Wild-type IDH1 maintains NSCLC stemness and chemoresistance through activation of the serine biosynthetic pathway.

Tumor-initiating cells (TICs) reprogram their metabolic features to meet their bioenergetic, biosynthetic, and redox demands. Our previous study established a role for wild-type isocitrate dehydrogenase 1 (IDH1WT) as a potential diagnostic and prognostic biomarker for non-small cell lung cancer (NSCLC), but how IDH1WT modulates NSCLC progression remains elusive. Here, we report that IDH1WT activates serine biosynthesis by enhancing the expression of phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1), the first and second enzymes of de novo serine synthetic pathway. Augmented serine synthesis leads to GSH/ROS imbalance and supports pyrimidine biosynthesis, maintaining tumor initiation capacity and enhancing gemcitabine chemoresistance. Mechanistically, we identify that IDH1WT interacts with and stabilizes PHGDH and fragile X-related protein-1 (FXR1) by impeding their association with the E3 ubiquitin ligase parkin by coimmunoprecipitation assay and proximity ligation assay. Subsequently, stabilized FXR1 supports PSAT1 mRNA stability and translation, as determined by actinomycin D chase experiment and in vitro translation assay. Disrupting IDH1WT-PHGDH and IDH1WT-FXR1 interactions synergistically reduces NSCLC stemness and sensitizes NSCLC cells to gemcitabine and serine/glycine-depleted diet therapy in lung cancer xenograft models. Collectively, our findings offer insights into the role of IDH1WT in serine metabolism, highlighting IDH1WT as a potential therapeutic target for eradicating TICs and overcoming gemcitabine chemoresistance in NSCLC.

Burn Intensity Drives the Alteration of Phenolic Lignin to (Poly) Aromatic Hydrocarbons as Revealed by Pyrolysis Gas Chromatography-Mass Spectrometry (Py-GC/MS).

High-intensity wildfires alter the chemical composition of organic matter, which is expected to be distinctly different from low-intensity prescribed fires. Herein, we used pyrolysis gas chromatography/mass spectrometry (Py-GC/MS), in conjunction with solid-state 13C nuclear magnetic resonance (NMR) and Fourier transform infrared (FT-IR) spectroscopy, to assess chemical alterations from three wildfires and a long-term frequent prescribed fire site. Our results showed that black ash formed under moderate intensity burns contained less aromatic (ArH), polyaromatic hydrocarbon (PAH), and nitrogen-containing compounds (Ntg) but more lignin (LgC) and phenol compounds (PhC), compared to white ash formed under high intensity burns. Both 13C NMR and FT-IR confirmed a higher relative percentage of carboxyl carbon in white ash, indicating the potential for higher water solubility and more mobile carbon, relative to black ash. Compared to wildfires, ash from low-intensity prescribed fire contained less ArH, PAH, and Ntg and more LgC and PhC. Controlled laboratory burning trials indicated that organic matter alteration was sensitive to the burn temperature, but not related to the fuel type (pine vs fir) nor oxygen absence/presence at high burn temperatures. This study concludes that higher burn temperatures resulted in higher (poly)aromatic carbon/nitrogen and lower lignin/phenol compounds.

Potential use of arbuscular mycorrhizal fungi for simultaneous mitigation of arsenic and cadmium accumulation in rice.

Rice polluted by metal(loid)s, especially arsenic (As) and cadmium (Cd), imposes serious health risks. Numerous studies have demonstrated that the obligate plant symbionts arbuscular mycorrhizal fungi (AMF) can reduce As and Cd concentrations in rice. The behaviours of metal(loid)s in the soil-rice-AMF system are of significant interest for scientists in the fields of plant biology, microbiology, agriculture, and environmental science. We review the mechanisms of As and Cd accumulation in rice with and without the involvement of AMF. In the context of the soil-rice-AMF system, we assess and discuss the role of AMF in affecting soil ion mobility, chemical forms, transport pathways (including the symplast and apoplast), and genotype variation. A potential strategy for AMF application in rice fields is considered, followed by future research directions to improve theoretical understanding and encourage field application.

The m6A demethylase FTO promotes the osteogenesis of mesenchymal stem cells by downregulating PPARG.

N6-methyladenosine (m6A) is the most abundant posttranscriptional methylation modification that occurs in mRNA and modulates the fine-tuning of various biological processes in mammalian development and human diseases. In this study we investigated the role of m6A modification in the osteogenesis of mesenchymal stem cells (MSCs), and the possible mechanisms by which m6A modification regulated the processes of osteoporosis and bone necrosis. We performed systematic analysis of the differential gene signatures in patients with osteoporosis and bone necrosis and conducted m6A-RNA immunoprecipitation (m6A-RIP) sequencing to identify the potential regulatory genes involved in osteogenesis. We showed that fat mass and obesity (FTO), a primary m6A demethylase, was significantly downregulated in patients with osteoporosis and osteonecrosis. During the differentiation of human MSCs into osteoblasts, FTO was markedly upregulated. Both depletion of FTO and application of the FTO inhibitor FB23 or FB23-2 impaired osteogenic differentiation of human MSCs. Knockout of FTO in mice resulted in decreased bone mineral density and impaired bone formation. PPARG, a biomarker for osteoporosis, was identified as a critical downstream target of FTO. We further revealed that FTO mediated m6A demethylation in the 3'UTR of PPARG mRNA, and reduced PPARG mRNA stability in an YTHDF1-dependent manner. Overexpression of PPARG alleviated FTO-mediated osteogenic differentiation of MSCs, whereas knockdown of PPARG promoted FTO-induced expression of the osteoblast biomarkers ALPL and OPN during osteogenic differentiation. Taken together, this study demonstrates the functional significance of the FTO-PPARG axis in promoting the osteogenesis of human MSCs and sheds light on the role of m6A modification in mediating osteoporosis and osteonecrosis.

The novel indomethacin derivative CZ-212-3 exerts antitumor effects on castration-resistant prostate cancer by degrading androgen receptor and its variants.

Androgen receptor (AR) serves as a main therapeutic target for prostate cancer (PCa). However, resistance to anti-androgen therapy (SAT) inevitably occurs. Indomethacin is a nonsteroidal anti-inflammatory drug that exhibits activity against prostate cancer. Recently, we designed and synthesized a series of new indomethacin derivatives (CZ compounds) via Pd (II)-catalyzed synthesis of substituted N-benzoylindole. In this study, we evaluated the antitumor effect of these novel indomethacin derivatives in castration-resistant prostate cancer (CRPC). Upon employing CCK-8 cell viability assays and colony formation assays, we found that these derivatives had high efficacy against CRPC tumor growth in vitro. Among these derivatives, CZ-212-3 exhibited the most potent efficacy against CRPC cell survival and on apoptosis induction. Mechanistically, CZ-212-3 significantly suppressed the expression of AR target gene networks by degrading AR and its variants. Consistently, CZ-212-3 significantly inhibited tumor growth in CRPC cell line-based xenograft and PDX models in vivo. Taken together, the data show that the indomethacin derivative CZ-212-3 significantly inhibited CRPC tumor growth by degrading AR and its variants and could be a promising agent for CRPC therapy.

Antioxidant CPA-type indole alkaloids produced from the deep-sea derived fungus Aspergillus sp. SCSIO 41024.

Twelve indole alkaloids, including α-cyclopiazonic acid (CPA) (1), nine 2-oxo indole CPA derivatives (2-10), and two open-ring indole CPA derivatives (11 and 12), were isolated from the fermentation broth of a deep-sea derived fungus Aspergillus sp. SCSIO 41024. Their structures and absolute configurations were elucidated mainly by using extensive NMR spectroscopic, mass spectrometric and single crystal X-ray diffraction analysis. To the best of our knowledge, the crystallographic data of 3 and 7 were firstly reported, and the absolute configuration of 3 was confirmed for the first time by the single crystal X-ray diffraction analysis. Most isolated compounds were tested for their antimicrobial, antitumor and radical scavenging activities. In addition, compounds 1, 2 and 11 showed moderate antioxidative activity against DPPH with IC50 values of 190.1, 31.9, 228.4 µg/mL, respectively.

Cytotoxic benzopyranone and xanthone derivatives from a coral symbiotic fungus Cladosporium halotolerans GXIMD 02502.

Coral-derived microorganisms have been historically proven to be prolific sources of bioactive secondary metabolites. Twelve benzopyranone and/or xanthone derivatives, including a new benzopyranone with an uncommon carboxyl group at C-8, coniochaetone K (1), were obtained from the Beibu Gulf-derived coral symbiotic fungus Cladosporium halotolerans GXIMD 02502. Their structures were determined by extensive spectroscopic data interpretation and comparison with literature values. The absolute configuration of 1 was accomplished by comparison of specific optical rotation as well as quantum chemical ECD calculations. The in vitro cytotoxicity of compounds 1-12 against two human prostatic cancer cell lines, C4-2B and 22RV1, were evaluated. And compounds 1, 3, 6-8, and 10-11 demonstrated significant cytotoxicity with inhibitions ranging from 55.8% to 82.1% at the concentration of 10 µM.

sFRP1 protects H9c2 cardiac myoblasts from doxorubicin-induced apoptosis by inhibiting the Wnt/PCP-JNK pathway.

Doxorubicin (Dox) is an effective chemotherapy drug against a wide range of cancers, including both hematological and solid tumors. However, the serious cardiotoxic effect restricted its clinical application. We previously have illuminated the protective role of canonical Wnt/ß-catenin signaling in Dox-induced cardiotoxicity. Secreted frizzled-related protein 1 (sFRP1) is one of the endogenous inhibitors of both canonical and noncanonical Wnt signaling. In this study, we investigated the relationship between sFRP1 and noncanonical Wnt/PCP-JNK (Wnt/planar cell polarity-c-Jun N-terminal kinase) pathway in Dox-induced cardiotoxicity in vitro and in vivo. We showed that treatment of H9c2 cardiac myoblasts with Dox (1 µM) time-dependently suppressed cell viability accompanied by significantly decreased sFRP1 protein level and increased Wnt/PCP-JNK signaling. Pretreatment with SP600125, the Wnt/PCP-JNK signaling inhibitor, attenuated Dox-induced apoptosis of H9c2 cells. Overexpression of sFRP1 protected H9c2 cells from Dox-induced apoptosis by inhibiting the Wnt/PCP-JNK pathway. After intraperitoneal injection of a cumulative dose of 15 mg/kg Dox, rats displayed significant cardiac dysfunction; their heart showed inhibited Wnt/ß-catenin signaling and activated Wnt/PCP-JNK signaling. These results suggest that sFRP1 may be a novel target for Dox-induced cardiotoxicity.

Histone methyltransferase NSD2 mediates the survival and invasion of triple-negative breast cancer cells via stimulating ADAM9-EGFR-AKT signaling.

Triple-negative breast cancer (TNBC) is a heterogeneous disease with a poor prognosis due to the lack of an effective targeted therapy. Histone lysine methyltransferases (KMTs) have emerged as attractive drug targets for cancer therapy. However, the function of the majority of KMTs in TNBC has remained largely unknown. In the current study, we found that KMT nuclear receptor binding SET domain protein 2 (NSD2) is overexpressed in TNBC tumors and that its overexpression is associated with poor survival of TNBC patients. NSD2 regulates TNBC cell survival and invasion and is required for tumorigenesis and tumor growth. Mechanistically, NSD2 directly controls the expression of EGFR and ADAM9, a member of the ADAM (a disintegrin and metalloproteinase) family that mediates the release of growth factors, such as HB-EGF. Through its methylase activity, NSD2 overexpression stimulates EGFR-AKT signaling and promotes TNBC cell resistance to the EGFR inhibitor gefitinib. Together, our results identify NSD2 as a major epigenetic regulator in TNBC and provide a rationale for targeting NSD2 alone or in combination with EGFR inhibitors as a targeted therapy for TNBC.

Wildfire altering terrestrial precursors of disinfection byproducts in forest detritus.

Wildfire occurrence and intensity are increasing worldwide causing severe disturbances to forest watersheds used for potable water supply. The effects of wildfire on drinking water quality are not well understood, especially in terms of terrestrial dissolved organic matter (DOM) and DOM-associated formation of disinfection byproducts (DBP). As the forest floor layer is a major source of terrestrial DOM, we investigated characteristics and DBP formation of water extractable organic matter (WEOM) from the 0-5 cm depth of nonburned detritus (control) and burned detritus with black ash (moderate severity) and white ash (high severity) associated with the 2013 Rim Fire in California. Spectroscopic results suggested that the aromaticity of WEOM followed white ash > control > black ash and fluorescence region II (excitation 220-250 nm; emission 330-380 nm) of the emission-excitation-matrix was identified as a potential burn severity indicator. Compared to the control, WEOM from white and black ashes had lower reactivity in forming trihalomethanes (55%-of-control) and haloacetic acids (67%-of-control), but higher reactivity in forming the more carcinogenic haloacetonitrile after chlorination (244%-of-control) and N-nitrosodimethylamine after chloramination (229%-of-control). There was no change in reactivity for chloral hydrate formation, while WEOM from black ash showed a higher reactivity for haloketone formation (150%-of-control). Because wildfire consumed a large portion of organic matter from the detritus layer, there was lower water extractable organic carbon (27%-of-control) and organic nitrogen (19%-of-control) yields in ashes. Consequently, the wildfire caused an overall reduction in water extractable terrestrial DBP precursor yield from detritus materials.

Trihalomethanes in marine mammal aquaria: occurrences, sources, and health risks.

Disinfecting water containing the high levels of dissolved organic carbon (DOC) commonly generated during pinniped husbandry may cause the formation of carcinogenic disinfection byproducts (DBPs). Little information is available on DBP levels, sources, and health risks in marine mammal aquaria. Using the commonly observed trihalomethanes (THMs) as a DBP indicator, we monitored concentrations for seven months at The Marine Mammal Center in Sausalito, California, one of the largest pinniped rehabilitation facilities in the world. Concentrations of THMs ranged 1.1-144.2 µg/L in pool waters and generally increased with number of animals housed (P < 0.05). To identify the sources of THM precursors in marine mammal aquaria, we intensively monitored the mass flows of potential THM precursors (i.e. food and wastes) in an isolated system with nine individual California sea lions to evaluate the sources and reactivity of dissolved organic carbon (DOC) for 2-5 weeks. The common frozen foods used in feeding pinnipeds, including herring, sardine, and squid, produced an average of 22-34 mg-DOC/g-food in water and 836-1066 µg-THM/g-food after chlorination, whereas the fecal materials, including fresh scat, decomposed scat, and urine, produced 2-16 mg-DOC/g-waste and 116-768 µg-THM/g-waste. Food not eaten by animals could cause a sharp increase of DOC and DBP production and therefore should be removed rapidly from pools. Marine mammal husbandry staff and trainers are at risk (5.16 × 10(-4) to 1.30 × 10(-3)) through exposure of THMs, exceeding the negligible risk level (10(-6)) defined by the US Environmental Protection Agency.