Identification of polyunsaturated fatty acids as potential biomarkers of osteoarthritis after sodium hyaluronate and mesenchymal stem cell treatment through metabolomics

Introduction: Osteoarthritis (OA) is a prevalent joint disorder worldwide. Sodium hyaluronate (SH) and mesenchymal stem cells (MSCs) are promising therapeutic strategies for OA. Previous studies showed they could improve knee function and clinical symptoms of OA. However, the mechanism of the therapeutic effects on the improvement of OA has not been clearly explained.Methods: In our study, we used a technique called 5-(diisopropylamino)amylamine derivatization liquid chromatography coupled with mass spectrometry to find the metabolites in OA synovial fluid under different treatments.Results and Discussion: After looking into the metabolomics, we discovered that SH and MSC treatment led to the downregulation of ω-6 polyunsaturated fatty acids (PUFAs) and the upregulation of ω-3 PUFAs. Significantly, the contents of 5(S)-HETE, PGA2, PGB2, and PGJ2 were lower in the MSC group than in the SH group after quantification using 5-(diisopropylamino)amylamine derivatization–UHPLC–QQQ-MS. This is the first report on the relationship of 11(S)-HETE, PGA2, PGB2, PGF2β, 11β-PGF2α, and DK-PGE2 with OA. Moreover, the correlation analysis of metabolites and inflammation factors showed the positive association of ω-6 PUFAs with pro-inflammation cytokines, and of ω-3 PUFAs with anti-inflammation cytokines. Our results indicated the therapeutic effect of SH and MSCs in patients with OA. In addition, this reliable metabolic approach could uncover novel biomarkers to treat OA

Signaling pathways in rheumatoid arthritis: implications for targeted therapy

Rheumatoid arthritis (RA) is an incurable systemic autoimmune disease. Disease progression leads to joint deformity and associated loss of function, which significantly impacts the quality of life for sufferers and adds to losses in the labor force. In the past few decades, RA has attracted increased attention from researchers, the abnormal signaling pathways in RA are a very important research field in the diagnosis and treatment of RA, which provides important evidence for understanding this complex disease and developing novel RA-linked intervention targets. The current review intends to provide a comprehensive overview of RA, including a general introduction to the disease, historical events, epidemiology, risk factors, and pathological process, highlight the primary research progress of the disease and various signaling pathways and molecular mechanisms, including genetic factors, epigenetic factors, summarize the most recent developments in identifying novel signaling pathways in RA and new inhibitors for treating RA. therapeutic interventions including approved drugs, clinical drugs, pre-clinical drugs, and cutting-edge therapeutic technologies. These developments will hopefully drive progress in new strategically targeted therapies and hope to provide novel ideas for RA treatment options in the future

Transition of tumor-associated macrophages from MHC class IIhi to MHC class IIlow mediates tumor progression in mice

<p>Abstract</p> <p>Background</p> <p>Tumor-associated macrophages (TAMs) are the most abundant immune cells within the tumor stroma and play a crucial role in tumor development. Although clinical investigations indicate that high levels of macrophage (MΦ) infiltration into tumors are associated with a poor prognosis, the exact role played by TAMs during tumor development remains unclear. The present study aimed to investigate dynamic changes in TAM major histocompatibility complex (MHC) class II expression levels and to assess the effects of these changes on tumor progression.</p> <p>Results</p> <p>Significant inhibition of tumor growth in the murine hepatocellular carcinoma Hepa1-6 model was closely associated with partial TAM depletion. Strikingly, two distinct TAM subsets were found to coexist within the tumor microenvironment during Hepa1-6 tumor development. An MHC class II^hiTAM population appeared during the early phase of tumor development and was associated with tumor suppression; however, an MHC class II^lowTAM population became increasingly predominant as the tumor progressed.</p> <p>Conclusions</p> <p>Tumor progression was positively correlated with increasing infiltration of the tumor tissues by MHC class II^lowTAMs. Thus, targeting the transition of MΦ may be a novel strategy for drug development and immunotherapy.</p

Antitumor Effect of Malaria Parasite Infection in a Murine Lewis Lung Cancer Model through Induction of Innate and Adaptive Immunity

BACKGROUND: Lung cancer is the most common malignancy in humans and its high fatality means that no effective treatment is available. Developing new therapeutic strategies for lung cancer is urgently needed. Malaria has been reported to stimulate host immune responses, which are believed to be efficacious for combating some clinical cancers. This study is aimed to provide evidence that malaria parasite infection is therapeutic for lung cancer. METHODOLOGY/PRINCIPAL FINDINGS: Antitumor effect of malaria infection was examined in both subcutaneously and intravenously implanted murine Lewis lung cancer (LLC) model. The results showed that malaria infection inhibited LLC growth and metastasis and prolonged the survival of tumor-bearing mice. Histological analysis of tumors from mice infected with malaria revealed that angiogenesis was inhibited, which correlated with increased terminal deoxynucleotidyl transferase-mediated (TUNEL) staining and decreased Ki-67 expression in tumors. Through natural killer (NK) cell cytotoxicity activity, cytokine assays, enzyme-linked immunospot assay, lymphocyte proliferation, and flow cytometry, we demonstrated that malaria infection provided anti-tumor effects by inducing both a potent anti-tumor innate immune response, including the secretion of IFN-γ and TNF-α and the activation of NK cells as well as adaptive anti-tumor immunity with increasing tumor-specific T-cell proliferation and cytolytic activity of CD8(+) T cells. Notably, tumor-bearing mice infected with the parasite developed long-lasting and effective tumor-specific immunity. Consequently, we found that malaria parasite infection could enhance the immune response of lung cancer DNA vaccine pcDNA3.1-hMUC1 and the combination produced a synergistic antitumor effect. CONCLUSIONS/SIGNIFICANCE: Malaria infection significantly suppresses LLC growth via induction of innate and adaptive antitumor responses in a mouse model. These data suggest that the malaria parasite may provide a novel strategy or therapeutic vaccine vector for anti-lung cancer immune-based therapy

Clinical utility of Liqui-PREP™ cytology system for primary cervical cancer screening in a large urban hospital setting in China

<b>Background:</b> Liquid based cytology (LBC) has been reported to increase the sensitivity of cervical cytology, in comparison with conventional cytology Pap smear (CPS). Most LBC systems though require expensive automated devices. <b> Aims:</b> To evaluate the efficiency of a new and inexpensive LBC system - LPT cytology system. <b> Materials and Methods:</b> Cervical screening was performed on 31500 patients utilizing the LPT cytology system test from January 2006 to May 2007. A similar number (n = 31500) of CPS were performed from January 2004 to July 2006. All cytology positive patients underwent colposcopy and cervical biopsy with histopathology examination. Fifty cases positive both on cytology and biopsy were submitted to the high-risk human papillomavirus (HPV) L1 protein (HR-HPV L1) tests. <b> Results:</b> The LPT cytology system adequately preserved cellular structure for morphologic evaluation. There was a significant difference of the histology/cytology diagnosis concordant rate between that of the CPS and LPT systems [93.6 vs. 78.4&#x0025;, <i>p</i>=0.001]. The significant higher concordant rate was also seen in the low grade intraepithelial lesion (LSIL) (95.4 vs. 78.9&#x0025;, <i>p</i>=0.001) and in high grade intraepithelial lesion (HSIL) (90.2 vs. 76.1&#x0025;, p=0.001) cytology diagnosis. There was no statistical difference in rate in atypical glandular cells (AGC) (61.5 vs. 60&#x0025;) and glandular cell carcinoma (GCC) (83.3 vs. 80&#x0025;). LPT resulted in a marked increased global detection over the CPS. Nuclear expression of HPV L1 was seen in 34&#x0025; (17/50) of cases. <b> Conclusions:</b> LPT showed an increase in detection rate compared to CPS (<i>P</i> = 0.001) and a significantly higher histological versus cytological concordant referral rate

Exosomes derived from human adipose mesenchymal stem cells improve ovary function of premature ovarian insufficiency by targeting SMAD

Abstract Background Although many reports show that various kinds of stem cells have the ability to recover the function of premature ovarian insufficiency (POI), few studies are associated with the mechanism of stem cell treatment of POI. We designed this experimental study to investigate whether human adipose stem cell-derived exosomes (hADSC-Exos) retain the ability to restore ovarian function and how hADSC-Exos work in this process. Methods A POI mouse model was established and human ovarian granule cells (hGCs) collected from individuals with POI were prepared to assess the therapeutic effects and illuminate the mechanism of hADSCs in curing POI. The hematoxylin and eosin assay method was employed to assess the number of follicles. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum levels of sex hormones. The proliferation rate and marker expression levels of hGCs were measured by flow cytometry (fluorescence-activated cell sorting). Real-time PCR and western blot assays were used to determine the mRNA and protein expression levels of SMAD2, SMAD3, and SMAD5. Western blot assays were used to test the protein expression levels of apoptosis genes (Fas, FasL, caspase-3, and caspase-8). Results After the hADSC-Exos were transplanted into the POI mice model, they exerted better therapeutic activity on mouse ovarian function, improving follicle numbers during four stages. ELISA results showed that hADSC-Exos elevated the hormone levels to the normal levels. In addition, after hADSC-Exos were cocultured with POI hGCs, our results showed that hADSC-Exos significantly promoted the proliferation rate and inhibited the apoptosis rate. Furthermore, hADSC-Exos also increased the marker expression of hGCs to the normal level. Besides, mRNA and protein assays demonstrated that hADSC-Exos downregulated the expression of SMAD2, SMAD3, and SMAD5 in vivo and in vitro. Western blot assay demonstrated that hADSC-Exos inhibited expression of the apoptosis genes in POI hGCs, and SMAD knockdown increased the protein expression of apoptosis genes. Conclusions These findings demonstrate for the first time the molecular cascade and related cell biology events involved in the mechanism by which exosomes derived from hADSCs improved ovarian function of POI disease via regulation of the SMAD signaling pathway

Patient with CATSPER3

Abstract Purpose This study is intended to investigate the candidate pathogenic gene in a patient with primary infertility but without the defect in routine semen parameters from a consanguineous family and explore the potential impacts of mutations on assisted reproductive technology outcome. Methods Whole‐exome sequencing (WES) was carried out. A variant in his family found by WES was verified by Sanger sequencing. Intracytoplasmic sperm injection (ICSI) was applied to obtain a successful outcome. Results A Cation Channel of Sperm 3(CATSPER3) homozygous variant (NM_ 178019.3:exon5:c.707T>A, p.L236*) was identified for the first time. The anti‐CD46 immunofluorescence analysis revealed the failure of sperm acrosome reaction (AR) caused by the mutation. ICSI treatment was successful. Conclusion This is the first report of a homozygous pathogenic CATSPER3 mutation. This mutation may cause male infertility with the failure of AR but without the defect in routine semen parameters. ICSI was supposed to be the most appropriate therapy

HGF and BFGF Secretion by Human Adipose-Derived Stem Cells Improves Ovarian Function During Natural Aging via Activation of the SIRT1/FOXO1 Signaling Pathway

Background/Aims: Human adipose-derived stem cells (hADSCs) are a potential therapeutic option for clinical applications because of their ability to produce cytokines and their capacity for trilineage differentiation. To date, few researchers have investigated the effects of hADSCs on natural ovarian aging (NOA). Methods: An NOA mouse model and human ovarian granule cells (hGCs) collected from individuals with NOA were prepared to assess the therapeutic effects and illuminate the mechanism of hADSCs in curing NOA. Enzyme-linked immunosorbent assay was used to detect the serum levels of sex hormones and antioxidative enzymes. The proliferation rate and marker expression level of hGCs were measured by flow cytometry (FACS). Cytokines were measured by a protein antibody array methodology. Western blot assays were used to determine the protein expression levels of SIRT1 and FOXO1. Results: Our results showed that hADSCs displayed therapeutic activity against ovarian function in an NOA mouse model, increasing the proliferation rate and marker expression level of hGCs. Furthermore, the yields of hADSC-secreted HGF and bFGF were higher than those of other growth factors. FACS showed that combination treatment with the growth factors HGF and bFGF more strongly promoted proliferation and inhibited apoptosis in hGCs than HGF or bFGF treatment alone. FACS and ELISA revealed that the combination treatment with both growth factors inhibited oxidative stress more forcefully than treatments with only one of these growth factors. In addition, protein assays demonstrated that combination treatment with both growth factors suppressed oxidative stress by up-regulating the expression of SIRT1 and FOXO1. Conclusion: These findings demonstrate for the first time the molecular cascade and related cell biology events involved in the mechanism by which HGF and bFGF derived from hADSCs improved ovarian function during natural aging via reduction of oxidative stress by activating the SIRT1/FOXO1 signaling pathway