NAD+ salvage governs the immunosuppressive capacity of mesenchymal stem cells.

Mesenchymal stem/stromal cells (MSCs) possess robust immunoregulatory functions and are promising therapeutics for inflammatory disorders. This capacity is not innate but is activated or 'licensed' by inflammatory cytokines. The licensing mechanism remains unclear. Here, we examined whether inflammatory cytokines metabolically reprogrammed MSCs to confer this immunoregulatory capacity. In response to stimulation by inflammatory cytokines, MSCs exhibited a dramatic increase in the consumption of glucose, which was accompanied by an enhanced use of nicotinamide adenine dinucleotide (NAD+) and increased expression of nicotinamide phosphoribosyltransferase (NAMPT), a central enzyme in the salvage pathway for NAD+ production. When NAD+ synthesis was blocked by inhibiting or depleting NAMPT, the immunosuppressive function of MSCs induced by inflammatory cytokines was greatly attenuated. Consequently, when NAD+ metabolism in MSCs was perturbed, their therapeutic benefit was decreased in mice suffering from inflammatory bowel disease and acute liver injury. Further analysis revealed that NAMPT-driven production of NAD+ was critical for the inflammatory cytokine-induced increase in glycolysis in MSCs. Furthermore, the increase in glycolysis led to succinate accumulation in the tricarboxylic acid cycle, which led to hypoxia-inducible factor 1α (HIF-1α) stabilization and subsequently increased the transcription of key glycolytic genes, thereby persistently maintaining glycolytic flux. This study demonstrated that unlike its proinflammatory role in immune cells, NAD+ metabolism governs the anti-inflammatory function of MSCs during inflammation.

IL4I1-catalyzed tryptophan metabolites mediate the anti-inflammatory function of cytokine-primed human muscle stem cells.

Muscle stem cells (MuSCs) have been demonstrated to exert impressive therapeutic efficacy in disease settings through orchestrating inflammatory microenvironments. Nevertheless, the mechanisms underlying the immunoregulatory property of MuSCs remain largely uncharacterized. Here, we showed that interleukin-4-induced-1 (IL4I1), an essential enzyme that catalyzes indole metabolism in humans, was highly expressed in human MuSCs exposed to IFN-γ and TNF-α. Functionally, the MuSCs were found to inhibit the infiltration of neutrophils into sites of inflammation in a IL4I1-dependent manner and thus ameliorate acute lung injury in mice. Mechanistically, the indole metabolites, including indole-3-pyruvic acid (I3P) and indole-3-aldehyde (I3A), produced by IL4I1, acted as ligands to activate aryl hydrocarbon receptor (AHR), leading to augmented expression of TNF-stimulated gene 6 (TSG-6) in inflammatory cytokine-primed MuSCs. Furthermore, I3P administration alone suppressed neutrophil infiltration into damaged lungs. I3P could also reduce the level of reactive oxygen species in neutrophils. Therefore, our study has uncovered a novel mechanism by which MuSCs acquire their immunoregulatory property and may help to develop or optimize MuSC-based therapies for inflammatory diseases.

NAD+ metabolism-based immunoregulation and therapeutic potential.

Nicotinamide adenine dinucleotide (NAD+) is a critical metabolite that acts as a cofactor in energy metabolism, and serves as a cosubstrate for non-redox NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD+ metabolism can regulate functionality attributes of innate and adaptive immune cells and contribute to inflammatory responses. Thus, the manipulation of NAD+ bioavailability can reshape the courses of immunological diseases. Here, we review the basics of NAD+ biochemistry and its roles in the immune response, and discuss current challenges and the future translational potential of NAD+ research in the development of therapeutics for inflammatory diseases, such as COVID-19.

Establishment and clinical application value of an automatic diagnosis platform for rectal cancer T-staging based on a deep neural network.

BACKGROUND: Colorectal cancer is harmful to the patient's life. The treatment of patients is determined by accurate preoperative staging. Magnetic resonance imaging (MRI) played an important role in the preoperative examination of patients with rectal cancer, and artificial intelligence (AI) in the learning of images made significant achievements in recent years. Introducing AI into MRI recognition, a stable platform for image recognition and judgment can be established in a short period. This study aimed to establish an automatic diagnostic platform for predicting preoperative T staging of rectal cancer through a deep neural network. METHODS: A total of 183 rectal cancer patients' data were collected retrospectively as research objects. Faster region-based convolutional neural networks (Faster R-CNN) were used to build the platform. And the platform was evaluated according to the receiver operating characteristic (ROC) curve. RESULTS: An automatic diagnosis platform for T staging of rectal cancer was established through the study of MRI. The areas under the ROC curve (AUC) were 0.99 in the horizontal plane, 0.97 in the sagittal plane, and 0.98 in the coronal plane. In the horizontal plane, the AUC of T1 stage was 1, AUC of T2 stage was 1, AUC of T3 stage was 1, AUC of T4 stage was 1. In the coronal plane, AUC of T1 stage was 0.96, AUC of T2 stage was 0.97, AUC of T3 stage was 0.97, AUC of T4 stage was 0.97. In the sagittal plane, AUC of T1 stage was 0.95, AUC of T2 stage was 0.99, AUC of T3 stage was 0.96, and AUC of T4 stage was 1.00. CONCLUSION: Faster R-CNN AI might be an effective and objective method to build the platform for predicting rectal cancer T-staging. TRIAL REGISTRATION: chictr.org.cn: ChiCTR1900023575; http://www.chictr.org.cn/showproj.aspx?proj=39665.

Accuracy of endoscopic ultrasound in rectal cancer and its use in transanal endoscopic microsurgery.

Introduction: This study evaluated the accuracy of endoscopic ultrasound (EUS) for preoperative staging of rectal cancer and guiding the treatment of transanal endoscopic microsurgery (TEM) in early rectal cancer.Material and methods: One-hundred-twenty-six patients with rectal cancer were staged preoperatively using EUS and the results were compared with postoperative histopathology results. Radical surgeries, including low anterior resection (LAR), abdominal-perineal resection (APR) and Hartmann surgeries, were performed on patients with advanced rectal cancers, and TEM was performed on patients with stage T1. The Kappa statistic was used to determine agreement between EUS-based staging and pathology staging.Results: The overall accuracies of EUS for T and N stage were 90.8% (Kappa = 0.709) and 76.7% (Kappa = 0.419), respectively. The accuracies of EUS for uT1, uT2, uT3, and uT4 stages were 96.8%, 92.1%, 84.1%, and 88.9%, respectively, and for uN0, uN1, and uN2 stages, they were 71.9%, 64.9%, and 93.0%, respectively. Twelve patients underwent TEM and received confirmed pathology results of early rectal cancer. After postoperative follow-up, there were no local recurrences or distant metastases.Conclusion: EUS is a good and comparable technique for postoperative staging of rectal cancer. Moreover, EUS is used as indicator for preoperative staging and tumor assessment strategy when considering TEM.

Use of Hisense Computer-Assisted Surgery System Enhances Infrapyloric Lymph Node Dissection for Gastric Cancer.

BACKGROUND: This study aimed to establish a three-dimensional model of infrapyloric vessels using the Hisense computer-assisted surgery (CAS) system before the operation to understand blood vessel variation types and determine the group 6 lymph node (LN) metastasis status. METHODS: One hundred and four gastric cancer patients were randomly assigned to a CAS group and a computed tomography (CT) group. Intraoperative and postoperative complications in the two groups were recorded. The number of group 6 LNs dissected and the metastasis status were compared between the groups. The independent risk factors influencing group 6 LN metastasis were determined by multiple logistic regression analysis. RESULTS: In the 50 CAS group patients, the gastrocolic trunk of Henle was divided into a gastrocolic type (34.0%) and a gastropancreatic colonic type (66.0%); the right gastroepiploic artery was divided into a coarse blood supply type (24.0%) and a fine blood supply type (76.0%); and the relationship between the right gastroepiploic artery and right gastroepiploic vein was divided into an adjacent type (58.0%) and a separated type (42.0%). Although the difference was not significant, the CAS group had fewer cases of intraoperative gastrocolic trunk injury and postoperative pancreatic leakage in trend than the CT group. The CAS group had more dissected LNs (P < 0.001) and metastatic LNs (P = 0.011) than the CT group; meanwhile, it had higher LN metastasis rate and LN metastasis degree in trend than the CT group. According to the multiple logistic regression model, tumor location and TNM stage were significantly correlated with group 6 LN metastases. CONCLUSIONS: By establishing a three-dimensional model of the infrapyloric vessels using the Hisense CAS system, we comprehensively determined the anatomic variations in each collateral vessel. The application of the Hisense CAS system significantly improved the number of LNs dissected and the discovery rate of LN metastases without increasing the incidence of complications.

Exosomes as critical mediators of cell-to-cell communication in cancer pathogenesis and their potential clinical application.

Exosomes are small membrane vesicles that measure 20 to 100 nm in diameter and are released by many cell types, including lymphocytes, dendritic cells (DCs) and tumor cells. As efficient messengers in cell-to-cell communication, exosomes released by tumors play an important role in regulating tumor malignancy. Tumor-derived exosomes contain proteins, mRNAs, and miRNAs, which can be delivered between different types of cells and even transferred to distant locations to influence the biological activities of tumors, such as proliferation, invasion and metastasis, immunoregulation, generation of a premetastatic niche and stimulation of angiogenesis. This review highlights advances in the understanding of exosome secretion and the role of exosomes in cancer molecular behavior. Moreover, we also discuss the potential clinical application of exosomes as biomarkers and therapeutic tools. Tumor-derived exosomes may represent a target for therapeutic intervention and for the development of early diagnostic biomarkers.

The human natural killer-1 (HNK-1) glycan mimetic ursolic acid promotes functional recovery after spinal cord injury in mouse.

Human natural killer-1 (HNK-1) cell antigen is a glycan epitope involved in several neural events, such as neuritogenesis, myelination, synaptic plasticity and regeneration of the nervous system after injury. We have recently identified the small organic compound ursolic acid (UA) as a HNK-1 mimetic with the aim to test its therapeutic potential in the central nervous system. UA, a plant-derived pentacyclic triterpenoid, is well known for its multiple biological functions, including neuroprotective, antioxidant and anti-inflammatory activities. In the present study, we evaluated its functions in a mouse model of spinal cord injury (SCI) and explored the molecular mechanisms underlying its positive effects. Oral administration of UA to mice 1 h after SCI and thereafter once daily for 6 weeks enhanced the regaining of motor functions and axonal regrowth, and decreased astrogliosis. UA administration decreased levels of proinflammatory markers, including interleukin-6 and tumor necrosis factor-α, in the injured spinal cord at the acute phase of inflammation and activated the mitogen-activated protein kinase and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathways in the injured spinal cord. Taken together, these results suggest that UA may be a candidate for treatment of nervous system injuries.

The impact of grape seed extract treatment on blood pressure changes: A meta-analysis of 16 randomized controlled trials.

BACKGROUNDS AND OBJECTIVE: Several clinical trials have shown that grape seed extract can reduce blood pressure, but the results are often irreproducible. We therefore sought to systematically evaluate the impact of grape seed extract treatment on the changes of systolic/diastolic blood pressure (SBP/DBP) by meta-analyzing available randomized controlled trials. METHODS: Trial selection and data extraction were completed independently by 2 investigators. Effect-size estimates were expressed as weighted mean difference (WMD) and 95% confidence interval (CI). RESULTS: Twelve articles involving 16 clinical trials and 810 study subjects were analyzed. Overall analyses found significant reductions for SBP (WMD = -6.077; 95% CI: -10.736 to -1.419; P = 0.011) and DBP (WMD = -2.803; 95% CI: -4.417 to -1.189; P = 0.001) after grape seed extract treatment. In subgroup analyses, there were significant reductions in younger subjects (mean age < 50 years) for SBP (WMD = -6.049; 95% CI: -10.223 to -1.875; P = 0.005) and DBP (WMD = -3.116; 95% CI: -4.773 to -1.459; P < 0.001), in obese subjects (mean body mass index ≥ 25 kg/m) for SBP (WMD = -4.469; 95% CI: -6.628 to -2.310; P < 0.001), and in patients with metabolic syndrome for SBP (WMD = -8.487; 95% CI: -11.869 to -5.106; P < 0.001). Further meta-regression analyses showed that age, body mass index, and baseline blood pressure were negatively associated with the significant reductions of SBP and DBP after treatment. There was no indication of publication bias. CONCLUSION: Our findings demonstrate that grape seed extract exerted a beneficial impact on blood pressure, and this impact was more obvious in younger or obese subjects, as well as in patients with metabolic disorders. In view of the small sample size involved, we agree that confirmation of our findings in a large-scale, long-term, multiple-dose randomized controlled trial, especially among hypertensive patients is warranted.

Activation of NF-B upregulates Snail and consequent repression of E-cadherin in cholangiocarcinoma cell invasion.

BACKGROUND/AIMS: A wide variety of evidence has pointed to a critical role of transcriptional nuclear factor Kappa B (NF-kappaB) in tumour migration and invasion,but the mechanisms involved are not clear.In the present study, we reported that activation of NF-kappaB promotes migration and invasion in cholangiocarcinoma cell through upregulating Snail and consequent repression of E-cadherin. METHODOLOGY: We examined the expression of the NF-kappaB subunit P65 (NF-kappaBP65) after being treated by tumour necrosis factor (TNF)-a, a strong NF-kappaB activator or PDTC, a specific NF-kappaB inhibitor. Snail and E-cadherin in cholangiocarcinoma cell lines QBC939 and FRH 0201 was examined by Western blotting and RT-PCR. To confirm the involvement of NF-kappaB in snail activation, small interfering RNA (siRNA) specific for snail was used to suppress the expression of Snail, then the Snail siRNA- transfected cells were treated by TNF-a,and the migration and invasion was assayed. RESULTS: The results showed that Snail activation and consequent repression of E-cadherin may depend on NF-kappaB activation, and NF-KB promotes migration and invasion by upregulating Snail and consequent repression of E-cadherin in cholangiocarcinoma cell. CONCLUSIONS: NF-kappaB-Snail-E-cadherin signal is a potential target for antimetastatic therapeutics in cholangiocarcinoma.

Clinicopathologic significance of slug expression in human intrahepatic cholangiocarcinoma.

AIM: To explore the expression and function of slug, a transcriptional repressor, in human intrahepatic cholangiocarcinoma (IHCC) and identify its role in IHCC progression. METHODS: Expression of slug was detected in 36 cases of IHCC and 12 cases of normal intrahepatic bile ducts and liver parenchyma by immunohistochemistry. The patients were divided into low slug expression group (< 20% of carcinoma cells stained) and high slug expression group (> or = 20% of carcinoma cells stained). Slug expression was correlated with clinicopathological parameters of IHCC patients. The patients were defined as short-term survivors if their survival time was < 12 mo and as long-term survivors if their survival time was > or = 12 mo. RESULTS: Slug was not expressed in normal liver epithelium samples, lowly expressed in 15 tissue samples (10 -, 5 +) and highly expressed in 21 tissue samples (16 ++; 5 +++) from IHCC patients. The survival rate of patients with a low slug expression was 33.3% (n = 5) and 66.7% (n = 10), respectively. The survival rate of patients with a high slug expression was 61.9% (n = 13) and 38.1% (n = 8), respectively (P = 0.02). Lymph node metastasis was found in 4 (26.7%) out of the 15 patients with a low slug expression and in 14 (66.7%) out of the 21 patients with a high slug expression, respectively. The incidence rate of lymph node metastasis increased with the increasing slug expression level (P = 0.003), and higher in patients with a high slug expression than in those with a low slug expression. Slug expression did not significantly correlate with the tumor size and stage or histologic grade, or with the gender and age of patients CONCLUSION: Slug expression is a novel prognostic marker for IHCC with lymph node metastasis.