Obstetric outcomes in the expectant management of cesarean scar pregnancy with fetal heart activity: a single-center retrospective cohort study.

Background: Cesarean scar pregnancy (CSP) is a high-risk complication characterized by the implantation of a pregnancy within a cesarean scar resulting from a previous delivery. Currently, clinical indicators guiding the expectant management of patients with CSP are lacking. We thus aimed to evaluate pregnancy and neonatal outcomes among women who underwent expectant CSP management and to investigate whether sonographic signs correlated with obstetric outcomes. Methods: We retrospective reviewed the electronic medical records and first-trimester transvaginal ultrasonography reports of consecutive patients diagnosed with CSP in the first trimester at the West China Second University Hospital from January 1, 2010 to December 31, 2022. Pregnancy outcomes (emergency surgery, blood loss, and rescue) and neonatal outcomes (gestational age at delivery, neonatal weight, and Apgar scores) were examined. A binary logistic regression analysis was conducted to identify independent risk factors that could predict severe complications. Results: The final analysis included 54 patients. The mean age of the pregnant women was 34±4 years. Among the 54 patients, 14 (25.9%) did not progress to 20 weeks of gestation. Pregnancy continued beyond 20 weeks in 40 patients, with 37 live births (92.5%) and 3 stillbirths (7.5%). Moreover, 7 (17.5%) and 33 (82.5%) patients delivered before and after 34 weeks, respectively. Placenta accreta spectrum (PAS) and placenta previa were confirmed in 29 (72.5%) and 17 (42.5%) patients, respectively. Hysterectomy, emergency cesarean section, and rescue surgery were performed in 5 (12.5%), 15 (37.5%), and 22 (55.5%) patients, respectively. Patients with a visible niche were significantly more likely to have preterm labor, PAS, placenta previa, low-birth-weight newborns, higher blood loss, intraoperative rescue, blood transfusion, and first-trimester vaginal bleeding than were those without one (all P values <0.05). Conclusions: Our study showed that expectant management of CSP to achieve live birth might be feasible. Patients with a visible niche exhibited worse outcomes, with a higher incidence of severe delivery complications.

ROS-responsive nanoparticle delivery of obeticholic acid mitigate primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a challenging cholestatic liver disease marked by progressive bile duct inflammation and fibrosis that has no FDA-approved therapy. Although obeticholic acid (OCA) has been sanctioned for PSC, its clinical utility in PSC is constrained by its potential hepatotoxicity. Here, we introduce a novel therapeutic construct consisting of OCA encapsulated within a reactive oxygen species (ROS)-responsive, biodegradable polymer, further cloaked with human placenta-derived mesenchymal stem cell (hP-MSC) membrane (MPPFTU@OCA). Using PSC patient-derived organoid models, we assessed its cellular uptake and cytotoxicity. Moreover, using a PSC mouse model induced by 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC), we demonstrated that intravenous administration of MPPFTU@OCA not only improved cholestasis via the FXR-SHP pathway but also reduced macrophage infiltration and the accumulation of intracellular ROS, and alleviated mitochondria-induced apoptosis. Finally, we verified the ability of MPPFTU@OCA to inhibit mitochondrial ROS thereby alleviating apoptosis by measuring the mitochondrial adenosine triphosphate (ATP) concentration, ROS levels, and membrane potential (ΔΨm) using H2O2-stimulated PSC-derived organoids. These results illuminate the synergistic benefits of integrating an ROS-responsive biomimetic platform with OCA, offering a promising therapeutic avenue for PSC.

Treatment of a Patient with Acute Promyelocytic Leukemia with Multiple Isolated Relapses in the Central Nervous System: A Case Report and Mini-Review of the Literature.

The efficacy of therapeutics for acute promyelocytic leukemia (APL) has exhibited an increase in recent years. Only a few patients experience relapse, including extramedullary relapse, and in patients with extramedullary relapse, the central nervous system (CNS) is the most common site. To date, there is no expert consensus or clinical guidelines available for CNS relapse, at least to the best of our knowledge. The optimal therapeutic strategy and management options for these patients remain unclear. The present study reports the treatment of a patient with APL with multiple isolated relapses in the CNS. In addition, through a mini-review of the literature, the present study provides a summary of various reports of this disease and discusses possible treatment options for these patients.

MSC-derived exosomes attenuate hepatic fibrosis in primary sclerosing cholangitis through inhibition of Th17 differentiation.

Primary sclerosing cholangitis (PSC) is an autoimmune cholangiopathy characterized by chronic inflammation of the biliary epithelium and periductal fibrosis, with no curative treatment available, and liver transplantation is inevitable for end-stage patients. Human placental mesenchymal stem cell (hpMSC)-derived exosomes have demonstrated the ability to prevent fibrosis, inhibit collagen production and possess immunomodulatory properties in autoimmune liver disease. Here, we prepared hpMSC-derived exosomes (ExoMSC) and further investigated the anti-fibrotic effects and detailed mechanism on PSC based on Mdr2-/- mice and multicellular organoids established from PSC patients. The results showed that ExoMSC ameliorated liver fibrosis in Mdr2-/- mice with significant collagen reduction in the preductal area where Th17 differentiation was inhibited as demonstrated by RNAseq analysis, and the percentage of CD4+IL-17A+T cells was reduced both in ExoMSC-treated Mdr2-/- mice (Mdr2-/--Exo) in vivo and ExoMSC-treated Th17 differentiation progressed in vitro. Furthermore, ExoMSC improved the hypersecretory phenotype and intercellular interactions in the hepatic Th17 microenvironment by regulating PERK/CHOP signaling as supported by multicellular organoids. Thus, our data demonstrate the anti-fibrosis effect of ExoMSC in PSC disease by inhibiting Th17 differentiation, and ameliorating the Th17-induced microenvironment, indicating the promising potential therapeutic role of ExoMSC in liver fibrosis of PSC or Th17-related diseases.

The oral administration of Lacticaseibacillus casei Shirota alleviates acetaminophen-induced liver injury through accelerated acetaminophen metabolism via the liver-gut axis in mice.

Acetaminophen is a widely used antipyretic and analgesic drug, and its overdose is the leading cause of drug-induced acute liver failure. This study aimed to investigate the effect and mechanism of Lacticaseibacillus casei Shirota (LcS), an extensively used and highly studied probiotic, on acetaminophen-induced acute liver injury. C57BL/6 mice were gavaged with LcS suspension or saline once daily for 7 days before acute liver injury was induced via intraperitoneal injection of 300 mg/kg acetaminophen. The results showed that LcS significantly decreased acetaminophen-induced liver and ileum injury, as demonstrated by reductions in the increases in aspartate aminotransferase, total bile acids, total bilirubin, indirect bilirubin, and hepatic cell necrosis. Moreover, LcS alleviated acetaminophen-induced intestinal mucosal permeability, decreased serum IL-1α and lipopolysaccharide levels, and elevated serum eosinophil chemokine (eotaxin) and hepatic glutathione levels. Furthermore, analysis of the gut microbiota and metabolome showed that LcS reduced the acetaminophen-enriched levels of Cyanobacteria, Oxyphotobacteria, long-chain fatty acids, cholesterol, and sugars in the gut. Additionally, the transcriptomic and proteomic results showed that LcS mitigated the decrease in metabolic and immune pathways as well as glutathione formation during acetaminophen-induced acute liver injury. This is the first study showing that pretreatment with LcS alleviates acetaminophen-enriched acute liver injury, and it provides a reference for the application of LcS.IMPORTANCEAcetaminophen is the most frequently used antipyretic analgesic worldwide. As a result, overdoses easily occur and lead to drug-induced acute liver injury, which quickly progresses to liver failure with a mortality of 60%-80% if not corrected in time. The current emergency treatment for overused acetaminophen needs to be administered within 8 hours to avoid liver injury or even liver failure. Therefore, developing preventive strategies for liver injury during planned acetaminophen medication is particularly important, preferably nonpharmacological methods. Lacticaseibacillus casei Shirota (LcS) is a famous probiotic that has been used for many years. Our study found that LcS significantly alleviated acetaminophen-induced acute liver injury, especially acetaminophen-induced liver injury toward fulminant hepatic failure. Here, we elucidated the function and potential mechanisms of LcS in alleviating acetaminophen-induced acute liver injury, hoping it will provide preventive strategies to people during acetaminophen treatment.

Ultrasound performance in pediatric deep soft-tissue tumor characterization.

This study investigated the performance of ultrasonography in diagnosing deep soft-tissue tumors and tumor-like lesions in children with histological results. Demographic information and ultrasound characteristics of benign and malignant masses were statistically analyzed. Three radiologists (Radiologists 1, 2, and 3) independently reviewed the ultrasonography studies while being blinded to the medical history and other imaging findings. The 82 lesions included in the study were histopathologically classified as malignant (n = 25) or benign (n = 57). No statistically significant differences were observed between the benign and malignant subgroups regarding age (p = 0.059), sex (p = 1.0), disease course (p = 0.812), presence or absence of symptoms (p = 0.534), maximum diameter (p = 0.359), margin (p = 1.0), calcification (p = 0.057), or blood Adler type (p = 0.563). However, statistically significant differences were observed between the benign and malignant subgroups in terms of isolated or Multiple occurrences (p < 0.001), history of malignancy (p < 0.001), shape (p < 0.001), and echogenicity (p < 0.001). Parameters such as tumor shape (p = 0.042, OR = 6.222), single or multiple occurrences (p = 0.008, OR = 17.000), and history of malignancy (p = 0.038, OR = 13.962) were identified as independent predictors of benign and malignant tumors. The diagnostic sensitivities evaluated by the three radiologists were 68.0%, 72.0%, 96.0%, respectively, while the specificities were 77.2%, 82.5%, 77.2%, respectively. Ultrasound demonstrates good performance in the diagnosis of benign deep lesions such as hemangiomas/venous malformation and adipocytic tumors. Multiple irregular morphologies and a history of malignancy were identified as independent risk factors for malignant masses. The experience of radiologists in recognizing specific tumors is important. Careful attention should be paid to masses with ambiguous ultrasound features, as well as small lesions.

[Artificial intelligence-assisted prediction of olfactory disorders in patients with chronic rhinosinusitis].

Objective:To analyze the influencing factors and perform the prediction of olfactory disorders in patients with chronic rhinosinusitis（CRS） based on artificial intelligence. Methods:The data of 75 patients with CRS who underwent nasal endoscopic surgery from October 2021 to February 2023 in the Department of Otorhinolaryngology Head and Neck Surgery, the Third Affiliated Hospital of Sun Yat-sen University were analyzed retrospectively. There were 53 males and 22 females enrolled in the study, with a median age of 42.0 years old. The CRS intelligent microscope interpretation system was used to calculate the proportion of area glands and blood vessels occupy in the pathological sections of each patient, and the absolute value and proportion of eosinophils, lymphocytes, plasma cells and neutrophils. The patients were grouped according to the results of the Sniffin' Sticks smell test, and the clinical baseline data, differences in nasal mucosal histopathological characteristics, laboratory test indicators and sinus CT were compared between the groups. Determine the independent influencing factors of olfactory disorders and receiver operating characteristic curves（ROC） were used to evaluate the performance of the prediction model. Statistical analysis was performed using SPSS 25.0 software. Results:Among the 75 CRS patients, 25 cases（33.3%） had normal olfaction and 50 cases（66.7%） had olfactory disorders. Multivariate Logistic regression analysis showed that tissue eosinophils percentage（OR=1.032, 95%CI 1.002-1.064, P=0.036）, Questionnaire of olfactory disorders-Negative statement（QOD-NS）（OR=1.079, 95%CI 1.004-1.160, P=0.040） and Anterior olfactory cleft score（AOCS）（OR=2.672, 95%CI 1.480-4.827, P=0.001） were independent risk factors for olfactory disorders in CRS patients. Further research found that the area under the ROC curve（AUC） of the combined prediction model established by the tissue eosinophil percentage, QOD-NS and AOCS was 0.836（95%CI 0.748-0.924, P<0.001）, which is better than the above single factor prediction model in predicting olfactory disorders in CRS. Conclusion:Based on pathological artificial intelligence, tissue eosinophil percentage, QOD-NS and AOCS are independent risk factors for olfactory disorders in CRS patients, and the combination of the three factors has a good predictive effect on CRS olfactory disorders.

A novel HIF2A mutation causes dyslipidemia and promotes hepatic lipid accumulation.

Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor responsible for regulating genes related to angiogenesis and metabolism. This study aims to explore the effect of a previously unreported mutation c.C2473T (p.R825S) in the C-terminal transactivation domain (CTAD) of HIF-2α that we detected in tissue of patients with liver disease. We sequenced available liver and matched blood samples obtained during partial liver resection or liver transplantation performed for clinical indications including hepatocellular carcinoma and liver failure. In tandem, we constructed cell lines and a transgenic mouse model bearing the corresponding identified mutation in HIF-2α from which we extracted primary hepatocytes. Lipid accumulation was evaluated in these cells and liver tissue from the mouse model using Oil Red O staining and biochemical measurements. We identified a mutation in the CTAD of HIF-2α (c.C2473T; p.R825S) in 5 of 356 liver samples obtained from patients with hepatopathy and dyslipidemia. We found that introduction of this mutation into the mouse model led to an elevated triglyceride level, lipid droplet accumulation in liver of the mutant mice and in their extracted primary hepatocytes, and increased transcription of genes related to hepatic fatty acid transport and synthesis in the mutant compared to the control groups. In mutant mice and cells, the protein levels of nuclear HIF-2α and its target perilipin-2 (PLIN2), a lipid droplet-related gene, were also elevated. Decreased lipophagy was observed in mutant groups. Our study defines a subpopulation of dyslipidemia that is caused by this HIF-2α mutation. This may have implications for personalized treatment.

Development of FAP-Targeted Chimeric Antigen Receptor NK-92 Cells for Non-Small Cell Lung Cancer.

OBJECTIVES: Over the past two decades, great progress has been made in advancing the early detection and multimodal treatment of non-small cell lung cancer (NSCLC). However, overall cure rates and survival rates of NSCLC are still not satisfactory, and research into new therapies is needed. This study attempted to construct human Fibroblast Activation Protein-Chimeric Antigen Receptor Natural killer (NK)-92 cells (hFAP-CAR-NK-92 cells) and explore their potential therapeutic effects in NSCLC. METHODS: Immunohistochemistry analysis was carried out to examine fibroblast activation protein (FAP) and Gasdermin E (GSDME) expression in clinical specimens of lung adenocarcinoma and squamous cell carcinoma tissue. Then the engineered hFAP-CAR-NK-92 cells efficiency was determined in vitro with lactate dehydrogenase (LDH) cytotoxicity assay and the cell morphology of A549, H226, and cancer-related fibroblast (CAF) was observed by electron microscopy. After the co-culture of target cells and effect cells, flow cytometry was employed for examining the CD107a expression in the effect cells, and western blotting was conducted for the cleavage levels of Caspase 3 and GSDME proteins in the target cells. The safety and efficacy of hFAP-CAR-NK-92 cells adoptive transfer immunotherapy in a tumor-bearing mouse were evaluated. RESULTS: Clinical studies have shown FAP positivity in patients with NSCLC. Compared with A549 or H226 cells alone, FAP expression was notably raised in A549+CAF cells or H226+CAF cells in nude mice, respectively (p < 0.05). The killing efficiency of K562 cells was not significantly different between hFAP-CAR-NK-92 and NK-92 cells (p > 0.05). The hFAP-CAR-NK-92 cells presented a higher killing efficiency against the hFAP-target (A549-hFAP, H226-hFAP and CAF-hFAP) cells than the NK-92 cells (p < 0.05). The degranulation of CD107a and cleavage levels of GSDME and Caspase 3 protein in the hFAP-CAR-NK-92 group were higher than those in the NK-92 group (p < 0.05). The 300 nM Granzyme B also induced pyroptosis in hFAP- or GSDME-positive cells (p < 0.05). In vivo experiments revealed that hFAP-CAR-NK-92 cells inhibited tumor progression of hFAP-positive NSCLC (p < 0.05). CONCLUSIONS: In this study, we successfully constructed hFAP-CAR-NK-92 cells and confirmed that hFAP-CAR-NK-92 cells could target hFAP-positive NSCLC to inhibit the progression of NSCLC by activating the Caspase-3/GSDME pyroptosis pathway.

Grain Refinement Mechanism of 5A06 Aluminum Alloy Sheets during Cold Rotary Forging.

This paper studies the grain refinement mechanisms of 5A06 aluminum alloy sheets in cold rotary forging (CRF). The results show that the grains are clearly refined from 25.1 µm to 11.8 µm during the CRF process. The grain refinement mechanism can be divided into two modes: (1) The grains with a small Schmid factor (SF) are activated by multi-slip systems, and dense dislocations are segregated along the boundaries of interior regions with different slip systems, which results in a rapidly increasing strain localization along these boundaries. Since the strain localization restrains the coordinate slip deformation between different interior regions, the grains are directly separated into several finer grains. (2) The grains with a large SF are primarily activated by a single slip system, and the dislocation migrates smoothly along most microband boundaries. Then, a more severe lattice rotation causes a transformation to a hard orientation and multi-slip system activation, which contributes to an increase in the rapid misorientation across microband boundaries and thus promotes significant SF grain refinement.

Characteristic Analysis of Featured Genes Associated with Cholangiocarcinoma Progression.

The noninvasive diagnosis of cholangiocarcinoma (CCA) is insufficiently accurate. Therefore, the discovery of new prognostic markers is vital for the understanding of the CCA mechanism and related treatment. The information on CCA patients in The Cancer Genome Atlas database was used for weighted gene co-expression network analysis. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were applied to analyze the modules of interest. By using receiver operating characteristic (ROC) analysis to analyze the Human Protein Atlas (HPA), the featured genes were subsequently verified. In addition, clinical samples and GSE119336 cohort data were also collected for the validation of these hub genes. Using WGCNA, we identified 61 hub genes that regulated the progression and prognosis of CCA. Eight hub genes (VSNL1, TH, PCP4, IGDCC3, RAD51AP2, MUC2, BUB1, and BUB1B) were identified which exhibited significant interactions with the tumorigenic mechanism and prognosis of CCA. In addition, GO and KEGG clarified that the blue and magenta modules were involved with chromosome segregation, mitotic and oocyte meiosis, the cell cycle, and sister chromatid segregation. Four hub genes (VSNL1, PCP4, BUB1, and BUB1B) were also verified as featured genes of progression and prognosis by the GSE119336 cohort data and five human tissue samples.

Predictive significance of Charcot-Leyden crystal structures for nasal polyp recurrence.

BACKGROUND: Charcot-Leyden crystals (CLCs) are recognized to be classic hallmarks of eosinophilic inflammation. Both protein and mRNA levels of CLC in nasal secretions and nasal brushing samples have been associated with nasal polyp recurrence. However, whether the crystalline CLC structures in nasal tissue could serve as an effective biomarker to predict polyp recurrence remains unclear. METHODS: A total of 110 patients with chronic rhinosinusitis with nasal polyps (CRSwNP) completing the postoperative follow-up over a period of 24 months were recruited. Hematoxylin and eosin staining was employed for CLCs identification. The predictive factors for polyp recurrence were determined by binary logistic regression analysis. RESULTS: Thirty three (30.00%) patients developed recurrence during a 24-month postoperative follow-up, in which 84.85% (28/33) patients had crystalline CLC structures. Logistic regression analysis showed that crystalline CLC structure in nasal tissues is predictive of polyp recurrence. Youden index demonstrated crystalline CLC structure higher than 1 per high power field can predict postoperative polyp recurrence with 84.80% sensitivity and 98.70% specificity. CONCLUSIONS: The crystalline CLC structures in nasal tissues may serve as an easy-counting and promising biomarker to predict CRSwNP recurrence.

Effect of light-emitting diodes with different color rendering indexes on the ocular tissues of rat.

AIM: To compare the damage of light-emitting diodes (LEDs) with different color rendering indexes (CRIs) to the ocular surface and retina of rats. METHODS: Totally 20 Sprague-Dawley (SD) rats were randomly divided into four groups: the first group was normal control group without any intervention, other three groups were exposed by LEDs with low (LED-L), medium (LED-M), and high (LED-H) CRI respectively for 12h a day, continuously for 4wk. The changes in tear secretion (Schirmer I test, SIt), tear film break-up time (BUT), and corneal fluorescein sodium staining (CFS) scores were compared at different times (1d before experiment, 2 and 4wk after the experiment). The histopathological changes of rat lacrimal gland and retina were observed at 4wk, and the expressions of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in lacrimal gland were detected by immunofluorescence method. RESULTS: With the increase of light exposed time, the CFS value of each light exposed group continued to increase, and the BUT and SIt scores continued to decrease, which were different from the control group, and the differences between the light exposed groups were statistically significant. Hematoxylin-eosin (HE) results showed that the lacrimal glands of each exposed group were seen varying degrees of acinar atrophy, vacuole distribution, increasing of eosinophil granules, etc.; the retina showed obvious reduction of photoreceptor cell layer and changes in retinal thickness; LED-L group has the most significant change in all tests. Immunofluorescence suggested that the positive expressions of TNF-α and IL-6 in the lacrimal glands of each exposed group were higher than those of the control group. CONCLUSION: LED exposure for 4wk can cause the pathological changes of lacrimal gland and retina of rats, and increase the expression of TNF-α and IL-6 in lacrimal gland, the degree of damage is negatively correlated with the CRI.

Diagnostic and Prognostic Roles of Thrombospondin-2 in Digestive System Cancers.

Background: Cancers of digestive system have high case-fatality rate. It is important to find more appropriate methods in diagnosing and predicting gastrointestinal malignances. And thrombospondin-2 (TSP-2) was reported to have the functions, although results were not identical. So we performed this meta-analysis to clarify the significance of TSP-2 in this area. Methods: PubMed, Embase, Web of Science, Cochrane Library, and Clinicaltrial.gov were searched for relevant studies. Data were extracted from these involved records. For the meta-analysis of diagnostic test, bivariate mixed effect model was used to estimate diagnostic accuracy. For prognosis part, HRs and their 95% CIs were pooled to compare the overall survival (OS) and disease-free survival (DFS) between patients with high TSP-2 and low TSP-2. Results: Nine records were eligible for the analysis of diagnostic test. Pooled results were as follows: sensitivity 0.60 (0.52, 0.68), specificity 0.96 (0.91, 0.98), positive likelihood ratio (PLR) 15.4 (7.3, 32.2), negative likelihood ratio (NLR) 0.42 (0.34, 0.50), and diagnostic odds ratio (DOR) 37 (18, 76). While in prognosis part, 10 articles were included. Patients with increased TSP-2 had shorter OS (HR = 1.64, 95% CI = 1.21-2.22); however, no difference was found in DFS between TSP-2 high and low groups (HR = 1.44, 95% CI = 0.28-7.33). Conclusions: TSP-2, as a diagnostic marker, has a high specificity but a moderate sensitivity. Meanwhile, it plays a role in predicting OS. Therefore, making TSP-2 a routine assay could be beneficial to high-risk individuals and patients with digestive malignances.

Highly Efficient Methods to Culture Mouse Cholangiocytes and Small Intestine Organoids.

Background: Organoids, which enable disease modeling and drug screening closer to an in vivo environment, can be isolated and grown from organs such as the brain, small intestine, kidney, lungs, and liver. To facilitate the establishment of liver and small intestinal organoids, we developed efficient protocols for cholangiocytes and intestine crypts collecting and organoid culturing. Methods: Cholangiocytes were collected from intrahepatic bile ducts, the gallbladder, and small intestine crypts by gravity settling and multistep centrifugation methods. The cells isolated were embedded with Matrigel and grew in three-dimensional spheroids in a suitable culture medium. The stability of organoid cells was assessed by subculture, cryopreservation, and thawing. RNA and DNA extraction of organoids, as well as immunostaining procedure, were also optimized. Hand-picking procedures were developed and performed to ensure similar growth characteristics of organoids. Results: A large number of cholangiocytes and small intestine crypts were collected under these protocols. Cholangiocytes developed into cyst-like structures after 3-4 days in Matrigel. After 1-2 weeks of cultivation, small intestinal organoids (in-orgs) developed buds and formed a mature structure. Compared to organoids derived from the gallbladder, cholangiocyte organoids (Cho-orgs) from intrahepatic the bile ducts grew more slowly but had a longer culture term, expressed the cholangiocytes markers Krt19 and Krt7, and recapitulated in vivo tissue organization. Conclusions: Our protocols simplified the cell collection procedure and avoided the possibility of exposing tissue-derived stem cells to mechanical damage or chemical injury by gravity settling and multistep centrifugation. In addition, our approach allowed similar growth characteristics of organoids from different mammalian tissue sources. The protocol requires 2-4 weeks to establish a stable organoid growth system. Organoids could be stably passaged, cryopreserved, and recovered under protocol guidance. Besides, the organoids of cholangiocytes and small intestines retained their original tissue characteristics, such as tissue-specific marker expression, which prepares them for further experiments such as preclinical in vitro trials and mechanism research studies.

Immobilization of Lecitase® Ultra onto the Organic Modified SBA-15 for Soybean Oil Degumming.

In this study, SBA-15 was functionalized by organic groups (-CH3, -C4H9, -C8H17, -CH2CH2NH2, -C6H5, et al.), and then Lecitase® Ultra (LU) was immobilized onto the modified SBA-15 for soybean oil degumming. The hydrolysis activity, degumming performance, reusability in degumming, and the composition of phospholipids in the gum, of the immobilized LU samples, were carefully studied. Hydrolysis activities over 1800 U/g were obtained from all the immobilized LU samples. The highest activity of up to 4554.17 U/g was observed from the 3-ureidopropyl group-modified SBA-15-supported LU. Most of the immobilized LU samples removed the phospholipids effectively from crude soybean oil (initial phosphorous content 314.23 mg/kg), with a residual phosphorus content of less than 10 mg/kg. The reusability of the immobilized LU samples in the degumming process was evaluated. No loss of activity was observed from the methyl and N-(2-aminoethyl)-3-aminopropyl group-modified SBA-15-supported LU samples after five cycles of reuse. In addition, 3-aminopropyl and 3-glycidyloxypropyl group-modified SBA-15-supported LU samples retained over 90% of their initial activity; N-phenylaminomethyl and 1-isocyanatopropane group-functionalized SBA-15-supported LU samples retained approximately 80% of their initial activity. The phospholipids in the gum were analyzed. The n-octadecyl and N-(2-aminoethyl)-3-aminopropyl group-functionalized SBA-15-supported LU samples were selective for lysophosphatidylethanolamine (LPE) preparation, and LPE percentages up to 37.14 and 38.80% were obtained, respectively. The N-phenylaminomethyl group-modified SBA-15-supported LU showed selectivity toward lysophosphatidylcholine (LPC) production, with an LPC percentage of up to 38.5%.

Probiotic-fermented rice buckwheat alleviates high-fat diet-induced hyperlipidemia in mice by suppressing lipid accumulation and modulating gut microbiota.

Hyperlipidemia is associated with lipid metabolic disorders, chronic inflammation, and intestinal dysbiosis. Previous studies have shown that the metabolic improvement of high-fat diet (HFD)-induced mice by buckwheat is correlated with gut microbiota; however, the anti-hyperlipidemia effects and potential mechanism of probiotics-fermented rice buckwheat (FRB) are not well understood. Here, we aimed to investigate the lipid-lowering and gut microbiota regulation of FRB in HFD-induced hyperlipidemic mice. We observed that probiotic fermentation markedly increased the contents of γ-aminobutyric acid, rutin, total polyphenols, and total flavonoids in rice buckwheat. FRB supplementation over eight weeks significantly reduced body weight gain and visceral obesity, as well as alleviating dyslipidemia in HFD-fed mice. Moreover, FRB treatment effectively ameliorated oxidative stress and chronic inflammation. We further demonstrated that FRB intervention significantly inhibited hepatic cholesterol synthesis and lipogenesis, and promoted lipolysis. More important, FRB treatment reversed HFD-induced gut dysbiosis by decreasing the ratio of Firmicutes to Bacteroidetes and increasing the abundance of SCFA-producing bacteria such as Bacteroides, Lactobacillus, and Blautia, along with increasing the total SCFAs contents. Overall, these results show that FRB is a beneficial nutraceutical for hyperlipidemia amelioration.

Mesenchymal stem cells protect against ferroptosis via exosome-mediated stabilization of SLC7A11 in acute liver injury.

Mesenchymal stem cells (MSCs) have attracted interest for their potential to alleviate liver injury. Here, the protective effect of MSCs on carbon tetrachloride (CCl4)-induced acute liver injury (ALI) was investigated. In this study, we illustrated a novel mechanism that ferroptosis, a newly recognized form of regulated cell death, contributed to CCl4-induced ALI. Subsequently, based on the in vitro and in vivo evidence that MSCs and MSC-derived exosomes (MSC-Exo) treatment achieved pathological remission and inhibited the production of lipid peroxidation, we proposed an MSC-based therapy for CCl4-induced ALI. More intriguingly, treatment with MSCs and MSC-Exo downregulated the mRNA level of prostaglandin-endoperoxide synthase 2 (Ptgs2) and lipoxygenases (LOXs) while it restored the protein level of SLC7A11 in primary hepatocytes and mouse liver, indicating that the inhibition of ferroptosis partly accounted for the protective effect of MSCs and MSC-Exo on ALI. We further revealed that MSC-Exo-induced expression of SLC7A11 protein was accompanied by increasing of CD44 and OTUB1. The aberrant expression of ubiquitinated SLC7A11 triggered by CCl4 could be rescued with OTUB1-mediated deubiquitination, thus strengthening SLC7A11 stability and thereby leading to the activation of system XC- to prevent CCl4-induced hepatocyte ferroptosis. In conclusion, we showed that MSC-Exo had a protective role against ferroptosis by maintaining SLC7A11 function, thus proposing a novel therapeutic strategy for ferroptosis-induced ALI.

Curcumin is a Potential Adjuvant to Alleviates Diabetic Retinal Injury via Reducing Oxidative Stress and Maintaining Nrf2 Pathway Homeostasis.

Curcumin is a natural polyphenol compound with anti-diabetic, anti-oxidative, and anti-inflammatory effects. Although many studies have reported the protective effect of curcumin in diabetes mellitus or diabetic nephropathy, there is a lack of research on curcumin in diabetic retinopathy. The purpose of this study was to investigate the therapeutic effects of curcumin on the diabetic retinal injury. Streptozotocin (STZ)-induced diabetic rats (60, n = 12 each) were respectively given curcumin orally (200 mg/kg/day), insulin subcutaneously (4-6 IU/day), and combined therapy with curcumin and insulin for 4 weeks. Retinal histopathological changes, oxidative stress markers, and transcriptome profiles from each group were observed. Curcumin, insulin, or combination therapy significantly reduced blood glucose, alleviated oxidative stress, and improved pathological damage in diabetic rats. Curcumin not only significantly reduced retinal edema but also had a better anti-photoreceptor apoptosis effect than insulin. In the early stage of diabetes, the enhancement of oxidative stress in the retina induced the adaptive activation of the nuclear factor E2-associated factor 2 (Nrf2) pathway. Treatment of curcumin alleviated the compensatory activation of the Nrf2 pathway induced by oxidative stress, by virtue of its antioxidant ability to transfer hydrogen atoms to free radicals. When curcumin combined with insulin, the effect of maintaining Nrf2 pathway homeostasis in diabetic rats was better than that of insulin alone. Transcriptomic analyses revealed that curcumin either alone, or combined with insulin, inhibited the AGE-RAGE signaling pathway and the extracellular matrix (ECM)-receptor interaction in the diabetic retina. Thus, at the early stage of diabetes, curcumin can be used to alleviate diabetic retinal injury through its anti-oxidative effect. If taking curcumin as a potential complementary therapeutic option in combination with antihyperglycemic agents, which would lead to more effective therapeutic outcomes against diabetic complications.

Stem cell therapy for Crohn's disease: systematic review and meta-analysis of preclinical and clinical studies.

BACKGROUND: We explored whether stem cell therapy was effective for animal models and patients with Crohn's disease (CD). METHODS: We searched five online databases. The relative outcomes were analyzed with the aid of GetData Graph Digitizer 2.26 and Stata 16.0 software. The SYRCLE risk of bias tool and the MINORS tool were used to assess study quality. RESULTS: We evaluated 46 studies including 28 animal works (n = 567) and 18 human trials (n = 360). In the animal studies, the disease activity index dramatically decreased in the mesenchymal stem cell (MSC) treatment groups compared to the control group. Rats and mice receiving MSCs exhibited longer colons [mice: standardized mean difference (SMD) 2.84, P = 0.000; rats: SMD 1.44, P = 0.029], lower histopathological scores (mice: SMD - 4.58, p = 0.000; rats: SMD - 1.41, P = 0.000) and lower myeloperoxidase levels (SMD - 6.22, P = 0.000). In clinical trials, stem cell transplantation reduced the CD activity index (SMD - 2.10, P = 0.000), the CD endoscopic index of severity (SMD - 3.40, P = 0.000) and simplified endoscopy score for CD (SMD - 1.71, P = 0.000) and improved the inflammatory bowel disease questionnaire score (SMD 1.33, P = 0.305) compared to control values. CD patients maintained high remission rates for 3-24 months after transplantation. CONCLUSIONS: Stem cell transplantation is a valuable supplementary therapy for CD.