Diabetes mellitus (DM) and breast cancer (BC) can simultaneously occur in the same patient populations, but the molecular relationship between them remains unknown. In this study, we constructed genetic networks and used modularized analysis approaches to investigate the multi-dimensional characteristics of two diseases and one disease subtype. A text search engine (Agilent Literature Search 2.71) and MCODE software were applied to validate potential subnetworks and to divide the modules, respectively. A total of 793 DM-related genes, 386 type 2 diabetes (T2DM) genes and 873 BC-related genes were identified from the Online Mendelian Inheritance in Man database. For DM and BC, a total of 99 overlapping genes, 9 modules, 29 biological processes and 7 pathways were identified. Meanwhile, for T2DM and BC, 56 overlapping genes, 5 modules, 20 biological processes and 12 pathways were identified. Based on the Gene Ontology functional enrichment analysis of the top 10 non-overlapping modules of the two diseases, 10 biological functions and 5 pathways overlapped between them. The glycosphingolipid and lysosome pathways verified molecular mechanisms of cell death related to both DM and BC. We also identified new biological functions of dopamine receptors and four signalling pathways (Parkinson's disease, Alzheimer's disease, Huntington's disease and long-term depression) related to both diseases; these warrant further investigation. Our results illustrate the landscape of the novel molecular substructures between DM and BC, which may support a new model for complex disease classification and rational therapies for multiple diseases.

Bone defects caused heavy social and economic burdens worldwide. Nel-like molecule, type 1 (NELL-1) could enhance the osteogenesis and the repairment of bone defects, while the specific mechanism remains to be elucidated. Circular RNAs (circRNAs) have been found to play critical roles in the tissue development and serve as biomarkers for various diseases. However, it remains unclear that the expression patterns of circRNAs and the roles of them played in recombinant NELL-1-induced osteogenesis of human adipose-derived stem cells (hASCs). In this study, we performed RNA-sequencing to investigate the expression profiles of circRNAs in recombinant NELL-1-induced osteogenic differentiation and identified two key circRNAs, namely circRFWD2 and circINO80. These two circRNAs were confirmed to be up-regulated during recombinant NELL-1-induced osteogenesis, and knockdown of them affected the positive effect of NELL-1 on osteogenesis. CircRFWD2 and circINO80 could interact with hsa-miR-6817-5p, which could inhibit the osteogenesis. Silencing hsa-miR-6817-5p could partially reverse the negative effect of si-circRFWD2 and si-circINO80 on the osteogenesis. Therefore, circRFWD2 and circINO80 could regulate the expression of hsa-miR-6817-5p and influence the recombinant NELL-1-induced osteogenic differentiation of hASCs. It opens a new window to better understanding the effects of NELL-1 on the osteogenic differentiation of hASCs and provides potential molecular targets and novel methods for bone regeneration efficiently and safely.

Under steady-state conditions, the pool size of peripheral CD8+ T cells is maintained through turnover and survival. Beyond TCR and IL-7R signals, the underlying mechanisms are less well understood. In the present study, we found a significant reduction of CD8+ T cell proportion in spleens but not in thymi of mice with T cell-specific deletion of Mediator Subunit 1 (Med1). A competitive transfer of wild-type (WT) and Med1-deficient CD8+ T cells reproduced the phenotype in the same recipients and confirmed intrinsic role of Med1. Furthermore, we observed a comparable degree of migration and proliferation but a significant increase of cell death in Med1-deficient CD8+ T cells compared with WT counterparts. Finally, Med1-deficient CD8+ T cells exhibited a decreased expression of interleukin-7 receptor α (IL-7Rα), down-regulation of phosphorylated-STAT5 (pSTAT5) and Bim up-regulation. Collectively, our study reveals a novel role of Med1 in the maintenance of CD8+ T cells through IL-7Rα/STAT5 pathway-mediated cell survival.

Under static condition, the pool size of peripheral invariant natural killer T (iNKT) cells is determined by their homeostatic proliferation, survival and thymic input. However, the underlying mechanism is not fully understood. In the present study, we found that the percentage and number of iNKT cells were significantly reduced in the spleen, but not in the thymus of mice with deletion of polybromo-1 (Pbrm1) compared to wild type (WT) mice. Pbrm1 deletion did not affect iNKT cell proliferation and survival, instead significantly impaired their development from stage 1 to stage 2. Importantly, loss of Pbrm1 led to a dysfunction of RORγt expression and iNKT17 cell differentiation, but not iNKT1 and iNKT2 proportion. Collectively, our study reveals a novel mechanism of Pbrm1 controlling the peripheral size of iNKT cells through regulating their development and differentiation.

In this study, a homogenous polysaccharide (FSP), with an average molecular weight of 9.08 × 104  Da, was isolated from Forsythia suspense and its antibacterial potential against Enterobacter cloacae producing SHV-12 ESBL was investigated. Growth kinetics, in vitro competition and biofilm formation experiments demonstrated that SHV-12 ESBL contributed to a fitness benefit to E cloacae strain. The antibacterial activity of FSP (2.5, 5.0 and 10.0 μg/mL) was tested against E cloacae bearing SHV-12 ESBL gene using bacterial sensitivity, agar bioassay and agar well diffusion assays. It was found that the addition of FSP demonstrated potent antibacterial activities against this bacterial as showed by the decrease of bacterial growth and the increase of the inhibition zone diameter. Furthermore, SHV-12 ESBL gene expression was decreased in E cloacae strain following different FSP treatment in a concentration-dependent manner. In conclusion, these data showed that FSP exhibited potent good antibacterial activity against E cloacae producing SHV-12 ESBL via inhibition of SHV-12 ESBL gene expression, which may promote the development of novel natural antibacterial agents to treat infections caused by this drug-resistant bacterial pathogen.

Syndecan-1 (SDC1), with a variable ectodomain carrying heparan sulphate (HS) chains between different Syndecans, participates in many steps of inflammatory responses. In the process of proteolysis, the HS chains of the complete extracellular domain can be shed from the cell surface, by which they can mediate most of SDC1's function. However, the exact impact on SDC1 which anchored on the cell surface has not been clearly reported. In our study, we established the models by transfection with the cleavable resistant SDC1 mutant plasmid, in which SDC1 shedding can be suppressed during stimulation. Role of membrane SDC1 in inflammatory pathway, pro-inflammatory cytokine secretion as well as neutrophil transmigration, and how suppressing its shedding will benefit colitis were further investigated. We found that the patients suffered ulcerative colitis had high serum SDC1 levels,presented with increased levels of P65, tumour necrosis factor alpha (TNF-α) and IL-1β and higher circulating neutrophils. NF-κB pathway was activated, and secretion of TNF-α, interleukin-1beta (IL-1β), IL-6 and IL-8 were increased upon lipopolysaccharide stimuli in intestinal epithelial cells. Syndecan-1, via its anchored ectodomain, significantly lessened these up-regulation extents. It also functioned in inhibiting transmigration of neutrophils by decreasing CXCL-1 secretion. Moreover, SDC1 ameliorated colitis activity and improved histological disturbances of colon in mice. Taken together, we conclude that suppression of SDC1 shedding from intestinal epithelial cells relieves severity of intestinal inflammation and neutrophil transmigration by inactivating key inflammatory regulators NF-κB, and down-regulating pro-inflammatory cytokine expressions. These indicated that compenstion and shedding suppression of cytomembrane SDC1 might be the optional therapy for intestinal inflammation.

Osteoarthritis (OA) is a whole-joint disease characterized by synovial inflammation and cartilage degeneration. However, the relationship between synovial inflammation and cartilage degeneration remains unclear. The modified Hulth's method was adopted to establish a knee OA (KOA) rabbit model. Synovial tissue was collected after 8 weeks, and synovial tissue-derived extracellular vesicles (ST-EVs) were extracted by filtration combined with size exclusion chromatography (SECF), followed by identification through transmission electron microscopy (TEM), nanoparticle tracer analysis (NTA) and Western blot (WB). The collagenase digestion method was used to extract normal rabbit chondrocytes, which were then treated with the SF-EVs to observe the effect and mechanism of SF-EVs on chondrocytes. The morphology, particle size and labelled protein marker detection confirmed that SECF successfully extract ST-EVs. The ST-EVs in the KOA state significantly inhibited chondrocyte proliferation and promoted chondrocytes apoptosis. Moreover, the ST-EVs also promoted the expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α and COX-2) and cartilage degradation-related enzymes (MMP13, MMP9 and ADAMTS5) in the chondrocytes. Mechanistically, the ST-EVs significantly promoted the activation of NF-κB signalling pathway in chondrocytes. Inhibition the activation of the NF-κB signalling pathway significantly rescued the expression of inflammatory cytokines and cartilage degradation-related enzymes in the ST-EVs-induced chondrocytes. In conclusion, the ST-EVs promote chondrocytes inflammation and degradation by activating the NF-κB signalling pathway, providing novel insights into the occurrence and development of OA.

Numerous single nucleotide polymorphisms (SNPs), which have been identified as susceptibility factors for Parkinson's disease (PD) as per genome-wide association studies, have not been fully characterized for PD patients in China. This study aimed to replicate the relationship between 12 novel SNPs of 12 genes and PD risk in southern Chinese population. Twelve SNPs of 12 genes were detected in 231 PD patients and 249 controls, using the SNaPshot technique. Meta-analysis was used to assess heterogeneity of effect sizes between this study and published data. The impact of SNPs on gene expression was investigated by analysing the SNP-gene association in the expression quantitative trait loci (eQTL) data sets. rs8180209 of SNCA (allele model: P = .047, OR = 0.77; additive model: P = .047, OR = 0.77), rs2270968 of MCCC1 (dominant model: P = .024, OR = 1.52), rs7479949 of DLG2 (recessive model; P = .019, OR = 1.52), rs10748818 of GBF1 (additive model: P < .001, OR = 0.37), and rs4771268 of MBNL2 (recessive model: P = .003, OR = 0.48) were replicated to be significantly associated with the increased risk of PD. Noteworthy, a meta-analysis of previous studies suggested rs8180209, rs2270968, rs7479949 and rs4771268 were in line with those of our cohort. Our study replicated five novel functional SNPs in SNCA, MCCC1, DLG2, GBF1 and MBNL2 could be associated with increased risk of PD in southern Chinese population.

Polycystic ovary syndrome (PCOS), the most common female endocrine disease that causes anovulatory infertility, still lacks promising strategy for the accurate diagnosis and effective therapeutics of PCOS attributed to its unclear aetiology. In this study, we determined the abnormal reduction in circPSMC3 expression by comparing the ovarian tissue samples of PCOS patients and normal individuals. The symptom relief caused by up-regulation of circPSMC3 in PCOS model mice suggested the potential for further study. In vitro functional experiments confirmed that circPSMC3 can inhibit cell proliferation and promote apoptosis by blocking the cell cycle in human-like granular tumour cell lines. Mechanism study revealed that circPSMC3 may play its role through sponging miR-296-3p to regulate PTEN expression. Collectively, we preliminarily characterized the role and possible insights of circPSMC3/miR-296-3p/PTEN axis in the proliferation and apoptosis of KGN cells. We hope that this work provides some original and valuable information for the research of circRNAs in PCOS, not only to better understand the pathogenesis but also to help provide new clues for seeking for the future therapeutic target of PCOS.

Myocardial ischaemia-reperfusion (I/R) injury is a serious illness with high morbidity and mortality. Mounting evidence indicates the utility of sevoflurane (SEV) in the treatment of myocardial I/R injury. This study aimed to explore the molecular mechanisms underlying the protective action of SEV against myocardial I/R injury. A rat model of myocardial I/R injury was established, and I/R rats were treated with different concentrations of SEV. MicroRNA-203 (miR-203) and doublecortin (DCX) expression levels were determined using reverse transcription-quantitative polymerase chain reaction. Putative target relationship between miR-203 and DCX was explored using dual-luciferase reporter gene assay and RNA-binding protein immunoprecipitation assay. Ischaemia-reperfusion rats were treated with SEV, miR-203 antagomir or sh-DCX, followed by determination of oxidative stress- and inflammation-related factor levels using nitrite and enzyme-linked immunosorbent assays, and that of apoptosis-related factors using Western blot analysis. The apoptotic rate of myocardial tissues was determined using TdT-mediated dUTP-biotin nick end labeling (TUNEL) staining, and the infract area was evaluated using triphenyltetrazolium chloride staining. The results showed miR-203 was poorly expressed and DCX was highly expressed in myocardial tissues of I/R rats. Sevoflurane was found to elevate miR-203, and miR-203, in turn, could target and reduce DCX expression. Sevoflurane, miR-203 overexpression or DCX silencing resulted in declined oxidative stress, inflammation, apoptosis and infarct area, ultimately alleviating myocardial I/R injury. Collectively, these findings showed that SEV-activated miR-203 exhibited suppressive effects on myocardial I/R injury in rats and highlighted the SEV/miR-203/DCX axis as a promising therapeutic target for myocardial I/R injury management.

Andrographolide (Andro), a component from Chinese medicinal herb Andrographis paniculata, could alleviate pulmonary fibrosis in rodents. Yet, whether and how Andro mitigates epithelial-mesenchymal transition (EMT) induced by TGF-β1 remain unknown. This study aimed to explore the effect of Andro on TGF-β1-induced EMT in human alveolar epithelial cells (AECs) and the mechanisms involved. We illustrated that Andro inhibited TGF-β1-induced EMT and EMT-related transcription factors in alveolar epithelial A549 cells. Andro also reduced TGF-β1-induced cell migration and synthesis of pro-fibrotic factors (ie CCN-2, TGF-β1), matrix metalloproteinases (ie MMP-2, MMP-9) and extracellular matrix (ECM) components (ie collagen 1), implying the inhibiting effect of Andro on TGF-β1-induced EMT-like cell behaviours. Mechanistically, Andro treatment not only repressed TGF-β1-induced Smad2/3 phosphorylation and Smad4 nuclear translocation, but also suppressed TGF-β1-induced Erk1/2 phosphorylation and nuclear translocation in A549 cells. And treatment with ALK5 inhibitor (SB431542) or Erk1/2 inhibitors (SCH772984 and PD98059) remarkably reduced EMT evoked by TGF-β1. In addition, Andro also reduced TGF-β1-induced intracellular ROS generation and NOX4 expression, and elevated antioxidant superoxide dismutase 2 (SOD2) expression, demonstrating the inhibiting effect of Andro on TGF-β1-induced oxidative stress, which is closely linked to EMT. Furthermore, Andro remarkably attenuated TGF-β1-induced down-regulation of sirtuin1 (Sirt1) and forkhead box O3 (FOXO3), implying that Andro protects AECs from EMT partially by activating Sirt1/FOXO3-mediated anti-oxidative stress pathway. In conclusion, Andro represses TGF-β1-induced EMT in AECs by suppressing Smad2/3 and Erk1/2 signalling pathways and is also closely linked to the activation of sirt1/FOXO3-mediated anti-oxidative stress pathway.

The activation of Wnt/β-catenin pathway plays a pivotal role in promoting renal fibrosis. The activation of Wnt/β-catenin pathway relies on the binding of Wnts to Frizzled receptors on cell membrane. However, the factor regulating Wnts production remains unclear. Here, we demonstrated that transcriptional factor FoxM1 was significantly increased in obstructed kidneys and patients' kidneys with fibrosis. The up-regulation of FoxM1 mainly distributed in tubular epithelial cells. Pharmacological inhibition of FoxM1 down-regulated multi-Wnts elevation in UUO mice and attenuated renal fibrosis. In cultured renal tubular epithelial cells, overexpression of FoxM1 promoted 8 Wnts expression, while knock-down on FoxM1-suppressed multi-Wnts including Wnt1, Wnt2b and Wnt3 expression induced by Ang II. Chromatin immunoprecipitation PCR confirmed that FoxM1 bound to Wnt1, Wnt2b, Wnt3 promoters and luciferase assay further identified that the transcriptions of Wnt1, Wnt2b and Wnt3 were regulated by FoxM1. Thus, our findings show that multi-Wnt family members were regulated by transcriptional factor FoxM1. FoxM1 might be a key switch for activating β-catenin pathway and renal fibrosis. Therefore, FoxM1 might be a potential therapeutic target in manipulating renal fibrosis.

Excessive post-epidural fibrosis is a common cause of recurrent back pain after spinal surgery. Though various treatment methods have been conducted, the safe and effective drug for alleviating post-epidural fibrosis remains largely unknown. Metformin, a medicine used in the treatment of type 2 diabetes, has been noted to relieve fibrosis in various organs. In the present study, we aimed to explore the roles and mechanisms of metformin in scar formation in a mouse model of laminectomy. Post-epidural fibrosis developed in a mouse model of laminectomy by spinous process and the T12-L2 vertebral plate with a rongeur. With the administration of metformin, post-epidural fibrosis was reduced, accompanied with decreased collagen and fibronectin in the scar tissues. Mechanistically, metformin decreased fibronectin and collagen deposition in fibroblast cells, and this effect was dependent on the HMGB1/TLR4 and TGF-β1/Smad3 signalling pathways. In addition, metformin influenced the metabolomics of the fibroblast cells. Taken together, our study suggests that metformin may be a potential option to mitigate epidural fibrosis after laminectomy.

Cinnamon is a wildly used traditional Chinese herbal medicine for osteoarthritis (OA) treatment, but the underlying mechanism remains ambiguous. The purpose of this study is to explore the mechanism of cinnamic aldehyde (CA), a bioactive substance extracted from Cinnamon, on synovial inflammation in OA. A total of 144 CA-OA co-targeted genes were identified by detect databases (PubChem, HIT, TCMSP, TTD, DrugBank and GeneCards). The results of GO enrichment analysis indicated that these co-targeted genes have participated in many biological processes including 'inflammatory response', 'cellular response to lipopolysaccharide', 'response to drug', 'immune response', 'lipopolysaccharide-mediated signalling pathway', etc. KEGG pathway analysis showed these co-targeted genes were mainly enriched in 'Toll-like receptor signalling pathway', 'TNF signalling pathway', 'NF-kappa B signalling pathway', etc. Molecular docking demonstrated that CA could successfully bind to TLR2 and TLR4. The results of in vitro experiments showed no potential toxicity of 10, 20 and 50 μM/L CA on human OA FLS, and CA can significantly inhibit the inflammation in LPS-induced human FLS. Further experimental mechanism evidence confirmed CA can inhibited the inflammation in LPS-induced human OA FLS via blocking the TLR4/MyD88 signalling pathway. Our results demonstrated that CA exhibited strong anti-inflammation effect in OA FLS through blocking the activation of TLR4/MyD88 signalling pathway, suggesting its potential as a hopeful candidate for the development of novel agents for the treatment of OA.

Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is a common orthopaedic disease. GIONFH primarily manifests clinically as hip pain in the early stages, followed by the collapse of the femoral head, narrowing of the hip joint space and damage to the acetabulum, resulting in severely impaired mobility. However, the pathogenesis of GIONFH is not clearly understood. Recently, biomechanical forces and non-coding RNAs have been suggested to play important roles in the pathogenesis of GIONFH. This study aimed to evaluate the role of biomechanical forced and non-coding RNAs in GIONFH. We utilized an in vivo, rat model of GIONFH and used MRI, μCT, GIONFH-TST (tail suspension test), GIONFH-treadmill, haematoxylin and eosin staining, qRT-PCR and Western blot analysis to analyse the roles of biomechanical forces and non-coding RNAs in GIONFH. We used RAW264.7 cells and MC3T3E1 cells to verify the role of MALAT1/miR-329-5p/PRIP signalling using a dual luciferase reporter assay, qRT-PCR and Western blot analysis. The results demonstrated that MALAT1 and PRIP were up-regulated in the femoral head tissues of GIONFH rats, RAW264.7 cells, and MC3T3E1 cells exposed to dexamethasone (Dex). Knockdown of MALAT1 decreased PRIP expression in rats and cultured cells and rescued glucocorticoid-induced osteonecrosis of femoral head in rats. The dual luciferase reporter gene assay revealed a targeting relationship for MALAT1/miR-329-5p and miR-329-5p/PRIP in MC3T3E1 and RAW264.7 cells. In conclusion, MALAT1 played a vital role in the pathogenesis of GIONFH by binding to ('sponging') miR-329-5p to up-regulate PRIP. Also, biomechanical forces aggravated the pathogenesis of GIONFH through MALAT1/miR-329-5p/PRIP signalling.

Little is known about the incidence, clinical characteristics and prognostic factors in HIV associated lymphoma as these are less common than HIV-negative lymphoma in China. Currently, there are no standard guidelines for treatment of these patients. Therefore, we performed a study to analyse the clinical characteristics and outcomes of newly diagnosed HIV-associated aggressive B-cell non-Hodgkin's lymphoma (NHL) patients in Chongqing University Cancer Hospital (CUCH). Totally 86 newly diagnosed HIV-associated aggressive B-cell NHL patients in CUCH, southwest China, from July 2008 to August 2021, were analysed. In the entire cohort, median age was 48 years (range, 23-87 years), and more patients were male (87.2%). Most patients had elevated lactate dehydrogenase (LDH) (82.6%), advanced ann arbor stage (80.2%) and high IPI score (IPI score, 3-5) (62.7%) at diagnosis. Median CD4+ T-cell count at diagnosis was 191/μl (range, 4-1022), 84 patients (97.7%) were on combination antiretroviral therapy (cART) at lymphoma diagnosis. In DLBCL patients, cox multivariate analysis showed that age ≥ 60 (HR = 2.251, 95%CI 1.122-4.516; p = 0.012), elevated LDH (HR = 4.452, 95%CI 1.027-19.297; p = 0.041) and received less than two cycles of chemotherapy (HR = 0.629, 95%CI 0.589-1.071; p = 0.012) were independent risk factors for adverse prognosis based on PFS. Age ≥ 60 (HR = 3.162, 95%CI 1.500-6.665; p = 0.002) and received less than two cycles of chemotherapy (HR = 0.524, 95%CI 0.347-0.791; p = 0.002) were also independent risk factor for adverse prognosis based on OS. In BL patients, cox multivariate analysis showed that elevated LDH and received less than two cycles of chemotherapy were independent risk factors for adverse prognosis. In the DLBCL group, median PFS times in the received rituximab and no received rituximab groups were not reached and 12 months, respectively (p = 0.006). Median OS times were not reached and 36 months, respectively (p = 0.021). In the BL group, median PFS times in the received rituximab and no received rituximab groups were not reached and 4.8 months, respectively (p = 0.046). Median OS times were not reached and 10.1 months, respectively (p = 0.035). Overall, these data indicated that standardized anti-lymphoma therapy and rituximab administration were significantly associated with improved outcomes in patients with HIV-associated DLBCL and BL.