Tetracyclic Steroids Bearing a Bicyclo[4.4.1] Ring System as Potent Antiosteoporosis Agents from the Deep-Sea-Derived Fungus Rhizopus sp. W23.

Chemical investigation of the deep-sea-derived fungus Rhizopus sp. W23 resulted in the identification of six new (1-3, 6, 8, 9) and 12 known (4, 5, 10-19) cyclocitrinol analogues, together with one handling artifact (7), all featuring an unusual 7/7/6/5-tetracyclic scaffold and bicyclo[4.4.1] A/B rings. Norcyclocitrinoic acids A and B (1, 2) represent the second occurrence of 24,25-bisnor cyclocitrinols. Structures were assigned to new steroids on the basis of extensive spectroscopic analysis and X-ray crystallography. Compound 13 significantly enhances osteoblastogenesis and inhibits adipogenesis in mature bone marrow stromal cells at 5 µM, indicating a potential to be an antiosteoporosis lead.

Brefeldin A from the Deep-Sea-Derived Fungus Fusarium sp. Targets on RIPK3 to Inhibit TNFα-Induced Necroptosis.

From the deep-sea-derived Fusarium sp. ZEN-48, four known compounds were obtained. Their structures were established by extensive analyses of the NMR, HR-ESI-MS, and the X-ray crystallographic data as brefeldin A (BFA, 1), brevianamide F (2), N-acetyltryptamine (3), and (+)-diaporthin (4). Although BFA was extensively investigated for its potent bioactivities, its role on TNFα-induced necroptosis was incompletely understood. In this study, BFA showed significant inhibition on TNFα-induced necroptosis by disrupting the necrosome formation and suppressing the phosphorylation of RIPK3 and MLKL (IC50 =0.5 µM). While, it had no effect on TNFα-induced NF-κB/MAPKs activation and apoptosis. The finding raised significant implications of BFA for necroptosis-related inflammatory disease therapy and new drug development from marine fungi.

Chemical Constituents of the Deep-Sea-Derived Fungus Cladosporium oxysporum 170103 and Their Antibacterial Effects.

The Cladosporium fungi, one of the largest genera of dematiaceous hyphomycetes, could produce various bioactive secondary metabolites. From the AcOEt-soluble extract of Cladosporium oxysporum 170103, three new secopatulolides (1-3) and thirteen known compounds (4-16) were obtained. Their structures were established by detailed analysis of the NMR and HR-ESI-MS data. All sixteen compounds were tested for antibacterial activity against Vibrio parahemolyticus, ergosterol (10) presented moderate effect with the minimum inhibitory concentration (MIC) of 32 µM. It can destruct the membrane integrity of Vibrio parahemolyticus to change the cell shape.

Cladosporioles A and B, Two New Indole Derivatives from the Deep-Sea-Derived Fungus Cladosporium cladosporioides 170056.

Two new (cladosporioles A and B, 1 and 2) and fourteen known (3-16) compounds were isolated from the deep-sea-derived fungus Cladosporium cladosporioides 170056. The relative structures of the new compounds were elucidated mainly by detailed analysis of their NMR and HR-ESI-MS spectroscopic data. Their absolute configurations were determined by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. All isolates were tested for antimicrobial activity against Vibrio parahaemolyticus. Compound 15 exhibited weak effect with the MIC value of 156.25 µg/mL.

Solitumergosterol A, a unique 6/6/6/6/5 steroid from the deep-sea-derived Penicillium solitum MCCC 3A00215.

A unique C30 steroid, solitumergosterol A (1), was isolated from the deep-sea-derived fungus Penicillium solitum MCCC 3A00215. The planar structure and relative configuration of 1 were established mainly on the basis of extensive analysis of its 1D and 2D NMR as well as HRESIMS data, while its absolute configuration was clarified by comparison of the experimental and theoretical ECD spectra. Noteworthily, 1 is a Diels-Alder adduct of a heterogeneous steroid bearing a 6/6/6/6/5 pentacyclic carbon skeleton. Solitumergosterol A (1) exhibited weak in vitro anti-tumor activity against MB231 cells by a RXRα-dependent mechanism.

Chemical Constituents of the Marine Fungus Penicillium sp. MCCC 3A00228.

One new (d-arabinitol-anofinicate, 1) and fourteen known (2-15) compounds were isolated from the marine Penicillium sp. MCCC 3A00228. The structure of the new compound was established mainly by extensive spectroscopic analyses. Compound 1 exhibited weak transcriptional effect on Nur77. While compound 13 showed moderate in vitro anti-proliferative effect against QGY7701, H1299, and HCT116 tumor cells with IC50 values of 21.2 µM, 18.2 µM, and 17.6 µM, respectively.

The Association between Admission Serum Phosphorus and Preoperative Deep Venous Thrombosis in Geriatric Hip Fracture: A Retrospective Study.

OBJECTIVE: This study aimed to evaluate the association between serum phosphorus level and preoperative deep vein thrombosis (DVT) in geriatric hip fractures. METHODS: Older adults with hip fractures were screened between January 2015 and September 2019. Demographic and clinical characteristics of the patients were collected. Multivariate binary logistic regression and generalized additive models were used to identify the linear and nonlinear associations between serum phosphorus levels and preoperative DVT. Analyses were performed using Empower Stats and R software. RESULTS: In this study, 1818 patients were included, with an average age of 79.39 ± 6.87. Of these, 30.25% were males, and 580 patients had DVT. The study found that when serum phosphorus was used as a continuous variable, there was a statistically significant difference in the relationship between blood phosphorus and the occurrence of DVT (p < 0.05). Furthermore, we also found curvilinear relationships. Serum phosphorus = 0.71 mmol/L was the inflection point in the curve. When serum phosphorus was <0.71 mmol/L, the serum phosphorus was associated with DVT (OR = 1.64; 95% CI: 1.04-2.59; p = 0.0333). With a 0.1 mmol/L increase, the DVT increased 0.64 times. When phosphorus was >0.71 mmol/L, there was no significant difference in the correlation between serum phosphorus levels and DVT (OR = 1.03; 95% CI: 0.98-1.09; p = 0.186). CONCLUSION: Serum phosphorus was nonlinearly associated with preoperative DVT in geriatric patients with hip fractures, and serum phosphorus level could be considered a predictor of DVT risk.

BMP7-Based Functionalized Self-Assembling Peptides Protect Nucleus Pulposus-Derived Stem Cells From Apoptosis In Vitro.

Tissue engineering has shown great success in the treatment of intervertebral disk degeneration (IVDD) in the past decade. However, the adverse and harsh microenvironment associated in the intervertebral disks remains a great obstacle for the survival of transplanted cells. Although increasing numbers of new materials have been created or modified to overcome this hurdle, a new effective strategy of biological therapy is still required. In this study, bone morphogenic protein 7 (BMP7)-based functionalized self-assembling peptides were developed by conjugating a bioactive motif from BMP-7 (RKPS) onto the C-terminal of the peptide RADARADARADARADA (RADA16-I) at a ratio of 1:1 to form a new RADARKPS peptide. Human nucleus pulposus-derived stem cells (NPDCs) were cultured in the presence of RADA-RKPS or RADA16-I in an apoptosis-promoting environment that was induced by tumor necrosis factor-alpha, and cells were cultured with RADA16-I in normal medium that served as the control group. After 48 h of apoptosis induction, the viability, proliferation, apoptosis rate, and expression of apoptosis-related genes of NPDCs in the different groups were evaluated, and the differentiation of NPDCs toward nucleus pulposus-like cells was tested. The results showed that the RADA-RKPS peptide could significantly protect the survival and proliferation of NPDCs. In addition, the application of RADA-RKPS decreased the rate of cell apoptosis, as detected by TUNEL-positive staining. Furthermore, our in vitro study confirmed the apoptosis-protecting effects of RADA-RKPS peptides, which significantly reduced the BAX/BCL-2 ratio of NPDCs and upregulated the gene expression of collagen II a1, aggrecan, and Sox-9 after 48 h of apoptosis induction. Collectively, these lines of evidence suggest that RADA-RKPS peptides confer a protective effect to NPDCs in an apoptosis environment, suggesting their potential application in the development of new biological treatment strategies for IVDD.

Biological evaluation of human degenerated nucleus pulposus cells in functionalized self-assembling peptide nanofiber hydrogel scaffold.

Nucleus pulposus (NP) tissue engineering has been proposed as a novel biological treatment for early-stage intervertebral disc degeneration. In this study, a novel functional self-assembling peptide PKP was first designed by linking the short functional motif of bone morphogenetic protein-7 (BMP7) to the C-terminal of RADA16-I, and another new functional self-assembling peptide was obtained by mixing RKP with RADA16-I. Then, the biocompatibilities and bioactivities of RKP and RAD-RKP for human degenerated nucleus pulposus cells (hNPCs) were studied in vitro. Atomic force microscopy and scanning electron microscopy (SEM) confirmed that both RKP and RAD-RKP could self-assemble into three-dimensional (3D) nanofiber hydrogel scaffolds in a culture medium at 37°C. After the hNPCs were cultured in 3D scaffolds, both RKP and RAD-RKP exhibited reliable attachment and extremely low cytotoxicities (<14%), which were verified by SEM and cytotoxity assays, respectively. Our results also showed that the functional-based scaffolds could increase the proliferation and migration of hNPCs after 7 days compared with culture plates and pure RADA16-I. Quantitative real-time polymerase chain reaction demonstrated that the expressions of collagen II α1, Sox-9, and aggrecan were upregulated, while collagen I α1 was downregulated by functional-based scaffolds after 28 days. Furthermore, we also confirmed that RAD-RKP exhibited a higher hNPC proliferation, migration, and expression of Sox-9 and aggrecan compared with pure RKP. Therefore, the results of this study indicated that the BMP7 short motif-designed functional self-assembling peptide nanofiber hydrogels could be used as excellent scaffolds in NP tissue engineering, and RAD-RKP might have further potential application in human mild degenerated NP tissue regeneration.