Primary cilia abnormalities participate in the occurrence of spontaneous abortion through TGF-ß/SMAD2/3 signaling pathway.

Spontaneous abortion is the most common complication in early pregnancy, the exact etiology of most cases cannot be determined. Emerging studies suggest that mutations in ciliary genes may be associated with progression of pregnancy loss. However, the involvement of primary cilia on spontaneous abortion and the underlying molecular mechanisms remains poorly understood. We observed the number and length of primary cilia were significantly decreased in decidua of spontaneous abortion in human and lipopolysaccharide (LPS)-induced abortion mice model, accompanied with increased expression of proinflammatory cytokines interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α. The length of primary cilia in human endometrial stromal cell (hESC) was significantly shortened after TNF-α treatment. Knocking down intraflagellar transport 88 (IFT88), involved in cilia formation and maintenance, promoted the expression of TNF-α. There was a reverse regulatory relationship between cilia shortening and TNF-α expression. Further research found that shortened cilia impair decidualization in hESC through transforming growth factor (TGF)-ß/SMAD2/3 signaling. Primary cilia were impaired in decidua tissue of spontaneous abortion, which might be mainly caused by inflammatory injury. Primary cilia abnormalities resulted in dysregulation of TGF-ß/SMAD2/3 signaling transduction and decidualization impairment, which led to spontaneous abortion.

Moyamoya syndrome may result from psoriasis: Four case reports.

BACKGROUND: Moyamoya syndrome (MMS) is a group of diseases that involves more than one underlying disease and is accompanied by moyamoya vascular phenomena. Psoriasis is a chronic immune skin disease closely linked to high blood pressure and heart disease. However, psoriasis-related MMS has not been reported. CASE SUMMARY: We collected data on patients with stroke due to MMS between January 2017 and December 2019 and identified four cases of psoriasis. Case histories, imaging, and hematological data were collected. The average age of the initial stroke onset was 58.25 ± 11.52 years; three cases of hemorrhagic and one case of ischemic stroke were included. The average duration from psoriasis confirmation to the initial MMS-mediated stroke onset was 17 ± 3.56 years. All MMS-related stenoses involved the bilateral cerebral arteries: Suzuki grade III in one case, grade IV in two cases, and grade V in one case. Abnormally elevated plasma interleukin-6 levels were observed in four patients. Two patients had abnormally elevated immunoglobulin E levels, and two had thrombocytosis. All four patients received medication instead of surgery. With an average follow-up time of 2 years, two causing transient ischemic attacks occurred in two patients, and no hemorrhagic events occurred. CONCLUSION: Psoriasis may be a potential risk factor for MMS. Patients with psoriasis should be screened for MMS when they present with neurological symptoms.

The immune checkpoint TIGIT/CD155 promotes the exhaustion of CD8 + T cells in TNBC through glucose metabolic reprogramming mediated by PI3K/AKT/mTOR signaling.

OBJECTIVE: The CD155/TIGIT axis has attracted considerable interest as an emerging immune checkpoint with potential applications in cancer immunotherapy. Our research focused on investigating the role of CD155/TIGIT checkpoints in the progression of triple-negative breast cancer (TNBC). METHODS: We evaluated CD155 and TIGIT expression in TNBC tissues using both immunohistochemistry (IHC) and gene expression profiling. Our experiments, both in vivo and in vitro, provided evidence that inhibiting the CD155/TIGIT pathway reinstates the ability of CD8 + T cells to generate cytokines. To assess the impact of CD155/TIGIT signaling blockade, we utilized Glucose Assay Kits and Lactate Assay Kits to measure alterations in glucose and lactate levels within CD8 + T cells. We employed western blotting (WB) to investigate alterations in glycolytic-related proteins within the PI3K/AKT/mTOR pathways following the inhibition of CD155/TIGIT signaling. RESULTS: CD155 exhibits heightened expression within TNBC tissues and exhibits a negative correlation with the extent of infiltrating CD8 + T cells. Furthermore, patients with TNBC demonstrate elevated levels of TIGIT expression. Our findings indicate that the interaction between CD155 and TIGIT disrupts the glucose metabolism of CD8 + T cells by suppressing the activation of the PI3K/AKT/mTOR signaling pathway, ultimately leading to the reduced production of cytokines by CD8 + T cells. Both in vivo and in vitro experiments have conclusively demonstrated that the inhibition of CD155/TIGIT interaction reinstates the capacity of CD8 + T cells to generate cytokines. Moreover, in vivo administration of the blocking antibody against TIGIT not only inhibits tumor growth but also augments the functionality of CD8 + T lymphocytes. CONCLUSIONS: Our research findings strongly suggest that CD155/TIGIT represents a promising therapeutic target for treating TNBC.

Recent advance of ATP citrate lyase inhibitors for the treatment of cancer and related diseases.

ATP citrate lyase (ACLY), a strategic metabolic enzyme that catalyzes the glycolytic to lipidic metabolism, has gained increasing attention as an attractive therapeutic target for hyperlipidemia, cancers and other human diseases. Despite of continual research efforts, targeting ACLY has been very challenging. In this field, most reported ACLY inhibitors are "substrate-like" analogues, which occupied with the same active pockets. Besides, some ACLY inhibitors have been disclosed through biochemical screening or high throughput virtual screening. In this review, we briefly summarized the cancer-related functions and the recent advance of ACLY inhibitors with a particular focus on the SAR studies and their modes of action. We hope to provide a timely and updated overview of ACLY and the discovery of new ACLY inhibitors.

ß-catenin promotes resistance to trastuzumab in breast cancer cells through enhancing interaction between HER2 and SRC.

More than 1 million women worldwide are diagnosed with breast cancer (BC) each year. This study aims to explore the molecular mechanisms of ß-catenin affecting the trastuzumab tolerance in HER2-positive BC. ß-catenin in BC and non-BC tissue samples were assessed by immunohistochemistry. ß-catenin and HER2 were over-expressed and knockdown to evaluate their role in tumorigenicity and trastuzumab resistance in cell and animal models using soft-agar and xenograft assays. Confocal laser immunofluorescence assay and co-immunoprecipitation were used to assess protein-protein binding. Expression of genes was detected using Western blot analysis. ß-catenin was highly expressed in primary and metastatic BC, overexpression of ß-catenin increased the colony formation of MCF7 cells when it was co-expressed with HER2 and synergically increased the tumor size in immunodeficient mice. Overexpression of ß-catenin also increased the phosphorylation of HER2 and HER3 and increased the size of tumor derived from HER2-elevated cells. Confocal laser immunofluorescence assay showed that ß-catenin and HER2 were co-localized on the membrane of MDA-MB-231 cells, suggesting that ß-catenin binds HER2 to activate the HER2 signaling pathway. Immunoprecipitation of ß-catenin and HER2 also confirmed this binding. On the other hand, knockdown of ß-catenin in MDA-MB-231 cell lines decreased the activity of SRC and decreased phosphorylation of HER2 at Y877 and Y1248. The interaction between HER2 and SRC was enhanced when ß-catenin was overexpressed, and ß-catenin increased the resistance of tumor derived from HER2 elevated BT474 cells to trastuzumab. Further analysis showed that trastuzumab inhibited the activation of HER3, but SRC was still highly expressed in cells overexpressing ß-catenin. Our work demonstrates that ß-catenin is highly expressed in BC and it synergically promotes formation and progress of BC with HER2. ß-catenin binds with HER2 leading to enhanced interaction with SRC and resistance to trastuzumab.

Epidemiology and a Predictive Model of Prognosis Index Based on Machine Learning in Primary Breast Lymphoma: Population-Based Study.

BACKGROUND: Primary breast lymphoma (PBL) is a rare disease whose epidemiological features, treatment principles, and factors used for the patients' prognosis remain controversial. OBJECTIVE: The aim of this study was to explore the epidemiology of PBL and to develop a better model based on machine learning to predict the prognosis for patients with primary breast lymphoma. METHODS: The annual incidence of PBL was extracted from the surveillance, epidemiology, and end results database between 1975 and 2019 to examine disease occurrence trends using Joinpoint software (version 4.9; National Cancer Institute). We enrolled data from 1251 female patients with primary breast lymphoma from the surveillance, epidemiology, and end results database for survival analysis. Univariable and multivariable analyses were performed to explore independent prognostic factors for overall survival and disease-specific survival of patients with primary breast lymphoma. Eight machine learning algorithms were developed to predict the 5-year survival of patients with primary breast lymphoma. RESULTS: The overall incidence of PBL increased drastically between 1975 and 2004, followed by a significant downward trend in incidence around 2004, with an average annual percent change (AAPC) of -0.8 (95% CI -1.1 to -0.6). Disparities in trends of PBL exist by age and race. The AAPC of the 65 years or older cohort was about 1.2 higher than that for the younger than 65 years cohort. The AAPC of White patients is 0.9 (95% CI 0.0-1.8), while that of Black patients was significantly higher at 2.1 (95% CI -2.5 to 6.9). We also identified that the risk of death from PBL is multifactorial and includes patient factors and treatment factors. Survival analysis revealed that the patients diagnosed between 2007 and 2015 had a significant risk reduction of mortality compared to those diagnosed between 1983 and 1990. The gradient booster model outperforms other models, with 0.752 for sensitivity and 0.817 for area under the curve. The important features established with the gradient booster model were the year of diagnosis, age, histologic type, and primary site, which were the 4 most relevant variables to explain 5-year survival status. CONCLUSIONS: The incidence of PBL started demonstrating a tendency to decrease after 2004, which varied by age and race. In recent years, the prognosis of patients with primary breast lymphoma has been remarkably improved. The gradient booster model had a promising performance. This model can help clinicians identify the early prognosis of patients with primary breast lymphoma and therefore improve the clinical outcome by changing management strategies and patient health care.

Polyacetylene Isomers Isolated from Bidens pilosa L. Suppress the Metastasis of Gastric Cancer Cells by Inhibiting Wnt/ß-Catenin and Hippo/YAP Signaling Pathways.

(E)-7-Phenyl-2-hepten-4,6-diyn-1-ol (1) and (Z)-7-Phenyl-2-hepten-4,6-diyn-1-ol (2) are isomeric natural polyacetylenes isolated from the Chinese medicinal plant Bidens pilosa L. This study first revealed the excellent anti-metastasis potential of these two polyacetylenes on human gastric cancer HGC-27 cells and the distinctive molecular mechanisms underlying their activities. Polyacetylenes 1 and 2 significantly inhibited the migration, invasion, and adhesion of HGC-27 cells at their non-toxic concentrations in a dose-dependent manner. The results of a further mechanism investigation showed that polyacetylene 1 inhibited the expressions of Vimentin, Snail, ß-catenin, GSK3ß, MST1, YAP, YAP/TAZ, and their phosphorylation, and upregulated the expression of E-cadherin and p-LATS1. In addition, the expressions of various downstream metastasis-related proteins, such as MMP2/7/9/14, c-Myc, ICAM-1, VCAM-1, MAPK, p-MAPK, Sox2, Cox2, and Cyr61, were also suppressed in a dose-dependent manner. These findings suggested that polyacetylene 1 exhibited its anti-metastasis activities on HGC-27 cells through the reversal of the EMT process and the suppression of the Wnt/ß-catenin and Hippo/YAP signaling pathways.

Rainstorms drive export of aromatic and concurrent bio-labile organic matter to a large eutrophic lake and its major tributaries.

Lakes are hotspots for global carbon cycling, yet few studies have explored how rainstorms alter the flux, composition, and bio-lability of dissolved organic matter (DOM) in inflowing rivers using high-frequency monitoring. We conducted extensive campaigns in the watershed of Lake Taihu and made daily observations for three years in its two largest inflowing tributaries, River Dapu and River Yincun. We found higher DOC, bio-labile DOC (BDOC), and specific UV absorbance (SUVA254) levels in the northwestern inflowing regions compared with the remaining lake regions. DOC and BDOC increased during rainstorms in River Dapu, and DOC declined due to local dilution and BDOC increased during rainstorms in River Yincun. We found that rainstorms resulted in increased DOM absorbance a350, SUVA254, and humification index (HIX) and enhanced percentages of humic-like fluorescent components, %polycyclic condensed aromatic and %polyphenolic compounds as revealed from ultrahigh-resolution mass spectrometry (FT-ICR MS), while spectral slope (S275-295) and the percentages of protein-like C1 and C3 declined during rainstorms compared with other seasons. This can be explained by a combined flushing of catchment soil organic matter and household effluents. The annual inflows of DOC and BDOC to Lake Taihu were 1.15 ± 0.18 × 104 t C yr-1 and 0.23 ± 0.06 × 104 t C yr-1 from River Dapu and 2.92 ± 0.42 × 103 t C yr-1 and 0.53 ± 0.07 × 103 t C yr-1 from River Yincun, respectively, and the fluxes of DOC and BDOC from both rivers increased during rainstorms. We found an elevated frequency of heavy rainfall and rainstorms in the lake watershed during the past six decades. We conclude that an elevated input of terrestrial organic-rich DOM with concurrent high aromaticity and high bio-lability from inflowing rivers is likely to occur in a future wetter climate.

Caryophyllene-type sesquiterpenes from the endophytic fungus Pestalotiopsis lespedezae through an OSMAC approach.

Two new caryophyllene-type sesquiterpenes pestalotiopsins U and V (1 and 2) and three known compounds pestalotiopsin B (7), pestaloporinate B (8), and pestalotiopsin C (9) were isolated by the cultivation of the endophytic fungus Pestalotiopsis lespedezae on solid rice medium, while four additional new caryophyllene pestalotiopsins W-Z (3-6) were obtained when 3.5% NaI was added to the fungal culture medium. The structures of the new compounds were determined by HRESIMS and 1D/2D nuclear magnetic resonance data. Compounds 1-9 were tested for cytotoxicity against the mouse lymphoma cell line L5178Y, but only 6 displayed significant activity with an IC50 value of 2.4 µM.

A retrospective study on comparing the surgery and microneedles radiofrequency and microwaves treatment in axillary osmidrosis.

OBJECTIVE: To compare the traditional treatment of minimally invasion surgery with the evolving treatments of microneedles radiofrequency and microwaves, this study mainly focused on the clinical efficacy and the incidence rate (IR) of complications among three treatments. METHODS: From August 2017 to August 2018, a total of 76 patients with bilateral axillary osmidrosis were enrolled respectively underwent minimally invasion surgery, microneedles radiofrequency and microwaves treatment. All these subjects were evaluated the clinical outcomes and collected the complications by themselves or physicians. The difference of objective recovery or effective rate, subjective effective rate, the intense of sweat secretion or armpits hair, IR of complications among these three groups were studied. RESULTS: The baseline characteristics of 33 patients in surgery group, 24 patients in microneedles group and 19 patients in microwaves group were similar. Firstly, the objective clinical efficacy was similar, but the subjective effective rate in surgery group was the soundest. In addition, the reduction of sweat secretion was homologous in three group, but the intense of armpits hair reduction in microneedles group was the minimum in three groups. Moreover, surgery treatment caused the highest IR of complications and the broadest types of complications, especially for the IR of 87.9% in postoperative scar formation. Meanwhile, the microwaves treatment had the best safety profile. At last, the recurrence rate on 6 months postoperatively was also identical with no significant difference. CONCLUSIONS: For the advantages and disadvantages of these three treatments, axillary osmidrosis patients should choose the proper therapy with comprehensive considerations.

Abundance and characteristics of microplastics in the surface water and sediment of parks in Xi'an city, Northwest China.

Microplastics (MPs), as a new type of pollutants, have attracted wide attention especially in recent years, but there was insufficient research on the distribution and characteristics of MPs in urban park water body. In this study, the pollution of MPs in water and sediment of Xi'an, the largest city in northwest China, was investigated. The MPs concentration in the surface water and sediment was 2900-6970 items/m3 and 940-3560 items/kg, respectively. According to the urban functions, the parks were divided into residential areas, commercial areas, tourism areas and industrial areas, and the highest abundance of MPs was observed in the tourism and residential areas, suggesting the impacts of human activities. MPs in these parks were mainly in four kinds of shapes, namely fiber, pellet, fragment and film, and dominated by fibers and fragments. Most of the extracted MPs were small in size, and 63-92% of them were smaller than 0.5 mm. Polypropylene and polyethylene terephthalate were the main polymer types in surface water and sediments, respectively. This study showed that the park water and sediment can be used as an important "sink" in MPs, which is of great significance for monitoring and alleviating the pollution of urban MPs. This study provided important reference for better understanding MPs levels in inland freshwaters.

Molecular cloning, immunological characterization, and expression analysis of gonadotropin-releasing hormone (GnRH) in the brain of the Chinese alligator during different stages of reproductive cycle.

The neurohormone gonadotropin-releasing hormone (GnRH) plays an essential role in the control of reproductive functions in vertebrates. However, the full-length complementary DNA (cDNA) encoding the GnRHs precursor and it role in the reproductive cycles regulating has not been illustrated in crocodilian species. In the present study, full-length cDNAs encoding GnRH1 forms, its predominant localization within brain and peripheral tissues, and GnRH1 peptide concentrations in the hypothalamus and pituitary in relation to seasonal gonadal development of Chinese alligator were investigated. The cDNA of GnRH1 is consisted of 282 bp open reading frame encoding 93 amino acids. The deduced amino acid sequence of alligator GnRH1 contains several conserved regions and shows a closer genetic relationship to the avian species than to other reptile species. The GnRH1 immunopositive cells were not only detected widely in cerebrum, diencephalon, medulla oblongata but also observed in peripheral tissues, these widespread distribution characteristics indicated that GnRH1 possibly possess the multi-functionality in Chinese Alligator. GnRH1 peptide concentration within hypothalamus were observed be the highest in RP group (P < 0.05), in association with an peak value in GSI and emerging of late vitellogenic follicles in the ovary. Taken together, our results suggested that GnRH1 was predominantly involved in the vitellogenesis process of seasonal gonadal development of Chinese Alligator.

Pattern recognition receptor-initiated innate immune responses in mouse prostatic epithelial cells‡.

Three major pathogenic states of the prostate, including benign prostatic hyperplasia, prostate cancer, and prostatitis, are related to the local inflammation. However, the mechanisms underlying the initiation of prostate inflammation remain largely unknown. Given that the innate immune responses of the tissue-specific cells to microbial infection or autoantigens contribute to local inflammation, this study focused on pattern recognition receptor (PRR)-initiated innate immune responses in mouse prostatic epithelial cells (PECs). Primary mouse PECs abundantly expressed Toll-like receptor 3 (TLR3), TLR4, TLR5, melanoma differentiation-associated protein 5 (MDA5), and IFN-inducible protein 16 (p204 in mouse). These PRRs can be activated by their respective ligands: lipopolysaccharide (LPS) and flagellin of Gram-negative bacteria for TLR4 and TLR5, polyinosinic-polycytidylic acid (poly(I:C)) for TLR3 and MDA5, and herpes simplex virus DNA analog (HSV60) for p204. LPS and flagellin predominantly induced the expression of inflammatory cytokines, including tumor necrosis factor alpha (TNFA), interleukin 6 (IL6), chemokines monocyte chemoattractant protein-1 (MCP1), and C-X-C motif chemokine 10 (CXCL10). Poly(I:C) and HSV60 predominantly induced the expression of type 1 interferons (IFNA and IFNB) and antiviral proteins: Mx GTPase 1, 2',5'-oligoadenylate synthetase 1, and IFN-stimulated gene 15. The replication of mumps virus in PECs was inhibited by type 1 IFN signaling. These findings provide insights into the mechanisms underlying innate immune response in the prostate.

Characterization of an Antiviral Component in Human Seminal Plasma.

Numerous types of viruses have been found in human semen, which raises concerns about the sexual transmission of these viruses. The overall effect of semen on viral infection and transmission have yet to be fully investigated. In the present study, we aimed at the effect of seminal plasma (SP) on viral infection by focusing on the mumps viral (MuV) infection of HeLa cells. MuV efficiently infected HeLa cells in vitro. MuV infection was strongly inhibited by the pre-treatment of viruses with SP. SP inhibited MuV infection through the impairment of the virus's attachment to cells. The antiviral activity of SP was resistant to the treatment of SP with boiling water, Proteinase K, RNase A, and DNase I, suggesting that the antiviral factor would not be proteins and nucleic acids. PNGase or PLA2 treatments did not abrogate the antiviral effect of SP against MuV. Further, we showed that the prostatic fluid (PF) showed similar inhibition as SP, whereas the epididymal fluid and seminal vesicle extract did not inhibit MuV infection. Both SP and PF also inhibited MuV infection of other cell types, including another human cervical carcinoma cell line C33a, mouse primary epididymal epithelial cells, and Sertoli cell line 15P1. Moreover, this inhibitory effect was not specific to MuV, as the herpes simplex virus 1, dengue virus 2, and adenovirus 5 infections were also inhibited by SP and PF. Our findings suggest that SP contains a prostate-derived pan-antiviral factor that may limit the sexual transmission of various viruses.

Effect of cadmium on the sorption of tylosin by polystyrene microplastics.

Microplastics are widespread in the environment and might transport readily by ocean currents, wind and atmospheric deposition. Simultaneously, antibiotics and heavy metals could often be detected in the environment. They are both positively charged, it is necessary to clarify the interactions of these pollutants with microplastics when they were coexist. In this study, the most commonly used polystyrene (PS) was selected as a representative microplastic. This study investigated the effect of Cd(II) on the sorption of TYL by PS in different coexistence systems. The results showed that: in the composite system, when TYL and Cd(II) coexist, the presence of Cd(II) could inhibit the sorption of TYL by PS, and the inhibitory effect increases with the increase of the concentration of Cd(II), indicating that competitive sorption dominates the sorption. When PS adsorbed Cd(II) first and then adsorbed TYL, the presence of Cd(II) was conducive to the sorption of TYL, and the sorption strengthened with the increase of Cd(II) concentration, indicating that the complexation between TYL and Cd(II) enhanced the sorption of TYL. In addition, initial pH values and ionic strength were essential in the sorption process. Therefore, this study could provide an important basis for evaluating the environmental behavior and ecological risk of microplastics in the process of compound pollution.

[Low-magnitude vibration promotes osteogenesis of osteoblasts in ovariectomized osteoporotic rats via the estrogen receptor α].

The purpose of this study was to investigate the effect of low-magnitude vibration on osteogenesis of osteoblasts in ovariectomized rats with osteoporosis via estrogen receptor α(ERα). The mRNA expression of osteogenic markers were examined with qRT-PCR, based on which the optimal vibration parameter for promoting osteogenesis was determined (45 Hz × 0.9 g, g = 9.8 m/s2). Then we loaded the optimal vibration parameter on the osteoblasts of ovariectomized rats with osteoporosis. The protein expression of osteogenic markers and ERα were detected with Western blot; the distribution of ERα was examined with immunofluorescence technique. Finally, through inhibiting the expression of ERα with estrogen receptor inhibitor ICI182780, the protein and mRNA expression of osteogenic markers were examined. First, the results showed that low-magnitude vibration could promote the expression of osteogenic markers and ERα in osteoblasts of ovariectomized rats with osteoporosis (P < 0.05), and make ERα transfer to the nucleus. On the other hand, the results also showed that after inhibiting the expression of ERα in osteoblasts of ovariectomized rats with osteoporosis, the protein and mRNA expression of osteogenic marker were decreased (P < 0.05). In our study, low-magnitude vibration played an important role in the osteogenesis of osteoblasts in ovariectomized rats with osteoporosis through increasing the expression and causing translocation of ERα. Furthermore, it provides a theoretical basis for the application of low-magnitude vibration in the prevention and treatment of postmenopausal osteoporosis.

Low-magnitude vibration induces osteogenic differentiation of bone marrow mesenchymal stem cells via miR-378a-3p/Grb2 pathway to promote bone formation in a rat model of age-related bone loss.

The dysfunction of bone marrow mesenchymal stem cells (BMSCs) in osteogenic differentiation is one of the main causes of age-related bone loss. Our previous studies have shown that low-magnitude vibration (LMV) induces the osteogenic differentiation of BMSCs derived from ovariectomized osteoporotic rats. To investigate whether LMV promotes osteogenic differentiation of BMSCs and its underlying mechanisms in aged rats, 20-month-old female Sprague-Dawley rats (n = 20) were randomly divided into LMV group (rats were vibrated at 0.3 g and 90 Hz for 30 minutes, once daily, 5 days a week until 12 weeks for subsequent analysis, n = 10), static group (rats were placed in the box on the vibration platform without vibration, n = 10); 6-month-old female Sprague-Dawley rats were used as control (young group, n = 10). The bone mineral density and bone strength of aged rats were significantly decreased compared with the young rats. Furthermore, the primary BMSCs isolated and cultured from the aged rats with the whole-bone marrow differential pasting method showed a decreased ability in osteogenic differentiation compared with that from the young rats. Then the differentially expressed miRNAs between the aged and young rat-derived BMSCs were screened by high-throughput sequencing and verified by qRT-PCR, and we found that miR-378a-3p was significantly downregulated in the aged rat-derived BMSCs compared with the young rat-derived BMSCs. By transfecting miRNA mimics and inhibitors, miR-378a-3p was confirmed to promote the expression levels of osteogenic genes (Runx2, ALP, Col I, and OCN) and ALP activity of the aged rat-derived BMSCs. Meanwhile, the expression levels of osteogenic genes and miR-378a-3p of aged rat-derived BMSCs were significantly upregulated by LMV (cells were vibrated at 0.3 g and 90 Hz for 30 minutes a day, until 5 days for subsequent analysis), while the LMV-induced osteogenic gene expression levels of aged rat-derived BMSCs were suppressed by miR-378a-3p inhibitors. Furthermore, the inhibition of growth factor receptor-bound protein 2 (Grb2) by miR-378a-3p and Grb2-siRNA promoted the LMV-induced osteogenic differentiation of aged rat-derived BMSCs. Additionally, LMV was found to promote bone mineral density and bone strength of aged rats in vivo, as well as upregulating the expression level of miR-378a-3p and downregulating the expression level of Grb2 of BMSCs from aged rats. These results suggest that LMV induces osteogenic differentiation of BMSCs through miR-378a-3p/Grb2 pathway to improve bone mineral density and mechanical properties in a rat model of age-related bone loss.

Secondary Metabolites from Marine-Derived Fungi from China.

Marine-derived fungi play an important role in the search for structurally unique secondary metabolites, some of which show promising pharmacological activities that make them useful leads for drug discovery. Marine natural product research in China in general has made enormous progress in the last two decades as described in this chapter on fungal metabolites. This contribution covers 613 new natural products reported from 2001 to 2017 from marine-derived fungi obtained from algae, sponges, corals, and other marine organisms from Chinese waters. The genera Aspergillus (170 new natural products, 28%) and Penicillium (70 new natural products, 11%) were the main fungal producers of new natural products during the time period covered, whereas sponges (184 new natural products, 30%) were the most abundant source of new natural products, followed by corals (154 new natural products, 25%) and algae (130 new natural products, 21%). Close to 40% of all natural products covered in this contribution displayed various bioactivities. The major bioactivities reported were cytotoxicity against different cancer cell lines, antimicrobial (mainly antibacterial) activity, and antiviral activity, which accounted for 13%, 9%, and 3% of all natural products reported. In terms of structural classes, polyketides (188 new natural products, 31%) play a dominant role, and if prenylated polyketides and nitrogen-containing polyketides (included in meroterpenes and alkaloids in this contribution) are taken into account, their total number even exceeds 50%. Nitrogen-containing compounds including peptides (65 new natural products, 10%) and alkaloids (103 new natural products, 17%) are the second largest group.

Polyketide Derivatives from Mangrove Derived Endophytic Fungus Pseudopestalotiopsis theae.

Chemical investigation of secondary metabolites from the endophytic fungus Pseudopestalotiopsis theae led to the isolation of eighteen new polyketide derivatives, pestalotheols I-Q (1-9) and cytosporins O-W (15-23), together with eight known analogs (10-14 and 24-26). The structures of the new compounds were elucidated by HRMS and 1D and 2D NMR data, as well as by comparison with literature data. Modified Mosher's method was applied to determine the absolute configuration of some compounds. Compound 23 showed significant cytotoxicity against the mouse lymphoma cell line L5178Y with an IC50 value of 3.0 µM. Furthermore, compounds 22 and 23 showed moderate antibacterial activity against drug-resistant Acinetobacter baumannii (ATCC BAA-1605) in combination with sublethal colistin concentrations.

Knockdown of CTCF reduces the binding of EZH2 and affects the methylation of the SOCS3 promoter in hepatocellular carcinoma.

The epigenetic silencing mechanism of suppressor 3 of cytokine signaling (SOCS3) in cancers has not been fully elucidated. Polycomb repressive complexes 2 (PRC2), an important epigenetic regulatory factors, exerts a critical role in repressing the initial phase of gene transcription. Whether PRC2 participates the down- regulation of SOCS3 in Hepatocellular carcinoma (HCC) remains unclear and how does PRC2 be recruited target gene still needs to explore. In this study, Using TCGA HCC dataset, and detecting HCC tissue specimens and cell lines, we found that SOCS3 expression in HCC was inversely related to that of EZH2, and depended on its promoter methylation status. CTCF, vigilin, EZH2 and H3K27me3 were enriched at CTCF and EZH2 binding sites on the methylated SOCS3 gene promoter. The depletion of CTCF did not affect expression of EZH2 and DNMT1, but decrease recruitment of CTCF, vigilin, EZH2 and H3K27me3. Further, knockdown of CTCF led to a loss of methylation of the methylated SOCS3 promoter, which sequentially increased the expression of SOCS3 and decreased the expression of pSTAT3, the downstream effector. These findings suggest that the CTCF dependent recruitment of EZH2 to the SOCS3 gene promoter is likely to participate in the epigenetic silencing of SOCS3 and in regulating its gene expression.