Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial final results.

Claudin18.2 (CLDN18.2) is highly expressed with the development of various malignant tumors, especially gastrointestinal cancers, and is emerging as a new target for cancer treatment. Satricabtagene autoleucel (satri-cel)/CT041 is an autologous chimeric antigen receptor (CAR) T cell targeting CLDN18.2, and the interim results of the CT041-CG4006 trial were reported in June 2022. Here we present the final results of this single-arm, open-label, phase 1 trial, which evaluated the safety and efficacy of satri-cel in patients with CLDN18.2-positive advanced gastrointestinal cancers. This trial included a dose-escalation stage (n = 15) and a dose-expansion stage in four different cohorts (total n = 83): cohort 1, satri-cel monotherapy in 61 patients with standard chemotherapy-refractory gastrointestinal cancers; cohort 2, satri-cel plus anti-PD-1 therapy in 15 patients with standard chemotherapy-refractory gastrointestinal cancers; cohort 3, satri-cel as sequential treatment after first-line therapy in five patients with gastrointestinal cancers; and cohort 4, satri-cel monotherapy in two patients with anti-CLDN18.2 monoclonal antibody-refractory gastric cancer. The primary endpoint was safety; secondary endpoints included efficacy, pharmacokinetics and immunogenicity. A total of 98 patients received satri-cel infusion, among whom 89 were dosed with 2.5 × 108, six with 3.75 × 108 and three with 5.0 × 108 CAR T cells. Median follow-up was 32.4 months (95% confidence interval (CI): 27.3, 36.5) since apheresis. No dose-limiting toxicities, treatment-related deaths or immune effector cell-associated neurotoxicity syndrome were reported. Cytokine release syndrome occurred in 96.9% of patients, all classified as grade 1-2. Gastric mucosal injuries were identified in eight (8.2%) patients. The overall response rate and disease control rate in all 98 patients were 38.8% and 91.8%, respectively, and the median progression-free survival and overall survival were 4.4 months (95% CI: 3.7, 6.6) and 8.8 months (95% CI: 7.1, 10.2), respectively. Satri-cel demonstrates therapeutic potential with a manageable safety profile in patients with CLDN18.2-positive advanced gastrointestinal cancer. ClinicalTrials.gov identifier: NCT03874897 .

A20 functions as a negative regulator of the lipopolysaccharide-induced inflammation in corneal epithelial cells.

A20, also called TNFAIP3, is a crucial regulator of inflammation in various diseases but has not evidenced its function in the cornea. We aimed to evaluate the existence and the functions of A20 in human corneal epithelial (HCE-T) cells. After being treated with lipopolysaccharide (LPS) in different concentrations or at separate times, cells were collected to analyze A20 expressions. We then constructed the A20 knockdown system by siRNA and the A20 overexpressing system by lentivirus transduction. Systems were further exposed to medium with or without LPS for indicated times. Next, we evaluated the production of inflammatory cytokines (IL-6 and IL-8) by qRT-PCR and ELISA. Also, the translocation of P65 and the phosphorylation of P65, P38 and JNK were observed in two systems. In addition, we used the nuclear factor kappa-B (NF-κB) antagonist TPCA-1 for the pretreatment in cells and then detected the A20 expressions. We found a low basal expression of A20 in HCE-T cells, and the expressions could be dose-dependently induced by LPS, peaking at 4 h in protein level after stimulation. Both the A20 knockdown and A20 overexpressing systems were confirmed to be effective. After the LPS treatment, productions of IL-6 and IL-8 were enhanced in the A20 knockdown system and reduced in the A20 overexpressing system. A20 reduced the translocation of P65 into the nucleus and the phosphorylation of P65, P38 and JNK. Furthermore, TPCA-1 pretreatment reduced the expression of A20 in cells. We concluded that A20 is a potent regulator for corneal epithelium's reaction to inflammation, and it thus is expected to be a potential therapy target for ocular surface diseases.

P-element-Induced Wimpy-Testis-Like Protein 1 Regulates the Activation of Pancreatic Stellate Cells Through the PI3K/AKT/mTOR Signaling Pathway.

AIM: Pancreatic fibrosis is the main pathological characteristic of chronic pancreatitis (CP) and pancreatic cancer. Pancreatic stellate cells (PSCs) play a critical role in pancreatic fibrosis. Any targets that may have an impact on the activation of PSCs could become potential treatment candidates for CP and pancreatic cancer. Our goal was to investigate the effect of P-element-induced wimpy-testis (PIWI) protein 1 (PIWIL1) on PSC activation. METHODS: Lentivirus-based RNA interference (RNAi) and overexpression vector construction were used to knock down and over-express the PIWIL1 protein. Immunocytofluorescent staining, western blotting, wound healing assay, transwell assay, and phalloidin staining were used to investigate the effects of PIWIL1 on the secretion of extracellular matrix components (EMC), actin cytoskeleton, and on the invasion and migration abilities of primary PSCs isolated from C57BL/6 mice. Moreover, pancreatic fibrosis was induced by L-arginine in C57BL/6 mice. The expression of PIWIL1 and collagen deposition in vivo were tested by western blotting and Sirius red staining. RESULTS: Expression levels of collagen I, collagen III, and α-smooth muscle actin were significantly decreased in the LV-PIWIL1 group. Compared with the si-PIWIL1 group, significant differences were observed in the expression of desmin, p-PI3K, p-AKT, and p-mTOR in the LV-PIWIL1 group. Furthermore, PIWIL1 suppressed the PSCs' invasion and migration abilities. In a rescue experiment, the PI3K/AKT/mTOR signaling pathway was found to be the underlying mechanism in PSCs activation mediated by PIWIL1. CONCLUSIONS: Our findings suggest that PIWIL1 inhibits the activation of PSCs via the PI3K/AKT/mTOR signaling pathway. PIWIL1 is a potential therapeutic target for pancreatic fibrosis.

Galangin inhibited ferroptosis through activation of the PI3K/AKT pathway in vitro and in vivo.

Ferroptosis is an iron-dependent form of nonapoptotic cell death characterized by the accumulation of lipid peroxides in cells. In recent years, extensive attention has been dedicated to exploring safe and effective natural ferroptosis regulators which can provide novel treatment strategies for ferroptosis-related diseases. This study identified galangin, a natural flavonoid, as an effective inhibitor of ferroptosis, which could increase cell viability in RSL3-inhibited HT1080 cells, decrease levels of lipid ROS and MDA, improve PTGS2 mRNA expression, and enhance the expression of glutathione peroxidase 4 (GPX4). Ferroptosis is widely present in ischemia-reperfusion (IR) injury. This study found that galangin significantly ameliorated the pathological damage of liver tissue in mice with IR, reduced levels of serum ALT, AST, and MDA, and increased the expression of GPX4. The results of RNA-seq exhibited ferroptosis was significant and the PI3K/AKT pathway deserved to explore the inhibition effects of galangin on ferroptosis. Indeed, galangin treatment significantly rescued RSL3-inhibited phosphorylation levels of PI3K, AKT, and CREB proteins, and the ferroptosis inhibitory effects of galangin were counteracted by PI3K inhibitor LY294002. These findings indicated that galangin may exert its anti-ferroptosis effects via activating the PI3K/AKT/CREB signaling pathway and it will hopefully serve as a promising effective measure to attenuate IR injury by inhibiting ferroptosis.

Disitamab vedotin: a novel antibody-drug conjugates for cancer therapy.

Human epidermal growth factor receptor 2 (HER2) regulates cell mitosis, proliferation, and apoptosis. Trastuzumab is a HER2-targeted monoclonal antibody (mAB), which can prolong the overall survival rate of patients with HER2 overexpression in later periods of gastric cancer and breast cancer. Although anti-HER2 monoclonal antibody has a curative effect, adjuvant chemotherapy is still necessary to upgrade the curative effect maximumly. Antibody-drug conjugate (ADC) is a kind of therapeutic drug that contains antigen-specific antibody and cytotoxic payload, which can improve the survival time of tumor patients. To date, there are several HER2-ADC products on the market, for which two anti-HER2 ADC (trastuzumab emtansine and trastuzumab deruxtecan) have been authorized by the FDA for distinct types of HER2-positive carcinoma in the breast. Disitamab vedotin (RC48) is a newly developed ADC drug targeting HER2 that is comprised of hertuzumab coupling monomethyl auristatin E (MMAE) via a cleavable linker. This paper aims to offer a general insight and summary of the mechanism of action and the currently completed and ongoing clinical studies of RC-48 in HER-2 positive solid tumors.

Characterization of metabolic landscape in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide, accounting for approximately 75%-85% of primary liver cancers. Metabolic alterations have been labeled as an emerging hallmark of tumors. Specially, the last decades have registered a significant improvement in our understanding of the role of metabolism in driving the carcinogenesis and progression of HCC. In this paper, we provide a review of recent studies that investigated the metabolic traits of HCC with a specific focus on three common metabolic alterations involving glycolysis, lipid metabolism, and glutamine addiction which have been gaining much attention in the field of HCC. Next, we describe some representative diagnostic markers or tools, and promising treatment agents that are proposed on the basis of the aforementioned metabolic alterations for HCC. Finally, we present some challenges and directions that may promisingly speed up the process of developing objective diagnostic markers and therapeutic options underlying HCC. Specifically, we recommend future investigations to carefully take into account the influence of heterogeneity, control for study-specific confounds, and invite the validation of existing biomarkers.

Ferroptosis in liver disease: new insights into disease mechanisms.

Characterized by excessive iron accumulation and lipid peroxidation, ferroptosis is a novel form of iron-dependent cell death, which is morphologically, genetically, and biochemically distinct from other well-known cell death. In recent years, ferroptosis has been quickly gaining attention in the field of liver diseases, as the liver is predisposed to oxidative injury and generally, excessive iron accumulation is a primary characteristic of most major liver diseases. In the current review, we first delineate three cellular defense mechanisms against ferroptosis (GPx4 in the mitochondria and cytosol, FSP1 on plasma membrane, and DHODH in mitochondria), along with four canonical modulators of ferroptosis (system Xc-, nuclear factor erythroid 2-related factor 2, p53, and GTP cyclohydrolase-1). Next, we review recent progress of ferroptosis studies delineating molecular mechanisms underlying the pathophysiology of several common liver diseases including ischemia/reperfusion-related injury (IRI), nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), hemochromatosis (HH), drug-induced liver injury (DILI), and hepatocellular carcinoma (HCC). Furthermore, we also highlight both challenges and promises that emerged from recent studies that should be addressed and pursued in future investigations before ferroptosis regulation could be adopted as an effective therapeutic target in clinical practice.

Telitacicept as a BLyS/APRIL dual inhibitor for autoimmune disease.

The pathogenic roles for B cells in autoimmunity include produce pathogenic autoantibodies and modulate immune responses via the production of cytokines and chemokines. The B lymphocyte stimulator BLyS (also known as B-cell-activating factor, BAFF) and APRIL (a proliferation-inducing ligand) are critical factors in the maintenance of the B-cell pool and humoral immunity, namely BLyS modulates the differentiation and maturation of immature B cell, while APRIL modulates the function and survival of long-lived plasma cell, which plays a prominent role in the pathogenesis of autoimmune diseases. Telitacicept is a novel recombinant fusion protein of both the ligand-binding domain of the TACI receptor and the Fc component of human IgG and which is a BLyS/APRIL dual inhibitor. Moreover, telitacicept was developed by Remegen Co., Ltd. in China and is approved to treat systemic lupus erythematosus in China. We review the rationale, clinical evidence, and future perspectives of telitacicept for the treatment of autoimmune disease.HighlightThe B lymphocyte stimulator BLyS (also known as B-cell-activating factor, BAFF) and APRIL (a proliferation-inducing ligand), members of tumor necrosis factor (TNF) family, and which are critical factors in the maintenance of the B-cell pool and humoral immunity.BAFF and APRIL are implicated in the pathogenesis of several human autoimmune diseases with autoreactive B-cell involvement, and targeting both is beneficial for the treatment of autoimmune diseases.Telitacicept is a novel recombinant fusion protein of both the ligand-binding domain of the TACI receptor and the Fc component of human IgG, as a BLyS/APRIL dual inhibitor and which has been approved by National Medical Products Administration (MNPA) for the treatment of patients with SLE in China.With more clinical trials underway, telitacicept may also be approved for the treatment of other autoimmune diseases in the future.

Horizons on the Therapy of Biliary Tract Cancers: A State-of-the-art Review.

Biliary tract cancers (BTCs) comprise a group of heterogeneous poor prognosis cancers with increasing incidence recent years. The combination chemotherapy with cisplatin and gemcitabine is the first-line therapy for advanced BTC. There remains no accepted standard treatment in the second-line setting. Nowadays, more and more novel treatment strategies have entered development, with some encouraging results being seen. Here, we review the current treatment status and clinical characteristics of BTC, the role of immunotherapy in BTC as well as the design of clinical trials for oncology drugs for BTC which aim to focus on the future profiles of clinical care and resolution of BTC.

Biotransformation of Phlorizin by Eurotium cristatum to Increase the Antioxidant and Antibacterial Activity of Docynia indica Leaves.

Docynia indica is used as a plant resource for both medicine and food in minority areas of southwestern China and Southeast of Asia, especially Docynia indica leaves, which are often used as a kind of functional tea in daily life. In our previous research, it has found that D. indica is rich in polyphenols (mainly phlorizin (PHZ)). Although PHZ is the first polyphenolic competitive inhibitor of sodium-dependent glucose transporters (SGLTs) to be discovered, the promotion and application of PHZ are limited due to its extremely low bioavailability. As a kind of aglycons, phloretin (PHT) possesses a better bioavailability and bioactivity than PHZ. Therefore, the conversion of PHZ to PHT in D. indica leaves by the method of biotransformation can be applied to solve the above issue. In this study, Aspergillus niger and Eurotium cristatum were used to transform PHZ to PHT in D. indica. Compared with Aspergillus niger, Eurotium cristatum can cause the equimolar conversion of PHZ to PHT. However, Aspergillus niger resulted in the complete degradation of PHZ. In the process of deep fermentation, PHZ in D. indica leaves was gradually biotransformed into PHT, and its content was as high as ~ 12% after fermentation. With the increase of PHT content, the antioxidant and antibacterial activity of Docynia indica leaves increased. By the acute toxicity evaluation, it was confirmed that Docynia indica leaves and Eurotium cristatum fermented leaves were much safer. These results indicate that Eurotium cristatum fermentation has the ability to transform the functional compounds in Docynia indica leaves and increase the antioxidant and antibacterial activity of Docynia indica, thus making it a substitute for PHT and functional tea.

A prediction modeling based on SNOT-22 score for endoscopic nasal septoplasty: a retrospective study.

BACKGROUND: To create a nomogram prediction model for the efficacy of endoscopic nasal septoplasty, and the likelihood of patient benefiting from the operation. METHODS: A retrospective analysis of 155 patients with nasal septum deviation (NSD) was performed to develop a predictive model for the efficacy of endoscopic nasal septoplasty. Quality of life (QoL) data was collected before and after surgery using Sinonasal Outcome Test-22 (SNOT-22) scores to evaluate the surgical outcome. An effective surgical outcome was defined as a SNOT-22 score change ≥ 9 points after surgery. Multivariate logistic regression analysis was then used to establish a predictive model for the NSD treatment. The predictive quality and clinical utility of the predictive model were assessed by C-index, calibration plots, and decision curve analysis. RESULTS: The identified risk factors for inclusion in the predictive model were included. The model had a good predictive power, with a AUC of 0.920 in the training group and a C index of 0.911 in the overall sample. Decision curve analysis revealed that the prediction model had a good clinical applicability. CONCLUSIONS: Our prediction model is efficient in predicting the efficacy of endoscopic surgery for NSD through evaluation of factors including: history of nasal surgery, preoperative SNOT-22 score, sinusitis, middle turbinate plasty, BMI, smoking, follow-up time, seasonal allergies, and advanced age. Therefore, it can be cost-effective for individualized preoperative assessment.

MiR-1908/EXO1 and MiR-203a/FOS, regulated by scd1, are associated with fracture risk and bone health in postmenopausal diabetic women.

BACKGROUND: Stearoyl-coenzyme A desaturase-1 (SCD1) can inhibit the development of diabetic bone disease by promoting osteogenesis. In this study, we examined whether this regulation by SCD1 is achieved by regulating the expression of related miRNAs. METHODS: SCD1 expression levels were observed in human bone-marrow mesenchymal stem cells (BM-MSCs) of patients with type 2 diabetes mellitus (T2DM), and the effect of SCD1 on osteogenesis was observed in human adipose-derived MSCs transfected with the SCD1 lentiviral system. We designed a bioinformatics prediction model to select important differentially expressed miRNAs, and established protein-protein interaction and miRNA-mRNA networks. miRNAs and mRNAs were extracted and their differential expression was detected. The SCD1-miRNA-mRNA network was validated. FINDINGS: SCD1 expression in bone marrow was downregulated in patients with T2DM and low-energy fracture, and SCD1 expression promotes BM-MSC osteogenic differentiation. The predictors in the nomogram were seven microRNAs, including hsa-miR-1908 and hsa-miR-203a. SCD1 inhibited the expression of CDKN1A and FOS, but promoted the expression of EXO1 and PLS1. miR-1908 was a regulator of EXO1 expression, and miR-203a was a regulator of FOS expression. INTERPRETATION: The regulation of BM-MSCs by SCD1 is a necessary condition for osteogenesis through the miR-203a/FOS and miR-1908/EXO1 regulatory pathways.

Predicting the risk of sarcopenia in elderly patients with patellar fracture: development and assessment of a new predictive nomogram.

PURPOSE: To develop a risk prediction model for postoperative sarcopenia in elderly patients with patellar fractures in China. PATIENTS AND METHODS: We conducted a community survey of patients aged ≥55 years who underwent surgery for patellar fractures between January 2013 and October 2018, through telephone interviews, community visits, and outpatient follow-up. We established a predictive model for assessing the risk of sarcopenia after patellar fractures. We developed the prediction model by combining multivariate logistic regression analysis with the least absolute shrinkage model and selection operator regression (lasso analysis) as well as the Support Vector Machine (SVM) algorithm. The predictive quality and clinical utility of the predictive model were determined using C-index, calibration plots, and decision curve analysis. We also conducted internal sampling methods for qualitative assessment. RESULT: We recruited 137 participants (53 male; mean age, 65.7 years). Various risk factors were assessed, and low body mass index and advanced age were identified as the most important risk factor (P < 0.05). The prediction rate of the model was good (C-index: 0.88; 95% CI [0.80552-0.95448]), with a satisfactory correction effect. The C index is 0.97 in the validation queue and 0.894 in the entire cohort. Decision curve analysis suggested good clinical practicability. CONCLUSION: Our prediction model shows promise as a cost-effective tool for predicting the risk of postoperative sarcopenia in elderly patients based on the following: advanced age, low body mass index, diabetes, less outdoor exercise, no postoperative rehabilitation, different surgical methods, diabetes, open fracture, and removal of internal fixation.

The neuroprotective effect and action mechanism of polyphenols in diabetes mellitus-related cognitive dysfunction.

BACKGROUND: Diabetes mellitus (DM) is a complex and prevalent metabolic disorder worldwide. Strong evidence has emerged that DM is a risk factor for the accelerated rate of cognitive decline and the development of dementia. Though traditional pharmaceutical agents are efficient for the management of DM and DM-related cognitive decrement, long-term use of these drugs are along with undesired side effects. Therefore, tremendous studies have focused on the therapeutic benefits of natural compounds at present. Ample evidence exists to prove that polyphenols are capable to modulate diabetic neuropathy with minimal toxicity and adverse effects. PURPOSE: To describe the benefits and mechanisms of polyphenols on DM-induced cognitive dysfunction. In this review, we introduce an updated overview of associations between DM and cognitive dysfunction. The risk factors as well as pathological and molecular mechanisms of DM-induced cognitive dysfunction are summarized. More importantly, many active polyphenols that possess preventive and therapeutic effects on DM-induced cognitive dysfunction and the potential signaling pathways involved in the action are highlighted. CONCLUSIONS: The therapeutic effects of polyphenols on DM-related cognitive dysfunction pave a novel way for the management of diabetic encephalopathy.

Corticotropin-releasing hormone 1 receptor antagonism attenuates chronic unpredictable mild stress-induced depressive-like behaviors in rats.

Hyperactivity of the hypothalamic-pituitary-adrenal axis and impairment of the central corticotropin-releasing factor system are factors in the pathogenesis of depression. Though several antagonists of the corticotropin-releasing factor 1 receptor were effective in the recognized behavioral tests for antidepressant activity, there is still little information on the potential interactions between corticotropin-releasing factor 1 receptor inhibitors and conventional antidepressant therapy. The aim of our study was to assess the influence of CP154526, a corticotropin-releasing factor 1 receptor blocker, which presented some signs of depression. Our results revealed that CP154526 (5 and 10 mg/kg) or fluoxetine (10 mg/kg) treatment notably improved the sucrose consumption, produced anti-depressive-like behavior in open-field test, as well as immobility time in forced swimming test. The levels of interleukin-6, interleukin-1ß, tumor necrosis factor-α, and corticotropin-releasing hormone concentration in the serum were inhibited effectively by CP154526 or fluoxetine administration. Real-time quantitative PCR and western blot analysis showed the upregulated levels of brain-derived neurotrophic factor and growth associated protein 43 (GAP43) in the hypothalamus of the rats exposed to chronic unpredictable mild stress (CUMS), while different degrees of downregulation in their expression were detected after CP154526 (5 and 10 mg/kg) or fluoxetine (10 mg/kg) treatment, respectively. Thus, our data demonstrated that CP154526 exhibited antidepressant effect in CUMS rats, which might be mediated by decreasing the brain-derived neurotrophic factor and GAP43 expression in the hypothalamus.

Mitofusin2, a rising star in acute-on-chronic liver failure, triggers macroautophagy via the mTOR signalling pathway.

Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome with poor prognosis. Several studies have begun to prove that mitochondria play a crucial role in liver failure. Mitofusin2 (Mfn2) plays a key role in maintaining the integrity of mitochondrial morphology and function. However, the role and underlying mechanisms of Mfn2 on cell autophagy of ACLF remain unclear. Our aim was to explore the effect of Mfn2 on several biological functions involving cell autophagy in ACLF. In this study, we constructed an ACLF animal model and a hepatocyte autophagy model, using adenovirus and lentivirus to deliver Mfn2 to liver cells, in order to assess the effect of Mfn2 on autophagy and apoptosis in ACLF. Furthermore, we explored the biological mechanism of Mfn2-induced autophagy of ACLF using Western blotting, RT-PCR and electron microscopy. We found that Mfn2 significantly attenuated ACLF, characterized by ameliorated gross appearance and microscopic histopathology of liver, and reduced serum AST, ALT, and TBIL levels. Mfn2 improved the expressions of LC3-II, Atg5 and Bcl-2 and down-regulated the expression of P62 and Bax in ACLF. Like rapamycin, Mfn2 also significantly inhibited the expressions of p-PI3K, p-Akt and p-mTOR in ACLF. In conclusion, our findings suggest that Mfn2 influences multiple biological functions of ACLF via the PI3K/Akt/mTOR signalling pathway. This study will provide a reliable theoretical basis for the application of Mfn2 as an effective target for ACLF treatment, reversing or delaying the process of ACLF.

Mitofusin2, as a Protective Target in the Liver, Controls the Balance of Apoptosis and Autophagy in Acute-on-Chronic Liver Failure.

Aim: Acute-on-chronic liver failure (ACLF) is closely related to mitochondrial dysfunction. Previous studies showed the vital role of mitofusin2 (Mfn2) in the regulation of mitochondrial function. However, the effect of Mfn2 on ACLF remains unknown. As one of mitochondrial-related pathways, BNIP3-mediated pathway controls the balance between apoptosis and autophagy. However, the relationship between Mfn2 and BNIP3-mediated pathway in ACLF is still obscure. The aim of our study is to clarify the effect of Mfn2 and potential molecular mechanisms in ACLF. Methods: We collected liver tissue from ACLF patients and constructed an ACLF animal model and a hepatocyte autophagy injury model, using adenovirus and lentivirus to deliver Mfn2 and Mfn2-siRNA to liver cells, in order to assess the effect of Mfn2 on autophagy and apoptosis in ACLF. We explored the biological mechanisms of Mfn2-induced autophagy and apoptosis of ACLF through Western blotting, Quantitative Real-Time PCR (RT-PCR), transmission electron microscopy, immunofluorescence, immunohistochemical staining, and hematoxylin-eosin staining. Results: Compared with the normal liver tissue, the expressions of Mfn2, Atg5, Beclin1, and LC3-II/I were significantly decreased and the expression of P62 was much higher in patients with ACLF. Mfn2 significantly attenuated ACLF, characterized via microscopic histopathology and reduced serum AST and ALT levels. Mfn2 promoted the expressions of ATP synthase ß, Atg5, Beclin1, LC3-II/I, and Bcl2 and reduced the expressions of P62, Bax, and BNIP3. Conclusions: Mfn2 plays a protective role in the progression of ACLF. BNIP3-mediated signaling pathway is not the only factor associated with Mfn2 controlling the balance of apoptosis and autophagy in ACLF. Mfn2 will provide a promising therapeutic target for patients with ACLF.

Liver function and energy metabolism in hepatocellular carcinoma developed in patients with hepatitis B-related cirrhosis.

Energy metabolism in patients with Hepatocellular carcinoma (HCC) accompanying by hepatitis B cirrhosis is unknown.To compare the differences in liver functions and energy metabolism between patients with hepatitis B-related cirrhosis and patients with HCC.This was a retrospective study of patients with hepatitis B-related cirrhosis (LC group, n = 75) and patients with HCC accompanying by hepatitis B cirrhosis (HCC group, n = 80) treated in Beijing You'an Hospital between January 2013 and June 2017. The resting energy expenditure (REE), respiratory quotient (RQ), carbohydrate oxidation rate (CHO%), fat oxidation rate (FAT%), and protein oxidation rate (PRO%) were measured using a metabolic cart. Liver function, renal function, blood coagulation, etc. were collected.Compared to the LC group, patients with HCC had normal metabolism, but RQ (0.83 ±â€Š0.07 vs 0.85 ±â€Š0.08, P = .073) and CHO% (35.5% vs 49%, P = .013) were lower and FAT% was higher (41% vs 33%, P = .030). Compared with patients with LC group, albumin (ALB), γ-glutamyltranspeptadase (GGT), alkaline phosphatase (AKP), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and prothrombin time activity (PTA) were elevated in the HCC group, while total bilirubin (TB), total bile acid (TBA), and international normalized ratio (INR) were reduced (P < .05). Cholinesterase (CHE) was positively correlated with RQ, CHO, and CHO% (P < .05), while negatively correlated with FAT and FAT% (P < .05). AKP was negatively correlated with RQ, CHO, and CHO% (P < .05), while positively correlated with FAT and FAT% (P < .05). TBA was negatively correlated with RQ and CHO (P < .05), while positively correlated with FAT (P < .05).HCC leads to increased liver synthetic function and improve the liver functions of patients with LC, at least to some extent, but the nutritional metabolism was poor.

Hemp seed polysaccharides protect intestinal epithelial cells from hydrogen peroxide-induced oxidative stress.

The purpose of this study was to investigate structure of Hemp seed polysaccharide (HSP) and the protective effect of HSP from H2O2-induced oxidative damage in IPEC-1 cells and the possible mechanism of this protection. Analysis of monosaccharide composition and structure of two fractions HSP0 and HSP0.2 from polysaccharide of Hemp seed (HSPc) were analyzed by high performance liquid chromatography (HPLC) and Fourier transform infrared spectroscopy (FT-IR). The results showed that both HSP0 and HSP0.2 contain sulfate groups, which are sulfated polysaccharides. In IPEC-1 cells model, the release of LDH and MDA was significantly decreased, and the activities of SOD, GSH-Px and CAT were significantly increased in HSP0 and HSP0.2-treated group. HSP0.2 dramatically increased the gene expression of antioxidant enzymes and phase II detoxification enzymes measured by real-time fluorescent quantitative reverse transcription-polymerase chain reaction (qRT-PCR). In addition, HSP0.2 up-regulated the expression level of intracellular transcription factor Nuclear factor erythroid-2-related factor 2 (Nrf2) and inhibited the level of Kelch-like ECH-associated protein 1 (Keap1) with Western blot analysis. Collectively, the present study suggested that HSP0.2 has the protective effect of IPEC-1 cells against H2O2-induecd oxidative stress. This protection mechanism may be related to activation of the Keap1/Nrf2 signaling pathway.

Coenzyme Q10 Ameliorates Pancreatic Fibrosis via the ROS-Triggered mTOR Signaling Pathway.

AIM: Pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrosis. Any remedies that inhibit the activation of PSCs can be potential candidates for therapeutic strategies in pancreatic fibrosis-related pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). Our study is aimed at exploring the protective effect of coenzyme Q10 (CoQ10) against pancreatic fibrosis. METHODS: Pancreatic fibrosis was induced by 20% L-arginine (250 mg/100 g) at 1 h intervals twice per week for 8 weeks in C57BL/6 mice. CoQ10 was administered for 4 weeks. Isolated primary PSCs from C57BL/6 mice were treated with 100 µM CoQ10 for 72 h, as well as Rosup and specific inhibitors. The effects of CoQ10 on the activation of PSCs, autophagy, collagen deposition, histological changes, and oxidative stress were analyzed by western blotting, biochemical estimations, immunofluorescence staining, and hematoxylin-eosin, Masson, and Sirius red staining, as well as with a reactive oxygen species (ROS) assay. RESULTS: Pretreatment and posttreatment of CoQ10 decreased autophagy, activation of PSCs, oxidative stress, histological changes, and collagen deposition in the CP mouse model. In primary PSCs, expression levels of p-PI3K, p-AKT, and p-mTOR were upregulated with CoQ10. A rescue experiment using specific inhibitors of the PI3K-AKT-mTOR pathway demonstrated that the PI3K-AKT-mTOR signaling pathway was the underlying mechanism by which CoQ10 ameliorated fibrosis. With the addition of Rosup, expression levels of the autophagy biomarkers LC3 and Atg5 were elevated. Meanwhile, the levels of p-PI3K, p-AKT, and p-mTOR were lower. CONCLUSIONS: Our findings demonstrated that CoQ10 alleviates pancreatic fibrosis by the ROS-triggered PI3K/AKT/mTOR signaling pathway. CoQ10 may be a therapeutic candidate for antifibrotic methods.