Fecal bacteria from ulcerative colitis patients downregulate Tim-3-mediated inhibitory effects on monocytes in vitro.

Tim-3 is highly expressed on monocytes and macrophages. Blocking Tim-3 was shown to promote macrophage activation. We previously showed that fecal bacteria from patients with active ulcerative colitis (UC) presented significantly higher capacity to stimulate monocyte activation, resulting in higher expression of MHC molecules, costimulatory molecules, and proinflammatory cytokines, but the underlying mechanism remained unclear. Here, we found that fecal bacteria could significantly downregulate the expression of Tim-3 on CD14+ classical monocytes in vitro. Compared to the monocytes from healthy individuals, the monocytes from UC patients not only presented lower Tim-3 expression directly ex vivo, but also presented lower Tim-3 expression after stimulation. Moreover, the extent of Tim-3 downregulation was higher in UC monocytes than in control monocytes. This effect was, at least in part, attributable to differences in fecal bacterium composition between UC patients and healthy controls, since when tested in unrelated volunteers, the fecal bacteria from UC patients presented higher capacity at mediating Tim-3 downregulation. Fecal bacteria also induced TNF-α and IL-6 secretion from monocytes, which was repressible by the Tim-3 ligand Galectin 9 (Gal-9). Interestingly, we found that monocytes from UC patients presented significantly reduced response to exogenous Gal-9, and the extent of Gal-9-mediated inhibition was directly correlated with the level of Tim-3 expression. Overall, our data suggested that the monocytes from UC patients presented lower Tim-3 expression and reduced response to exogenous Gal-9, and the fecal bacteria from UC patients could potently downregulate Tim-3 expression on monocytes in vitro.

The effect of liraglutide on the proliferation, migration, and osteogenic differentiation of human periodontal ligament cells.

OBJECTIVE: Liraglutide (LIRA) is a novel antidiabetic therapy that may have anti-inflammatory and bone protective effects. Thus, we studied the potential therapeutic effect of LIRA on periodontitis by assessing the effects of LIRA on the proliferation, migration, inflammation, and osteogenic differentiation of human periodontal ligament cells (hPDLCs) after LPS stimulation. MATERIAL AND METHODS: The expression of glucagon like-peptide 1 receptor (GLP-1R) was measured using qRT-PCR. HPDLCs proliferation after LIRA were analyzed using MTT assays. Cell migration was quantified using a wound-healing assay. The expression of inflammatory (IL-6 and TNF-α) was measured by qRT-PCR and ELISA in hPDLCs. The effect of LIRA on the mineralization potential of hPDLCs was assessed by alizarin red S staining. Furthermore, the expression of Runx2 and ALP was measured by qRT-PCR and Western blot in hPDLCs. RESULTS: GLP-1R mRNA was present on hPDLCs, and LIRA increased the expression of GLP-1R mRNA. When cultured with 25, 50, 75, 100 and 125 nM LIRA for 24 h, hPDLCs proliferation was enhanced in a dose-dependent manner (P < 0.05), and 100 nM was optimal. LIRA promoted hPDLCs migration in a time-dependent manner. LPS significantly increased the expression of IL-6 and TNF-α (P < 0.01), decreased the formation of mineralization nodes (P < 0.01), and inhibited the expression of ALP and Runx2 (P < 0.05). LIRA treatment blocked the expression of IL-6 and TNF-α (P < 0.01), increased the formation of mineralization nodes (P < 0.01), and enhanced the expression of ALP and Runx2 (P < 0.05). CONCLUSION: LIRA can enhance the proliferation, migration, and osteogenic differentiation of hPDLCs and inhibit the inflammatory response. Thus, LIRA may have potential therapeutic use as an adjuvant treatment for human periodontitis, and this effect is independent of hypoglycemic activity.

Preliminary Study of the Role F-Box Protein 32 (FBXO32) in Colorectal Neoplasms Through the Transforming Growth Factor beta (TGF-ß)/Smad4 Signalling Pathway.

BACKGROUND F-box protein 32 (FBXO32) (also known as atrogin-1), a member of the F-box protein family, was recently shown to be a transforming growth factor beta (TGF-ß)/Smad4 target gene involved in regulating cell survival. It can be transcriptionally silenced by epigenetic mechanisms in some cancers, but its role in colorectal carcinoma (CRC) is unclear. We investigated the role of FBXO32 in CRC and determined its prognostic significance. MATERIAL AND METHODS We used real-time quantitative PCR, Western blot, and immunohistochemistry to elucidate the role of FBXO32 in clinical specimens and primary CRC cell lines. Differences in patient survival were determined by the Kaplan-Meier method and log-rank test. RESULTS We found that the FBXO32 and SMAD4 levels were higher in normal tissues than in CRC tissues, but PAI-1 and VEGF levels showed the opposite pattern. The expressions of FBXO32 and SMAD4 were related to clinicopathological parameters in CRC. Kaplan-Meier analyses showed that the 5-year overall survival of the low-FBXO32 expression group was significantly shorter than that of the high-FBXO32 expression group (p=0.010). CONCLUSIONS The fbxo32 gene is a novel tumor suppressor that inhibits CRC progression by inducing differentiation. Elevated expression of FBXO32 predicts longer survival in CRC patients.

Exosomes promote pre-metastatic niche formation in colorectal cancer.

It is well known that colorectal cancer (CRC) has a high morbidity rate, a poor prognosis when metastasized, and a greatly shortened 5-year survival rate. Therefore, understanding the mechanism of tumor metastasis is still important. Based on the "seed and soil" theory, the concept of " premetastatic niche (PMN)" was introduced by Kaplan et al. The complex interaction between primary tumors and the metastatic organ provides a beneficial microenvironment for tumor cells to colonize at a distance. With further exploration of the PMN, exosomes have gradually attracted interest from researchers. Exosomes are extracellular vesicles secreted from cells that include various biological information and are involved in communication between cells. As a key molecule in the PMN, exosomes are closely related to tumor metastasis. In this article, we obtained information by conducting a comprehensive search across academic databases including PubMed and Web of Science using relevant keywords. Only recent, peer-reviewed articles published in the English language were considered for inclusion. This study aims to explore in depth how exosomes promote the formation of pre-metastatic microenvironment (PMN) in colorectal cancer and its related mechanisms.

Progress of lymphocyte activation gene 3 and programmed cell death protein 1 antibodies for cancer treatment: A review.

The application of immune checkpoint inhibitors has proven to be an effective treatment for cancer. Immune checkpoints such as programmed cell death protein 1/programmed cell death protein 1 ligand 1 (PD-1/PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T-cell immunoglobulin-3 (TIM-3), T-cell immunoglobulin and ITIM domain (TIGIT), and lymphocyte activation gene-3 (LAG-3) have received extensive attention, and the efficacy of antibodies or inhibitors against these checkpoints (either alone or in combination) has been evaluated in many tumors. This paper provides a brief overview of the PD-1 and LAG-3 checkpoints, and then shifts focus to the combined use of PD-1 and LAG-3 antibodies in both in vivo and in vitro experiments. In the in vitro experiments, we examined the correlation between the expression and activation of these inhibitors on T cells, and also assessed toxicity in animals in preparation for in vivo experiments. The effects of the combined use of PD-1 and LAG-3 antibodies were then summarized in animal models of melanoma, MC38 carcinoma, and other tumors. In clinical studies, the combined application of these antibodies was assessed in patients with melanoma, colorectal, breast, and renal cell cancers, as well as other solid tumors. In general, the combination of PD-1 and LAG-3 antibodies has shown promising results in both in vivo and in vitro studies.

Progress of new-onset diabetes after liver and kidney transplantation.

Organ transplantation is currently the most effective treatment for end-stage organ failure. Post transplantation diabetes mellitus (PTDM) is a severe complication after organ transplantation that seriously affects the short-term and long-term survival of recipients. However, PTDM is often overlooked or poorly managed in its early stage. This article provides an overview of the incidence, and pathogenesis of and risk factors for PTDM, aiming to gain a deeper understanding of PTDM and improve the quality of life of recipients.

Understanding the motivational mechanisms behind the usage frequency of ride-hailing during COVID-19 pandemic.

Introduction: This study aimed to explore the factors influencing people's utilization of ride-hailing services, particularly in the context of the COVID-19 pandemic. Methods: A two-stage survey was conducted among the same group of passengers pre and post COVID-19 pandemic, resulting in a total of 670 valid samples. Exploratory factor analysis (EFA) was applied to the data, followed by the ordered probit and ordered logit models to identify the motivational factors behind passengers' frequency of using ride-hailing. Results: The findings indicated that trust and loyalty were the most influential factors in determining passengers' frequency of using ride-hailing services. However, passengers' perception of the COVID-19 pandemic did not have a significant effect on the frequency of using ride-hailing. Discussion: This research provides empirical evidence and policy implications for understanding people's usage of the ride-hailing services in the context of public-health emergency.

Therapeutic Potential of Liraglutide for Diabetes-Periodontitis Comorbidity: Killing Two Birds with One Stone.

Background: The relationship between diabetes and periodontitis is bidirectional, and there is now consensus that periodontitis and diabetes are comorbid. There is a quest for a drug that can be used to treat both conditions simultaneously. This study evaluated the anti-inflammatory and osteoprotective effects of liraglutide (LIRA) on periodontitis in diabetic rats. Methods: Male Wistar rats (n = 46) were randomly divided into four groups: control group (n = 8), LIRA group (n = 8), diabetes-associated periodontitis+0.9% saline group (diabetic periodontitis (DP)+NaCl group, n = 15), and diabetes-associated periodontitis+LIRA group (DP+LIRA group, n = 15). LIRA treatment lasted for 4 weeks (300 µg/kg/d) after establishment of a rat model of DP. The expression of IL-6, TNF-α, and IL-1ß was detected by enzyme-linked immunosorbent assay. The morphological changes of periodontal tissues were observed by hematoxylin-eosin staining. The absorption of alveolar bone and its ultrastructural changes were observed by histomorphometry and microcomputed tomography. The expression of receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) in alveolar bone was detected by immunohistochemistry. The levels of Runx2 mRNA and ALP mRNA in the gingival epithelium were examined by quantitative real-time polymerase chain reaction. Results: LIRA decreased alveolar bone resorption, improved the microstructure of alveolar bone, and reduced periodontal inflammation and damage (P < 0.05). LIRA also reduced blood glucose level and inhibited the secretion of serum IL-6, TNF-α, and IL-1ß (P < 0.05). In addition, after treatment with LIRA, the ratio of RANKL/OPG was reduced, and the expression levels of ALP mRNA and Runx2 mRNA were upregulated (P < 0.05). Conclusions: LIRA not only controls blood glucose level but also reduces inflammation and bone loss and enhances osteogenic differentiation in diabetes-associated periodontitis. Those indicate that LIRA may be used as a potential medicine for the adjunctive therapy of diabetes-periodontitis comorbidity.

Hollow and mesoporous aluminosilica-encapsulated Pt-CoOx for the selective hydrogenation of substituted nitroaromatics.

Hollow and mesoporous aluminosilica nanoreactors (HMANs) with Pt-CoOx cores (∼4.7 nm) and hollow aluminosilica shells (∼50 nm) were designed by a selective etching method. The Pt-CoOx@HMANs demonstrate a greatly enhanced activity and selectivity for the hydrogenation of various substituted nitroaromatics compared to Pt@HMANs and Pt-CoOx@SiO2.

The Family Attitudes of Patients With End-Stage Renal Disease Toward Living Kidney Donation in China.

BACKGROUND: Organ shortages limit the progress of organ transplantation. The family attitudes of patients with end-stage renal disease (ESRD) play an important role in advocating organ transplantation and donation. The purpose of this study was to analyze the family attitudes of patients with ESRD toward living kidney donation in China. Ethical approval was obtained from the ethics committee of Linyi People's Hospital. This study was performed in compliance with the Declaration of Helsinki. MATERIALS AND METHODS: This research was performed at 5 third-level hospitals with hemodialysis and nephrology departments, and a small section comes from urology departments. The participants were surveyed from January to November 2018. Attitudes were evaluated using a validated questionnaire concerning the psychosocial aspects of organ donation. The self-administered questionnaire was completed anonymously. Statistical analyses employed t tests and the χ2 test. RESULTS: Regarding living kidney donation, 69.1% (n = 428) of patient families favored it; however, only 30.9% (n = 192) did not support it. A favorable attitude toward living donation was mainly associated with the following variables: 1. the recipient is not more than 50 years old; 2. the recipient is a member of the immediate family; 3. the living donation is from the recipient's family member; 4. the family has previous personal experience with organ transplantation and donation; and 5. the family has a concern about the possibility of needing a transplant within the family unit (P < .05). CONCLUSIONS: Economic burden and mental stress from long-term dialysis influenced the attitudes and behavioral intentions of the families of patients with ESRD on advocating organ donation. Repeated education and constant advocacy are advised to increase the participation of families of patients with ESRD in organ donation. The results showed favorable attitudes toward living kidney donation among the families of patients with ESRD.

Liraglutide regulates bone destruction and exhibits anti-inflammatory effects in periodontitis in vitro and in vivo.

OBJECTIVES: This study investigated the effect of Liraglutide (LIRA) on osteogenic differentiation of human periodontal ligament cells (hPDLCs) stimulated by Porphyromonas gingivalis lipopolysaccharide (Pg-LPS) and its mechanismin in vitro. Further, investigated the osteoprotective and anti-inflammatory effects of LIRA in periodontitis in vivo. MATERIALS AND METHODS: ALP staining, Alizarin red staining(AR-S), qRT-PCR, Western Blot, and immunofluorescence staining were used to elucidate the effect of LIRA on osteogenesis of hPDLCs. Western Blot was performed to evaluate the Wnt/ß-catenin signaling-related protein. Moreover, male Wistar rats model of periodontitis were established to assess the anti-inflammatory and osteoprotective effect of LIRA in vivo. RESULTS: After LIRA treatment, the formation of mineralized nodules was increased, the expression of ALP and Runx2 were upregulated. Moreover, Pg-LPS strongly activated the Wnt/ß-catenin signaling pathway and reduced the osteogenesis of hPDLCs. But these effects were reversed by LIRA. The in vivo results showed that treatment with LIRA resulted in reduced inflammatory cell infiltration in periodontal tissues and decreased concentrations of TNF-α, IL-1ß, and IL-6, and it reduced alveolar bone resorption. CONCLUSIONS: Systemic administration of LIRA solution is a potential treatment for reducing inflammation and bone loss in periodontal disease. This suggests that LIRA can be used as a potential drug for the treatment of periodontitis. CLINICAL SIGNIFICANCE: We showed that systemic administration of LIRA can have a beneficial effect in periodontitis. It can be used as a potential drug for the treatment of periodontitis.

Cancer Stem Cells are Regulated by STAT3 Signalling in Wilms Tumour.

The survival rates associated with Wilms tumour (WT) remain dismal despite advancements in detection and treatment strategies. Cancer stem cells (CSCs) are correlated with the initiation, recurrence and metastasis of tumours, but its impact on Wilms cancer stem cell (WCSC) maintenance remains unclear. In this study, CD133+ cells were successfully isolated from a single-cell suspension of the G401 Wilms tumour cell line using magnetic activated cell sorting (MACS). Signal transducers and activators of transcription 3 (STAT3) has been implicated in tumorigenesis, but its contribution to the metastatic progression of WCSCs has not been investigated. Here, we show that STAT3 is overexpressed in WCSCs. Activation of STAT3 in WCSCs initiated a forward feedback loop that was responsible for mediating the aggressive malignant character of Wilms tumour cells in vitro and in vivo. Treatment of CD133+ cells with stattic, a STAT3 inhibitor, also inhibited tumour formation and progression in xenograft animal models in vivo. Collectively, these studies revealed a critical role of STAT3 signalling in WCSC proliferation and motility and a role for CD133 in cancer stem-like cell function, providing evidence for CD133 as a potential therapeutic target in Wilms tumour.

Brain-derived neurotrophic factor enhances the contraction of intestinal muscle strips induced by SP and CGRP in mice.

BACKGROUND AND AIMS: Brain-derived neurotrophic factor (BDNF) has been found in the intestinal tract of a variety of species. Its effects on visceral hyperalgesia have been examined to some degree, but limited studies have focused on gut motility. The aim of the present study was to investigate the effects of BDNF on gut motility of mice. METHODS: Longitudinal muscle (LM) strips were prepared from mice ileum and distal colon. The motility of gut was evaluated by the contraction of LM strips, which was recorded by a polyphisograph in vitro. Firstly, the roles of substance P (SP), calcitonin gene-related peptide (CGRP), and acetylcholine (ACh) on the contraction of LM strips were clarified. Then the exogenous BDNF was administered, and the alterations of SP/CGRP/ACh-induced contractions of the muscle strips were explored. Finally, heterozygous BDNF(+/-) mice and antibody of TrkB were introduced to investigate the role of endogenous BDNF on the SP/CGRP/ACh-induced gut motility. KEY RESULTS: SP (10(-8)-10(-6) mol L(-1)), CGRP (10(-8)-10(-7) mol L(-1)) and ACh (10(-8)-10(-6) mol L(-1)) dose-dependently caused the contraction of LM strips from ileum and distal colon, while the excitatory effect of CGRP was preceded by a transient inhibition. But 10(-6) mol L(-1) CGRP inhibited the contraction of LM strips. Pretreatment with exogenous BDNF (10(-8) mol L(-1)) remarkably enhanced the contraction of LM strips induced by SP (10(-9)-10(-7) mol L(-1)) and CGRP (10(-8)-10(-9) mol L(-1)). However, exogenous BDNF couldn't affect the contraction induced by ACh (10(-9)-10(-7) mol L(-1)). The excitatory effects of SP (10(-8)-10(-6) mol L(-1)) and CGRP (10(-8)-10(-7) mol L(-1)) on the contractions of LM strips from ileum and distal colon were significantly attenuated in BDNF(+/-) mice compared with those in BDNF(+/+) mice, while no difference of the effects of ACh (10(-8)-10(-6) mol L(-1)) on LM strips was observed between BDNF(+/-) mice and BDNF(+/+) mice. The monoclonal antibody of TrkB (TrkB-Ab) dramatically attenuated the excitatory effects of SP and CGRP on the contractions of LM strips, without affecting the excitatory effects of ACh. CONCLUSIONS AND INFERENCES: These data clarified the excitatory effects of SP, ACh and bilateral effects of CGRP on gut motility of mice and confirmed an essential role of BDNF on accelerating gut motility by enhancing the excitatory effects of SP/CGRP.