GYY4137-induced p65 sulfhydration protects synovial macrophages against pyroptosis by improving mitochondrial function in osteoarthritis development.

INTRODUCTION: Osteoarthritis (OA) is the most common arthritis that is characterized by the progressive synovial inflammation and loss of articular cartilage. Although GYY4137 is a novel and slow-releasing hydrogen sulfide (H2S) donor with potent anti-inflammatory properties that may modulate the progression of OA, its underlying mechanism remains unclear. OBJECTIVES: In this study, we validated the protective role of GYY4137 against OA pathological courses and elucidated its underlying regulatory mechanisms. METHODS: Cell transfection, immunofluorescence staining, EdU assay, transmission electron microscopy, mitochondrial membrane potential measurement, electrophoretic mobility shift assay, sulfhydration assay, qPCR and western blot assays were performed in the primary mouse chondrocytes or the mouse macrophage cell line raw 264.7 for in vitro study. DMM-induced OA mice model and Macrophage-specific p65 knockout (p65f/f LysM-CreERT2) mice on the C57BL/6 background were used for in vivo study. RESULTS: We found that GYY4137 can alleviate OA progress by suppressing synovium pyroptosis in vivo. Moreover, our in vitro data revealed that GYY4137 attenuates inflammation-induced NLRP3 and caspase-1 activation and results in a decrease of IL-1ß production in macrophages. Mechanistically, GYY4137 increased persulfidation of NF-kB p65 in response to inflammatory stimuli that results in a decrease of cellular reactive oxygen species (ROS) accumulation and ameliorates mitochondrial dysfunctions. Using site-directed mutagenesis, we showed that H2S persulfidates cysteine38 in p65 protein and hampers p65 transcriptional activity, and p65 mutant impaired macrophage responses to GYY4137. CONCLUSION: These findings suggest a mechanism by which GYY4137 through redox modification of p65 participates in inhibiting NLRP3 activation by OA to regulate inflammatory responses. Thus, we propose that GYY4137 represents a promising novel therapeutic strategy for the treatment of OA.

Deficiency of CBL and CBLB ubiquitin ligases leads to hyper T follicular helper cell responses and lupus by reducing BCL6 degradation.

Recent evidence reveals hyper T follicular helper (Tfh) cell responses in systemic lupus erythematosus (SLE); however, molecular mechanisms responsible for hyper Tfh cell responses and whether they cause SLE are unclear. We found that SLE patients downregulated both ubiquitin ligases, casitas B-lineage lymphoma (CBL) and CBLB (CBLs), in CD4+ T cells. T cell-specific CBLs-deficient mice developed hyper Tfh cell responses and SLE, whereas blockade of Tfh cell development in the mutant mice was sufficient to prevent SLE. ICOS was upregulated in SLE Tfh cells, whose signaling increased BCL6 by attenuating BCL6 degradation via chaperone-mediated autophagy (CMA). Conversely, CBLs restrained BCL6 expression by ubiquitinating ICOS. Blockade of BCL6 degradation was sufficient to enhance Tfh cell responses. Thus, the compromised expression of CBLs is a prevalent risk trait shared by SLE patients and causative to hyper Tfh cell responses and SLE. The ICOS-CBLs axis may be a target to treat SLE.

Complete miRNA-15/16 loss in mice promotes hematopoietic progenitor expansion and a myeloid-biased hyperproliferative state.

Dysregulated apoptosis and proliferation are fundamental properties of cancer, and microRNAs (miRNA) are critical regulators of these processes. Loss of miR-15a/16-1 at chromosome 13q14 is the most common genomic aberration in chronic lymphocytic leukemia (CLL). Correspondingly, the deletion of either murine miR-15a/16-1 or miR-15b/16-2 locus in mice is linked to B cell lymphoproliferative malignancies. However, unexpectedly, when both miR-15/16 clusters are eliminated, most double knockout (DKO) mice develop acute myeloid leukemia (AML). Moreover, in patients with CLL, significantly reduced expression of miR-15a, miR-15b, and miR-16 associates with progression of myelodysplastic syndrome to AML, as well as blast crisis in chronic myeloid leukemia. Thus, the miR-15/16 clusters have a biological relevance for myeloid neoplasms. Here, we demonstrate that the myeloproliferative phenotype in DKO mice correlates with an increase of hematopoietic stem and progenitor cells (HSPC) early in life. Using single-cell transcriptomic analyses, we presented the molecular underpinning of increased myeloid output in the HSPC of DKO mice with gene signatures suggestive of dysregulated hematopoiesis, metabolic activities, and cell cycle stages. Functionally, we found that multipotent progenitors (MPP) of DKO mice have increased self-renewing capacities and give rise to significantly more progeny in the granulocytic compartment. Moreover, a unique transcriptomic signature of DKO MPP correlates with poor outcome in patients with AML. Together, these data point to a unique regulatory role for miR-15/16 during the early stages of hematopoiesis and to a potentially useful biomarker for the pathogenesis of myeloid neoplasms.

Host factor TIMP1 sustains long-lasting myeloid-biased hematopoiesis after severe infection.

Infection is able to promote innate immunity by enhancing a long-term myeloid output even after the inciting infectious agent has been cleared. However, the mechanisms underlying such a regulation are not fully understood. Using a mouse polymicrobial peritonitis (sepsis) model, we show that severe infection leads to increased, sustained myelopoiesis after the infection is resolved. In post-infection mice, the tissue inhibitor of metalloproteinases 1 (TIMP1) is constitutively upregulated. TIMP1 antagonizes the function of ADAM10, an essential cleavage enzyme for the activation of the Notch signaling pathway, which suppresses myelopoiesis. While TIMP1 is dispensable for myelopoiesis under the steady state, increased TIMP1 enhances myelopoiesis after infection. Thus, our data establish TIMP1 as a molecular reporter of past infection in the host, sustaining hyper myelopoiesis and serving as a potential therapeutic target for modulating HSPC cell fate.

Endothelial Cell-Derived Lactate Triggers Bone Mesenchymal Stem Cell Histone Lactylation to Attenuate Osteoporosis.

Blood vessels play a role in osteogenesis and osteoporosis; however, the role of vascular metabolism in these processes remains unclear. The present study finds that ovariectomized mice exhibit reduced blood vessel density in the bone and reduced expression of the endothelial glycolytic regulator pyruvate kinase M2 (PKM2). Endothelial cell (EC)-specific deletion of Pkm2 impairs osteogenesis and worsens osteoporosis in mice. This is attributed to the impaired ability of bone mesenchymal stem cells (BMSCs) to differentiate into osteoblasts. Mechanistically, EC-specific deletion of Pkm2 reduces serum lactate levels secreted by ECs, which affect histone lactylation in BMSCs. Using joint CUT&Tag and RNA sequencing analyses, collagen type I alpha 2 chain (COL1A2), cartilage oligomeric matrix protein (COMP), ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), and transcription factor 7 like 2 (TCF7L2) as osteogenic genes regulated by histone H3K18la lactylation are identified. PKM2 overexpression in ECs, lactate addition, and exercise restore the phenotype of endothelial PKM2-deficient mice. Furthermore, serum metabolomics indicate that patients with osteoporosis have relatively low lactate levels. Additionally, histone lactylation and related osteogenic genes of BMSCs are downregulated in patients with osteoporosis. In conclusion, glycolysis in ECs fuels BMSC differentiation into osteoblasts through histone lactylation, and exercise partially ameliorates osteoporosis by increasing serum lactate levels.

Percutaneous lordoplasty for the treatment of severe osteoporotic vertebral compression fractures with kyphosis.

Objective: The study aimed to explore the safety and effectiveness of percutaneous lordoplasty (PLP) in the treatment of severe osteoporotic vertebral compression fracture (OVCF). Methods: Included in this prospective study were patients with single-segment acute severe OVCF who were treated with PLP in our institution from July 2016 to October 2019. Patients' back pain and quality of life were assessed using the visual analog scale (VAS) and SF-36 scores. Lateral X-ray radiography of the spine was performed to measure the vertebral height, vertebral kyphotic angle, and segmental kyphotic angle, and to evaluate the outcome of fracture reduction and kyphotic correction. Intra-and postoperative complications were recorded. Results: Of the 51 included patients, 47 patients were followed up for 12 months. The VAS score decreased from preoperative 7.33 ± 1.92 to postoperative 1.76 ± 0.85 at the 12th month (p < 0.05), and the SF-36 score increased from preoperative 79.50 ± 9.22 to postoperative 136.94 ± 6.39 at the 12th month (p < 0.05). During the 1-year follow-up period, the anterior height of the vertebral body increased significantly from preoperative 10.49 ± 1.93 mm to 19.33 ± 1.86 mm (p < 0.05); the posterior height of the vertebral body increased insignificantly from preoperative 22.23 ± 2.36 mm to 23.05 ± 1.86 mm (p > 0.05); the vertebral kyphotic angle decreased significantly from preoperative 18.33° ± 11.49° to 8.73° ± 1.21° (p < 0.05); and the segmental kyphotic angle decreased significantly from preoperative 24.48° ± 4.64° to 11.70° ± 1.34° (p < 0.05). During the 1-year follow-up period, there was no significant difference in the radiologic parameters, VAS scores, and SF-36 scores, between the 1st day and the 12th month of post-operation (P > 0.05). No nerve damage occurred in any of the cases. Intraoperative cement leakage occurred in six cases, and the fracture of the adjacent vertebral body occurred in one case. Conclusion: PLP can well reduce the risk of fracture and achieve good kyphotic correction and may prove to be a safe, cost-effective and minimally invasive alternative option for the treatment of severe OVCF with kyphotic deformity.

Reclaimed and Up-Cycled Cathodes for Lithium-Ion Batteries.

As electric vehicles become more widely used, there is a higher demand for lithium-ion batteries (LIBs) and hence a greater incentive to find better ways to recycle these at their end-of-life (EOL). This work focuses on the process of reclamation and re-use of cathode material from LIBs. Black mass containing mixed LiMn2O4 and Ni0.8Co0.15Al0.05O2 from a Nissan Leaf pouch cell are recovered via two different recycling routes, shredding or disassembly. The waste material stream purity is compared for both processes, less aluminium and copper impurities are present in the disassembled waste stream. The reclaimed black mass is further treated to reclaim the transition metals in a salt solution, Ni, Mn, Co ratios are adjusted in order to synthesize an upcycled cathode, LiNi0.6Mn0.2Co0.2O2 via a co-precipitation method. The two reclamation processes (disassembly and shredding) are evaluated based on the purity of the reclaimed material, the performance of the remanufactured cell, and the energy required for the complete process. The electrochemical performance of recycled material is comparable to that of as-manufactured cathode material, indicating no detrimental effect of purified recycled transition metal content. This research represents an important step toward scalable approaches to the recycling of EOL cathode material in LIBs.

High-Voltage Stabilization of O3-Type Layered Oxide for Sodium-Ion Batteries by Simultaneous Tin Dual Modification.

O3-type layered oxide materials are considered to be a highly suitable cathode for sodium-ion batteries (NIBs) due to their appreciable specific capacity and energy density. However, rapid capacity fading caused by serious structural changes and interfacial degradation hampers their use. A novel Sn-modified O3-type layered NaNi1/3Fe1/3Mn1/3O2 cathode is presented, with improved high-voltage stability through simultaneous bulk Sn doping and surface coating in a scalable one-step process. The bulk substitution of Sn4+ stabilizes the crystal structure by alleviating the irreversible phase transition and lattice structure degradation and increases the observed average voltage. In the meantime, the nanolayer Sn/Na/O composite on the surface effectively inhibits surface parasitic reactions and improves the interfacial stability during cycling. A series of Sn-modified materials are reported. An 8%-Sn-modified NaNi1/3Fe1/3Mn1/3O2 cathode exhibits a doubling in capacity retention increase after 150 cycles in the wide voltage range of 2.0-4.1 V vs Na/Na+ compared to none, and 81% capacity retention is observed after 200 cycles in a full cell vs hard carbon. This work offers a facile process to simultaneously stabilize the bulk structure and interface for the O3-type layered cathodes for sodium-ion batteries and raises the possibility of similar effective strategies to be employed for other energy storage materials.

Resveratrol pretreatment mitigates LPS-induced acute lung injury by regulating conventional dendritic cells' maturation and function.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a severe syndrome lacking efficient therapy and resulting in high morbidity and mortality. Although resveratrol (RES), a natural phytoalexin, has been reported to protect the ALI by suppressing the inflammatory response, the detailed mechanism of how RES affected the immune system is poorly studied. Pulmonary conventional dendritic cells (cDCs) are critically involved in the pathogenesis of inflammatory lung diseases including ALI. In this study, we aimed to investigate the protective role of RES via pulmonary cDCs in lipopolysaccharide (LPS)-induced ALI mice. Murine ALI model was established by intratracheally challenging with 5 mg/kg LPS. We found that RES pretreatment could mitigate LPS-induced ALI. Additionally, proinflammatory-skewed cytokines decreased whereas anti-inflammatory-related cytokines increased in bronchoalveolar lavage fluid by RES pretreatment. Mechanistically, RES regulated pulmonary cDCs' maturation and function, exhibiting lower level of CD80, CD86, major histocompatibility complex (MHC) II expression, and IL-10 secretion in ALI mice. Furthermore, RES modulated the balance between proinflammation and anti-inflammation of cDCs. Moreover, in vitro RES pretreatment regulated the maturation and function of bone marrow derived dendritic cells (BMDCs). Finally, the adoptive transfer of RES-pretreated BMDCs enhanced recovery of ALI. Thus, these data might further extend our understanding of a protective role of RES in regulating pulmonary cDCs against ALI.

The magnitude of germinal center reactions is restricted by a fixed number of preexisting niches.

Antibody affinity maturation occurs in the germinal center (GC), a highly dynamic structure that arises upon antigen stimulation and recedes after infection is resolved. While the magnitude of the GC reaction is highly fluctuating and depends on antigens or pathological conditions, it is unclear whether GCs are assembled ad hoc in different locations or in preexisting niches within B cell follicles. We show that follicular dendritic cells (FDCs), the essential cellular components of the GC architecture, form a predetermined number of clusters. The total number of FDC clusters is the same on several different genetic backgrounds and is not altered by immunization or inflammatory conditions. In unimmunized and germ-free mice, a few FDC clusters contain GC B cells; in contrast, immunization or autoimmune milieu significantly increases the frequency of FDC clusters occupied by GC B cells. Excessive occupancy of GC niches by GC B cells after repeated immunizations or in autoimmune conditions suppresses subsequent antibody responses to new antigens. These data indicate that the magnitude of the GC reaction is restricted by a fixed number of permissive GC niches containing preassembled FDC clusters. This finding may help in the future design of vaccination strategies and in the modulation of antibody-mediated autoimmunity.

The calcium channel TRPV6 is a novel regulator of RANKL-induced osteoclastic differentiation and bone absorption activity through the IGF-PI3K-AKT pathway.

OBJECTIVES: Calcium ion signals are important for osteoclast differentiation. Transient receptor potential vanilloid 6 (TRPV6) is a regulator of bone homeostasis. However, it was unclear whether TRPV6 was involved in osteoclast formation. Therefore, the aim of this study was to evaluate the role of TPRV6 in bone metabolism and to clarify its regulatory role in osteoclasts at the cellular level. MATERIALS AND METHODS: Bone structure and histological changes in Trpv6 knockout mice were examined using micro-computed tomography and histological analyses. To investigate the effects of Trpv6 on osteoclast function, we silenced or overexpressed Trpv6 in osteoclasts via lentivirus transfection, respectively. Osteoclast differentiation and bone resorption viability were measured by tartrate-resistant acid phosphatase (TRAP) staining and pit formation assays. The expression of osteoclast marker genes, including cathepsin k, DC-STAMP, Atp6v0d2 and TRAP, was measured by qRT-PCR. Cell immunofluorescence and Western blotting were applied to explore the mechanisms by which the IGF-PI3K-AKT pathway was involved in the regulation of osteoclast formation and bone resorption by Trpv6. RESULTS: We found that knockout of Trpv6 induced osteoporosis and enhanced bone resorption in mice, but did not affect bone formation. Further studies showed that Trpv6, which was distributed on the cell membrane of osteoclasts, acted as a negative regulator for osteoclast differentiation and function. Mechanistically, Trpv6 suppressed osteoclastogenesis by decreasing the ratios of phosphoprotein/total protein in the IGF-PI3K-AKT signalling pathway. Blocking of the IGF-PI3K-AKT pathway significantly alleviated the inhibitory effect of Trpv6 on osteoclasts formation. CONCLUSIONS: Our study confirmed the important role of Trpv6 in bone metabolism and clarified its regulatory role in osteoclasts at the cellular level. Taken together, this study may inspire a new strategy for the treatment of osteoporosis.

gB co-immunization with GP96 enhances pulmonary-resident CD8 T cells and exerts a long-term defence against MCMV pneumonitis.

Human cytomegalovirus (HCMV) infection in the respiratory tract leads to pneumonitis in immunocompromised hosts without available vaccine. Considering cytomegalovirus (CMV) mainly invades through the respiratory tract, CMV-specific pulmonary mucosal vaccine development that provides a long-lasting protection against CMV challenge gains our attention. In this study, N-terminal domain of GP96 (GP96-NT) was used as a mucosal adjuvant to enhance the induction of pulmonary-resident CD8 T cells elicited by MCMV glycoprotein B (gB) vaccine. Mice were intranasally co-immunized with 50 µg pgB and equal amount of pGP96-NT vaccine 4 times at 2-week intervals, and then i.n. challenged with MCMV at 16 weeks after the last immunization. Compared with pgB immunization alone, co-immunization with pgB/pGP96-NT enhanced a long-lasting protection against MCMV pneumonitis by significantly improved pneumonitis pathology, enhanced bodyweight, reduced viral burdens and increased survival rate. Moreover, the increased CD8 T cells were observed in lung but not spleen from pgB/pGP96-NT co-immunized mice. The increments of pulmonary CD8 T cells might be mainly due to non-circulating pulmonary-resident CD8 T-cell subset expansion but not circulating CD8 T-cell populations that home to inflammation site upon MCMV challenge. Finally, the deterioration of MCMV pneumonitis by depletion of pulmonary site-specific CD8 T cells in mice that were pgB/pGP96-NT co-immunization might be a clue to interpret the non-circulating pulmonary-resident CD8 T subset expansion. These data might uncover a promising long-lasting prophylactic vaccine strategy against MCMV-induced pneumonitis.

Novel Bioactive Penicipyrroether A and Pyrrospirone J from the Marine-Derived Penicillium sp. ZZ380.

The marine-sourced fungus Penicillium sp. ZZ380 was previously reported to have the ability to produce a series of new pyrrospirone alkaloids. Further investigation on this strain resulted in the isolation and identification of novel penicipyrroether A and pyrrospirone J. Each of them represents the first example of its structural type, with a unique 6/5/6/5 polycyclic fusion that is different from the 6/5/6/6 fused ring system for the reported pyrrospirones. Their structures were elucidated by extensive nuclear magnetic resonance (NMR) and high resolution electrospray ionization mass spectroscopy (HRESIMS) spectroscopic analyses, electronic circular dichroism (ECD) and 13C NMR calculations and X-ray single crystal diffraction. Penicipyrroether A showed potent antiproliferative activity against human glioma U87MG and U251 cells with half maximal inhibitory concentration (IC50) values of 1.64-5.50 µM and antibacterial inhibitory activity with minimum inhibitory concentration (MIC) values of 1.7 µg/mL against methicillin-resistant Staphylococcus aureus and 3.0 µg/mL against Escherichia coli.

Bioactive Penicipyrrodiether A, an Adduct of GKK1032 Analogue and Phenol A Derivative, from a Marine-Sourced Fungus Penicillium sp. ZZ380.

Penicipyrrodiether A, an adduct of GKK1032 analogue and phenol A derivative, was isolated from a culture of marine-associated fungus Penicillium sp. ZZ380 and represents the first example of this type of fungal metabolite. Its structure was elucidated by extensive spectroscopic analyses, including 1D- and 2D-NMR, HRESIMS, MS/MS, and electronic circular dichroism calculation as well as single-crystal X-ray diffraction. Penicipyrrodiether A showed antibacterial activity in inhibiting the growth of methicillin-resistant Staphylococcus aureus with a MIC value of 5.0 µg/mL. Its plausible pathway for biosynthesis has been proposed.

Regulation of TRPV5 transcription and expression by E2/ERα signalling contributes to inhibition of osteoclastogenesis.

The increasing of osteoclasts formation and activity because of oestrogen (E2) deficiency is very important in the aetiology of postmenopausal osteoporosis. Our previous studies showed that E2 inhibited osteoclastic bone resorption by increasing the expression of Transient Receptor Potential Vanilloid 5 (TRPV5) channel. However, the exact mechanism by which E2 increases TRPV5 expression is not fully elucidated. In this study, Western blot, quantitative real-time PCR, tartrate-resistant acid phosphatase staining, F-actin ring staining, chromatin immunoprecipitation and luciferase assay were applied to explore the mechanisms that E2-induced TRPV5 expression contributes to the inhibition of osteoclastogenesis. The results showed that silencing or overexpressing of TRPV5 significantly affected osteoclasts differentiation and activity. Silencing of TRPV5 obviously alleviated E2-inhibited osteoclastogenesis, resulting in increasing of bone resorption. E2 stimulated mature osteoclasts apoptosis by increasing TRPV5 expression. Further studies showed that E2 increased TRPV5 expression through the interaction of the oestrogen receptor α (ERα) with NF-κB, which could directly bind to the fragment of -286 nt ~ -277 nt in the promoter region of trpv5. Taken together, we conclude that TRPV5 plays a dominant effect in E2-mediated osteoclasts formation, bone resorption activity and osteoclasts apoptosis. Furthermore, NF-κB plays an important role in the transcriptional activation of E2-ERα stimulated TRPV5 expression.

Anti-glioma Natural Products Downregulating Tumor Glycolytic Enzymes from Marine Actinomycete Streptomyces sp. ZZ406.

Marine natural products are important resources for discovering novel anticancer drugs. In this study, an extract prepared from the culture of a sea anemone-derived actinomycete Streptomyces sp. ZZ406 in soluble starch and casein-related liquid medium was found to have activity in inhibiting the proliferation of glioma cells and reducing the production of lactate in glioma cells. Chemical investigation of this active crude extract resulted in the isolation of four new compounds and seven known ones. Structures of the new compounds were determined by a combination of extensive NMR analyses, HRESIMS and MS-MS data, electronic circular dichroism calculation, chemical degradation, and Marfey's method. New compound 1 showed potent activity against the proliferation of different glioma cells with IC50 values of 4.7 to 8.1 µM, high selectivity index (>12.3 to 21.3), and good stability in human liver microsomes. Western blot analysis revealed that compound 1 remarkably downregulated the expressions of several important glioma glycolytic enzymes. The data from this study suggested that compound 1 might have potential as a novel anti-glioma agent to be further investigated.

Anti-colorectal cancer effects of tripolinolate A from Tripolium vulgare.

Tripolinolate A (TLA) is recently identified as a new compound from a halophyte plant Tripolium vulgare and has been shown to have significant in vitro activity against the proliferation of colorectal cancer and glioma cells. This study was designed to further investigate the effects of TLA on the proliferation of human normal cells, and the apoptosis and cell cycle in colorectal cancer cells, and the growth of tumors in the colorectal cancer-bearing animals. The data obtained from this study demonstrated that: 1) TLA had much less cytotoxicity in the human normal cells than the colorectal cancer cells; 2) TLA remarkably induced apoptosis in the human colorectal cancer cells and blocked cell cycle at G2/M phase, and 3) TLA had significant anti-colorectal cancer activity in the tumor-bearing animals.

Rare Polyene-polyol Macrolides from Mangrove-derived Streptomyces sp. ZQ4BG.

Bioactive natural products from mangrove-derived actinomycetes are important sources for discovery of drug lead compounds. In this study, an extract prepared from culture of an actinomycete Streptomyces sp. ZQ4BG isolated from mangrove soils was found to have activity in inhibiting proliferation of glioma cells. Large culture of this mangrove actinomycete in Gause's liquid medium resulted in isolation of seven novel polyene-polyol macrolides, named as flavofungins III-IX (3-9), together with known flavofungins I (1) and II (2) and spectinabilin (10). Structures of these isolated compounds were elucidated by extensive NMR analyses and HRESIMS data. The stereochemical assignments were achieved by a combination of NOE information, universal NMR database, and chemical reactions including preparation of acetonide derivatives and Mosher esters. Flavofungins IV-VIII (4-8) are rare 32-membered polyene-polyol macrolides with a tetrahydrofuran ring, while flavofungin IX (9) represents the first example of this type of macrolide with a unique oxepane ring. Flavofungins I (1) and II (2) and spectinabilin (10) showed anti-glioma and antifungal activities.

Cytotoxic Bagremycins from Mangrove-Derived Streptomyces sp. Q22.

New bagremycins C-E (3-5) and bagrelactone A (6), together with known bagremycins A (1) and B (2), 4-hydroxystyrene (7), and 4-hydroxystyrene 4-O-α-d-galactopyranoside (8), were isolated from a mangrove-derived actinomycete, Streptomyces sp. Q22. Structures of these new compounds were elucidated based on their NMR and HRESIMS spectroscopic data as well as chemical degradation. Bagremycin C (3) is a unique analogue with an N-acetyl-(S)-cysteine moiety, while bagrelactone A (6) represents the first example of this type of bagremycin-derived macrolide. Bagremycin C (3) was active against four glioma cell lines, with IC50 values in the range from 2.2 to 6.4 µM, induced apoptosis in human glioma U87MG cells in a dose- and time-dependent manner, and arrested the U87MG cell cycle at the G0/G1 phase.

Antiproliferative cyclodepsipeptides from the marine actinomycete Streptomyces sp. P11-23B downregulating the tumor metabolic enzymes of glycolysis, glutaminolysis, and lipogenesis.

Two cyclodepsipeptides and a known cyclodepsipeptide valinomycin were isolated from a culture of the marine actinomycete Streptomyces sp. P11-23B. Their structures were established based on NMR, HRESIMS, and MS-MS spectroscopic interpretation as well as by chemical degradation. Both streptodepsipeptides P11A and P11B inhibited proliferation of different glioma cell lines, with IC50 values ranging from 0.1 µM to 1.4 µM. Streptodepsipeptide P11A was found to block the cell cycle at the G0/G1 phase and induce apoptosis in glioma cells. Further investigation demonstrated that streptodepsipeptide P11A downregulated expression of HK2, PFKFB3, PKM2, GLS, and FASN, important tumor metabolic enzymes. Data from this study suggested that targeting multiple tumor metabolic regulators might be one anti-glioma mechanism of streptodepsipeptide P11A. A possible mechanism for this class of streptodepsipeptides is reported herein.