Intestinal mRNA expression profiles associated with mucosal healing in ustekinumab-treated Crohn's disease patients: bioinformatics analysis and prospective cohort validation.

BACKGROUND: Variations exist in the response of patients with Crohn's disease (CD) to ustekinumab (UST) treatment, but the underlying cause remains unknown. Our objective was to investigate the involvement of immune cells and identify potential biomarkers that could predict the response to interleukin (IL) 12/23 inhibitors in patients with CD. METHODS: The GSE207022 dataset, which consisted of 54 non-responders and 9 responders to UST in a CD cohort, was analyzed. Differentially expressed genes (DEGs) were identified and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Least absolute shrinkage and selection operator (LASSO) regression was used to screen the most powerful hub genes. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive performances of these genes. Single-sample Gene Set Enrichment Analysis (ssGSEA) was used to estimate the proportions of immune cell types. These significantly altered genes were subjected to cluster analysis into immune cell-related infiltration. To validate the reliability of the candidates, patients prescribed UST as a first-line biologic in a prospective cohort were included as an independent validation dataset. RESULTS: A total of 99 DEGs were identified in the integrated dataset. GO and KEGG analyses revealed significant enrichment of immune response pathways in patients with CD. Thirteen genes (SOCS3, CD55, KDM5D, IGFBP5, LCN2, SLC15A1, XPNPEP2, HLA-DQA2, HMGCS2, DDX3Y, ITGB2, CDKN2B and HLA-DQA1), which were primarily associated with the response versus nonresponse patients, were identified and included in the LASSO analysis. These genes accurately predicted treatment response, with an area under the curve (AUC) of 0.938. T helper cell type 1 (Th1) cell polarization was comparatively strong in nonresponse individuals. Positive connections were observed between Th1 cells and the LCN2 and KDM5D genes. Furthermore, we employed an independent validation dataset and early experimental verification to validate the LCN2 and KDM5D genes as effective predictive markers. CONCLUSIONS: Th1 cell polarization is an important cause of nonresponse to UST therapy in patients with CD. LCN2 and KDM5D can be used as predictive markers to effectively identify nonresponse patients. TRIAL REGISTRATION: Trial registration number: NCT05542459; Date of registration: 2022-09-14; URL: https://www. CLINICALTRIALS: gov .

The Significance of Combined OSTA, HU Value and VBQ Score in Osteoporosis Screening Before Spinal Surgery.

OBJECTIVE: This study aimed to assess the utility of a combined assessment using the Osteoporosis Self-Assessment Tool for Asians (OSTA), Hounsfield unit (HU) value, and vertebral bone quality (VBQ) score for preoperative osteoporosis (OP) screening in patients scheduled for spinal surgery. METHODS: This study encompassed 288 participants, including 128 males and 160 females. Patients were stratified into 2 groups: the OP group (T-score ≤ -2.5) and the non-OP group (T-score > -2.5), determined by dual-energy X-ray absorptiometry (DEXA). Binary logistic regression was used to construct a combined diagnostic model, and the receiver operating characteristic (ROC) curve evaluated the sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) of these metrics individually or in combination to screen for OP. RESULTS: Osteoporosis patients exhibited significantly lower OSTA and HU values in comparison to non-OP patients, while their VBQ scores were significantly higher (P < 0.001). The ROC curve analysis results indicated that within the male group, the combined diagnosis had a sensitivity of 93.8%, specificity of 82.3%, accuracy of 85.2%, PPV of 63.8%, and NPV of 97.5%. In the female group, the combined diagnosis had a sensitivity of 93.9%, specificity of 87.4%, accuracy of 90.0%, PPV of 83.6%, and NPV of 95.4%. CONCLUSIONS: The combined use of OSTA, HU values, and VBQ scores in preoperative OP screening for spinal surgery demonstrates significantly higher accuracy and superior screening value compared to individual assessments. These results establish a robust scientific foundation for conducting preoperative OP screening in patients undergoing spinal surgery.

Transcriptome and metabolomics analysis of adaptive mechanism of Chinese mitten crab (Eriocheir sinensis) to aflatoxin B1.

Aflatoxin B1 (AFB1), with the strong toxicity and carcinogenicity, has been reported to great toxicity to the liver and other organs of animals. It cause huge economic losses to breeding industry, including the aquaculture industry. Chinese mitten crabs (Eriocheir sinensis), as one of important species of freshwater aquaculture in China, are deeply disturbed by it. However, the molecular and metabolic mechanisms of hepatopancreas and ovary in crabs underlying coping ability are still unclear. Hence, we conducted targeted injection experiment with or without AFB1, and comprehensively analyzed transcriptome and metabolomics of hepatopancreas and ovary. As a result, 210 and 250 DEGs were identified in the L-C vs. L-30 m and L-C vs. L-60 m comparison, among which 14 common DEGs were related to six major functional categories, including antibacterial and detoxification, ATP energy reaction, redox reaction, nerve reaction, liver injury repair and immune reaction. A total of 228 and 401 DAMs in the ML-C vs. ML-30 m and ML-C vs. ML-60 m comparison both enriched 12 pathways, with clear functions of cutin, suberine and wax biosynthesis, tyrosine metabolism, purine metabolism, nucleotide metabolism, glycine, serine and threonine metabolism, ABC transporters and tryptophan metabolism. Integrated analysis of metabolomics and transcriptome in hepatopancreas discovered three Co-enriched pathways, including steroid biosynthesis, glycine, serine and threonine metabolism, and sphingolipid metabolism. In summary, the expression levels and functions of related genes and metabolites reveal the regulatory mechanism of Chinese mitten crab (Eriocheir sinensis) adaptability to the Aflatoxin B1, and the findings contribute to a new perspective for understanding Aflatoxin B1 and provide some ideas for dealing with it.

Comparative effectiveness of ustekinumab vs. vedolizumab for anti-TNF-naïve or anti-TNF-exposed Crohn's disease: a multicenter cohort study.

Background: Ustekinumab and vedolizumab are both effective for treating Crohn's disease (CD). However, no head-to-head trials have been conducted thus far. We aimed to compare the effectiveness of ustekinumab and vedolizumab in CD patients either naïve or exposed to tumor necrosis factor-alpha inhibitors (TNFi). Methods: Patients treated with vedolizumab or ustekinumab for luminal CD were included from six centers in China from May 2020 to July 2023. Steroid-free remission, clinical remission, objective response, and remission at Weeks 26 and 52 were evaluated in a retrospective multicenter propensity score-weighted cohort. Findings: A total of 536 patients were included (386 ustekinumab, and 150 vedolizumab). After adjustment, ustekinumab showed higher rates of clinical remission (56.4% vs. 47.8%, P = 0.005), steroid-free remission (55.4% vs. 46.1%, P = 0.003), and objective response (67.8% vs. 42.7%, P < 0.001) than vedolizumab at Week 26. At Week 52, ustekinumab exhibited significantly higher rates of clinical remission (65.8% vs. 37.5%, P < 0.001), steroid-free remission (65.8% vs. 37.5%, P < 0.001), objective response (66.7% vs. 23.8%, P < 0.001), and objective remission (31.4% vs. 12.7%, P < 0.001). Subgroup analyses revealed that ustekinumab had higher rates of clinical remission, steroid-free remission, and objective response at Weeks 26 and 52, and objective remission at Week 52 in TNFi-exposed patients, while ustekinumab showed higher rates of objective response at Weeks 26 and 52 and clinical remission, steroid-free remission and objective remission at Week 52 in TNFi-naïve patients. Adverse event rates were similar between the groups (4.9% ustekinumab vs. 6.7% vedolizumab, P = 0.423). Interpretation: Ustekinumab showed superior clinical and objective outcomes compared to vedolizumab, with comparable safety outcomes. The therapeutic superiority was observed in both short-term and long-term phases in TNFi-exposed patients, and the long-term phase in TNFi-naïve patients. Funding: National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research Foundation, Key Research Projects of the Sixth Affiliated Hospital, Sun Yat-sen University, the program of Guangdong Provincial Clinical Research Center for Digestive Diseases, and National Key Clinical Discipline.

Association of preoperative hypoprotein malnutrition with spinal postoperative complications and other conditions: A systematic review and meta-analysis.

BACKGROUND: Postoperative complications of spinal surgery are a common clinical problem, which impose significant economic and clinical burdens on patients and medical staff. Previous studies have suggested a close relationship between low-protein malnutrition and postoperative complications of surgery. However, the relationship between preoperative malnutrition and various orthopedic postoperative complications remains unclear. PURPOSE: To investigate the association between protein malnutrition and postoperative complications and outcomes. METHODS: We conducted a systematic search of the PubMed, Embase, Cochrane Library, and Web of Science databases for published research articles between the database inception and February 28th, 2023, that evaluated the association between malnutrition and the risk of postoperative complications and death in spinal surgery patients. Malnutrition was defined as low pre-albumin and albumin levels before surgery. Two evaluators independently extracted study data and assessed the risk of bias in each study. Fixed- or random-effect models were used to calculate the pooled effect estimates. Funnel plots and Egger's tests were used to detect publication bias, and the Trim-and -Fill method was conducted to evaluate the impact of publication bias on the results. RESULTS: A total of 26 studies were included in this meta-analysis, comprising 17 retrospective cohort studies and 9 case-control studies. The study included more than 86,000 participants. Analysis of postoperative complications revealed that the overall incidence of malnutrition-related complications after surgery was 3.17 times higher (OR = 3.17, 95% CI 2.69-3.75, z = 13.57, P < 0.05). The incidence of surgical site infections was 2.08 times higher (OR = 2.08, 95% CI 1.66-2.62, z = 6.307, P < 0.05), and the incidence of postoperative urinary tract infections was 2.55 times higher (OR = 2.55, 95% CI 1.80-3.60, z = 5.30, P < 0.05). The incidence of postoperative sepsis was 3.31 times higher (OR = 3.31, 95% CI 2.31-4.75, z = 6.51, P < 0.05), and the incidence of postoperative pneumonia was 3.02 times higher (OR = 3.02, 95% CI 1.331-6.857, z = 2.64, P = 0.008 < 0.05). The incidence of postoperative cardiac complications was 4.24 times higher (OR = 4.24, 95% CI 2.45-7.35, z = 5.15, P < 0.05), and the incidence of postoperative renal complications was 4.04 times higher (OR = 4.04, 95% CI 2.06-7.93, z = 4.05, P < 0.05). The incidence of postoperative pulmonary complications was 2.38 times higher (OR = 2.38, 95% CI 1.46-3.87, z = 6.98, P < 0.05), while the incidence of postoperative thrombotic complications was 2.76 times higher (OR = 2.76, 95% CI 1.756-4.345, z = 4.40, P < 0.05). Furthermore, the incidence of transfusion during and after surgery was 1.33 times higher (OR = 1.33, 95% CI 1.13-1.56, z = 3.40, P = 0.001 < 0.05), the incidence of postoperative readmission was 1.67 times higher (OR = 1.67, 95% CI 1.24-2.27, z = 3.33, P = 0.001 < 0.05), and the risk of postoperative death was 6.01 times higher (OR = 6.01, 95% CI 4.51-8.01, z = 12.27, P < 0.05). After conducting a publication bias test and Trim-and -Fill method analysis, we found no evidence of publication bias, and the results remained stable. CONCLUSION: Preoperative low protein malnutrition is closely related to the incidence of postoperative complications and postoperative status. More prospective multicenter studies should be conducted to validate this conclusion. Furthermore, more effective assessment and intervention of preoperative nutritional status should be carried out to prevent the occurrence of postoperative complications and mortality risk.

Balloon-assisted enteroscopy-based endoscopic stricturotomy for deep small bowel strictures from Crohn's disease: First cohort study of a novel approach.

BACKGROUND: There is little data on the role of endoscopic stricturotomy (ES) in treating deep small bowel strictures. We aimed to investigate the efficacy and safety of balloon-assisted enteroscopy-based ES (BAE-based ES) for deep small bowel strictures associated with Crohn's disease (CD). METHODS: This multicentre retrospective cohort study included consecutive patients with CD-associated deep small bowel strictures treated with BAE-based ES between 2017 and 2023. The outcomes included technical success, clinical improvement, surgery-free rate, reintervention-free rate, and adverse events. RESULTS: Twenty-eight patients with CD underwent 58 BAE-based ES procedures for non-passable deep small bowel strictures, with a median follow-up time of 519.5 days (interquartile range, 306-728 days). Fifty-six (96.0%) procedures were technically successful in 26 (92.9%) patients. Twenty patients (71.4%) showed clinical improvement at week 8. The cumulative surgery-free rate at 1 year was 74.8% (95% confidence interval [CI], 60.3-92.9%). A higher body mass index was associated with a decreased need for surgery (hazard ratio = 0.084, 95% CI, 0.016-0.45, P = 0.0036). Postprocedural adverse events (bleeding and perforation) requiring reintervention occurred in 3.4% of the procedures. CONCLUSIONS: The novel BAE-based ES provides high technical success, favorable efficacy, and safety in CD-associated deep small bowel strictures, which may provide an alternative for endoscopic balloon dilation and surgery.

Microplastics in canned, salt-dried, and instant sea cucumbers sold for human consumption.

Determining the amount of microplastics (MPs) in food is key to clarifying their potential toxicity to humans. Here, we collected canned, instant, and salt-dried sea cucumbers Apostichopus japonicus, the most valued sea cucumbers, from Chinese markets to determine their content of MPs. Sea cucumbers contained MPs in the range of 0-4 MP individual-1, an average of 1.44 MP individual-1, and 0.081 MP g-1. Accordingly, consuming 3 g of sea cucumbers could result in an exposure risk of an average of 0.51 MPs, 0.135 MPs, and 0.078 MPs day-1 for canned, instant, and salt-dried sea cucumbers, respectively. MPs were in size range of 12-575 µm, and fibrous shape was dominant. Furthermore, among the five polymers identified, polypropylene showed the highest energy binding with two catalysts engaged in organic chemical oxidation. This study extends the knowledge regarding MPs occurrence in food and provides a theoretical basis for MPs toxicity in humans.

Comparative study of pelvic sarcoma patients undergoing internal and external hemipelvectomy: A meta-analysis study.

Introduction: Malignant and giant pelvic tumors are complex and rare, and hemipelvectomies are complex procedures performed for this malignant lesion. Only a few studies had been conducted on the survival and recurrence of pelvic sarcomas patients undergoing internal or external hemipelvectomy. In the present study, we compared internal with external hemipelvectomy in pelvic sarcomas on clinical outcomes by a meta-analysis. Methods: The survival and recurrence rates of pelvic sarcomas patients were collected from research reports from CNKI, MEDLINE, EMBASE, the Cochrane Database, and Google Scholar until April 2022. The quality of included articles was evaluated by two independent reviewers. Differences between patients undergoing internal and external hemipelvectomy were analyzed based on postoperative survival and recurrence rates. Results: Five articles were included according to selection criteria. There were 183 patients in total from these studies. Our results showed that there was no significant difference between limb salvage surgery and amputation according to survival; however, patients with internal hemipelvectomy had a lower recurrence rate. Conclusions: Internal hemipelvectomy results in a lower recurrence rate and similar survival rate, while not increasing the risk of metastasis and complications. This study provided more pieces of evidence to support internal hemipelvectomy as a favorable treatment of pelvic sarcomas.

The effect of 2,2',4,4'-Tetrabromodiphenyl ether (BDE-47) on locomotor behaviour and muscle physiology of the sea cucumber Apostichopus japonicus.

The 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) is the predominant congener of polybrominated diphenyl ethers, and it is also a persistent organic pollutant that with a higher detection rate in samples from environment and animals. To date, there have been few studies of the effects of BDE-47 on locomotion in sea cucumbers. In this study, we investigated the influence of different concentrations of BDE-47 (low: 0.1 µg/L; moderate: 1.0 µg/L; high: 10.0 µg/L) on locomotion of Apostichopus japonicus and evaluated changes in their muscle physiology using ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry. The behavioural studies showed that the average and maximum velocity of movement decreased significantly in both the moderate and high BDE-47 groups after 1 day of exposure. In addition, levels of 55 metabolites were identified and characterized in the longitudinal muscle of A. japonicus exposed to BDE-47. The alteration of taurine and norepinephrine levels indicated that BDE-47 had drastic physiological effects on the longitudinal muscle of A. japonicus.

Upconverting nanoparticles based nanodevice for DNAzymes amplified miRNAs detection and artificially controlled chemo-gene therapy.

Despite the great promise of cancer theranostic platforms, accurate diagnosis and effective treatment are still highly challenging. In this work, nanodevice for intracellular miRNAs detection and artificially controlled drug releasement was developed based on upconverting nanoparticles (UCNPs). For analysis aspect, DNAzymes amplified miRNA-21 detection was carried out, giving excellent sensitivity with detection limits of 1.8 × 10-11 M. Moreover, intracellular fluorescence imaging permitted in situ diagnoses of miRNA-21 expression in living cells. Once the test identifies tumor markers, treatment can be performed. Here, artificially controlled chemo-gene synergetic therapy nanodevice was obtained by integrating UCNPs with photocleavable linkers (PC-linkers). In vitro and in vivo experiments verified the potential application of prepared nanodevice in cancer theranostics.

3D Customized Biological Tibial Intramedullary Nail Fixation for the Treatment of Fracture after Massive Allograft Bone Transplantation of Tibial Osteosarcoma: A Case Report.

Allograft bone fractures are critical complications in massive allograft bone transplantations. There are limited studies available on the application of 3D printing for massive allograft bone transplantation complications, and no related reports on the treatment of an allograft bone fracture with a complete biological intramedullary nail. A complex case of allograft bone fracture after massive bone transplantation for a right tibial osteosarcoma was treated with fixation of an individualized 3D printed biological tibial intramedullary nail. Prior to the operation, the intramedullary nail was designed and printed based on the results of computed tomography examination of the affected limb, and the surface of the intramedullary nail was treated with a hydroxyapatite coating. Intraoperatively, the intramedullary nail was implanted according to the preoperative 3D design plan. The intraoperative and postoperative examinations showed that the 3D printed intramedullary nail achieved good matching between the implant and the medullary cavity, and the biological coating integrated well with surrounding bone. The follow-up results 44 months postoperatively showed that the patient was satisfied with the surgical results, where his ankle function met his daily needs, and the Musculoskeletal Tumor Society score was 24. 3D printing tibial intramedullary nail fixation can be successful in the treatment of allograft bone fractures and should be considered as a treatment of choice. In this case, the intramedullary nail matched the surrounding bone well, had good osseointegration, and the patient regained basic function.

Clinical Outcome and Fracture Risk Prediction of Benign Bone Tumors on the Acetabular Dome: 7-Year Clinical Experience and a Finite Element Analysis.

The treatment of benign pelvic lesions and tumors is still a challenge in clinical orthopedics. The surgical procedure was complicated and the postoperative complication was hard to avoid usually. The purpose of this study is to analyze the clinical outcome and predict the fracture risk of benign bone tumors on acetabular dome by finite element analysis. In our research, clinical data of 25 patients were collected from January 2010 to January 2017, including basic information of patients, reconstruction methods, complications, and postoperative MSTS function scores. Finite element analysis (FEA) was used to predict the fracture risk when a benign tumor involved an acetabular dome. 25 patients were followed up for 37.5 ± 5.6 (ranging from 24 to 78) months. Intraoperative bleeding was 100-3000 ml (mean 858.3 ml). The postoperative MSTS93 score was 19.61 ± 7.32 before operation and 26.28 ± 15.59 at the last follow-up. The results of finite element analysis suggest that there was a high risk for pathological fracture in the following: both columns were damaged by tumors; the anterior column and 50% of the posterior column were affected. Other cases were in the low fracture risk group. Based on this study, we believe that, according to the risk assessment results of tumor cavity fracture suggested by the FEA results, combined with the nature of tumor, it may become a useful tool which is a great significance to guide the operation plan, select the operation time, and guide the postoperative functional exercise.

Systematic review with meta-analysis: loss of response and requirement of ustekinumab dose escalation in inflammatory bowel diseases.

BACKGROUND: Ustekinumab is effective in treating Crohn's disease (CD) and ulcerative colitis (UC). However, the loss of response (LOR) to ustekinumab and the efficacy of dose escalation have not been systematically explored. METHODS: Databases were searched for eligible studies from inception through July 2021. Summary estimates were pooled, and subgroup analyses were performed to explore heterogeneity. RESULTS: We included 14 studies (CD: 13; UC: 1). In CD patients, the annual risk of LOR to ustekinumab and dose escalation among primary responders was 21% (95% confidence interval [CI] 12-31%, 1530 person-years, n = 9) per person-year and 25% (95% CI 12-32%, 657 person-years, n = 5) per person-year respectively. Clinical response was regained in 58% (95% CI 49-67%, 279 patients, n = 8) of secondary non-responders after dose escalation (interval reduction or intravenous reinduction). In UC patients, no studies provided data on LOR, but only one study showed that 35% (100/284) of patients underwent dose escalation (or sham dose adjustment), leading to an annual risk of dose escalation of 18% per person-year. After dose escalation, 58% (14/24) of the patients regained symptomatic remission. CONCLUSIONS: Primary responders with CD experienced LOR to ustekinumab at a risk of 21% per person-year and required dose escalation at a risk of 25% per person-year. Fifty-eight per cent of secondary non-responders with CD may benefit from dose escalation. LOR has not been well characterized in patients with UC.

Systematic review with meta-analysis of partial enteral nutrition for the maintenance of remission in Crohn's disease.

Although enteral nutrition (EN) is effective for induction therapy in Crohn's disease (CD), it remains unclear whether partial enteral nutrition (PEN), i.e., EN, along with a daily diet, is effective for maintenance therapy in CD. It was hypothesized that PEN would be effective as a maintenance therapy in CD. This meta-analysis aimed to evaluate the efficacy and safety of PEN for maintenance therapy in CD. PubMed, EMBASE, Web of Science, and Cochrane Library were searched up to January 2019 for eligible prospective controlled trials, and then a meta-analysis was conducted. The primary outcome was clinical relapse, as defined in the primary studies. Eight studies with 429 patients were included in the meta-analysis. The rate of clinical relapse at 0.5 to 2 years was significantly lower in patients receiving PEN (420-1800 kcal/d) than in those not receiving nutrition therapy (RR: 0.67, 95% CI: 0.54-0.82, P < .01; number needed to treat = 5, P < .01). Patients receiving PEN exhibited a higher frequency of clinical remission maintenance at 0.5 to 1 year (67%) than did those not receiving nutrition therapy (48%; RR: 1.32, 95% CI: 1.07-1.64, P = .01). The total adverse event rate was comparable in the two groups (RR: 3.60, 95% CI: 0.70-18.66, P = .13). PEN may be more effective than the absence of EN therapy for the maintenance of remission in CD with a good safety profile.

Plasticity of Respiratory Function Accommodates High Oxygen Demand in Breeding Sea Cucumbers.

Physiological plasticity allows animals to adjust their physiological function to abiotic and biotic variations. It has been mostly studied in the context of response to external factors and not much is known on how animals adjust their physiology to cope with variations in internal conditions. The process of reproduction implies gonadal maturation and other internal changes, bringing various challenges to the animal such as an increased demand for energy and oxygen. Here, the capacity of the sea cucumber, Apostichopus japonicus to adjust its respiratory function and physiological mechanisms during reproduction was studied using a time-lapse videography and metabolomics approach. The results showed that reproduction caused a significant increase in oxygen consumption in A. japonicus. Interestingly, breeding sea cucumbers can accommodate the high oxygen demand by accelerating respiratory rate. However, to maintain a necessary high level of respiratory activity during reproduction, sea cucumbers need consume large amounts of adenosine triphosphate (ATP). In addition, the metabolomic data suggests that oxidative stress and hormone regulation are the physiological mechanisms linking reproduction and respiratory function. Altogether, these findings suggest that plasticity of respiratory function is an effective tactic to cope with high oxygen demand during reproduction.

MiR-155 inhibition alleviates suppression of osteoblastic differentiation by high glucose and free fatty acids in human bone marrow stromal cells by upregulating SIRT1.

Diabetic osteoporosis is a severe and chronic complication of diabetes in the bone and joint system, and its pathogenesis is needed to be explored. In the present study, we examined the effect and underlying mechanism of miR-155 on osteogenic differentiation in human bone marrow-derived mesenchymal stem cells (hBMSCs) under high glucose and free fatty acids (HG-FFA) conditions. It was shown that miR-155 levels in hBMSCs increased corresponding to the time of exposure to HG-FFA treatment. MiR-155 expression was altered by transfecting miR-155 mimic or miR-155 inhibitor. HG-FFA exposure resulted in an obviously decrease in cell viability and alkaline phosphatase (ALP) activity, and downregulated the expressionof runt-related transcription factor 2 (Runx2) and osteocalcin (OCN) in hBMSCs. Transfection of miR-155 mimic further exacerbated HG-FFA-induced inhibitory effect on osteogenic differentiation, and miR-155 inhibitor neutralized this inhibitory effect. Luciferase assays confirmed that SIRT1 was a direct target of miR-155 and can be negatively modulated by miR-155. Furthermore, SIRT1 siRNA partially counteracted miR-155 inhibitor-induced upregulation of SIRT1in HG-FFA-treated hBMSCs. SIRT1 siRNA also reversed the promotional effect of the miR-155 inhibitor on ALP activity and expression of the Runx2 and OCN proteins under HG-FFA conditions. In conclusion, the results suggest that miR-155 suppression promoted osteogenic differentiation of hBMSCs under HG-FFA conditions by targeting SIRT1. Inhibition of MiR-155 may provide a new therapeutic method for the prevention and treatment of diabetic osteoporosis.

Strontium modulates osteogenic activity of bone cement composed of bioactive borosilicate glass particles by activating Wnt/ß-catenin signaling pathway.

There is a need for synthetic grafts to reconstruct large bone defects using minimal invasive surgery. Our previous study showed that incorporation of Sr into bioactive borate glass cement enhanced the osteogenic capacity in vivo. However, the amount of Sr in the cement to provide an optimal combination of physicochemical properties and capacity to stimulate bone regeneration and the underlying molecular mechanism of this stimulation is yet to be determined. In this study, bone cements composed of bioactive borosilicate glass particles substituted with varying amounts of Sr (0 mol% to 12 mol% SrO) were created and evaluated in vitro and in vivo. The setting time of the cement increased with Sr substitution of the glass. Upon immersion in PBS, the cement degraded and converted more slowly to HA (hydroxyapatite) with increasing Sr substitution. The released Sr2+ modulated the proliferation, differentiation, and mineralization of hBMSCs (human bone marrow mesenchymal stem cells) in vitro. Osteogenic characteristics were optimally enhanced with cement (designated BG6Sr) composed of particles substituted with 6mol% SrO. When implanted in rabbit femoral condyle defects, BG6Sr cement supported better peri-implant bone formation and bone-implant contact, comparing to cements substituted with 0mol% or 9mol% SrO. The underlying mechanism is involved in the activation of Wnt/ß-catenin signaling pathway in osteogenic differentiation of hBMSCs. These results indicate that BG6Sr cement has a promising combination of physicochemical properties and biological performance for minimally invasive healing of bone defects.

Human induced pluripotent stem cell-derived mesenchymal stem cells promote healing via TNF-α-stimulated gene-6 in inflammatory bowel disease models.

Therapeutic applications of tissue-derived mesenchymal stem cells (MSCs) are hindered by their limited expansion ability and variation across donors. Human induced pluripotent stem cell (iPSC)-derived MSCs show greater expandability and therefore offer potential for use in tissue repair therapies. Here we explored the regenerative effects of iPSC-MSCs and the mechanisms by which iPSC-MSCs promote mucosal healing via tumor necrosis factor-α-stimulated gene 6 (TSG-6) in mouse models of inflammatory bowel disease (IBD). Human iPSCs were induced to differentiate into MSCs following a clinically compliant protocol. The iPSC-MSC treatment promoted mucosal healing in colitic mice, accompanied by increased epithelial cell proliferation, CD44-positive cells, and Lgr5-positive cells. TSG-6 knockdown in iPSC-MSCs or blocking of hyaluronan-CD44 interactions by PEP-1 abrogated the therapeutic effects of iPSC-MSCs, whereas use of recombinant TSG-6 showed therapeutic effects similar to those of iPSC-MSCs. A mouse or patient-derived organoid culture system was developed. Organoids co-cultured with iPSC-MSCs showed increased epithelial cell proliferation, CD44-positive cells, and Lgr5-positive cells, which was abolished by TSG-6 knockdown. TSG-6-induced promoting effects in organoids were dependent on Akt activation and abrogated by the anti-CD44 antibody or MK2206. In conclusion, iPSC-MSCs promoted epithelial cell proliferation to accelerate mucosal healing in a murine colitis model via TSG-6 through hyaluronan-CD44 interactions in an Akt-dependent manner, demonstrating a patient-specific "off-the-shelf" format for IBD treatment.

The Effect of Melatonin on Locomotor Behavior and Muscle Physiology in the Sea Cucumber Apostichopus japonicus.

Melatonin is a highly conserved hormone in evolutionary history. It occurs in numerous organisms and plays a role in the endocrine and immune systems. Locomotor behavior is a basic behavior in animals and is an important indicator of circadian rhythms, which are coordinated by the nervous and endocrine systems. To date, the effect of melatonin on locomotor behavior has been studied in vertebrates, including syrian hamsters, sparrows, rats, zebrafish, goldfish, and flatworms. However, there have been few studies of the effects of melatonin on locomotor behavior in marine invertebrates. The goals of present study were to show the existence of melatonin in the sea cucumber Apostichopus japonicus and to evaluate its effect on locomotor activity. In addition, muscle tissues from control and melatonin-treated sea cucumbers were tested using ultra performance liquid chromatography and quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) to determine the changes of metabolic activity in muscle. Melatonin was present in the coelomic fluid of A. japonicus at a concentration of ∼135.0 ng/L. The total distance traveled and number steps taken over 9 h after melatonin administration decreased with increasing concentration of the melatonin dose. Mean and maximum velocity of movement and stride length and stride frequency also decreased, but their differences were not statistically significant. Overall, these results suggest that melatonin administration had a sedative effect on A. japonicus. The levels of 22 different metabolites were altered in the muscle tissues of melatonin-treated sea cucumbers. Serotonin, 9-cis retinoic acid, all-trans retinoic acid, flavin mononucleotide in muscles were downregulated after melatonin administration. Moreover, a high free fatty acid (FFA) concentration and a decrease in the adenosine 5'-triphosphate (ATP) concentration in the muscle tissues of the melatonin-treated group were detected as well. These results suggest that the sedative effect of melatonin involves some other metabolic pathways, and the reduced locomotor modulator-serotonin, inhibited fatty acid oxidation and disturbed oxidative phosphorylation are potential physiological mechanisms that result in the inhibitory effect of melatonin on locomotion in sea cucumbers.

De Novo assembly and comparative transcriptome analyses of purple and green morphs of Apostichopus japonicus during body wall pigmentation process.

Pigmentation processes provide a traceable and relevant trait for understanding key issues in evolutionary biology such as adaptation, speciation and the maintenance of balanced polymorphisms. The sea cucumber Apostichopus japonicus, which has nutritive and medical properties, is considered the most valuable commercial species in many parts of Asia. Compared with the green morph, the purple morph is rare and has great appeal to consumers. However, little is currently known about the molecular mechanism of body color formation in A. japonicus, even in echinoderm. Here, we employ illumina sequencing to examine expression patterns of the gene network underlying body wall development in purple and green morphs of A. japonicus. Overall, the number of down-regulated genes in the green morph was significantly more than in the purple morph during the pigmentation stage. We observed dynamic expression patterns of a large number of pigment, regulation and growth genes from the "Melanogenesis", "Melanoma", "Wnt signaling pathway", "Notch signaling pathway", "epithelium development", "epidermal growth factor receptor binding","growth factor activity" and "growth", including contrasting expression patterns of these genes in green and purple morph. This study provides comprehensive lists of differentially expressed genes during body wall development in the green and purple morphs, revealing potential candidate genes that may be involved in regulating body color formation and polymorphism. These data will provide valuable information for future genetic studies on sea cucumbers elucidating the molecular mechanisms underlying pigmentation, and may support the culture of desirable color morphs.