Exploring the association of physical activity on cognitive function in older adults from observational and genetic insights: a combined NHANES and Mendelian randomization study.

Background: Cognitive function (CF) deterioration is a pressing concern in geriatric research. This study aimed to explore the relationship between physical activity (PA) and CF in older adults. Methods: This study adopted a dual approach, employing both observational and genetic approaches through data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014 and Mendelian Randomization (MR) analysis. For the NHANES component, PA levels were evaluated using the Global Physical Activity Questionnaire, and CF was assessed via standardized tests. Multivariate regression, threshold effect analysis, smoothing curve fitting, and subgroup analyses were conducted to examine the association between PA and CF. In parallel, MR methods, using genetic variants as instrumental variables, assessed the causal impact of PA on CF and related conditions such as Alzheimer's disease and dementia. Results: Observational findings from NHANES demonstrated a positive correlation between PA and CF, notably among female participants. The detailed analysis identified specific thresholds of PA that correlate with cognitive enhancements. However, MR results did not support a significant causal relationship between PA and CF or dementia-related outcomes, indicating an absence of a direct genetic basis for the observational associations. Conclusion: Although observational data from NHANES suggest that PA is positively associated with CF in older adults, particularly among women, MR analysis did not confirm these findings as causally related. The discrepancy highlights the complexity of the PA-CF relationship and underscores the need for further research. These results emphasize the potential of PA as a modifiable risk factor for CF, though causal effects remain to be definitively established.

Integrative analysis of microbiome and metabolome revealed the effect of microbial inoculant on microbial community diversity and function in rhizospheric soil under tobacco monoculture.

Over-application of chemical fertilizers and continuous cropping obstacles seriously restrict the sustainable development of tobacco production. Localized fertilization of beneficial microbes has potential advantages in achieving higher productivity, but the underlying biological mechanisms of interactions between rhizospheric microorganisms and the related metabolic cycle remain poorly characterized. Here, an integrative analysis of microbiomes with non-targeted metabolomics was performed on 30 soil samples of rhizosphere, root surrounding, and bulk soils from flue-cured tobacco under continuous and non-continuous monocropping systems. The analysis was conducted using UPLC-MS/MS platforms and high-throughput amplicon sequencing targeting the bacterial 16S rRNA gene and fungal ITS gene. The microbial inoculant consisted of Bacillus subtilis, B. velezensis, and B. licheniformis at the ratio of 1:1:1 in effective microbial counts, improved the cured leaf yield and disease resistance of tobacco, and enhanced nicotine and nitrogen contents of tobacco leaves. The bacterial taxa Rhizobium, Pseudomonas, Sphingomonadaceae, and Burkholderiaceae of the phylum Proteobacteria accumulated in high relative abundance and were identified as biomarkers following the application of the microbial inoculant. Under continuous monocropping, metabolomics demonstrated that the application of the microbial inoculant significantly affected the soil metabolite spectrum, and the differential metabolites were significantly enriched to the synthesis and degradation of nicotine (nicotinate and nicotinamide metabolism and biosynthesis of alkaloids derived from nicotinic acid). In addition, microbes were closely related to the accumulation of metabolites through correlation analysis. The interactions between plant roots and rhizospheric microorganisms provide valuable information for understanding how these beneficial microbes affect complex biological processes and the adaption capacity of plants to environments.IMPORTANCEThis study elaborated on how the microbial fertilizer significantly changed overall community structures and metabolite spectrum of rhizospheric microbes, which provide insights into the process of rhizosphere microbial remolding in response to continuous monocropping. we verified the hypothesis that the application of the microbial inoculant in continuous cropping would lead to the selection of distinct microbiota communities by establishing models to correlate biomarkers. Through correlation analysis of the microbiome and metabolome, we proved that rhizospheric microbes were closely related to the accumulation of metabolites, including the synthesis and degradation of nicotine. The interactions between plant roots and rhizospheric microorganisms provide valuable information for understanding how these beneficial microbes affect complex biological processes and the adaption capacity of plants to environments.

A prospective, randomized, single-blinded study comparing the efficacy and safety of dexmedetomidine and propofol for sedation during endoscopic retrograde cholangiopancreatography.

BACKGROUND: Balanced propofol sedation is extensively used in endoscopic retrograde cholangiopancreatography (ERCP), but sedation-related adverse events (SRAEs) are common. In various clinical settings, the combination of dexmedetomidine with opioids and benzodiazepines has provided effective sedation with increased safety. The aim of this investigation was to compare the efficacy and safety of dexmedetomidine and propofol for sedation during ERCP. METHODS: Forty-one patients were randomly divided into two groups: the dexmedetomidine (DEX) group and the propofol (PRO) group. Patients in the DEX group received an additional bolus of 0.6 µg kg-1 dexmedetomidine followed by a dexmedetomidine infusion at 1.2 µg kg-1 h-1, whereas the PRO group received 1-2 mg kg-1 of propofol bolus followed by a propofol infusion at 2-3 mg kg-1 h-1. During ERCP, the primary outcome was the incidence of hypoxemia (SpO2 < 90% for > 10 s). Other intraoperative adverse events were also recorded as secondary outcomes, including respiratory depression (respiratory rate of < 10 bpm min-1), hypotension (MAP < 65 mmHg), and bradycardia (HR < 45 beats min-1). RESULTS: The incidence of hypoxemia was significantly reduced in the DEX group compared to the PRO group (0% versus 28.6%, respectively; P = 0.032). Patients in the PRO group exhibited respiratory depression more frequently than patients in the DEX group (35% versus 81%, respectively; P = 0.003). There were no significant differences in terms of hypotension and bradycardia episodes between groups. During the procedures, the satisfaction scores of endoscopists and patients, as well as the pain and procedure memory scores of patients were comparable between groups. CONCLUSION: In comparison with propofol, dexmedetomidine provided adequate sedation safety with no adverse effects on sedation efficacy during ERCP. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2200061468, 25/06/2022.

The multifaceted roles of GSDME-mediated pyroptosis in cancer: therapeutic strategies and persisting obstacles.

Pyroptosis is a novel regulated cell death (RCD) mode associated with inflammation and innate immunity. Gasdermin E (GSDME), a crucial component of the gasdermin (GSDM) family proteins, has the ability to convert caspase-3-mediated apoptosis to pyroptosis of cancer cells and activate anti-tumor immunity. Accumulating evidence indicates that GSDME methylation holds tremendous potential as a biomarker for early detection, diagnosis, prognosis, and treatment of tumors. In fact, GSDME-mediated pyroptosis performs a dual role in anti-tumor therapy. On the one side, pyroptotic cell death in tumors caused by GSDME contributes to inflammatory cytokines release, which transform the tumor immune microenvironment (TIME) from a 'cold' to a 'hot' state and significantly improve anti-tumor immunotherapy. However, due to GSDME is expressed in nearly all body tissues and immune cells, it can exacerbate chemotherapy toxicity and partially block immune response. How to achieve a balance between the two sides is a crucial research topic. Meanwhile, the potential functions of GSDME-mediated pyroptosis in anti-programmed cell death protein 1 (PD-1) therapy, antibody-drug conjugates (ADCs) therapy, and chimeric antigen receptor T cells (CAR-T cells) therapy have not yet been fully understood, and how to improve clinical outcomes persists obscure. In this review, we systematically summarize the latest research regarding the molecular mechanisms of pyroptosis and discuss the role of GSDME-mediated pyroptosis in anti-tumor immunity and its potential applications in cancer treatment.

Multipart Build Effects on Temperature and Residual Stress by Laser Beam Powder Bed Fusion Additive Manufacturing.

Laser beam powder bed fusion (PBF-LB) is a leading technique among metal additive manufacturing (AM), and it has a wide range of applications in aerospace and medical devices. Most of the existing PBF-LB process modeling is mainly based on the fabrication of a single part on a large build plate, which is not reflective of the practical multipart PBF-LB manufacturing. The effects of batch size on the thermal and mechanical behavior of additively manufactured parts have not been investigated. In this work, the multipart PBF-LB thermomechanical modeling framework was proposed for the first time. The effects of sample numbers (1, 2, and 4) on temperature and residual stress (RS) of part-scale components were computationally investigated. It is found that RS within the parts decreased with increasing number of components per build. Parts located at the central areas of the build plate had larger RS than at the border. These findings can be beneficial for informing AM designers and operators of the optimum printing setup to minimize RS of metal parts in PBF-LB.

Pyroptosis in renal inflammation and fibrosis: current knowledge and clinical significance.

Pyroptosis is a novel inflammatory form of regulated cell death (RCD), characterized by cell swelling, membrane rupture, and pro-inflammatory effects. It is recognized as a potent inflammatory response required for maintaining organismal homeostasis. However, excessive and persistent pyroptosis contributes to severe inflammatory responses and accelerates the progression of numerous inflammation-related disorders. In pyroptosis, activated inflammasomes cleave gasdermins (GSDMs) and generate membrane holes, releasing interleukin (IL)-1ß/18, ultimately causing pyroptotic cell death. Mechanistically, pyroptosis is categorized into caspase-1-mediated classical pyroptotic pathway and caspase-4/5/11-mediated non-classical pyroptotic pathway. Renal fibrosis is a kidney disease characterized by the loss of structural and functional units, the proliferation of fibroblasts and myofibroblasts, and extracellular matrix (ECM) accumulation, which leads to interstitial fibrosis of the kidney tubules. Histologically, renal fibrosis is the terminal stage of chronic inflammatory kidney disease. Although there is a multitude of newly discovered information regarding pyroptosis, the regulatory roles of pyroptosis involved in renal fibrosis still need to be fully comprehended, and how to improve clinical outcomes remains obscure. Hence, this review systematically summarizes the novel findings regarding the role of pyroptosis in the pathogenesis of renal fibrosis and discusses potential biomarkers and drugs for anti-fibrotic therapeutic strategies.

Senescent Phenotype of Astrocytes Leads to Activation of BV2 Microglia and N2a Neuronal Cells Death.

(1) Background: Astrocytes, the most abundant cell type in the central nervous system, are essential to tune individual-to-network neuronal activity. Senescence in astrocytes has been discovered as a crucial contributor to several age-related neurological diseases. Here, we aim to observe if astrocytes demonstrate senescence in the process of brain aging, and whether they bring adverse factors, especially harm to neuronal cells. (2) Methods: In vivo, mice were housed for four, 18, and 26 months. An in vitro cell model of aged astrocytes was constructed by serial passaging until passage 20-25, and those within 1-5 were invoked as young astrocytes. Meanwhile, an oxidative induced astrocyte senescence model was constructed by H2O2 induction. (3) Results: In vitro aged astrocytes all showed manifest changes in several established markers of cellular senescence, e.g., P53, P21, and the release of inflammatory cytokine IL-6 and SA-ß-gal positive cells. Results also showed mitochondrial dysfunction in the oxidative stress-induced astrocyte senescence model and treatment of berberine could ameliorate these alterations. Two types of senescent astrocytes' conditioned medium could impact on neuron apoptosis in direct or indirect ways. (4) Conclusions: Senescent astrocyte might affect neurons directly or indirectly acting on the regulation of normal and pathological brain aging.

Long intergenic noncoding RNA LINC01287 drives the progression of cervical cancer via regulating miR-513a-5p/SERP1.

Cervical cancer is one of the most frequent types of cancer in women, which is characterized by high invasion and metastatic tendency in its advanced stage. Emerging evidence indicated that long non-coding RNAs (LncRNAs) are involved in the pathogenesis of cervical cancer. LINC01287 has been reported to play crucial regulatory roles in the pathogenesis and progression of multiple cancers. However, up until now, whether LINC01287 is associated with the initiation and development of cervical cancer remains largely unknown. In the present study, expression levels of LINC01287, miR-513a-5p and stress-associated endoplasmic reticulum protein 1 (SERP1) mRNA were quantified utilizing qRT-PCR. A series of functional experiments including CCK-8 assay, colony formation assay, transwell assay, flow cytometry, and tumor xenograft growth of cervical cancer cells were performed for studying the effects of LINC01287. The luciferase reporter assay, pull-down assay, and western blot were used to confirm the downstream targets of LINC01287 and miR-513a-5p. The results demonstrate that LINC01287 was highly expressed in cervical cancer tissue samples and cell lines. High LINC01287 predicts a poor prognosis for cervical cancer patients. Additional gain- and loss-of-function experiments demonstrated that silencing LINC01287 inhibited cervical cancer cells proliferation, colony formation, migration, apoptosis in vitro and retarded tumor growth and metastasis in vivo. Furthermore, the dual-luciferase reporter gene system and RNA pulldown assay validated that LINC01287 positively regulated SERP1 expressions by sponging miR-513a-5p, and LINC01287 inhibited cervical cancer progression by regulating miR-513a-5p/SERP1 axis. In conclusion, the current study first identified that LINC01287/miR-513a-5p/SERP1 axis played an important role in cervical cancer progression. LINC01287 might be a prognostic biomarker and a target for new therapies in patients with cervical cancer.

Study on the Effect of PDA-PLGA Scaffold Loaded With Islet Cells for Skeletal Muscle Transplantation in the Treatment of Diabetes.

At present, islet cells transplantation was limited by the way in which islet cells are implanted into the body, their ability to adapt to the microenvironment and the maintenance time for relieving diabetic symptoms. In order to solve this problem, we made PDA-PLGA scaffold loaded with islet cells and used it for skeletal muscle transplantation to investigate its therapeutic effect in the treatment of diabetes. The PLGA scaffold was prepared by the electrospinning method, and modified by polydopamine coating. A rat diabetic model was established to evaluate the efficacy of PDA-PLGA scaffold loaded with RINm5f islet cells through skeletal muscle transplantation. The results showed that the PDA-PLGA scaffold has good biosafety performance. At the same time, transplantation of the stent to the skeletal muscle site had little effect on the serum biochemical indicators of rats, which was conducive to angiogenesis. The PDA-PLGA scaffold had no effect on the secretory function of pancreatic islet cells. The PDA-PLGA scaffold carrying RINm5f cells was transplanted into the skeletal muscle of type I diabetic rats. 1 week after the transplantation of the PDA-PLGA cell scaffold complex, the blood glucose of the treatment group was significantly lower than that of the model group (p < 0.001) and lasted for approximately 3 weeks, which further indicated the skeletal muscle transplantation site was a new choice for islet cell transplantation in the future.

Protective effects of Radix Isatidis polysaccharide ameliorates obesity via promotion AMPK pathway in high-fat-diet-induced obese rats and 3T3-L1 adipocyte cells.

OBJECTIVES: The purpose of this paper is to ascertain the effect and mechanism of Radix Isatidis polysaccharide (RIP) on obesity. METHODS: High fat diet (HFD)-induced obese rats and the MDI-induced 3T3-L1 adipocyte cells were established to evaluate the ameliorated obesity effect and mechanism from RIP. KEY FINDINGS: Experiments in vivo show that oral administration of RIP has significant preventive effects on HFD-induced obesity and metabolic disorders in rats. With treatment of RIP (20, 40 and 80 mg/kg BW), the body weight, fat accumulation, adipocyte cell size, serum lipid levels and antioxidant enzyme activity were progressively improved. On the other hand, the treatment of 3T3-L1 cells with RIP (25, 50 and 100 mg/L) led to a decrease in lipid accumulation and glucose consumption. In addition, during adipogenesis in 3T3-L1 cells, RIP remarkably down-regulated mRNA levels of peroxisome proliferator-activated receptor-γ (PPARγ), CCAAT/enhancer binding protein-α (C/EBPα), sterol regulatory element-binding protein-1c (SREBP-1c), fatty acid synthase (FAS), acetyl-CoA carboxylase and glycerol-3-phosphate dehydrogenase. Furthermore, after RIP treatment, the protein expression of PPARγ, C/EBPα, FAS, HMG-CoA reductase and acetyl-CoA synthetase-1 (AceCS1) were significantly decreased and the expression of p-AMPK was increased. CONCLUSION: These results highlight the potential of RIP for obesity interventions and suggest that RIP inhibited adipocyte differentiation and lipid synthesis by activating adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signalling pathway and down-regulating the expression of major adipogenic transcription factors, PPARγ, C/EBPα, etc.

Material Characterisation and Computational Thermal Modelling of Electron Beam Powder Bed Fusion Additive Manufacturing of Ti2448 Titanium Alloy.

Ti-24Nb-4Zr-8Sn (Ti2448) is a metastable ß-type titanium alloy developed for biomedical applications. In this work, cylindrical samples of Ti2448 alloy have been successfully manufactured by using the electron beam powder bed fusion (PBF-EB) technique. The thermal history and microstructure of manufactured samples are characterised using computational and experimental methods. To analyse the influence of thermal history on the microstructure of materials, the thermal process of PBF-EB has been computationally predicted using the layer-by-layer modelling method. The microstructure of the Ti2448 alloy mainly includes ß phase and a small amount of α″ phase. By comparing the experimental results of material microstructure with the computational modelling results of material thermal history, it can be seen that aging time and aging temperature lead to the variation of α″ phase content in manufactured samples. The computational modelling proves to be an effective tool that can help experimentalists to understand the influence of macroscopic processes on material microstructural evolution and hence potentially optimise the process parameters of PBF-EB to eliminate or otherwise modify such microstructural gradients.

Exogenous Plant gma-miR-159a, Identified by miRNA Library Functional Screening, Ameliorated Hepatic Stellate Cell Activation and Inflammation via Inhibiting GSK-3ß-Mediated Pathways.

PURPOSE: Plant-derived exogenous microRNAs (miRNAs) regulate human physiological functions by blocking the translation of target mRNAs. Although several computational approaches have been developed to elucidate the interactions of cross-species miRNAs and their targets in mammals, the number of verified plant miRNAs is still limited, and the biological roles of most exogenous plant miRNAs remain unknown. METHODS: A miRNA mimic library-based phenotypic screening, which contained 8394 plant mature miRNAs published in the official database miRbase, was performed to identify more novel bioactive plant miRNAs for the prevention of hepatic fibrosis. Inhibition of candidates for the activation of hepatic stellate cells (HSCs) and the underlying mechanisms were evaluated in TGF-ß1- and PDGF-exposed HSC models. The protective effects of the candidates against CCl4-induced liver fibrosis were evaluated in a mouse model. RESULTS: Among the 8394 plant mature miRNAs reported in the official database miRBase, five candidates were found to effectively inhibit the differentiation of HSCs. gma-miR-159a (miR159a) exerted the strongest inhibitory activities on both TGF-ß1- and PDGF-induced HSC activation and proliferation by inhibiting the GSK-3ß-mediated NF-κB and TGF-ß1 pathways. Moreover, miR159a was mainly accumulated in the liver after intravenous injection, and it reduced CCl4-induced hepatic fibrosis and inflammation in mice. CONCLUSION: Results indicated that miR159a has the therapeutic potential for preventing hepatic fibrosis. This study provides a novel strategy for achieving natural nucleic acid drugs.

Temporal Bacterial Community Diversity in the Nicotiana tabacum Rhizosphere Over Years of Continuous Monocropping.

Long-term continuous monocropping negatively influences the physicochemical and biological characteristics of cultivated soil, especially for the economically important crop of flue-cured tobacco that is intolerant to continuous monocropping. The underlying mechanism of soil sickness under continuous monoculture and the temporal dynamic changes over the tobacco life cycle among different monoculture time spans remain poorly characterized. In this study, high-throughput sequencing targeting the 16S rRNA gene phylogenetic marker was performed on 60 soil samples of rhizosphere soil from flue-cured tobacco in the replanting, growth and harvest period across 5, 10, and 20 years of a continuous monocropping system. Bacterial community diversity decreased with the increase in duration of continuous monocropping, and the rhizosphere microbiota was highly dynamic in the harvest period. The random forests algorithm identified 17 taxa as biomarkers and a model was established to correlate root microbiota with continuous monocropping time of flue-cured tobacco. Molecular ecological network analysis elaborated the differences and interactions in bacterial co-occurrence patterns under different monocropping systems. The co-occurrence microbial network was larger in size but there were fewer interactions among microbial communities with the increase in continuous monocropping duration. These results provide insights into the changes of flue-cured tobacco root microbiome diversity in response to continuous monocropping and suggest a model for successional dynamics of the root-associated microbiota over continuous monocropping time and development stage. This study may help elucidate the theoretical basis underlying obstacles to continuous monocropping and could contribute to improving guidance for tobacco production.

Data on a computationally efficient approximation of part-powder conduction as surface free convection in powder bed fusion process modelling.

This article is related to research article entitled "Resolution, energy and time dependency on layer scaling in finite element modelling of laser beam powder bed fusion additive manufacturing" [1]. This data article presents a computationally efficient approximation of part-powder interface conduction heat transfer, as convection heat transfer, thus eliminating the need for powder elements in the finite element model. The heat loss profile due to part-powder conduction was first characterised for a Ti6Al4V Powder Bed Fusion process. Cooling rate data was obtained for a range of powder in-plane depths. A matching cooling rate profile was obtained from free convection from the part surface, by calibration of the convection coefficient.

Amorphous solid dispersion of Berberine mitigates apoptosis via iPLA2ß/Cardiolipin/Opa1 pathway in db/db mice and in Palmitate-treated MIN6 ß-cells.

Aims: Berberine (BBR) improves beta-cell function in Type 2 diabetes (T2D) because of its anti-apoptotic activity, and our laboratory developed a new preparation named Huang-Gui Solid Dispersion (HGSD) to improve the oral bioavailability of BBR. However, the mechanism by which BBR inhibits beta-cell apoptosis is unclear. We hypothesized that the Group VIA Ca2+-Independent Phospholipase A2 (iPLA2ß)/Cardiolipin(CL)/Opa1 signaling pathway could exert a protective role in T2D by regulating beta-cell apoptosis and that HGSD could inhibit ß-cell apoptosis through iPLA2ß/CL/Opa1 upregulation. Methods: We examined how iPLA2ß and BBR regulated apoptosis and insulin secretion through CL/Opa1 in vivo and in vitro. In in vitro studies, we developed Palmitate(PA)-induced apoptotic cell death model in mouse insulinoma cells (MIN6). iPLA2ß overexpression and silencing technology were used to examine how the iPLA2ß/CL/Opa1 interaction may play an important role in BBR treatment. In in vivo studies, db/db mice were used as a diabetic animal model. The pancreatic islet function and morphology, beta-cell apoptosis and mitochondrial injury were examined to explore the effects of HGSD. The expression of iPLA2ß/CL/Opa1 was measured to explore whether the signaling pathway was damaged in T2D and was involved in HGSD treatment. Results: The overexpression of iPLA2ß and BBR treatment significantly attenuated Palmitate- induced mitochondrial injury and apoptotic death compared with Palmitate-treated MIN6 cell. In addition, iPLA2ß silencing could simultaneously partly abolish the anti-apoptotic effect of BBR and decrease CL/Opa1 signaling in MIN6 cells. Moreover, HGSD treatment significantly decreased beta-cell apoptosis and resulted in the upregulation of iPLA2ß/CL/Opa1 compared to those of the db/db mice. Conclusion: The results indicated that the regulation of iPLA2ß/CL/Opa1 by HGSD may prevent beta-cell apoptosis and may improve islet beta-cell function in Type 2 diabetic mice and in palmitate-treated MIN6 cells.

Effect of Radix isatidis polysaccharide on alleviating insulin resistance in type 2 diabetes mellitus cells and rats.

OBJECTIVES: The objective of this paper was to explore the effects of Radix isatidis polysaccharide (RIP) extracted from Radix isatis on alleviating insulin resistance. METHODS: The insulin resistance models of 3T3-L1 preadipocytes and type 2 diabetic rats were established to evaluate the insulin resistance activity of RIP. KEY FINDINGS: Radix isatidis polysaccharide within the concentration range of 25-100 µg/ml could reduce cell supernatant glucose and TNF-α levels (P < 0.01) and increase the expression of PI-3K P85, Glut4, IRS-1 and Akt protein in symptoms of IR 3T3-L1 preadipocytes. In the meantime, RIP contributed to relieve the weight loss of diabetic rats whose liver weight and liver index were decreased due to the effects of RIP. Experiments in rats also showed that RIP had capacity in reduced serum TC, TG, LDL-C, FFA, FBG, FINS, MDA, ALT, AST activities and increased serum HDL-C, SOD, ISI (P < 0.05 or 0.01). In addition, the oral glucose tolerance in rats was improved (P < 0.05) and liver damage was restored due to RIP. CONCLUSIONS: Radix isatidis polysaccharide significantly alleviates insulin resistance in 3T3-L1 preadipocytes and type 2 diabetic rats. These beneficial effects of RIP may associate with their roles in improving the glucose metabolism, lipid metabolism and oxidative stress.

MiR27a Promotes the Development of Macrophage-like Characteristics in 3T3-L1 Preadipocytes.

Recruitment and polarization of classically activated (M1) macrophages within adipose tissue contribute to chronic low-grade inflammation in obesity. Adipose tissue precursor cells exhibit the capacity to develop macrophage-like characteristics and adipocyte-derived miR27a is known to promote reprogramming of somatic cells. It was unknown whether exogenous addition of miR27a promote the development of macrophage-like characteristics of adipose precursor cells. We examined macrophage surface antigen, phagocytosis and migration ability in 3T3-L1 preadipocytes transfected with miR27a mimics. Transfection of 3T3-L1 preadipocytes with miR27a mimics increased phagocytosis and migration and increased the number of cells expressing the macrophage makers F4/80 and MHC compared to controls. M2 and CD206 macrophage markers were unaltered. In addition, transfection of 3T3-L1 preadipocytes with miR27a mimics reduced PPARγ expression, activated NF-κB and promoted secretion of the inflammatory cytokines MCP-1, TNF-α and IL-1ß compared to controls. The level of anti-inflammatory factors Arg-1, IL-10, Ym1 and Fizz1 were unaltered. Secretion of miR27a was increased in conditioned medium prepared from palmitic acid-treated differentiated 3T3-L1 adipocytes compared to controls. Incubation of 3T3-L1 preadipocytes with this conditioned medium increased phagocytosis and migration compared to controls. Finally, conditioned medium prepared from differentiated 3T3-L1 adipocytes transfection with miR27a inhibitors reduced phagocytosis and migration in 3T3-L1 preadipocytes compared to controls. The data indicate that PPARγ agonists may reverse the activation of NF-κB pathway mediated by miR27a overexpression and reduce phagocytosis and migration of adipose precursor cells. In addition, miR27a may promote the development of macrophage-like characteristics in 3T3-L1 preadipocytes.

PDGF signaling pathway in hepatic fibrosis pathogenesis and therapeutics (Review).

The platelet­derived growth factor (PDFG) signaling pathway exerts persistent activation in response to a variety of stimuli and facilitates the progression of hepatic fibrosis. Since this pathway modulates a broad spectrum of cellular processes, including cell growth, differentiation, inflammation and carcinogenesis, it has emerged as a therapeutic target for hepatic fibrosis and liver­associated disorders. The present review exhibits the current knowledge of the role of the PDGF signaling pathway and its pathological profiles in hepatic fibrosis, and assesses the potential of inhibitors which have been investigated in the experimental hepatic fibrosis model, in addition to the clinical challenges associated with these inhibitors.

Total glucosides of paeony ameliorates TNBS­induced colitis by modulating differentiation of Th17/Treg cells and the secretion of cytokines.

The imbalance between effector CD4+ T helper 17 (Th17) and regulatory CD4+ T cells (Treg) cells and their associated cytokines, have been associated with the pathogenesis of inflammatory bowel disease (IBD). Total glycosides of paeony (TGP) is an alternative immunomodulatory agent that is widely used for the treatment of autoimmune diseases. The present study aimed to evaluate the modulatory effect of TGP in a rat model of colitis induced by 2,4,6­trinitrobenzene sulfonic acid (TNBS). TGP was administered intragastrically 24 h after the TNBS intrarectal instillation for 7 days. TGP treatment ameliorated the clinical status and reversed the histopathologic severity of acute TNBS colitis. Furthermore, TGP inhibited the levels of Th17­associated cytokines interleukin (IL)­17, IL­6, tumor necrosis factor­α, whereas the expression levels of Treg­associated cytokines IL­10, transforming growth factor­ß in the plasma, colon, spleen and mesenteric lymph nodes (MLN). Additionally, TGP reduced the percentage of Th17 cells; however, the proportion of Treg cells in the spleen and MLN was increased. The present study also observed a suppression of Th17­associated transcription factor, termed retinoid­related orphan receptor­Î³t (ROR­Î³t). However, expression of the Treg­associated transcription factor forkhead boxp3 was increased in the TGP treatment group. Therefore, the present findings suggest that TGP has a regulatory role in modulating the balance of Th17 and Treg cells to ameliorate the TNBS­induced colitis and support the strategy of using TGP to treat IBD.

Studies on anti-angiogenesis of ginsenoside structure modification HRG in vitro.

This study investigates the anti-angiogenic effect of 3ß, 12ß, 20(S)-trihydroxy dammarane-3-O-ß-d-glucopyranosyl(1-2)-ß-d-glucopyranoside(HRG), a new chemical compound obtained by structure modification on Ginseng saponins Rg3, associated with the regulation of matrix metalloproteinases(MMPs) and its upstream signal-regulated molecule of vascular endothelial growth factor(VEGF) and basic fibroblast growth factor(b-FGF) in vitro, which plays an critical role in angiogenesis during the process of carcinoma. In our study, to investigate the anti-angiogenesis effect of HRG in HUVECs, we utilized cell proliferation assay, tube formation assay, wound-healing assay, Semi-quantitative reverse transcription PCR, and Western blot assay. Our results demonstrated that HRG plays a major role in the regulation of proliferation, migration and tube formation of HUVECs by suppressing the expression of VEGF and b-FGF in both transcriptional and post-transcriptional levels. In addition, the expression of MMP-2 and MMP-9, which were related to the ECM degradation, were down-regulated after administration of HRG as well. Overall, our results revealed that HRG strongly inhibited the process of angiogenesis and shows better effectiveness than Rg3.