Re-analysis of gene mutations found in pituitary stalk interruption syndrome and a new hypothesis on the etiology.

Background: Pituitary stalk interruption syndrome (PSIS) is a complex clinical syndrome characterized by varied pituitary hormone deficiencies, leading to severe manifestations across multiple systems. These include lifelong infertility, short stature, mental retardation, and potentially life-threatening pituitary crises if not promptly diagnosed and treated. Despite extensive research, the precise pathogenesis of PSIS remains unclear. Currently, there are two proposed theories regarding the pathogenic mechanisms: the genetic defect theory and the perinatal injury theory. Methods: We systematically searched English databases (PubMed, Web of Science, Embase) and Chinese databases (CNKI, WanFang Med Online, Sinomed) up to February 24, 2023, to summarize studies on gene sequencing in PSIS patients. Enrichment analyses of reported mutated genes were subsequently performed using the Metascape platform. Results: Our study included 37 articles. KEGG enrichment analysis revealed mutated genes were enriched in the Notch signaling pathway, Wnt signaling pathway, and Hedgehog signaling pathway. GO enrichment analysis demonstrated mutated genes were enriched in biological processes such as embryonic development, brain development, axon development and guidance, and development of other organs. Conclusion: Based on our summary and analyses, we propose a new hypothesis: disruptions in normal embryonic development, partially stemming from the genetic background and/or specific gene mutations in individuals, may increase the likelihood of abnormal fetal deliveries, where different degrees of traction during delivery may lead to different levels of pituitary stalk interruption and posterior lobe ectopia. The clinical diversity observed in PSIS patients may result from a combination of genetic background, specific mutations, and variable degrees of traction during delivery.

New insights into the influence of encapsulation materials on the feasibility of ultrasonic-assisted encapsulation of Mosla chinensis essential oil.

The study aimed to estimate the feasibility of α-cyclodextrin (α-CD), ß-cyclodextrin (ß-CD), and γ-cyclodextrin (γ-CD) to encapsulate Mosla chinensis essential oil (EO) by ultrasonic-assisted method. The physical properties variations, stabilization mechanisms, and formation processes of the inclusion complexes (ICs) were investigated using experimental methods, molecular docking, and molecular dynamics (MD) simulation. Scanning electron microscopy, fourier transform infrared spectroscopy, thermogravimetric analysis, and gas chromatography-mass spectrometry showed that the ICs were successfully prepared, which differentially improved the thermal stability and retained the chemical composition of EO. The dissolution profile showed that the Peppas model can be used to describe the diffuse release mechanism of EO. Finally, molecular docking and MD simulation theoretically confirmed the interaction and conformational changes of carvacrol (the main active component of Mosla chinensis EO) inside the cavity of CDs. The results indicate that hydrogen bonding was the primary driving force for the carvacrol spontaneous access to the cavity. Further, a binding dynamic balance occurs between carvacrol and ß-CD, whereas a bind and away dynamic balance occurs in the IC between carvacrol and α-CD, γ-CD. The comprehensive results show that the medium cavity size of ß-CD is a suitable host molecule for Mosla chinensis EO of encapsulation, release, and stabilization. A combination of experimental and theoretical calculations is useful for the pinpoint targeted design and optimization of CD molecular encapsulation of small entity molecules. ß-CD was rationally screened as a better candidate for stabilizing EO, which provides an option for a meaningful path to realistic EO applications.

Oral polyphenol-armored nanomedicine for targeted modulation of gut microbiota-brain interactions in colitis.

Developing oral nanomedicines that suppress intestinal inflammation while modulating gut microbiota and brain interactions is essential for effectively treating inflammatory bowel disease. Here, we report an oral polyphenol-armored nanomedicine based on tumor necrosis factor-α (TNF-α)-small interfering RNA and gallic acid-mediated graphene quantum dot (GAGQD)-encapsulated bovine serum albumin nanoparticle, with a chitosan and tannin acid (CHI/TA) multilayer. Referred to "armor," the CHI/TA multilayer resists the harsh environment of the gastrointestinal tract and adheres to inflamed colon sites in a targeted manner. TA provides antioxidative stress and prebiotic activities that modulate the diverse gut microbiota. Moreover, GAGQD protected TNF-α-siRNA delivery. Unexpectedly, the armored nanomedicine suppressed hyperactive immune responses and modulated bacterial gut microbiota homeostasis in a mouse model of acute colitis. Notably, the armored nanomedicine alleviated anxiety- and depression-like behaviors and cognitive impairment in mice with colitis. This armor strategy sheds light on the effect of oral nanomedicines on bacterial gut microbiome-brain interactions.

GDNF promotes the proliferation and osteogenic differentiation of jaw bone marrow mesenchymal stem cells via the Nr4a1/PI3K/Akt pathway.

How to efficiently regenerate jawbone defects caused by trauma, jaw osteomyelitis, tumors, or intrinsic genetic diseases is still challenging. Ectoderm-derived jawbone defect has been reported to be regenerated by selectively recruiting cells from its embryonic origin. Therefore, it is important to explore the strategy for promoting ectoderm-derived jaw bone marrow mesenchymal stem cells (JBMMSCs) on the repair of homoblastic jaw bone. Glial cell-derived neurotrophic factor (GDNF) is an important growth factor and is essential in the process of proliferation, migration and differentiation of nerve cells. However, whether GDNF promoting the function of JBMMSCs and the relative mechanism are not clear. Our results showed that activated astrocytes and GDNF were induced in the hippocampus after mandibular jaw defect. In addition, the expression of GDNF in the bone tissue around the injured area was also significantly increased after injury. Data from in vitro experiments demonstrated that GDNF could effectively promote the proliferation and osteogenic differentiation of JBMMSCs. Furthermore, when implanted in the defected jaw bone, JBMMSCs pretreated with GDNF exhibited enhanced repair effect compared with JBMMSCs without treatment. Mechanical studies found that GDNF induced the expression of Nr4a1 in JBMMSCs, activated PI3K/Akt signaling pathway and then enhanced the proliferation and osteogenic differentiation capacities of JBMMSCs. Our studies reveal that JBMMSCs are good candidates for repairing jawbone injury and pretreated with GDNF is an efficient strategy for enhancing bone regeneration.

Immunoenhancing Effects of Cyclina sinensis Pentadecapeptide through Modulation of Signaling Pathways in Mice with Cyclophosphamide-Induced Immunosuppression.

Our study aimed to investigate the immune-enhancing mechanism of the pentadecapeptide (RVAPEEHPVEGRYLV) from Cyclina sinensis (SCSP) in a cyclophosphamide (CTX)-induced murine model of immunosuppression. Our results showed that SCSP treatment significantly increased mouse body weight, immune organ indices, and the production of serum IL-6, IL-1ß, and tumor necrosis factor (TNF)-α in CTX-treated mice. In addition, SCSP treatment enhanced the proliferation of splenic lymphocytes and peritoneal macrophages, as well as phagocytosis of the latter in a dose-dependent manner. Moreover, SCSP elevated the phosphorylation levels of p38, ERK, JNK, PI3K and Akt, and up-regulated IKKα, IKKß, p50 NF-κB and p65 NF-κB protein levels, while down-regulating IκBα protein levels. Our results indicate that SCSP has immune-enhancing activities, and that it can activate the MAPK/NF-κB and PI3K/Akt pathways to enhance immunity in CTX-induced immunosuppressed mice.

Ectoderm-derived frontal bone mesenchymal stem cells promote traumatic brain injury recovery by alleviating neuroinflammation and glutamate excitotoxicity partially via FGF1.

BACKGROUND: Traumatic brain injury (TBI) leads to cell and tissue impairment, as well as functional deficits. Stem cells promote structural and functional recovery and thus are considered as a promising therapy for various nerve injuries. Here, we aimed to investigate the role of ectoderm-derived frontal bone mesenchymal stem cells (FbMSCs) in promoting cerebral repair and functional recovery in a murine TBI model. METHODS: A murine TBI model was established by injuring C57BL/6 N mice with moderate-controlled cortical impact to evaluate the extent of brain damage and behavioral deficits. Ectoderm-derived FbMSCs were isolated from the frontal bone and their characteristics were assessed using multiple differentiation assays, flow cytometry and microarray analysis. Brain repairment and functional recovery were analyzed at different days post-injury with or without FbMSC application. Behavioral tests were performed to assess learning and memory improvements. RNA sequencing analysis, immunofluorescence staining, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) were used to examine inflammation reaction and neural regeneration. In vitro co-culture analysis and quantification of glutamate transportation were carried out to explore the possible mechanism of neurogenesis and functional recovery promoted by FbMSCs. RESULTS: Ectoderm-derived FbMSCs showed fibroblast like morphology and osteogenic differentiation capacity. FbMSCs were CD105, CD29 positive and CD45, CD31 negative. Different from mesoderm-derived MSCs, FbMSCs expressed the ectoderm-specific transcription factor Tfap2ß. TBI mice showed impaired learning and memory deficits. Microglia and astrocyte activation, as well as neural damage, were significantly increased post-injury. FbMSC application ameliorated the behavioral deficits of TBI mice and promoted neural regeneration. RNA sequencing analysis showed that signal pathways related to inflammation decreased, whereas those related to neural activation increased. Immunofluorescence staining and qRT-PCR data revealed that microglial activation and astrocyte polarization to the A1 phenotype were suppressed by FbMSC application. In addition, FGF1 secreted from FbMSCs enhanced glutamate transportation by astrocytes and alleviated the cytotoxic effect of excessive glutamate on neurons. CONCLUSIONS: Ectoderm-derived FbMSC application significantly alleviated neuroinflammation, brain injury, and excitatory toxicity to neurons, improved cognition and behavioral deficits in TBI mice. Therefore, ectoderm-derived FbMSCs could be ideal therapeutic candidates for TBI which mostly affect cells from the same embryonic origins as FbMSCs.

Protective Effects of Cannabidiol on Chemotherapy-Induced Oral Mucositis via the Nrf2/Keap1/ARE Signaling Pathways.

Oral mucositis (OM) is a common complication during chemotherapy characterized by ulceration, mucosa atrophy, and necrosis, which seriously interferes with nutritional intake and oncotherapy procedures among patients. However, the efficacy of current treatments for OM remains limited. Cannabidiol (CBD) is a natural cannabinoid with multiple biological activities, including antioxidant and anti-inflammatory potential. In this study, we aimed to investigate the chemopreventive effects and mechanisms of CBD in protecting C57BL/6N mice and human oral keratinocytes (HOK) from 5-fluorouracil- (5-FU-) induced OM. Here, we found that CBD alleviated the severity of 5-FU-induced OM in mice, including improved survival, decreased body weight loss, reduced ulcer sizes, and improved clinical scores. Histologically, CBD restored epithelial thickness and normal structure in tongue tissues. Meanwhile, CBD attenuated reactive oxygen species (ROS) overproduction and improved the antioxidant response, suppressed the inflammatory response, promoted the proliferation of epithelial cells, and inhibited 5-FU-induced apoptosis. In vitro, consistent outcomes showed that CBD suppressed cellular ROS levels, enhanced antioxidant ability, reduced inflammatory response, promoted proliferation, and inhibited apoptosis in 5-FU-treated HOK cells. In particular, CBD upregulated the expression levels of antioxidant enzymes, heme oxygenase-1 (HO-1) and NAD(P)H quinine oxidoreductase 1 (NQO1), by increasing the expression and nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and decreasing Kelch-like ECH-associated protein 1 (Keap1). Notably, the Nrf2 inhibitor ML385 reversed the protective effect of CBD. Nrf2-siRNA transfection also significantly blunted the antioxidant effect of CBD in in vitro OM model. Collectively, our findings suggested that CBD protected against 5-FU-induced OM injury at least partially via the Nrf2/Keap1/ARE signaling pathways, highlighting the therapeutic prospects of CBD as a novel strategy for chemotherapy-induced OM.

Chitosan/zein films incorporated with essential oil nanoparticles and nanoemulsions: Similarities and differences.

The purpose of this study was to prepare chitosan/zein (CS/Zein) edible films reinforced with Mosla chinensis essential oils (EOs) nanoemulsions (NEs) and nanoparticles (NPs) in order to compare their properties. NEs and NPs containing EOs could be used to fabricate films with functional properties, and the films were prepared using a casting method. The influence of EO concentration and mixing methods on the physical, mechanical, and functional properties of the films was investigated. The results indicated that the films formulated with EO NEs generated favorable fundamental and functional characteristics with excellent mechanical properties, moisture barrier capacity, and significant antioxidant and antibacterial activity. In addition, the use of NEs-based films improved the release of bioactive compounds, and the mechanism of EO release was found to follow a first order model. In summary, EO NEs were more effective in preserving the fundamental and functional properties of CS/Zein nanocomposite edible films than NP-based films. These differences may reflect different forms and methods of dispersing EOs in NEs and NPs. This study demonstrated that NEs reinforced films could be used to enhance the effectiveness of EOs in food products and develop new strategies for their delivery and application.

Evaluation of Hydrophilic and Hydrophobic Silica Particles on the Release Kinetics of Essential Oil Pickering Emulsions.

Colloidal particle-stabilized emulsions have recently gained increasing interest as delivery systems for essential oils. Despite the use of silica particles in food and pharmaceutical applications, the formation and release of hydrophilic and hydrophobic silica particle-stabilized emulsions are still not well studied. Thus, in this study, the structures of hydrophilic (A200, A380, 244FP, and 3150) and hydrophobic (R202 and R106) silica were deeply characterized using the solid state, contact angle, and other properties that could affect the formation of emulsions. Following that, Mosla chinensis essential oil emulsions were stabilized with different types of silica, and their characteristics, particularly their release behavior, were studied. Fick's second law was used to investigate the mechanism of release. Additionally, six mathematical models were employed to assess the experimental data of release: zero-order, first-order, Higuchi, Hixson-Crowell, Peppas, and Page models. The release mechanism of essential oils demonstrated that diffusion was the dominant mechanism, and the fitting results for the release kinetics confirmed that the release profiles were governed by the Higuchi model. The contact angle and specific surface area were the key properties that affect the release of essential oils from emulsions. Hydrophilic A200 was found to be capable of delivering essential oils more efficiently, and silica particles could be extended to achieve the controlled release of bioactives. This study showed that understanding the impact of silica particles on the release behavior provided the basis for modulating and mapping material properties to optimize the performance of emulsion products.

Disruption of hematopoiesis attenuates the osteogenic differentiation capacity of bone marrow stromal cells.

BACKGROUND: The homeostasis of mesenchymal stem cells (MSCs) is modulated by both their own intracellular molecules and extracellular milieu signals. Hematopoiesis in the bone marrow is maintained by niche cells, including MSCs, and it is indispensable for life. The role of MSCs in maintaining hematopoietic homeostasis has been fully elucidated. However, little is known about the mechanism by which hematopoietic cells reciprocally regulate niche cells. The present study aimed to explore the close relationship between MSCs and hematopoietic cells, which may be exploited for the development of new therapeutic strategies for related diseases. METHODS: In this study, we isolated cells from the offspring of Tie2Cre + and Ptenflox/flox mice. After cell isolation and culture, we investigated the effect of hematopoietic cells on MSCs using various methods, including flow cytometry, adipogenic and osteogenic differentiation analyses, quantitative PCR, western bloting, and microCT analysis. RESULTS: Our results showed that when the phosphatase and tensin homolog deleted on chromosome 10 (Pten) gene was half-deleted in hematopoietic cells, hematopoiesis and osteogenesis were normal in young mice; the frequency of erythroid progenitor cells in the bone marrow gradually decreased and osteogenesis in the femoral epiphysis weakened as the mice grew. The heterozygous loss of Pten in hematopoietic cells leads to the attenuation of osteogenic differentiation and enhanced adipogenic differentiation of MSCs in vitro. Co-culture with normal hematopoietic cells rescued the abnormal differentiation of MSCs, and in contrast, MSCs co-cultured with heterozygous null Pten hematopoietic cells showed abnormal differentiation activity. Co-culture with erythroid progenitor cells also revealed them to play an important role in MSC differentiation. CONCLUSION: Our data suggest that hematopoietic cells function as niche cells of MSCs to balance the differentiation activity of MSCs and may ultimately affect bone development.

Fabrication and Characterization of ß-Cyclodextrin/Mosla Chinensis Essential Oil Inclusion Complexes: Experimental Design and Molecular Modeling.

Essential oils (EOs) are primarily isolated from medicinal plants and possess various biological properties. However, their low water solubility and volatility substantially limit their application potential. Therefore, the aim of the current study was to improve the solubility and stability of the Mosla Chinensis (M. Chinensis) EO by forming an inclusion complex (IC) with ß-cyclodextrin (ß-CD). Furthermore, the IC formation process was investigated using experimental techniques and molecular modeling. The major components of M. Chinensis 'Jiangxiangru' EOs were carvacrol, thymol, o-cymene, and terpinene, and its IC with ß-CD were prepared using the ultrasonication method. Multivariable optimization was studied using a Plackett-Burman design (step 1, identifying key parameters) followed by a central composite design for optimization of the parameters (step 2, optimizing the key parameters). SEM, FT-IR, TGA, and dissolution experiments were performed to analyze the physicochemical properties of the ICs. In addition, the interaction between EO and ß-CD was further investigated using phase solubility, molecular docking, and molecular simulation studies. The results showed that the optimal encapsulation efficiency and loading capacity of EO in the ICs were 86.17% and 8.92%, respectively. Results of physicochemical properties were different after being encapsulated, indicating that the ICs had been successfully fabricated. Additionally, molecular docking and dynamics simulation showed that ß-CD could encapsulate the EO component (carvacrol) via noncovalent interactions. In conclusion, a comprehensive methodology was developed for determining key parameters under multivariate conditions by utilizing two-step optimization experiments to obtain ICs of EO with ß-CD. Furthermore, molecular modeling was used to study the mechanisms involved in molecular inclusion complexation.

Laminaria japonica fucoidan ameliorates cyclophosphamide-induced liver and kidney injury possibly by regulating Nrf2/HO-1 and TLR4/NF-κB signaling pathways.

BACKGROUND: During clinical practice, cyclophosphamide (CTX) can lead to liver and kidney injury in vivo. In this study, we established a liver and kidney injury model by injecting CTX (80 mg kg-1 d-1 ) into male ICR mice, and then mice were treated with saline and fucoidan (20 or 40 mg kg-1 ), respectively. Subsequently, the liver and kidney toxicity indices, the expression levels of malonic dialdehyde (MDA), inflammatory factors, and the main protein levels of the Nrf2/HO-1 and TLR4/NF-κB pathways were determined. RESULTS: Our results indicated that fucoidan could significantly decrease serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CRE), and urea (BUN) in the test group compared to the model group. Fucoidan administration caused reductions in MDA, interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor alpha (TNF-α) levels and improved superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities in the liver and kidney of CTX-induced mice. Fucoidan up-regulated the Nrf2/HO-1 pathway and enhanced the protein levels of Nrf2, HO-1, GCLM, and NQO1. Moreover, fucoidan down-regulated the TLR4/NF-κB pathway, as indicated by decreased levels of TLR4, NF-κB p65, NF-κB p50, and increased IκBα level in liver and kidney tissues. CONCLUSION: Our studies suggest that fucoidan can ameliorate CTX-induced liver and kidney injury, potentially via up-regulating the Nrf2/HO-1 pathway and inhibiting the TLR4/NF-κB pathway. © 2021 Society of Chemical Industry.

Cyclopropenium Cationic-Based Covalent Organic Polymer-Enhanced Poly(ethylene oxide) Composite Polymer Electrolyte for All-Solid-State Li-S Battery.

Cyclopropenium cationic-based covalent organic polymer (iCP@TFSI) was successfully prepared through the SN2 reaction and ion replacement process, which can be incorporated into the PEO/LiTFSI matrix as a filler. The obtained solid-state polymer electrolytes were utilized for an all-solid-state lithium-sulfur (Li-S) battery. Padding iCP@TFSI into the PEO matrix not only has a positive influence on both the ionic conductivity and the mechanical capacity of solid-state polymer electrolytes but also increases the stability of the lithium metal anode, which essentially improves the overall cycling ability of all-solid-state Li-S batteries. Among the membranes attained, the PEO-10%iCP@TFSI electrolyte displays the best ionic conductivity up to 1.2 × 10-3 S·cm-1 at 80 °C. The symmetrical lithium battery exhibits higher cycle stability (600 h) due to the higher mechanical properties related to more stable lithium metal interfaces. The Li-S battery based on the PEO-10%iCP@TFSI electrolyte exhibits excellent electrochemical performance with better Coulombic efficiency and outstanding cycling stability. Its capacity is maintained at 490 mAh·g-1 after 500 cycles at 1 C with a 0.032% decay rate each cycle, and the Coulombic efficiency is close to 100% during the whole cycling.

Ameliorating Effect of Pentadecapeptide Derived from Cyclina sinensis on Cyclophosphamide-Induced Nephrotoxicity.

Cyclophosphamide (CTX) is a widely used anticancer drug with severe nephrotoxicity. The pentadecapeptide (RVAPEEHPVEGRYLV) from Cyclina sinensis (SCSP) has been shown to affect immunity and to protect the liver. Hence, the purpose of this study was to investigate the ameliorating effect of SCSP on CTX-induced nephrotoxicity in mice. We injected male ICR mice with CTX (80 mg/kg·day) and measured the nephrotoxicity indices, levels of antioxidant enzymes, malondialdehyde (MDA), inflammatory factors, as well as the major proteins of the NF-κB and apoptotic pathways. Cyclophosphamide induced kidney injury; the levels of kidney-injury indicators and cytokines recovered remarkably in mice after receiving SCSP. The activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) increased, while there was a significant decrease in MDA levels. The kidney tissue damage induced by CTX was also repaired to a certain extent. In addition, SCSP significantly inhibited inflammatory factors and apoptosis by regulating the NF-κB and apoptotic pathways. Our study shows that SCSP has the potential to ameliorate CTX-induced nephrotoxicity and may be used as a therapeutic adjuvant to ameliorate CTX-induced nephrotoxicity.

VCAM-1 Upregulation Contributes to Insensitivity of Vemurafenib in BRAF-Mutant Thyroid Cancer.

Vemurafenib, an inhibitor of mutant BRAF activity, is a promising anticancer agent for patients with BRAF-mutant metastatic melanoma. However, it is less effective in BRAF-mutant thyroid cancer, and the reason for this discrepancy is not yet fully elucidated. By RNA sequencing analysis, we identified vascular cell adhesion molecular-1 (VCAM-1) to be highly upregulated in both time- and dose-dependent manners during BRAF inhibition (BRAFi) in a BRAF-mutant papillary thyroid cancer cell line (BCPAP). Cell cytotoxicity and apoptosis assays showed that knockdown of the induced VCAM-1 in BCPAP cells augmented the antitumor effects of vemurafenib, with decreased IC50 values of 1.4 to 0.8 µM. Meanwhile, overexpression of VCAM-1 in a BRAF-mutant anaplastic thyroid cancer cell line (FRO) reduced the sensitivity to vemurafenib, with increased IC50 values of 1.9 to 5.8 µM. Further investigation showed that PI3K-Akt-mTOR pathway was activated during BRAFi. Co-treatment with Akt signaling inhibitor MK2206 decreased the induced expression of VCAM-1 during BRAFi. This combination further improved the efficacy of vemurafenib. Moreover, VCAM-1 promoted migration and invasion in thyroid cancer cells in vitro, which was also indicated in thyroid cancer patients. The present study is the first to demonstrate that VCAM-1 is upregulated in thyroid cancer cells treated with vemurafenib and contributes to vemurafenib resistance in BRAF-mutant thyroid cancer cells. Targeting the PI3K-Akt-mTOR pathway-mediated VCAM-1 response may be an alternative strategy to sensitize BRAF-mutant thyroid cancers to vemurafenib.

miR-129-5p Regulates the Immunomodulatory Functions of Adipose-Derived Stem Cells via Targeting Stat1 Signaling.

Adipose-derived stem cells (ASCs) have become one of the most promising stem cell populations for cell-based therapies in regenerative medicine and for autoimmune disorders owing to their multilineage differentiation and immunomodulatory capacities, respectively. One advantage of ASC-based therapy lies in their immunosuppressive potential. However, how to get ASCs to provide consistent immunosuppression remains unclear. In the current study, we found that miR-129-5p was induced in ASCs treated with inflammatory factors. ASCs with miR-129-5p knockdown exhibited enhanced immunosuppressive capacity, as evidenced by reduced expression of proinflammatory factors, with concurrent increased expression of inducible nitric oxide synthases (iNOS) and nitric oxide (NO) production. These cells also had an increased capacity to inhibit T cell proliferation in vitro. ASCs with miR-129-5p knockdown alleviated inflammatory bowel diseases and promoted tumor growth in vivo. Consistently, ASCs that overexpressed miR-129-5p exhibited reduced iNOS expression. Furthermore, we show that miR-129-5p knockdown in ASCs results in hyperphosphorylation of signal transducer and activator of transcription 1 (Stat1). When fludarabine, an inhibitor of Stat1 activation, was added to ASCs with miR-129-5p knockdown, iNOS mRNA and protein levels were significantly reduced. Collectively, these results reveal a new role for miR-129-5p in regulating the immunomodulatory activities of ASCs by targeting Stat1 activation. These novel insights into the mechanisms of ASC immunoregulation may lead to the consistent production of ASCs with strong immunosuppressive functions and thus better clinical utility of these cells.

Protective effects of pentadecapeptide derived from Cyclaina sinensis against cyclophosphamide-induced hepatotoxicity.

Our study was aimed at investigating the hepatoprotective effects of pentadecapeptide (RVAPEEHPVEGRYLV) from Cyclaina sinensis (SCSP) against cyclophosphamide (CTX)-induced hepatotoxicity in mice. Our results show that SCSP can significantly alleviate CTX-induced hepatotoxicity by decreasing the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG) and malondialdehyde (MDA), and increasing the levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) in the liver. In addition, the levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α (TNF-α) were also significantly decreased in the liver tissues when treated with SCSP. Moreover, the protein levels of the toll-like receptor 4 (TLR4)-mediated nuclear factor-kappa B (NF-κB) pathway and apoptosis-related proteins were also restored by SCSP treatment. Overall, our results suggest that SCSP can potentially improve the CTX-induced hepatotoxicity.

COL12A1, a novel potential prognostic factor and therapeutic target in gastric cancer.

Dysregulation of collagen type XII α1 chain (COL12A1) has been found in several cancer types and could be involved in tumor progression. However, its clinical significance in gastric cancer (GC) remains under exploration. Online databases (Gene Expression Omnibus and UALCAN), reverse transcription­quantitative PCR and immunohistochemistry were utilized in the present study to evaluate the expression of COL12A1 in GC tissues and cell lines. It was found that COL12A1 expression was notably upregulated in GC. Clinicopathological analysis showed that elevated COL12A1 expression was positively correlated with tumor invasiveness, metastasis and advanced clinical stage. The prognostic analysis suggested that high COL12A1 expression contributed to poor overall survival. Multivariate Cox analysis indicated that COL12A1 overexpression was a powerful independent prognostic indicator in patients with GC (hazard ratio, 1.896; 95% CI, 1.267­2.837; P=0.002). The results highlighted the importance of COL12A1 in GC and suggested its potential role as a candidate for clinical outcome prediction and targeted therapy in patients with GC.

CKIP-1 regulates the immunomodulatory function of mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are self-renewing multipotent cells with immunoregulatory function, which makes them attractive candidates for regenerative medicine. However, the detailed mechanisms of their immunomodulatory capacity are not fully characterized. Here, we found that casein kinase 2 interacting protein-1 (CKIP-1) expression was induced in the murine MSC cell line C3H/10T1/2 by LPS. Knockdown of CKIP-1 did not cause significant differences on the cell cycle or immunophenotype of MSCs. However, MSCs with CKIP-1 knockdown showed enhanced immunosuppressive capacity. Real-time PCR and western blot analyses revealed that compared with the control group, MSCs with CKIP-1-knockdown exhibited higher IL-10 production and p38 MAPK phosphorylation following LPS treatment. Interestingly, the expression of CKIP-1 was decreased in MSCs following high glucose treatment. Furthermore, MSCs became more immunosuppressive after high glucose treatment, as shown by higher IL-10 production and enhanced inhibition of T cell proliferation. Collectively, our data reveal a novel role for CKIP-1 in regulating MSC-mediated immunomodulation, and indicate that MSCs become more immunosuppressive under high glucose conditions. These new insights may help in the development of future applications of MSCs.

Mysm1 epigenetically regulates the immunomodulatory function of adipose-derived stem cells in part by targeting miR-150.

Adipose-derived stem cells (ASCs) are highly attractive for cell-based therapies in tissue repair and regeneration because they have multilineage differentiation capacity and are immunosuppressive. However, the detailed epigenetic mechanisms of their immunoregulatory capacity are not fully defined. In this study, we found that Mysm1 was induced in ASCs treated with inflammatory cytokines. Adipose-derived stem cells with Mysm1 knockdown exhibited attenuated immunosuppressive capacity, evidenced by less inhibition of T cell proliferation, more pro-inflammatory factor secretion and less nitric oxide (NO) production in vitro. Mysm1-deficient ASCs exacerbated inflammatory bowel diseases but inhibited tumour growth in vivo. Mysm1-deficient ASCs also showed depressed miR-150 expression. When transduced with Mysm1 overexpression lentivirus, ASCs exhibited enhanced miR-150 expression. Furthermore, Mysm1-deficient cells transduced with lentivirus containing miR-150 mimics produced less pro-inflammatory factors and more NO. Our study reveals a new role of Mysm1 in regulating the immunomodulatory activities of ASCs by targeting miR-150. These novel insights into the mechanisms through which ASCs regulate immune reactions may lead to better clinical utility of these cells.