and insulin resistance. Momordica charantia is an antidiabetic agent often limited by bitterness. To improve palatability and efficacy, we developed EMS by combining M. charantia and Stevia rebaudiana (9:1). EMS’s antidiabetic effects were tested in streptozotocin (STZ)-induced and genetic db/db mouse models of diabetes. Mice received oral EMS at doses (40, 80, and 120 mg/kg) for six weeks, assessing glucose tolerance, insulin sensitivity, lipid profile, and hepatic markers. Additionally, muscle protein synthesis and degradation mechanisms were analyzed in gastrocnemius tissues. EMS significantly reduced fasting blood glucose and improved insulin sensitivity in both models. EMS decreased liver lipid accumulation and serum ALT and AST levels, indicating hepatic protection. EMS alleviated muscle atrophy by increasing muscle fiber area and was associated with increased expression or activity of AMPK/Sirt1/PGC-1α and IRS-1/PI3K/AKT insulin pathways. It also suppressed FOXO3a-mediated expression of Atrogin-1 and MuRF1, suggesting reduced activation of protein-degradation pathways. Moreover, EMS modulated the gut microbiota, increasing the abundance of beneficial species such as Barnesiella intestinihominis. These findings suggest EMS is a promising multitarget functional ingredient for metabolic complications and musculoskeletal decline in T2DM. Full article

Type 2 diabetes mellitus is associated with chronic low-grade inflammation contributing to endothelial dysfunction, metabolic imbalance, and cardiovascular complications. Although semaglutide (SEM) and tirzepatide (TIR) provide important metabolic and cardioprotective benefits, their early anti-inflammatory effects and potential sex-dependent differences remain incompletely understood. This study comparatively evaluated the effects of SEM and TIR on systemic inflammatory biomarkers in a murine model of streptozotocin-induced diabetes mellitus. Thirty BALB/c mice were allocated into six experimental groups according to sex and treatment: control, SEM, and TIR groups (n = 5/group). Diabetes was induced by intraperitoneal streptozotocin administration, followed by treatment with SEM or TIR. Circulating interleukin-1β (IL-1β) and pentraxin-3 (PTX-3) levels were measured at baseline, one week after streptozotocin administration, and after six weeks of treatment. Control groups exhibited progressive increases in IL-1β and PTX-3 levels, indicating sustained inflammatory activation. In contrast, SEM- and TIR-treated animals showed attenuated inflammatory responses characterized by transient or stabilized biomarker profiles. Differential inflammatory responses were observed between treatments and sexes. Male SEM and Male TIR groups demonstrated stable IL-1β levels, whereas female treated groups showed persistent elevations, particularly Female TIR animals. PTX-3 responses also displayed differential sex-dependent patterns, with Female SEM animals exhibiting the most stable inflammatory profile. These findings suggest differential early immunomodulatory effects of the two modern antidiabetic drugs, characterized by distinct biomarker responses according to sex and inflammatory marker profile. IL-1β and PTX-3 may represent complementary biomarkers for the assessment of early inflammatory activation associated with diabetes mellitus and its cardiometabolic complications. Full article

Type 2 diabetes (T2D) is a chronic metabolic disorder leading to increased cardiovascular risk and vascular dysfunction. Hyperglycemia, a hallmark of T2D, drives hypercontractility, thereby compromising vascular function. Heat shock protein 70 (HSP70) has emerged as an important player in vascular reactivity under physiological conditions via its interaction with calcium mobilization, and in T2D, blocking this protein prevents hypercontractility. Circulating extracellular HSP70 (eHSP70) has also been proposed as a biomarker in chronic diseases, as it can function as a damage-associated molecular pattern (DAMP) to activate the innate immune system and promote low-grade inflammation. Berberine (BBR), a natural alkaloid with anti-inflammatory properties, has been shown to attenuate vascular contraction by modulating intracellular calcium handling. Yet the link between HSP70 and BBR in modulating vascular contraction in T2D remains unknown. Therefore, we investigated whether acute and/or chronic BBR treatment modulates HSP70 to prevent vascular hypercontractility in the T2D mouse model. For acute ex vivo treatment, db/+ and db/db aortic rings were incubated for 30 min with or without the HSP70 inhibitor VER155008, in the presence or absence of BBR or vehicle. For chronic in vivo treatment, db/+ and db/db mice received intraperitoneal BBR injections (10 mg/kg, 3 times per week) and BBR in their drinking water (0.5 mg/mL) for 28 days. Following chronic (4 weeks, in vivo) or acute ex vivo (30 min) BBR treatment, vascular function was assessed in aortic rings isolated from male T2D (db/db) and age-matched non-diabetic (db/+) mice using wire myography. Rings were incubated with or without the HSP70 inhibitor VER155008, in the presence or absence of BBR or vehicle. Overt hyperglycemia and hypercontractility were observed in diabetic animals compared with non-diabetic controls. While acute BBR treatment attenuated vasoconstriction in both diabetic and nondiabetic groups, the combination of BBR and VER155008 produced a stronger inhibitory effect only in the diabetic group. Chronic BBR treatment prevented aortic hypercontractility in diabetic mice; however, the synergistic effect with VER155008 was no longer observed. Additionally, BBR reduced systemic HSP70 levels. Collectively, these findings indicate that BBR improves vascular smooth muscle cells’ function in T2D, at least in part, through HSP70-dependent mechanisms during chronic treatment. Full article

Type 2 diabetes mellitus (T2DM) accounts for over 90% of diabetes cases, and T2DM-related sarcopenia is a growing concern. Carnosine, abundant in human skeletal muscle, helps maintain muscle quality and function. This study investigated whether carnosine deficiency contributes to T2DM-related sarcopenia and whether exogenous carnosine supplementation alleviates muscle atrophy. A mouse model of T2DM sarcopenia was established using streptozotocin combined with a high-fat diet. LC-MS metabolomics revealed a significant reduction in carnosine content in the gastrocnemius muscle of model mice. A C2C12 myotube atrophy model was induced by high-glucose (HG), and qRT-PCR showed altered expression of carnosine metabolism-related enzymes, suggesting disrupted carnosine homeostasis under T2DM conditions. Mechanistic investigations using immunofluorescence, Western blotting, transcriptome sequencing, mitochondrial staining, and molecular docking indicated that carnosine may alleviate high-glucose-induced myotube atrophy through the PI3K/AMPK/PGC-1α signaling pathway. In vivo, carnosine supplementation increased the number of mitochondria and the proportion of slow muscle fibers in gastrocnemius muscle, ameliorating the atrophic phenotype. These findings suggest that carnosine has potential as a candidate for intervention in T2DM-related sarcopenia, though further validation of its direct molecular targets is required. Full article

Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, restores hyperglycemic conditions in patients with type 2 diabetes and has recently shown promising anti-inflammatory properties. In this study, we explored its potential to suppress osteoclast formation and bone loss triggered by lipopolysaccharide (LPS), an inflammatory agent. In animal models, the co-administration of liraglutide with LPS on the calvaria regions in mice markedly reduced osteoclast numbers and bone resorption areas relative to treatment with LPS alone. Furthermore, the expression levels of receptor activators of the NF-κB ligand (RANKL) and tumor necrosis factor (TNF)-α mRNA were notably lower in the group receiving liraglutide and LPS compared to treatment with LPS alone. Moreover, in vitro tests revealed that liraglutide has no direct inhibitory effect on RANKL-induced osteoclastogenesis and TNF-α-induced osteoclastogenesis. In addition, liraglutide had no direct inhibitory effect on LPS-stimulated RANKL expression in osteoblasts. Moreover, liraglutide effectively suppressed TNF-α mRNA expression in macrophages stimulated by LPS. These findings suggest that liraglutide prevents inflammatory bone destruction not by targeting osteoclast formation directly but by inhibiting the production of TNF-α within macrophages. Full article

Background: Pathological aggregation of islet amyloid polypeptide (IAPP) contributes to β-cell dysfunction in type 2 diabetes. Our previous studies demonstrated that caveolin-1 (Cav-1) deficiency protects β-cells from palmitate-induced apoptosis. Microarray profiling further indicated that Cav-1 silencing alters IAPP expression. This study aimed to investigate the effects of Cav-1 depletion on IAPP secretion and expression and to explore the potential involvement of thioredoxin-interacting protein (TXNIP). Methods: We performed lentiviral-mediated Cav-1 knockdown in NIT-1 cells and isolated murine islets, and simultaneously generated an inducible β-cell-specific Cav-1 knockout (iβ-Cav1 KO) mouse model. IAPP secretion and expression were assessed by ELISA, Western blot, qPCR and immunofluorescence. The expression of IAPP-processing enzymes (PAM, PC1, and PC2) and degradation factors (IDE and BACE2) was examined. Co-immunoprecipitation (Co-IP) and immunofluorescence were performed to investigate the interaction between Cav-1 and TXNIP. Results: Cav-1 depletion significantly reduced both IAPP secretion and expression in vitro and in vivo. High-fat-diet-fed iβ-Cav1 KO mice exhibited the lowest serum IAPP levels. Mechanistically, Cav-1 depletion was associated with downregulation of PAM, PC1, and PC2 and upregulation of IDE and BACE2. Additionally, Cav-1 depletion decreased TXNIP expression. Immunofluorescence revealed co-localization of Cav-1 and TXNIP, and co-immunoprecipitation further demonstrated their direct physical interaction. Conclusions: Cav-1 is essential for IAPP secretion and expression in β-cells. The direct physical interaction between Cav-1 and TXNIP suggests that TXNIP may mediate the regulatory effects of Cav-1 on IAPP processing or secretion. These findings identify the Cav-1–TXNIP axis as a potential target for mitigating IAPP-related β-cell dysfunction. Full article

Background/Objectives: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder associated with insulin resistance, β-cell dysfunction, and systemic complications. Methods: In this preliminary study, the metabolic effects of BE-FD-1, a water extract of Raphanus sativus L. leaves cultivated under a mineral-fortification protocol, were investigated in a high-fat-diet/streptozotocin (HFD/STZ)-induced diabetic mouse model. Inductively coupled plasma mass spectrometry analysis confirmed the presence of vanadium, chromium, magnesium, zinc, and calcium in radish leaf. Male C57BL/6 mice (n = 5/group) were orally administered BE-FD-1 at 250 or 500 mg/kg once daily for four weeks, with metformin (250 mg/kg) as a positive reference. Results: BE-FD-1 at 500 mg/kg significantly reduced the oral glucose tolerance test area under the curve and fasting blood glucose levels, significantly restored serum insulin levels, and significantly decreased serum ALT, triglyceride, and total cholesterol levels relative to the HFD/STZ control group. Body weight gain and AST showed non-significant decreasing tendencies. Serum creatinine remained within the normal range, providing a preliminary safety signal that should be interpreted with caution given the absence of additional renal biomarkers and histopathological evaluation. Conclusions: These exploratory findings suggest that BE-FD-1 may warrant further investigation as a candidate functional ingredient for T2DM-related metabolic dysfunction; however, larger studies with comprehensive phytochemical characterization, mechanistic validation, and broader safety evaluation are required. Full article

In skeletal muscle, there are two main progenitor populations crucial for growth, maintenance, and repair: satellite cells (SCs) and interstitial cells, of which fibro-adipogenic progenitor cells (FAPs) are the best characterized fraction. However, data on how specific diseases or physiological conditions affect the biological properties of FAPs are limited. In this review we analyze data obtained with FAPs purified from skeletal muscle tissue from Duchenne muscular dystrophy (both human patients and mdx mice models), hindlimb functional unloading (rats), and type 2 diabetes (T2DM, human patients). Here we discuss how disuse/disease affect FAP’s properties: the adaptive metabolic remodeling; the alterations in adipogenic differentiation in vitro; the possible role of particular subpopulations of FAPs in disease development; the role of FAPs in cell-to-cell interactions during skeletal muscle degeneration and regeneration. Current research has outlined how different physiological and pathological conditions alter FAPs’ behavior, highlighting FAPs as a potential target for clinical protocols aimed at treating or mitigating skeletal muscle disorders. Future studies should clarify how FAPs govern cell-to-cell interactions during skeletal muscle degeneration and regeneration, offering critical insights for therapies targeting diverse neuromuscular diseases. Full article

Background: Pyrroloquinoline quinone (PQQ), a naturally occurring redox cofactor with potent antioxidant and anti-inflammatory properties, has been shown to protect against cardiac injury. However, its therapeutic potential in diabetic cardiomyopathy (DCM) induced by Type 2 diabetes mellitus (T2DM) and the underlying mechanisms remain poorly understood. Methods: A T2DM mouse model was established via a high-fat diet and low-dose STZ. We investigated the cardioprotective effects of 12-week oral PQQ administration, assessing fasting blood glucose, oral glucose tolerance, cardiac function, myocardial histopathology, blood biochemistry, mitophagy, and NLRP3 inflammasome activation. In vitro experiments using AC16 cardiomyocytes exposed to palmitic acid and high glucose were also conducted. Results: Results showed PQQ significantly improved cardiac function, attenuated remodeling, and reduced proinflammatory cytokines in mice with T2DM, regulated key mitophagy-related proteins (Parkin, Beclin-1, LC3B-II, p62), and downregulated NLRP3 inflammasome pathway components (Caspase-1, NLRP3, IL-1β, IL-18). In vitro experiments demonstrated that PQQ reduced reactive oxygen species (ROS) production, improved mitochondrial membrane potential, promoted mitophagy, and inhibited NLRP3 inflammasome-mediated pyroptosis. Conclusions: PQQ alleviates DCM in mice with T2DM by improving mitochondrial quality control, promoting mitophagy, and subsequently inhibiting NLRP3 inflammasome-mediated pyroptosis, highlighting its potential as a promising therapeutic agent for T2DM-associated cardiomyopathy. Full article

Background: To investigate the effect of angiotensin-(1-7) [Ang-(1-7)] on serum metabolomics in obese type 2 diabetic (T2DM) mice. Methods: Four-week-old male C57BL/6 mice were fed a high-fat diet and intraperitoneally injected with streptozotocin (35 mg/kg) to establish an obese T2DM model. Mice were randomized into control, T2DM and T2DM+Ang-(1-7) groups (n = 6). Body weight and blood glucose were recorded weekly. At 10 weeks, blood glucose, serum inflammatory factors, lipid profiles, and pancreatic β-cell insulin secretion were detected; serum metabolite alterations were analyzed via untargeted metabolomics. Results: 1. Ang-(1-7) intervention decreased blood glucose (p < 0.05) and CRP levels (p < 0.01), and alleviated dyslipidemia (p < 0.05 or p < 0.01), as well as β-cell morphology and insulin expression in obese T2DM mice. 2. Non-targeted metabolomics analysis suggested that Ang-(1-7) may alleviate abnormal amino acid metabolic pathways by regulating levels of metabolites such as L-valine, L-proline, L-histidine, and glutamic acid. This intervention also tended to reduce multiple lipid metabolites, including Omega-3 Arachidonic Acid Ethyl Ester, phosphatidylcholine, and glycerophosphocholine, thereby participating in the modulation of lipid metabolism balance. KEGG enrichment analysis further indicated that Ang-(1-7) was involved in the regulation of protein digestion and the absorption pathway, as well as the HIF-1 signaling pathway related to oxidative stress, bile acid metabolism pathway, and other signaling pathways, and improving the insulin secretion pathway, pyrimidine metabolism, and TCA cycle energy metabolism pathway. Conclusions: Ang-(1-7) may partially improve metabolic disturbances in obese T2DM mice, which is potentially associated with the modulation of multiple metabolic processes, including amino acid metabolism, lipid metabolism, insulin secretion, and TCA cycle energy metabolism. Full article

This study developed a probiotic Eurotium cristatum-fermented Premna microphylla Turcz. (EFPT) and systematically evaluated its nutritional profile and antidiabetic effects in a type 2 diabetes mellitus (TIIDM) mouse model. After 8 days of fermentation, the contents of pectin (9.001% vs. 4.222%) and water-soluble polysaccharides (13.339% vs. 4.826%) increased significantly (p < 0.05), whereas the levels of polyphenols (12.12% vs. 15.917%) and soluble proteins (3.829% vs. 5.797%) decreased (p < 0.05). Notable alterations were also observed in short-chain fatty acids (SCFAs), monosaccharide composition, and amino acid profiles. Specifically, the levels of propionic acid, histidine, threonine, serine, glycine, lysine, glutamic acid, and methionine decreased significantly (p < 0.05), while those of butyric acid, valeric acid, galactose, valine, alanine, and proline increased (p < 0.05). Furthermore, EFPT exhibited dose-dependent antidiabetic effects and showed greater efficacy than non-fermented Premna microphylla Turcz. powder in high-fat diet combined with streptozotocin-induced TIIDM mice (p < 0.05). These effects were primarily associated with enhanced SCFAs production and the amelioration of liver and kidney damage. Overall, these findings suggest that Eurotium cristatum fermentation enhances the bioactive properties of Premna microphylla Turcz., contributing to its improved nutritional quality and potent antidiabetic activity. Full article

Intermittent fasting confers protection in diverse diseases through various mechanisms, including the clearance of senescent and pathogenic cells, modulation of tissue inflammation and enhancement of stem/progenitor cell niche and functionality. Our previous study demonstrated the beneficial impact of alternate-day fasting (ADF) on xerostomia and sialadenitis, along with an improvement in salivary gland ductal compartments, where salivary gland progenitor cells reside, in non-obese diabetic mice, a spontaneous model of Sjögren’s syndrome (SS). In the present study, we induced SS-associated hyposalivation in KRT5^CreERT2; R26^tdTomato lineage tracing mice by immunizing them with submandibular gland proteins from wild-type C57BL/6 mice. ADF alleviated salivary gland hypofunction, which was accompanied by decreased expression of the senescent cell marker p16^INK4a, reduced protein levels of anti-apoptotic proteins BCL-2, BCL-XL, and MCL-1, and attenuated NLRP3 inflammasome activity in the submandibular glands, particularly within the ductal compartments, of this inducible model. Furthermore, immunofluorescence staining of submandibular gland sections revealed the expression of the acinar cell marker aquaporin 5 in a small subset of Keratin 5⁺ cells in 2 of 9 mice that were subjected to ADF, whereas no such cells were detected in the control mice. Taken together, these findings indicate that ADF favorably modulates the salivary gland progenitor cell niche, potentially by promoting apoptosis-mediated senescent cell clearance, suppressing NLRP3 inflammasome signaling, and promoting Keratin 5⁺ progenitor cell-derived acinar cell replenishment, thereby contributing to the structural and functional restoration of damaged salivary glands in autoimmune exocrinopathy. Full article

Empagliflozin (EMPA), a sodium-glucose cotransporter 2 inhibitor, has garnered attention for its cardiovascular benefits beyond glycemic control. Ferroptosis, a novel form of regulated cell death, contributes to the pathogenesis of diabetic cardiomyopathy (DCM). However, whether EMPA mitigates DCM by suppressing ferroptosis remains unclear. Here, Type 2 diabetic db/db mice were used to establish a DCM model and treated with EMPA (10 mg/kg/day) for 12 weeks. EMPA significantly improved cardiac function, reduced myocardial fibrosis, and attenuated ferroptosis, concomitant with upregulated silent information regulator 3 (SIRT3) expression. In the rat cardiomyocytes (H9c2 cells) exposed to high glucose and palmitic acid, EMPA treatment or SIRT3 overexpression alleviated oxidative stress, mitochondrial dysfunction, and ferroptosis. Mechanistically, molecular docking, molecular dynamics simulation, cellular thermal shift assay and drug affinity responsive target stability assay confirmed that SIRT3 is the drug target of EMPA, stabilizing its protein levels and reducing acetylated p53 expression. Notably, SIRT3 silencing abolished EMPA’s beneficial effects on oxidative stress and ferroptosis. Our findings demonstrate that EMPA exerts cardioprotective effects by inhibiting oxidative stress and ferroptosis in cardiomyocytes, which is mediated by SIRT3. This study provides novel insights into the mechanisms underlying EMPA’s therapeutic effects in DCM. Full article

Background: Circadian disruption exacerbates type 2 diabetes mellitus (T2DM). Time-restricted feeding (TRF) and exercise (EX) improve metabolic health, but their combinatory effect remains unclear. This study investigated whether combined TRF and EX additively ameliorates metabolism via circadian reprogramming in db/db mice. Methods: Eight-week-old male db/db mice were assigned to control (Con), diabetic model (DM), TRF (8 h feeding window), EX (treadmill, 60 min/day, 5 days/week), or combined TRF + EX groups for 8 weeks (n = 8/group). Body weight, glucose/insulin tolerance, and 24 h energy metabolism (CLAMS) were assessed. Mitochondrial function, oxidative stress, inflammation, and expression of mitophagy (Pink1, Park2, Bnip3, Fundc1) and thermogenic (Ucp1, Pgc1a, Prdm16, Cidea) genes were measured. Results: Compared with the con group, DM mice showed obesity, hyperglycemia and blunted circadian metabolic rhythm. The TRF and EX groups improved these defects. Specifically, combined TRF + EX reduced fasting blood glucose from 25.3 ± 3.1 mmol/L (DM) to 13.2 ± 1.8 mmol/L (p < 0.05), body weight from 49.8 ± 2.5 g to 39.5 ± 1.7 g (p < 0.05), and body fat percentage from 45.6 ± 3.2% to 32.1 ± 2.2% (p < 0.05). GTT area under the curve (AUC) decreased from 3711.0 ± 186.5 (DM) to 2118.0 ± 112.4 (p < 0.05), and ITT AUC decreased from 2617.5 ± 135.8 to 1260.0 ± 68.9 (p < 0.05). Notably, the combination of TRF + EX produced greater effects than either intervention alone: body weight, fasting blood glucose, and glucose/insulin tolerance were greatly improved (p < 0.05). In addition, compared with the DM group, the diurnal metabolic amplitude and phase were improved in the TRF or EX group; the combination group showed further improvements in these parameters. Furthermore, TRF and EX each resulted in significantly higher expression of key thermogenic genes (Ucp1, Pgc1a, Prdm16, Cidea) in white adipose tissue (WAT) and brown adipose tissue (BAT) (p < 0.05), and the TRF + EX group showed the highest expression levels. Combined intervention also restored skeletal muscle SOD activity (31.2 ± 2.9 U/mg prot vs. DM 20.1 ± 2.5 U/mg prot, p < 0.05) and reduced serum TNF-α (28.5 ± 4.5 pg/mL vs. DM 65.8 ± 8.5 pg/mL, p < 0.05) and IL-6 (21.6 ± 3.8 pg/mL vs. DM 50.3 ± 7.1 pg/mL, p < 0.05). Conclusions: TRF + EX additively restores metabolic homeostasis in diabetes by re-entraining circadian energy rhythms, improving mitochondrial quality, and activating adipose thermogenesis, supporting further investigation of integrated lifestyle timing as a potential therapeutic strategy. Full article

GLP-1-based drugs are approved for the treatment of type 2 diabetes mellitus (T2DM) and obesity. Metabolic dysfunction-associated steatotic liver disease (MASLD) affects more than 60% of patients with T2DM, and the gut microbiome plays a critical role in its pathogenesis. The gut–liver axis represents a key mechanistic link between dysbiosis and hepatic steatosis. A narrative literature review was conducted using PubMed, Scopus, and ClinicalTrials.gov (2015–2026). Search terms included “GLP-1 receptor agonist,” “microbiome,” “MASLD,” “MASH,” “NAFLD,” “NASH,” “liraglutide,” “semaglutide,” “tirzepatide,” “dulaglutide,” and “exenatide.” Of 363 identified articles, 330 were excluded due to duplication or non-relevant study design; 33 studies (18 preclinical, 15 clinical) were included. In preclinical models, liraglutide demonstrated normalization of the Firmicutes/Bacteroidetes ratio and increased Bifidobacterium and Lactobacillus spp., while tirzepatide significantly reduced hepatic steatosis and increased Akkermansia abundance in diabetic mice. Semaglutide improved gut barrier integrity, increased Alloprevotella and Alistipes, and ameliorated MASLD in murine models. In clinical studies, tirzepatide achieved MASH resolution in 44–62% of patients in the phase 2 SYNERGY-NASH trial. In August 2025, the FDA approved semaglutide for MASH with fibrosis based on the Phase 3 ESSENCE trial. A recent longitudinal study in T2DM patients showed that baseline microbiome composition predicted glycemic response to semaglutide, without significant changes in microbiome diversity. In conclusion, GLP-1-based therapies demonstrate consistent preclinical associations with gut microbiome modulation and reduction in hepatic steatosis. Baseline microbiome composition has been suggested as a potential predictor of treatment response, supporting a personalized approach to MASLD management and warranting future clinical studies. Full article