Upregulation of Hepatic Glutathione S-Transferase Alpha 1 Ameliorates Metabolic Dysfunction-Associated Steatosis by Degrading Fatty Acid Binding Protein 1.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common metabolic disease of the liver, characterized by hepatic steatosis in more than 5% of hepatocytes. However, despite the recent approval of the first drug, resmetirom, for the management of metabolic dysfunction-associated steatohepatitis, decades of target exploration and hundreds of clinical trials have failed, highlighting the urgent need to find new druggable targets for the discovery of innovative drug candidates against MASLD. Here, we found that glutathione S-transferase alpha 1 (GSTA1) expression was negatively associated with lipid droplet accumulation in vitro and in vivo. Overexpression of GSTA1 significantly attenuated oleic acid-induced steatosis in hepatocytes or high-fat diet-induced steatosis in the mouse liver. The hepatoprotective and anti-inflammatory drug bicyclol also attenuated steatosis by upregulating GSTA1 expression. A detailed mechanism showed that GSTA1 directly interacts with fatty acid binding protein 1 (FABP1) and facilitates the degradation of FABP1, thereby inhibiting intracellular triglyceride synthesis by impeding the uptake and transportation of free fatty acids. Conclusion: GSTA1 may be a good target for the discovery of innovative drug candidates as GSTA1 stabilizers or enhancers against MASLD.

Bacteroides thetaiotaomicron ameliorates mouse hepatic steatosis through regulating gut microbial composition, gut-liver folate and unsaturated fatty acids metabolism.

Gut microbiota plays an essential role in the progression of nonalcoholic fatty liver disease (NAFLD), making the gut-liver axis a potential therapeutic strategy. Bacteroides genus, the enriched gut symbionts, has shown promise in treating fatty liver. However, further investigation is needed to identify specific beneficial Bacteroides strains for metabolic disorders in NAFLD and elucidate their underlying mechanisms. In this study, we observed a positive correlation between the abundance of Bacteroides thetaiotaomicron (B. theta) and the alleviation of metabolic syndrome in the early and end stages of NAFLD. Administration of B. theta to HFD-fed mice for 12 weeks reduced body weight and fat accumulation, decreased hyperlipidemia and insulin resistance, and prevented hepatic steatohepatitis and liver injury. Notably, B. theta did not affect these indicators in low-fat diet (LFD)-fed mice and exhibited good safety. Mechanistically, B. theta regulated gut microbial composition, characterized by a decreased Firmicutes/Bacteroidetes ratio in HFD-Fed mice. It also increased gut-liver folate levels and hepatic metabolites, alleviating metabolic dysfunction. Additionally, treatment with B. theta increased the proportion of polyunsaturated fatty acid in the mouse liver, offering a widely reported benefit for NAFLD improvement. In conclusion, this study provides evidence that B. theta ameliorates NAFLD by regulating gut microbial composition, enhancing gut-liver folate and unsaturated fatty acid metabolism, highlighting the therapeutic role of B. theta as a potential probiotic for NAFLD.

Pressure-controlled ventilation-volume guaranteed mode improves bronchial mucus transport velocity in patients during laparoscopic surgery for gynecological oncology: a randomized controlled study.

BACKGROUND: Mechanical ventilation during general anesthesia may impair airway mucosal function. This study aimed to investigate the effect of pressure-controlled ventilation-volume guaranteed (PCV-VG) on bronchial mucus transport velocity (BTV) in patients during laparoscopic surgery for gynecological oncology compared with volume controlled ventilation (VCV). METHODS: 66 patients undergoing elective a laparoscopic surgery for gynecological oncology. The patients were randomized into two group receiving either PCV-VG or VCV. a drop of methylene blue was placed on the surface of the airway mucosa under the bronchoscopeand, then the distance the dye movement was measured after 2, 4, and 6 min. Outcomes were assessed at T0 (5 min after endotracheal intubation and before initiation of pneumoperitoneum), T1 and T2 (1 and 2 h after stabilization of pneumoperitoneum respectively). BTV at T0, T1 and T2 was the primary outcome. Secondary outcomes included heart rate (HR), mean arterial pressure (MAP), body temperature, end-tidal CO2 pressure (PETCO2), tidal volume(VT), peak inspiratory pressure (PIP), mean inspiratory pressure (Pmean), respiratory rate (RR), and dynamic compliance (CDyn) at T0, T1, and T2. RESULTS: 64 patients were included in the analysis. The median [interquartile range] BTV was significantly lower in VCV group at T1 and T2 that at T0 (P < 0.05). Furthermore, BTV was slightly reduced in PCV-VG compared with VCV. BTV in PCV-VG was significantly decreased at T2 compared with BTV at T0 (P < 0.05) and slightly decreased at T1 compared with T0(P > 0.05). Compared with the PCV-VG group, BTV in VCV group significantly decreased at T2 (P < 0.05). No participants experienced respiratory complications. CONCLUSIONS: PCV-VG is more suitable for patients undergoing laparoscopic surgery for gynecological oncology than VCV since it can protect mucociliary clearance function. TRIAL REGISTRATION: This trial is registered on https://www.chictr.org.cn/ in Chinese Clinical Trial Registry (ChiCTR.2200064564: Date of registration 11/10/2022).

Establishment and application of a high-throughput screening model for cell adhesion inhibitors.

The cell adhesion between leukocytes and endothelial cells plays an important balanced role in the pathophysiological function, while excessive adhesion caused by etiological agents is associated with the occurrence and development of many acute and chronic diseases. Cell adhesion inhibitors have been shown to have a potential therapeutic effect on these diseases, therefore, efficient and specific inhibitors against cell adhesion are highly desirable. Here, using lipopolysaccharide-induced human umbilical vein endothelial cells (HUVECs) and calcein-AM-labeled human monocytic cell THP-1, we established a high-throughput screening model for cell adhesion inhibitors with excellent model evaluation parameters. Using the drug repurposing strategy, we screened out lifitegrast, a potent cell adhesion inhibitor, which inhibited cell adhesion between HUVEC and THP-1 cells by directly interrupting the adhesion interaction between HUVEC and THP-1 cells and showed a strong therapeutic effect on the mouse acute liver injury induced by poly (I:C)/D-GalN. Therefore, the screening model is suitable for screening and validating cell adhesion inhibitors, which will promote the research and development of inhibitors for the treatment of diseases caused by excessive cell adhesion.

Combined Use of Bicyclol and Berberine Alleviates Mouse Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD), ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), is a liver disease worldwide without approved therapeutic drugs. Anti-inflammatory and hepatoprotective drug bicyclol and multi-pharmacological active drug berberine, respectively, have shown beneficial effects on NAFLD in murine nutritional models and patients, though the therapeutic mechanisms remain to be illustrated. Here, we investigated the combined effects of bicyclol and berberine on mouse steatosis induced by Western diet (WD), and NASH induced by WD/CCl4. The combined use of these was rather safe and better reduced the levels of transaminase in serum and triglycerides and cholesterol in the liver than their respective monotherapy, accompanied with more significantly attenuating hepatic inflammation, steatosis, and ballooning in mice with steatosis and NASH. The combined therapy also significantly inhibited fibrogenesis, characterized by the decreased hepatic collagen deposition and fibrotic surface. As per mechanism, bicyclol enhanced lipolysis and ß-oxidation through restoring the p62-Nrf2-CES2 signaling axis and p62-Nrf2-PPARα signaling axis, respectively, while berberine suppressed de novo lipogenesis through downregulating the expression of acetyl-CoA carboxylase and fatty acid synthetase, along with enrichment of lipid metabolism-related Bacteroidaceae (family) and Bacteroides (genus). Of note, the combined use of bicyclol and berberine did not influence each other but enhanced the overall therapeutic role in the amelioration of NAFLD. Conclusion: Combined use of bicyclol and berberine might be a new available strategy to treat NAFLD.

Targeting Liver Sinusoidal Endothelial Cells: An Attractive Therapeutic Strategy to Control Inflammation in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD), especially its advanced stage nonalcoholic steatohepatitis (NASH), has become a threatened public health problem worldwide. However, no specific drug has been approved for clinical use to treat patients with NASH, though there are many promising candidates against NAFLD in the drug development pipeline. Recently, accumulated evidence showed that liver sinusoidal endothelial cells (LSECs) play an essential role in the occurrence and development of liver inflammation in patients with NAFLD. LSECs, as highly specialized endothelial cells with unique structure and anatomical location, contribute to the maintenance of liver homeostasis and could be a promising therapeutic target to control liver inflammation of NAFLD. In this review, we outline the pathophysiological roles of LSECs related to inflammation of NAFLD, highlight the pro-inflammatory and anti-inflammatory effects of LSECs, and discuss the potential drug development strategies against NAFLD based on targeting to LSECs.

TGF-ß isoforms inhibit hepatitis C virus propagation in transforming growth factor beta/SMAD protein signalling pathway dependent and independent manners.

Transforming growth factor beta (TGF-ß) plays an important role in the viral liver disease progression via controlling viral propagation and mediating inflammation-associated responses. However, the antiviral activities and mechanisms of TGF-ß isoforms, including TGF-ß1, TGF-ß2 and TGF-ß3, remain unclear. Here, we demonstrated that all of the three TGF-ß isoforms were increased in Huh7.5 cells infected by hepatitis C virus (HCV), but in turn, the elevated TGF-ß isoforms could inhibit HCV propagation with different potency in infectious HCV cell culture system. TGF-ß isoforms suppressed HCV propagation through interrupting several different stages in the whole HCV life cycle, including virus entry and intracellular replication, in TGF-ß/SMAD signalling pathway-dependent and TGF-ß/SMAD signalling pathway-independent manners. TGF-ß isoforms showed additional anti-HCV activities when combined with each other. However, the elevated TGF-ß1 and TGF-ß2, not TGF-ß3, could also induce liver fibrosis with a high expression of type I collagen alpha-1 and α-smooth muscle actin in LX-2 cells. Our results showed a new insight into TGF-ß isoforms in the HCV-related liver disease progression.

Curcumin, as a pleiotropic agent, improves doxorubicin-induced nephrotic syndrome in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Curcumin, a phenolic compound extracted from the rhizome of turmeric (Curcuma longa L.), has been reported to have broad biological functions including potent antioxidant and renoprotective effects. It has been reported that Curcumin has a certain protective effect on the kidney. However, its mechanism of action needs further study. AIM OF THE STUDY: The present research aims at investigating the therapeutic effects and its underlying mechanism of curcumin on NS. MATERIALS AND METHODS: The conditionally immortalized mouse podocyte cell line was utilized to evaluate the podocyte-protective effect of curcumin and its effects on NF-κB pathway and Nrf2/ARE pathway in podocyte in vitro. Furthermore, the DOX-induced NS rats were utilized to investigate the therapeutic effects and its underlying mechanism of curcumin against NS in vivo. RESULTS: The consequences of this study revealed that curcumin activated Nrf2, inhibited NF-κB pathway and up-regulated podocin in DOX-induced podocyte. Further research results showed that curcumin can considerably alleviate proteinuria and improve hypoalbuminemia in NS rats, and lower blood lipid levels to alleviate hyperlipidemia in NS rats, indicating that curcumin has significant therapeutic effects on rat NS. Further observation by electron microscopy and detection showed that curcumin can improve renal function and podocyte injury, which may be related to the repairment of mRNA expression and podocin protein. Interestingly, the results of the blood rheology test showed that curcumin can effectively reduce whole blood viscosity (WBV) and plasma viscosity (PV), and reduce hematocrit (Hct). In addition, the oxidative stress state of kidney in NS rats was considerably reversed by curcumin, which may be achieved by activating Nrf2 and increasing the expression of antioxidant enzymes HO-1, NQO-1. We also found that NF-κB pathway is activated in the kidney of NS rats, and curcumin can inhibit the activation of NF-κB by down-regulating the expression of NF-κB p65, reducing the level of p-IκBα and up-regulating the expression of IκBα. CONCLUSION: These findings suggest that curcumin, as a multifunctional agent, exerts a protective effect on DOX-induced nephrotic syndrome in rats, which provides a pharmacological basis for the further development of curcumin and also provides a basis for the advantages of multi-targeted drugs in the processing of NS.

Impact of wilting and additives on fermentation quality and carbohydrate composition of mulberry silage.

OBJECTIVE: The objective of this study was to investigate the effects of wilting and additives on the fermentation quality, structural and non-structural carbohydrate composition of mulberry silages. METHODS: The selected LAB strains Lactobacillus (L.) plantarum 'LC279063' (L1), commercial inoculant Gaofuji (GF), and Trichoderma viride cellulase (CE) were used as additives for silage preparation. Silage treatments were designed as control (CK), L1, GF, or CE under three wilting rates, that is wilting for 0, 2 or 4 hours (h). After ensiling for 30 days, the silages were analyzed for the chemical and fermentation characteristics. RESULTS: The results showed that wilting had superior effects on increasing the non-structural carbohydrate concentration and degrading the structural carbohydrate. After ensiling for 30 days, L1 generally had a higher fermentation quality than other treatments, indicated by the lower pH value, acetic acid, propionic acid and ammonia nitrogen (NH3-N) content, and the higher lactic acid, water soluble carbohydrate (WSC), glucose, galactose, sucrose and cellobiose concentration (p&lt;0.05) at any wilting rate. Wilting could increase the ratio of lactic acid/acetic acid and decrease the content of NH3-N. CONCLUSION: The results confirmed that wilting degraded the structural carbohydrate and increased the non-structural carbohydrate; and L1 exhibited better properties in improving fermentation quality and maintaining a high non-structural carbohydrates composition compared with the other treatments.

Fermentation quality and aerobic stability of mulberry silage prepared with lactic acid bacteria and propionic acid.

The objective of this study was to examine the fermentation quality and aerobic stability of mulberry (Morus alba L.) silage prepared with lactic acid bacteria (LAB) and propionic acid (PA). The selected LAB strains Lactobacillus (L.) plantarum LC365281 (L1) and L. brevis LC365282 (L2), and commercial inoculant strains L. plantarum Gaofuji (GF) and L. buchneri Fresh (FR), and PA were used as additives for silage preparation. Silage treatments were designed as control, L1, L2, GF, FR, PA, PA + L1, PA + L2, PA + GF, or PA + FR. After 30 days of ensiling, the fermentation quality of silages treated with PA + L1 was improved, with a lower (p < 0.05) pH and NH3 -N content than those of other treatments. During the aerobic exposure, the PA + LAB-treated silages displayed an aerobic stability with stable pH value and lactic acid content. The results confirm that L. plantarum L1 and PA were the best additive combination for ensiling mulberry.

Osthole protects sepsis-induced acute kidney injury via down-regulating NF-κB signal pathway.

BACKGROUND AND PURPOSE: As a natural coumarin derivative from the Cnidium monnieri(L)Cusson fruit, osthole consists of 7-methoxy-8-isopentenoxy-coumarin. The purpose of this research is to study the mechanism and effect of osthole on sepsis-induced acute kidney injury. EXPERIMENTAL APPROACH: The protective effect of osthole on mouse macrophage RAW 264.7 and HK-2 cells induced by LPS in vitro and on acute kidney injury model induced by sepsis and established by puncture and cecal ligation (CLP) in vivo were tested. KEY RESULTS: Osthole (20, 40 mg·kg-1) group can greatly attenuate the changes of the score and kidney histopathology damage and enhance the survival time of septic mice. After the CLP surgery, degrees of SCr and BUN related to kidney injury were upregulated. The concentrations of SCr and BUN can be greatly reduced by treatment with osthole. Furthermore, osthole could increase bacterial killing activity and phagocytic activities of macrophages impaired after CLP partly and attenuate blood bacterial counts and leukocyte infiltration markedly. Furthermore, osthole can suppress NF-κB signal pathway through the inhibition of the nuclear translocation by regulating phosphorylation of IκBα and IKKß and hinder the production of chemoattractant (MCP-1 and IL-8) and proinflammatory cytokines (TNF-α, IL-1ß and IL-6). CONCLUSION AND IMPLICATIONS: Mainly because of its immunomodulatory properties and anti-inflammatory activity, which might be closely associated with suppression of the stimulation of the NF-κB signal pathway, osthole has protective effect on sepsis-induced kidney injury. It can be seen from such evidence that osthole can be potentially applied in the treatment of acute kidney injury.

[Stereotactic microelectrode-guided posteroventral pallidotomy for Parkinson's disease].

OBJECTIVE: To assess postoperative effects of microelectrode-guided posteroventral pallidotomy (PVP) for Parkinson's disease. METHODS: Intraoperative microelectrode recordings and microstimulation were used to explore the globus pallidus to performance of posteroventral pallidotomy in 48 patients with Parkinson's disease (47 unilateral and 1 bilateral). Assessment was made at baseline preoperatively and at 6 months intervals postoperatively, with unified Parkinson's disease rating scale (UPDRS). RESULTS: All patients were significantly improved on the limbs contralateral to the lesion side 6 - 34 months after operation (mean 24 months). The improvement was seen in the 'on' or 'off' state: UPDRS scores with patients on levodopa were improved by an average of 28.7%, while off medication scores showed reductions (47.6%) at 24 months. There were no deaths and no visual complications, but there were 4 patients (8.3%) of a delayed contralateral limbs dystonia after pallidotomy. CONCLUSIONS: The techniques of microelectrode recording and microstimulation indicate the location of the internal capsule and optic tract, which allow easy identification of these structure and facilitate PVP target in conjunction with radiofrequency microelectrode stimulation.

[A retrospective clinical study of chronic high altitude disease complicated by acute exacerbation in high altitude environment].

OBJECTIVE: To study chronic high altitude disease (CHAD) with concurrent acute high altitude disease (AHAD) in regions of high altitude. METHODS: 18,090 inpatients from Feb. 1956 to Dec. 1995 conforming to a screening standard were observed in a hospital located at altitude 3658 m. 1,028 inpatients suffering from CHAD when hospitalized were collected as a study group. 17,020 inpatients suffering from non-HAD when first hospitalized served as a control group. The morbidity rate of AHAD in these two groups in a follow-up period of 1 - 20 years was analyzed. RESULTS: (1) AHAD morbidity rate was increasing with prolongation of observation time in the control group, but it was not so in the study group. Annual and accumulative morbidity of AHAD in the study group was obviously higher than that in the control group (P < 0.005, OR = 5.03, RR = 4.33). (2) The morbidity rates of three types of AHAD aside from high altitude pulmonary edema (HAPE) of high altitude hypertension (HAH) group and high altitude cerebral edema (HACE) of high altitude heart disease (HAHD) group was obviously higher in the study group than in the control (P < 0.05 - 0.005). AHAD morbidity rate in HAHD group and Monge's disease was 23.5% and 22.0% (OR = 7.33 - 6.71, RR = 5.86 - 5.47). (3) AHAD morbidity rate in HAHD group and Monge's disease group was obviously higher than that in the control, constituting mainly a high morbidity of mild acute high altitude disease. CONCLUSION: The risk of AHAD increases about 5-fold in CHAD patients than in the multitude of high altitude acclimatization, being most evident in HAHD and Monge's disease.