Improved Liver Function Research Articles

Silymarin: Unveiling its pharmacological spectrum and therapeutic potential in liver diseases-A comprehensive narrative review.

Liver diseases, encompassing conditions such as cirrhosis, present a substantial global health challenge with diverse etiologies, including viral infections, alcohol consumption, and non-alcoholic fatty liver disease (NAFLD). The exploration of natural compounds as therapeutic agents has gained traction, notably the herbal remedy milk thistle (Silybum marianum), with its active extract, silymarin, demonstrating remarkable antioxidant and hepatoprotective properties in extensive preclinical investigations. It can protect healthy liver cells or those that have not yet sustained permanent damage by reducing oxidative stress and mitigating cytotoxicity. Silymarin, a natural compound with antioxidant properties, anti-inflammatory effects, and antifibrotic activity, has shown potential in treating liver damage caused by alcohol, NAFLD, drug-induced toxicity, and viral hepatitis. Legalon® is a top-rated medication with excellent oral bioavailability, effective absorption, and therapeutic effectiveness. Its active component, silymarin, has antioxidant and hepatoprotective properties, Eurosil 85® also, a commercial product, has lipophilic properties enhanced by special formulation processes. Silymarin, during clinical trials, shows potential improvements in liver function, reduced mortality rates, and alleviation of symptoms across various liver disorders, with safety assessments showing low adverse effects. Overall, silymarin emerges as a promising natural compound with multifaceted hepatoprotective properties and therapeutic potential in liver diseases.

Linagliptin, a DPP-4 inhibitor, activates AMPK/FOXO3a and suppresses NFκB to mitigate the debilitating effects of diethylnitrosamine exposure in rat liver: Novel mechanistic insights.

Accumulating evidence suggests that dysregulation of FOXO3a plays a significant role in the progression of various malignancies, including hepatocellular carcinoma (HCC). FOXO3a inactivation, driven by oncogenic stimuli, can lead to abnormal cell growth, suppression of apoptosis, and resistance to anticancer drugs. Therefore, FOXO3a emerges as a potential molecular target for the development of innovative treatments in the era of oncology. Linagliptin (LNGTN), a DPP-4 inhibitor known for its safe profile, has exhibited noteworthy anti-inflammatory and anti-oxidative properties in previous invivo studies. Several potential molecular mechanisms have been proposed to explain these effects. However, the capacity of LNGTN to activate FOXO3a through AMPK activation has not been investigated. In our investigation, we examined the potential repurposing of LNGTN as a hepatoprotective agent against diethylnitrosamine (DENA) intoxication. Additionally, we assessed LNGTN's impact on apoptosis and autophagy. Following a 10-week administration of DENA, the liver underwent damage marked by inflammation and early neoplastic alterations. Our study presents the first experimental evidence demonstrating that LNGTN can reinstate the aberrantly regulated FOXO3a activity by elevating the nuclear fraction of FOXO3a in comparison to the cytosolic fraction, subsequent to AMPK activation. Moreover, noteworthy inactivation of NFκB induced by LNGTN was observed. These effects culminated in the initiation of apoptosis, the activation of autophagy, and the manifestation of anti-inflammatory, antiproliferative, and antiangiogenic outcomes. These effects were concomitant with improved liver function and microstructure. In conclusion, our findings open new avenues for the development of novel therapeutic strategies targeting the AMPK/FOXO3a signaling pathway in the management of chronic liver damage.

Adipose Tissue and Umbilical Cord Tissue: Potential Sources of Mesenchymal Stem Cells for Liver Fibrosis Treatment

Purpose of the studyMesenchymal stem cells (MSCs) are potential alternatives for liver fibrosis treatment; however, their optimal sources remain uncertain. This study compares the ex-vivo expansion characteristics of MSCs obtained from adipose tissue (AT) and umbilical cord (UC) and assesses their therapeutic potential for liver fibrosis treatment. MethodsSince MSCs from early to mid-passage numbers (P2–P6) are preferable for cellular therapy, we investigated the growth kinetics of AT-MSCs and UC-MSCs up to P6 and evaluated their therapeutic effects in a rat model of liver fibrosis induced by diethylnitrosamine. ResultsResults from the expansion studies demonstrated that both cell types exhibited bonafide characteristics of MSCs, including surface antigens, pluripotent gene expression, and differentiation potential. However, AT-MSCs demonstrated a shorter doubling time (58.2 ± 7.3 vs. 82.3 ± 4.3 h; p < 0.01) and a higher population doubling level (10.1 ± 0.7 vs. 8.2 ± 0.3; p < 0.01) compared to UC-MSCs, resulting in more cellular yield (230 ± 9.0 vs. 175 ± 13.2 million) in less time. Animal studies demonstrated that both MSC types significantly reduced liver fibrosis (p < 0.05 vs. the control group) while also improving liver function and downregulating fibrosis-associated gene expression. ConclusionAT-MSCs and UC-MSCs effectively reduce liver fibrosis. However, adipose cultures display an advantage by yielding a higher number of MSCs in a shorter duration, rendering them a viable choice for scenarios requiring immediate single-dose administration, often encountered in clinical settings.

Effects of High-Dose Vitamin C on Liver Function, Systemic Inflammatory and Immune Responses in Patients with Severe Acute Pancreatitis

The objective of this study was to explore the impact of high-dose vitamin C on severe acute pancreatitis patients. This study involved 76 hospital patients from November 2022 to November 2023, divided into two groups: a high-dose group (44 patients) receiving 10 g of vitamin C daily and a routine-dose group (32 patients) receiving 1 g daily. The study evaluated treatment effects, liver function, inflammation levels, and blood T-lymphocyte subsets and complications. At 14 days, the high-dose group showed better overall treatment effects, lower levels of liver enzymes and inflammatory markers, and higher levels of T lymphocytes, with no significant difference in complications compared to the routine-dose group. The findings suggest that high-dose vitamin C effectively improves liver function, reduces inflammation, and boosts immunity in severe acute pancreatitis patients.

Effect of recombinant human thrombopoietin on platelets in rats with D-galactosamine salt-induced acute liver failure

To evaluate the effects of recombinant human thrombopoietin (rhTPO) on platelet count (PLT) and liver function in acute liver failure (ALF) rats by observing the dynamic changes of PLT, thrombopoietin (TPO) and liver function during ALF. Twenty-four male Sprague-Dawley (SD) rats were divided into model group, TPO group and interleukin-11 (IL-11) group using a random number table method, with eight rats in each group. All rats were intraperitoneally injected with D-galactosamine (D-GalN, 1 500 mg/kg, dosed within 72 hours) to induce the ALF model. After modeling, rats in TPO group was received subcutaneous injection of 15 μg/kg of rhTPO for 5 days, and rats in IL-11 group was received subcutaneous injection of 0.45 mg/kg of IL-11 for 5 days. Venous blood samples were collected before and at 1, 3, 5, 7 and 12 days after molding for whole blood cell detection. The level of TPO in serum was detected by enzyme-linked immunosorbent assay (ELISA). Liver function indexes including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil) and albumin (ALB) were measured before and at 1, 3 and 5 days after modeling. The rats were sacrificed 12 days after the modeling, and the pathological changes of liver tissue were observed by hematoxylin-eosin (HE) staining. Two rats in each group died within 24-48 hours after modeling. HE staining showed that all three groups of ALF rats showed large flake necrosis of hepatocytes, disorder of hepatic lobular structure, mesh scaffold collapse, hepatic sinus congestion and hemorrhage, and flake infiltration of inflammatory cells on day 12 after modeling. The levels of serum ALT, AST and TBil of rats in each group were significantly increased 1 day after modeling and then decreased. The level of ALB decreased significantly on the first day after modeling and then increased, but there was no significant difference in the trend of liver function indexes among the three groups. PLT in the three groups decreased rapidly on day 1 after modeling, and then recovered gradually with the improvement of liver function. The PLT of the TPO group rose to the peak value 7 days after molding and was significantly higher than that of the model group [PLT (×109/L): 1 673.3±347.5 vs. 855.3±447.0, P < 0.05], while there was no significant difference between the IL-11 group and the model group [PLT (×109/L): 1 350.3±386.6 vs. 855.3±447.0, P > 0.05]. The level of serum TPO of the three groups increased significantly on day 1 after modeling, then decreased, and dropped to the lowest value on day 5, but there was no significant difference in the trend of serum TPO level among the three groups. PLT in ALF rats decreased rapidly in the early stage and recovered gradually with the improvement of liver function, and the serum TPO level increased first and then decreased. Injection of rhTPO can significantly increase PLT in ALF rats, but has no significant effect on liver function and survival rate.

Effect of Blend of Metanil Yellow and Tartrazine on Different Organs of Albino Rat

Background: Tartrazine and metanil yellow are organic azo dyes widely used in food products, drugs, and cosmetics. The present study was conducted to evaluate the toxic effect of these food colors on the liver, and kidneys of albino rats. The study also evaluates the protective effect of quercetin as an antioxidant against the toxic effect of these food colors. Methods: Eighty adult albino rats were divided into 8 groups. Control group, 3 groups were treated with a blend of tartrazine and metanil yellow in 3 doses of 25, 50, and 75 mg/kg for 30 days by gavage, one positive control group was treated with quercetin 50 mg/kg for 30 days, and three groups were treated with the blend of tartrazine and metanil yellow plus 50 mg/kg of quercetin. At the end of the experiment, serum samples were collected to evaluate liver and kidney functions. Liver, kidney samples were fixed in 10% formalin and routinely prepared for paraffin sectioning and staining for histopathological examination. Results: The study showed a significant elevation of liver and kidney function after treatment with the food color blend. Also, a significant improvement in liver and kidney function was observed after treatment with quercetin. Histopathological examination showed mild to moderate changes in the liver and kidney which improved after quercetin treatment. Conclusion: The current sub-chronic study concluded that a blend of tartrazine and metanil yellow caused significant biochemical and histological changes in different organs of albino rats. Therefore, prolonged consumption of these substances leads to adverse effects on human health. Also, quercetin is vital in protecting the body against the toxic effects of food color blends.

Zinc Oxide Nanoparticles Ameliorate Histological Alterations Through Apoptotic Gene Regulation in Rat Model of Liver Ischemia-Reperfusion Injury.

Organ ischemia-reperfusion (IR) is a common clinical condition associated with various situations such as trauma surgery, organ transplantation, and myocardial ischemia. Current therapeutic methods for IR injury have limitations, and nanotechnology, particularly zinc oxide nanoparticles (ZnO NPs), offers new approaches for disease diagnosis and treatment. In this study, we investigated the protective and anti-apoptotic effects of ZnO NPs in liver ischemia-reperfusion (IR) injury in rats. Forty-eight male rats were divided into six groups: sham, ZnO5, ZnO10, ischemia-reperfusion (IR), IR+ZnO5, and IR+ZnO10. The protective effect of ZnO NPs was evaluated by liver enzymes (AST, ALT, Bilirubin, ALP), biochemical (TAC, TNF-α, and MDA), molecular examinations (Bcl2, BAX), and histopathological evaluations (H&E, TUNEL). Pre-treatment with ZnO5 and ZnO10 improved hepatic function in IR liver injury, attenuated the levels of oxidants (P = 0.03) and inflammatory mediators, and reduced apoptosis (P = 0). ZnO10 was found to have a greater effect on ischemic reperfusion injury than ZnO5 did. Histopathological examination also showed a dose-dependent decrease in alterations in the IR+ZnO5 and IR+ZnO10 groups. Administration of ZnO5 and ZnO10 improved liver function after IR. The findings of this study suggest that ZnO NPs have a protective effect against oxidative stress and apoptosis in liver ischemia-reperfusion injury in rats. These results may have important implications for developing advanced methods in ischemia-reperfusion treatment.

Bulevirtide progressively improves liver function in liver transplant candidates with advanced HDV cirrhosis and severe portal hypertension

Bulevirtide progressively improves liver function in liver transplant candidates with advanced HDV cirrhosis and severe portal hypertension

Modulation of Gut Microbiota by Xylo-Oligosaccharides Helps Gestational Diabetes Mellitus Patients with Intrahepatic Cholestasis of Pregnancy

This study aimed to elucidate the therapeutic importance of xylo-oligosaccharides in modulating the gut microbiota for treating intrahepatic cholestasis of pregnancy complicated by gestational diabetes mellitus. Pregnant women diagnosed with intrahepatic cholestasis of pregnancy and gestational diabetes mellitus were enrolled in this study. The experimental group received continuous xylo-oligosaccharides treatment, whereas the placebo was administered to the control group. Comparisons were made between the two groups before and after therapy regarding oral glucose tolerance test, blood glucose levels, hemoglobin, oral glucose tolerance test, insulin, liver function indicators, and itching conditions. In terms of glucose metabolism indicators, the experimental cohort had significantly reduced (P &lt; 0.05) post-treatment blood glucose, hemoglobin A1c, and fasting insulin levels compared to those in the control cohort (P &lt; 0.05). The experimental participants indicated notably decreased levels of liver function indicators (P &lt; 0.05) compared to the control participants (P &lt; 0.05). The experimental cohort revealed a significant reduction in itching scores (P &lt; 0.05), which were significantly lower than those in the control cohort (P &lt; 0.05). Xylo-oligosaccharides can effectively reduce blood glucose levels in gestational diabetes mellitus in women with intrahepatic cholestasis of pregnancy, improve liver function indicators, and alleviate itching symptoms in pregnant women by modulating gut microbiota.

Role of fecal microbiota transplant in management of hepatic encephalopathy: Current trends and future directions.

Fecal microbiota transplantation (FMT) offers a potential treatment avenue for hepatic encephalopathy (HE) by leveraging beneficial bacterial displacement to restore a balanced gut microbiome. The prevalence of HE varies with liver disease severity and comorbidities. HE pathogenesis involves ammonia toxicity, gut-brain communication disruption, and inflammation. FMT aims to restore gut microbiota balance, addressing these factors. FMT's efficacy has been explored in various conditions, including HE. Studies suggest that FMT can modulate gut microbiota, reduce ammonia levels, and alleviate inflammation. FMT has shown promise in alcohol-associated, hepatitis B and C-associated, and non-alcoholic fatty liver disease. Benefits include improved liver function, cognitive function, and the slowing of disease progression. However, larger, controlled studies are needed to validate its effectiveness in these contexts. Studies have shown cognitive improvements through FMT, with potential benefits in cirrhotic patients. Notably, trials have demonstrated reduced serious adverse events and cognitive enhancements in FMT arms compared to the standard of care. Although evidence is promising, challenges remain: Limited patient numbers, varied dosages, administration routes, and donor profiles. Further large-scale, controlled trials are essential to establish standardized guidelines and ensure FMT's clinical applications and efficacy. While FMT holds potential for HE management, ongoing research is needed to address these challenges, optimize protocols, and expand its availability as a therapeutic option for diverse hepatic conditions.

Initial Experience of Anesthetic Management in Combined Liver-Kidney Transplantation: A Case Report

In this case report, we present a successful combined liver-kidney transplantation (CLKT) performed on a 41-year-old female with end-stage liver and renal disease. The patient, previously undergoing liver transplantation and regular hemodialysis, underwent CLKT with a focus on specific anesthesia management strategies. Key aspects included the use of desflurane for anesthesia, balanced crystalloid solutions for fluid management, and careful monitoring of hemodynamics without intraoperative renal replacement therapy. Despite substantial intraoperative fluid and blood product administration, careful management ensured stable vital signs and acid-base balance. The patient's postoperative recovery was notable for significant improvements in liver and renal functions, demonstrated by decreased creatinine and bilirubin levels, and improved estimated glomerular filtration rate, without the need for postoperative dialysis. This case underscores the effectiveness of CLKT in patients with concurrent liver and renal dysfunction, highlighting the importance of tailored anesthesia and fluid management strategies. The report contributes to the limited literature on anesthesia in CLKT, providing insights for better outcomes in such complex surgical procedures.

P729 Prospective observational study evaluating the effects of GLP1-RA on Inflammatory Bowel Disease (IBD) in patients with Type 2 Diabetes Mellitus (TDM2)

Abstract Background GLP-1 RA are antidiabetic drugs approved for treatment of TDM2 as second-choice therapy for long-term treatment in patients with TMD2 without previous cardiovascular events or as first-choice therapy in patients with previous cardiovascular events and without heart failure (SID/AMD guidelines). Their beneficial effect is not only associated with glycol-metabolic control, but also with a systemic anti-inflammatory action. In view of this anti-inflammatory action, we wanted to assess whether GLP1-RA could have a possible beneficial effect on IBD in terms of laboratory and clinical parameters. Moreover, these drugs have proven to improve liver function and histology, therefore, liver wellbeing may also be included as a cross-sectional element of evaluation in the possible benefits of these therapies. Methods Through the evaluation of 981 medical records of IBD patients followed in the gastroenterology department of the Hospital San Giovanni Antica Sede (SGAS), 71 TDM2 patients were identified. Among these, 21 were recruited for the study. The recruited patients were scheduled for a diabetological examination: GLP-1 RA treatment could then be introduced where indicated. At a 3-month follow-up interval, both the GLP-1 RA treatment group and the subjects that did not have any changes in therapy (control group) underwent re-evaluation of the parameters of interest. All patients in the study were offered the possibility to receive a FibroScan to measure liver stiffness at the start of the study and at the 3-months follow-up. Results A prevalence in the IBD population of TDM2 was found to be 7.2% (vs. Piedmont population prevalence 6.2%, p = 0.31). Out of the 21 patients recruited, 6 received GLP-1 RA treatment. At 3 months, an analysis of the results through the Wilcoxon test showed that the GLP-1 RA treated patients had a reduction in faecal calprotectin levels, an improvement in disease scores, an improvement in glycemic balance and a reduction in CAP and FIB4 when compared to the control group; these results did not reach statistical significance. In contrast, the reduction in BMI reached statistical significance. A comparison of the deltas for the variables under analysis between the two groups was also carried out using the Mann-Whitney test. Concordant and positive trends were observed in the GLP-1 RA-treated group: in this case the reduction in HbA1c reached statistical significance. Conclusion Treatment with GLP-1 RA in patients with TDM2 and IBD appears safe and seems to show benefits from an intestinal, metabolic and hepatic viewpoint. Studies with a larger number of subjects are certainly needed to effectively confirm the benefit of GLP-1 RA in this specific category of patients.

Effect of CT-Guided Microwave Ablation Combined with TACE on Liver Function and Survival of Patients with Primary Liver Cancer

Objective: To explore the effect of transarterial chemoembolization (TACE) + CT-guided microwave ablation (MWA) on treating patients with primary liver cancer. Methods: 78 primary liver cancer cases were enrolled and divided into groups according to their assigned surgical plans. The control group was treated with TACE alone, and the observation group was treated with TACE + CT-guided MWA. The efficacy of the treatment and the liver function indicators and follow-up results of the patients of the two groups were compared. Results: The efficacy of the treatment received by the observation group was higher than that of the control group. Besides, the patients in the observation group exhibited better improvement in liver function indicators after 3 months of treatment. Furthermore, the survival rates of 1 and 2 years after surgery of the observation group were all higher than those of the control group (P &lt; 0.05). Conclusion: TACE combined with CT-guided MWA is more effective in treating primary liver cancer compared to TACE alone. Besides, it resulted in better improvement of liver function and long-term survival rate. Therefore, this treatment regime should be popularized.

Periplaneta americana extract attenuates hepatic fibrosis progression by inhibiting collagen synthesis and regulating the TGF-β1/Smad signaling pathway.

Liver fibrosis is the damage repair response following chronic liver diseases. Activated hepatic stellate cells (HSCs) are the main extracellular matrix (ECM)-producing cells and key regulators in liver fibrosis. Periplaneta americana shows prominent antifibrotic effects in liver fibrosis; however, the underlying mechanisms remain undetermined. This study aimed to elucidate the therapeutic effects of P. americana extract (PA-B) on liver fibrosis based on the regulation of the TGF-β1/Smad signal pathway. HSCs and Sprague Dawley rats were treated with TGF-β1 and CCl4, respectively, to establish the hepatic fibrosis model in vitro and in vivo. The effect of PA-B on liver rat fibrosis was evaluated by biochemical (serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), hyaluronic acid (HA), laminin (LN), collagen type IV (Col-IV), pro-collagen type III (PC-III)) and histological examinations. Further, fibrogenic markers expression of alpha smooth muscle actin (α-SMA), collagen type I (Col-I), and collagen type III (Col-III), and the TGF-β1/Smad pathway-related factors were assessed by immunofluorescence (IF), real time quantitative polymerase chain reaction (RT-qPCR), and western blotting (WB). Treatment of HSC-T6 cells with PA-B suppressed the expression of α-SMA, Col-I, and Col-III, downregulated the expression of TGF-β1 receptors I and II (TβR I and TβR II, respectively), Smad2, and Smad3, and upregulated Smad7 expression. PA-B mitigates pathologic changes in the rat model of liver fibrosis, thus alleviating liver index, and improving liver function and fibrosis indices. The effects of PA-B on the expression of α-SMA, Col-I, Col-III, TβR I, TβR II, Smad2, Smad3, and Smad7 were consistent with the in vitro results, including reduced TGF-β1 expression. The therapeutic effect of PA-B on liver fibrosis might involve suppression of the secretion and expression of TGF-β1, regulation of the TGF-β1/Smad signaling pathway, and inhibition of collagen production and secretion.

Preoperative weight loss program for hepatocellular carcinoma patients with high body mass index in hepatectomy.

565 Background: This study aimed to investigate the usefulness of a weight-loss program (WLP) in patients with a high body mass index (BMI) prior to liver resection (Hx) for hepatocellular carcinoma (HCC). Methods: Among 445 patients with HCC who underwent initial Hx between 2000 and 2020, 19 with a high BMI (≥25.0) were enrolled in our WLP since 2014. For calorie restriction, the amount of energy consumed was calculated as the standard body weight (SBW) kg × 20–25 kcal/day. Protein mass was calculated as SBW kg × 1.0–1.2 g/day to maintain skeletal muscle mass. Patients also performed both aerobic and resistance exercises. The before-and-after changes were compared, and the effect of WLP on the short- and long-term results was investigated. Results: The average length of WLP was 21 days, and weight loss was successfully achieved in all patients. Body fat mass was reduced during the program, while skeletal muscle mass was maintained. WLP led to improvements in liver function and fibrotic markers, without tumor progression. There were no postoperative complications (≥Clavien–Dindo [CD] III). A retrospective comparison of postoperative outcomes revealed that those in the WLP group showed a significantly shorter operation time and improved postoperative morbidity rate (≥CD III) with decreased postoperative hospital stay. There were no significant differences in long-term prognosis based on participation in the WLP. Conclusions: WLP with multidisciplinary intervention improved short-term outcomes after Hx in patients with HCC and a high BMI.

Eriodictyol inhibits the motility, angiogenesis and tumor growth of hepatocellular carcinoma via NLRP3 inflammasome inactivation

NLRP3 involves in the development of hepatocellular carcinoma (HCC). Eriodictyol has shown its inhibitory effect on HCC cell proliferation. However, the underlying mechanism of eriodictyol in HCC is still unclear. This study aimed to explore the effect of and mechanism of eriodictyol on HCC. In this study, compared with eriodictyol (0 μM) group, eriodictyol significantly suppressed HepG2 cells (eriodictyol of 25, 50 and 100 μM) and Huh-7 cells (eriodictyol of 50 and 100 μM) viability, invasion, tube formation, metastasis-related genes MMP3, MMP16 and angiogenesis regulator VEGFA expressions with IC50 of 45.63 μM and 78.26 μM in vitro, respectively. Besides, eriodictyol significantly repressed NLRP3 expression, and reduced the protein levels of NLRP3 inflammasome-related proteins, adapter protein ASC, caspase-1, interleukin (IL)-18, and IL-1β in HepG2 (eriodictyol of 25, 50 and 100 μM) and Huh-7 cells (eriodictyol of 50 and 100 μM), respectively. Meanwhile, compared with control group, NLRP3 overexpression reversed the anti-metastatic effects of 100 μM eriodictyol on HCC cells invasion, tube formation, and metastasis-related genes MMP3, MMP16 and angiogenesis regulator VEGFA expressions, whereas NLRP3 knockdown enhanced the anti-metastatic effects of 100 μM eriodictyol on HCC cells. In vivo, compared with control group, eriodictyol significantly reduced the tumor growth, liver damage, inhibited the activation of NLRP3 inflammasome, and improved liver function, whereas NLRP3 overexpressing neutralized the anti-tumor effects of eriodictyol and degraded liver function. Hence, eriodictyol inhibited HCC cell viability, motility, angiogenesis and tumor growth via NLRP3 inflammasome inactivation both in vitro and in vivo.

Transjugular intrahepatic portosystemic shunts for adults with hepatorenal syndrome.

Transjugular intrahepatic portosystemic shunts for adults with hepatorenal syndrome.

Reversal of cholestatic liver disease by the inhibition of sphingosine 1-phosphate receptor 2 signaling.

The objective of this study is to examine the impact of inhibiting Sphingosine 1-phosphate receptor 2 (S1PR2) on liver inflammation, fibrogenesis, and changes of gut microbiome in the context of cholestasis-induced conditions. The cholestatic liver injury model was developed by common bile duct ligation (CBDL). Sprague-Dawley rats were randomly allocated to three groups, sham operation, CBDL group and JTE-013 treated CBDL group. Biochemical and histological assessments were conducted to investigate the influence of S1PR2 on the modulation of fibrogenic factors and inflammatory infiltration. We conducted an analysis of the fecal microbiome by using 16S rRNA sequencing. Serum bile acid composition was evaluated through the utilization of liquid chromatography-mass spectrometry techniques. In the BDL rat model, the study findings revealed a significant increase in serum levels of conjugated bile acids, accompanied by an overexpression of S1PR2. Treatment with the specific inhibitor of S1PR2, known as JTE-013, resulted in a range of specific effects on the BDL rats. These effects included the improvement of liver function, reduction of liver inflammation, inhibition of hepatocyte apoptosis, and suppression of NETosis. These effects are likely mediated through the TCA/S1PR2/NOX2/NLRP3 pathway. Furthermore, the administration of JTE-013 resulted in an augmentation of the diversity of the bacterial community's diversity, facilitating the proliferation of advantageous species while concurrently inhibiting the prevalence of detrimental bacteria. The results of our study suggest that the administration of JTE-013 may have a beneficial effect in alleviating cholestatic liver disease and restoring the balance of intestinal flora.

Transplantation of beige adipose organoids fabricated using adipose acellular matrix hydrogel improves metabolic dysfunction in high-fat diet-induced obesity and type 2 diabetes mice.

Transplantation of brown adipose tissue (BAT) is a promising approach for treating obesity and metabolic disorders. However, obtaining sufficient amounts of functional BAT or brown adipocytes for transplantation remains a major challenge. In this study, we developed a hydrogel that combining adipose acellular matrix (AAM) and GelMA and HAMA that can be adjusted for stiffness by modulating the duration of light-crosslinking. We used human white adipose tissue-derived microvascular fragments to create beige adipose organoids (BAO) that were encapsulated in either a soft or stiff AAM hydrogel. We found that BAOs cultivated in AAM hydrogels with high stiffness demonstrated increased metabolic activity and upregulation of thermogenesis-related genes. When transplanted into obese and type 2 diabetes mice, the HFD + BAO group showed sustained improvements in metabolic rate, resulting in significant weight loss and decreased blood glucose levels. Furthermore, the mice showed a marked reduction in nonalcoholic liver steatosis, indicating improved liver function. In contrast, transplantation of 2D-cultured beige adipocytes failed to produce these beneficial effects. Our findings demonstrate the feasibility of fabricating beige adipose organoids in vitro and administering them by injection, which may represent a promising therapeutic approach for obesity and diabetes.

Ginkgetin exhibits antifibrotic effects by inducing hepatic stellate cell apoptosis via STAT1 activation.

Liver fibrosis affects approximately 800 million patients worldwide, with over 2 million deaths each year. Nevertheless, there are no approved medications for treating liver fibrosis. In this study, we investigated the impacts of ginkgetin on liver fibrosis and the underlying mechanisms. The impacts of ginkgetin on liver fibrosis were assessed in mouse models induced by thioacetamide or bile duct ligation. Experiments on human LX-2 cells and primary mouse hepatic stellate cells (HSCs) were performed to explore the underlying mechanisms, which were also validated in the mouse models. Ginkgetin significantly decreased hepatic extracellular matrix deposition and HSC activation in the fibrotic models induced by thioacetamide (TAA) and bile duct ligation (BDL). Beneficial effects also existed in inhibiting hepatic inflammation and improving liver function. In vitro experiments showed that ginkgetin markedly inhibited HSC viability and induced HSC apoptosis dose-dependently. Mechanistic studies revealed that the antifibrotic effects of ginkgetin depend on STAT1 activation, as the effects were abolished in vitro after STAT1 silencing and in vivo after inhibiting STAT1 activation by fludarabine. Moreover, we observed a meaningful cross-talk between HSCs and hepatocytes, in which IL-6, released by ginkgetin-induced apoptotic HSCs, enhanced hepatocyte proliferation by activating STAT3 signaling. Ginkgetin exhibits antifibrotic effects by inducing HSC apoptosis via STAT1 activation and enhances hepatocyte proliferation secondary to HSC apoptosis via the IL-6/STAT3 pathway.