Feasibility study of the application of magnetic resonance elastography (MRE) to measure oral posture related changes in stiffness of zygomaticus major muscle.

PURPOSE: Development of a technique for measuring the mechanical properties of zygomaticus major (ZM) may aid advances in clinical treatments for correcting abnormal oral posture. The objective of this work was to demonstrate the feasibility of measuring the stiffness of ZM using an MR elastography technique that incorporates a custom local driver and a phase-gradient (PG) inversion. METHODS: 2D MRE investigations were performed for 3 healthy subjects using a vibration frequency of 90 Hz to test the prediction that the stiffness of ZM would be greater in the mouth-open compared to the mouth-closed position. MRE wave images were acquired along the long axis of ZM and processed using a 2D spatial-temporal directional filter applied in the direction of wave propagation along the long axis of the muscle. Stiffness measurements were obtained by applying the PG technique to a 1D-profile drawn in the phase image of the first harmonic of the wave images and a one-tailed paired t-test was used to compare the ZM stiffness between the two mouth postures for each participant (p < 0.05). RESULTS: The mean stiffness and standard deviation (SD) of ZM across the three participants in the mouth-closed and mouth-open postures was 6.75 kPa (SD 3.36 kPa) and 15.5 kPa (SD 5.15 kPa), respectively. Changes of ZM stiffness were significantly greater in the mouth-open than the mouth-closed posture (p = 0.038). CONCLUSION: The feasibility of using the PG MRE technique to measure stiffness changes in a small muscle such as ZM for different mouth postures has been demonstrated. Further investigations are required in a larger cohort of participants to investigate the sensitivity and reproducibility of the technique for potential clinical application as well as in health and beauty related studies.

Evaluating the mutagenicity of N-nitrosodimethylamine in 2D and 3D HepaRG cell cultures using error-corrected next generation sequencing.

Human liver-derived metabolically competent HepaRG cells have been successfully employed in both two-dimensional (2D) and 3D spheroid formats for performing the comet assay and micronucleus (MN) assay. In the present study, we have investigated expanding the genotoxicity endpoints evaluated in HepaRG cells by detecting mutagenesis using two error-corrected next generation sequencing (ecNGS) technologies, Duplex Sequencing (DS) and High-Fidelity (HiFi) Sequencing. Both HepaRG 2D cells and 3D spheroids were exposed for 72 h to N-nitrosodimethylamine (NDMA), followed by an additional incubation for the fixation of induced mutations. NDMA-induced DNA damage, chromosomal damage, and mutagenesis were determined using the comet assay, MN assay, and ecNGS, respectively. The 72-h treatment with NDMA resulted in concentration-dependent increases in cytotoxicity, DNA damage, MN formation, and mutation frequency in both 2D and 3D cultures, with greater responses observed in the 3D spheroids compared to 2D cells. The mutational spectrum analysis showed that NDMA induced predominantly A:T → G:C transitions, along with a lower frequency of G:C → A:T transitions, and exhibited a different trinucleotide signature relative to the negative control. These results demonstrate that the HepaRG 2D cells and 3D spheroid models can be used for mutagenesis assessment using both DS and HiFi Sequencing, with the caveat that severe cytotoxic concentrations should be avoided when conducting DS. With further validation, the HepaRG 2D/3D system may become a powerful human-based metabolically competent platform for genotoxicity testing.

Dithiophosphinylation of Allenyl Acetates: Access to 1,2-Bis(diphenylphosphino)ethane-Type Bidentate Ligands.

1,2-Bis(diphenylphosphino)ethanes (DPPEs) are versatile and immensely important ligands in transition metal catalysts. Here we report the dithiophosphinylation of readily available allenyl acetates to give DPPEs in high yields and regioselectivity. This protocol features a broad substrate scope and mild conditions, avoiding the use of transition metals and air-sensitive sources of phosphorus. Mechanism studies indicate that the reaction was accomplished via an SN2'-type addition-elimination followed by a 1,4-addition step.

Accelerated Wound Healing by Electrospun Multifunctional Fibers with Self-Powered Performance.

Wound healing has been a persistent clinical challenge for a long time. Electrical stimulation is an effective therapy with the potential to accelerate wound healing. In this work, the self-powered electrospun nanofiber membranes (triples) were constructed as multifunctional wound dressings with electrical stimulation and biochemical capabilities. Triple was composed of a hydrolyzable inner layer with antiseptic and hemostatic chitosan, a hydrophilic core layer loaded with conductive AgNWs, and a hydrophobic outer layer fabricated by self-powered PVDF. Triple exhibited presentable wettability and acceptable moisture permeability. Electrical performance tests indicated that triple can transmit electrical signals formed by the piezoelectric effect to the wound. High antibacterial activities were observed for triple against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa, with inhibition rates of 96.52, 98.63, and 97.26%, respectively. In vitro cell assays demonstrated that triple cells showed satisfactory proliferation and mobility. A whole blood clotting test showed that triple can enhance hemostasis. The innovative self-powered multifunctional fibers presented in this work offer a promising approach to addressing complications and expediting the promotion of chronic wound healing.

Astrocytic phagocytosis in the medial prefrontal cortex jeopardises postoperative memory consolidation in mice.

Memory impairment is one of the main characteristics of postoperative cognitive dysfunction. It remains elusive how postoperative pathological changes of the brain link to the memory impairment. The clinical setting of perioperation was mimicked via partial hepatectomy under sevoflurane anaesthesia together with preoperative restraint stress (Hep-Sev-stress) in mice. Memory changes were assessed with fear conditioning. The medial prefrontal cortex (mPFC)-dorsal hippocampus connectivity was evaluated with injecting neurotracer 28 days before surgery. Astrocytic activation was limited via injecting AAV-GFAP-hM4Di-eGFP into the mPFC. Astrocytic and microglial phagocytosis of synapses were visualised with co-labelling hippocampal neuronal axon terminals with PSD-95 and S100ß or Iba1. Neuroinflammation and oxidative stress status were also detected. Hep-Sev-stress impaired the memory consolidation (mean [standard error], 49.91 [2.55]% vs. 35.40 [3.97]% in the contextual memory, p = 0.007; 40.72 [2.78]% vs. 27.77 [2.22]% in cued memory, p = 0.002) and the cued memory retrieval (39.00 [3.08]% vs. 24.11 [2.06]%, p = 0.001) in mice when compared with these in the naïve controls. Hep-Sev-stress damaged the connectivity from the dorsal hippocampus to mPFC but not from the mPFC to the dorsal hippocampus and increased the astrocytic but not microglial phagocytosis of hippocampal neuronal axon terminals in the mPFC. The intervention also induced neuroinflammation and oxidative stress in the dorsal hippocampus and the mPFC in a regional-dependent manner. Limiting astrocyte activation in the mPFC alleviated memory consolidation impairment induced by Hep-Sev-stress. Postoperative memory consolidation was impaired due to astrocytic phagocytosis-induced connectivity injury from the dorsal hippocampus to the medial prefrontal cortex.

MYB/LINC00092 regulatory axis promotes the progression of papillary thyroid carcinoma.

INTRODUCTION: Thyroid carcinoma is the most frequent malignancy in different endocrine-related tumours. In this study, we demonstrated a long non-coding RNA LINC00092-associated molecular mechanism in promoting the progression of papillary thyroid carcinoma (PTC). MATERIAL AND METHODS: The expression of LINC00092 was analysed in the The Cancer Genome Atlas Thyroid Cancer (TCGA-THCA) patient cohorts and further determined by q-PCR. (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) (MTT) assay, and wound healing assay confirmed the function of LINC00092 in migration and proliferation. Q-ChIP validated the transcriptional target. Luciferase reporter assay validated the miRNA-mRNA target. RESULTS: The analysis in patient cohorts and in PTC TPC-1 cells showed that the expression of LINC00092 was repressed in thyroid carcinoma. In addition, the expression of LINC00092 was negatively associated with the advanced thyroid TNM stages. LINC00092 repressed epithelial-mesenchymal transition (EMT), migration, and proliferation of TPC-1 cells. Interestingly, we identified that MYB, a well-studied tumour promoter, is a transcription factor of LINC00092, thereby the expression of LINC00092 was directly repressed by MYB. Furthermore, miR-4741 was also validated as a direct target of MYB and was induced by MYB. Notably, LINC00092 was repressed by miR-4741 through the direct 3'-untranslational region (3'-UTR) target. Therefore, MYB induced EMT of TPC-1 cells by repressing LINC00092 directly or indirectly via miR-4741. CONCLUSIONS: Our study validated that LINC00092 is a tumour suppressor lncRNA in PTC. MYB directly or indirectly represses LINC00092, which contributes to the PTC progression. MYB, LINC00092, and miR-4741 form a coherent feed forward loop. The axis of MYB-LINC00092 promotes progression of PTC.

Single exposure to anesthesia/surgery in neonatal mice induces cognitive impairment in young adult mice.

BACKGROUND: The effects of a solitary neonatal exposure to anesthesia plus surgery (anesthesia/surgery) on cognitive function and the underlying mechanism in developing brains remains largely undetermined. We, therefore, set out to investigate the impact of single exposure to anesthesia/surgery in neonatal mice. METHODS: Six-day-old male and female mice received abdominal surgery under 3% sevoflurane plus 50% oxygen for 2 h. The new object recognition (NOR) and Morris water maze (MWM) were used to evaluate cognitive function in young adult mice. Western blot, ELISA and RT-PCR were used to measure levels of NR2B and IL-6 in medial prefrontal cortex and IL-6 in blood of the mice. We employed NR2B siRNA and IL-6 antibody in the interaction studies. RESULTS: The anesthesia/surgery decreased the ratio of novel time to novel plus familiar time in NOR and the number of platform crossings, but not escape latency, in MWM compared to sham condition. The mice in anesthesia/surgery group had increased NR2B expression in medial prefrontal cortex, and IL-6 amounts in blood and medial prefrontal cortex. Local injection of NR2B siRNA in medial prefrontal cortex alleviated the anesthesia/surgery-induced cognitive impairment. IL-6 antibody mitigated the anesthesia/surgery-induced upregulation of NR2B and cognitive impairment in young adult mice. CONCLUSIONS: These results suggest that a single neonatal exposure to anesthesia/surgery causes impairment of memory, but not learning, in young adult mice through IL-6-regulated increases in NR2B concentrations in medial prefrontal cortex, highlighting the need for further research on the underlying mechanisms of anesthesia/surgery's impact on cognitive function in developing brains.

[Expression of MicroRNA-3162-3p in Different Clinical Stages of Children with Primary Immune Thrombocytopenia and Its Significance].

OBJECTIVE: To explore the expression of microRNA-3162-3p in different clinical stages of childhood primary immune thrombocytopenia (ITP) and its significance. METHODS: Ninety-six children with ITP were enrolled and divided into new diagnosis group (n=40), persistent group (n=30) and chronic group (n=26) according to the course of disease. 80 healthy children were selected as the control group. Peripheral blood mononuclear cells (PBMNC) of ITP children and healthy children were isolated and cultured, and the expression of microRNA-3162-3p in PBMNC of subjects was detected by real-time fluorescence quantitative PCR. The contents of IL-17, IL-23, IL-10 and TGF-ß in PBMNC of subjects were determined by ELISA. The correlation between microRNA-3162-3p and platelet count, IL-17, IL-23, IL-10 and TGF-ß was analyzed. RESULTS: Compared with the control group, the expression of microRNA-3162-3p and IL-10 in PBMNC and platelet count of ITP children were significantly decreased（P < 0.05）, while IL-17, IL-23 and TGF-ß were significantly increased (P < 0.05). With the prolongation of the disease course, the expressions of microRNA-3162-3p and IL-10 in PBMNC and platelet count were significantly decreased（P < 0.05）, while the expressions of IL-17, IL-23 and TGF-ß were significantly increased (P < 0.05). The expression of microRNA-3162-3p in PBMNC was positively correlated with platelet count and IL-10 (r =0.716, 0.667), and negatively correlated with IL-17, IL-23, and TGF-ß (r =-0.540, -0.641, -0.560). CONCLUSION: MicroRNA-3162-3p expression is significantly reduced in PBMNC of children with ITP, and is involved in the regulation of Th17/Treg imbalance, which can be used as a potential therapeutic target of ITP.

Evaluation of weak genotoxicity of hydroxychloroquine in human TK6 cells.

Hydroxychloroquine (HCQ), a derivative of chloroquine (CQ), is an antimalarial and antirheumatic drug. Since there is limited data available on the genotoxicity of HCQ, in the current study, we used a battery of in vitro assays to systematically examine the genotoxicity of HCQ in human lymphoblastoid TK6 cells. We first showed that HCQ is not mutagenic in TK6 cells up to 80 µM with or without exogenous metabolic activation. Subsequently, we found that short-term (3-4 h) HCQ treatment did not cause DNA strand breakage as measured by the comet assay and the phosphorylation of histone H2A.X (γH2A.X), and did not induce chromosomal damage as determined by the micronucleus (MN) assay. However, after 24-h treatment, both CQ and HCQ induced comparable and weak DNA damage and MN formation in TK6 cells; upregulated p53 and p53-mediated DNA damage responsive genes; and triggered apoptosis and mitochondrial damage that may partially contribute to the observed MN formation. Using a benchmark dose (BMD) modeling analysis, the lower 95% confidence limit of BMD50 values (BMDL50) for MN induction in TK6 cells were about 19.7 µM for CQ and 16.3 µM for HCQ. These results provide additional information for quantitative genotoxic risk assessment of these drugs.

Highly Efficient Oral Iguratimod/Polyvinyl Alcohol Nanodrugs Fabricated by High-Gravity Nanoprecipitation Technique for Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA), a systemic autoimmune disease, poses a significant human health threat. Iguratimod (IGUR), a novel disease-modifying antirheumatic drug (DMARD), has attracted great attention for RA treatment. Due to IGUR's hydrophobic nature, there's a pressing need for effective pharmaceutical formulations to enhance bioavailability and therapeutic efficacy. The high-gravity nanoprecipitation technique (HGNPT) emerges as a promising approach for formulating poorly water-soluble drugs. In this study, IGUR nanodrugs (NanoIGUR) are synthesized using HGNPT, with a focus on optimizing various operational parameters. The outcomes revealed that HGNPT enabled the continuous production of NanoIGUR with smaller sizes (ranging from 300 to 1000 nm), more uniform shapes, and reduced crystallinity. In vitro drug release tests demonstrated improved dissolution rates with decreasing particle size and crystallinity. Notably, in vitro and in vivo investigations showcased NanoIGUR's efficacy in inhibiting synovial fibroblast proliferation, migration, and invasion, as well as reducing inflammation in collagen-induced arthritis. This study introduces a promising strategy to enhance and broaden the application of poorly water-soluble drugs.

Wavelet MRE: Imaging propagating broadband acoustic waves with wavelet-based motion-encoding gradients.

PURPOSE: To demonstrate a novel MR elastography (MRE) technique, termed here wavelet MRE. With this technique, broadband motion sensitivity is achievable. Moreover, the true tissue displacement can be reconstructed with a simple inverse transform. METHODS: A wavelet MRE sequence was developed with motion-encoding gradients based on Haar wavelets. From the phase images' displacement was estimated using an inverse transform. Simulations were performed using a frequency sweep and a transient as ground-truth motions. A PVC phantom was scanned using wavelet MRE and standard MRE with both transient (one and 10 cycles of 90-Hz motion) and steady-state dual-frequency motion (30 and 60 Hz) for comparison. The technique was tested in a human brain, and motion trajectories were estimated for each voxel. RESULTS: In simulation, the displacement information estimated from wavelet MRE closely matched the true motion. In the phantom test, the MRE phase data generated from the displacement information derived from wavelet MRE agreed well with standard MRE data. Testing of wavelet MRE to assess transient motion waveforms in the brain was successful, and the tissue motion observed was consistent with a previous study. CONCLUSION: The uniform and broadband frequency response of wavelet MRE makes it a promising method for imaging transient, multifrequency motion, or motion with unknown frequency content. One potential application is measuring the response of brain tissue undergoing low-amplitude, transient vibrations as a model for the study of traumatic brain injury.

Regulated cell death and inflammasome activation in gut injury following traumatic surgery in vitro and in vivo: implication for postoperative death due to multiorgan dysfunction.

Postoperative multi-organ dysfunction (MOD) is associated with significant mortality and morbidity. Necroptosis has been implicated in different types of solid organ injury; however, the mechanisms linking necroptosis to inflammation require further elucidation. The present study examines the involvement of necroptosis and NLR family pyrin domain containing 3 (NLRP3) inflammasome in small intestine injury following traumatic surgery. Kidney transplantation in rats and renal ischaemia-reperfusion (I/R) in mice were used as traumatic and laparotomic surgery models to study necroptosis and inflammasome activation in the small intestinal post-surgery; additional groups also received receptor-interacting protein kinase 1 (RIPK1) inhibitor necrostatin-1s (Nec-1s). To investigate whether necroptosis regulates inflammasome activity in vitro, necroptosis was induced in human colonic epithelial cancer cells (Caco-2) by a combination of tumour necrosis factor-alpha (TNFα), SMAC mimetic LCL-161 and pan-caspase inhibitor Q-VD-Oph (together, TLQ), and necroptosis was blocked by Nec-1s or mixed lineage kinase-domain like (MLKL) inhibitor necrosulfonamide (NSA). Renal transplantation and renal ischaemia-reperfusion (I/R) upregulated the expression of necroptosis mediators (RIPK1; RIPK3; phosphorylated-MLKL) and inflammasome components (P2X purinoceptor subfamily 7, P2X7R; NLRP3; caspase-1) in the small intestines at 24 h, and Nec-1s suppressed the expression of inflammasome components. TLQ treatment induced NLRP3 inflammasome, promoted cleavage of caspase-1 and interleukin-1 beta (IL-1ß), and stimulated extracellular ATP release from Caco-2 cells, and MLKL inhibitor NSA prevented TLQ-induced inflammasome activity and ATP release from Caco-2 cells. Our work suggested that necroptosis and inflammasome interactively promote remote postoperative small intestinal injury, at least in part, through ATP purinergic signalling. Necroptosis-inflammasome axis may be considered as novel therapeutic target for tackling postoperative MOD in the critical care settings.

[Mechanism of Proliferation and Apoptosis of Acute Promyelocytic Leukemia Cell Line NB4 Induced by TPA].

OBJECTIVE: To investigate the effect of phorbol-12-myristate-13-ace-tate (TPA) on the proliferation and apoptosis of acute promyelocytic leukemia cell line NB4 and its molecular mechanism. METHODS: The effect of different concentrations of TPA on the proliferation of NB4 cells at different time points was detected by CCK-8 assay. The morphological changes of NB4 cells were observed by Wright-Giemsa staining. The cell cycle and apoptosis of NB4 cells after TPA treatment were detected by flow cytometry. The mRNA expressions of NB4 cells after TPA treatment were analyzed by high-throughput microarray analysis and real-time quantitative PCR. Western blot was used to detect the protein expression of CDKN1A, CDKN1B, CCND1, MYC, Bax, Bcl-2, c-Caspase 3, c-Caspase 9, PIK3R6, AKT and p-AKT. RESULTS: Compared with the control group, TPA could inhibit the proliferation of NB4 cells, induce the cells to become mature granulocyte-monocyte differentiation, and also induce cell G1 phase arrest and apoptosis. Differentially expressed mRNAs were significantly enriched in PI3K/AKT pathway. TPA treatment could increase the mRNA levels of CCND1, CCNA1, and CDKN1A, while decrease the mRNA level of MYC. It could also up-regulate the protein levels of CDKN1A, CDKN1B, CCND1, Bax, c-Caspase 3, c-Caspase 9, and PIK3R6, while down-regulate MYC, Bcl-2, and p-AKT in NB4 cells. CONCLUSION: TPA induces NB4 cell cycle arrest in G1 phase and promotes its apoptosis by regulating PIK3/AKT signaling pathway.

Degradable PDA@PNIPAM-TA Nanocomposites for Temperature- and NIR light-Controlled Pesticide Release.

Controlled pesticide delivery systems offer many distinctive advantages over conventional pesticide formulations. In this work, degradable poly(N-isopropylacrylamide) (PNIPAM)-tannic acid (TA) microgels and multifunctional PDA@PNIPAM-TA nanocomposites were prepared in a high-gravity rotating packed bed reactor (RPB) for smart pesticide delivery and release. The as-prepared microgels and nanocomposites showed reversible temperature-dependent swelling/deswelling behavior and irreversible pH-induced degradation. A dynamic contact angle test suggested that the introduction of TA and PDA into the PNIPAM matrix could enhance foliar adhesion and deposition efficiency. The nanocomposites were further used for the encapsulation and delivery of imidacloprid (IMI) to protect it from rapid photolysis and improve its pest-control efficiency. Their thermoresponsive behavior as well as pesticide loading capacity could be tuned by tailoring the PNIPAM-TA shell thickness, which could be varied by the NIPAM amount. The release rate of IMI from the core/shell nanocomposites was positively correlated with environmental temperature and near-infrared (NIR) light, which was adaptive to the positive temperature-dependent toxicity correlation of IMI and the increasing trend of pests under high temperature. The cumulative release of IMI was 23.5% at 25 °C, while it was 81.2% at 40 °C after 24 h of incubation, and the release rate was greatly enhanced under NIR irradiation. The results indicated that the facile control of pesticide release could be realized by regulating environmental conditions. This work also provides an idea for using high-gravity technology to conveniently construct a smart, effective, and environmentally friendly pesticide delivery system for sustainable crop protection.

Using macromolecular electron densities to improve the enrichment of active compounds in virtual screening.

The quest for effective virtual screening algorithms is hindered by the scarcity of training data, calling for innovative approaches. This study presents the use of experimental electron density (ED) data for improving active compound enrichment in virtual screening, supported by ED's ability to reflect the time-averaged behavior of ligands and solvents in the binding pocket. Experimental ED-based grid matching score (ExptGMS) was developed to score compounds by measuring the degree of matching between their binding conformations and a series of multi-resolution experimental ED grids. The efficiency of ExptGMS was validated using both in silico tests with the Directory of Useful Decoys-Enhanced dataset and wet-lab tests on Covid-19 3CLpro-inhibitors. ExptGMS improved the active compound enrichment in top-ranked molecules by approximately 20%. Furthermore, ExptGMS identified four active inhibitors of 3CLpro, with the most effective showing an IC50 value of 1.9 µM. We also developed an online database containing experimental ED grids for over 17,000 proteins to facilitate the use of ExptGMS for academic users.

Reinforced mixture learning.

In this article, we formulate the standard mixture learning problem as a Markov Decision Process (MDP). We theoretically show that the objective value of the MDP is equivalent to the log-likelihood of the observed data with a slightly different parameter space constrained by the policy. Different from some classic mixture learning methods such as Expectation-Maximization (EM) algorithm, the proposed reinforced algorithm requires no distribution assumptions and can handle the non-convex clustered data by constructing a model-free reward to evaluate the mixture assignment based on the spectral graph theory and Linear Discriminant Analysis (LDA). Extensive experiments on both synthetic and real examples demonstrate that the proposed method is comparable with the EM algorithm when the Gaussian mixture assumption is satisfied, and significantly outperforms it and other clustering methods in most scenarios when the model is misspecified. A Python implementation of our proposed method is available at https://github.com/leyuanheart/Reinforced-Mixture-Learning.

Observation of hydrodynamization and local prethermalization in 1D Bose gases.

Hydrodynamics accurately describe relativistic heavy-ion collision experiments well before local thermal equilibrium is established1. This unexpectedly rapid onset of hydrodynamics-which takes place on the fastest available timescale-is called hydrodynamization2-4. It occurs when an interacting quantum system is quenched with an energy density that is much greater than its ground-state energy density5,6. During hydrodynamization, energy gets redistributed across very different energy scales. Hydrodynamization precedes local equilibration among momentum modes5, which is local prethermalization to a generalized Gibbs ensemble7,8 in nearly integrable systems or local thermalization in non-integrable systems9. Although many theories of quantum dynamics postulate local prethermalization10,11, the associated timescale has not been studied experimentally. Here we use an array of one-dimensional Bose gases to directly observe both hydrodynamization and local prethermalization. After we apply a Bragg scattering pulse, hydrodynamization is evident in the fast redistribution of energy among distant momentum modes, which occurs on timescales associated with the Bragg peak energies. Local prethermalization can be seen in the slower redistribution of occupation among nearby momentum modes. We find that the timescale for local prethermalization in our system is inversely proportional to the momenta involved. During hydrodynamization and local prethermalization, existing theories cannot quantitatively model our experiment. Exact theoretical calculations in the Tonks-Girardeau limit12 show qualitatively similar features.

Diterpenoids with an unusual tricyclo[10.3.0.02,9]pentadecane skeleton from Pedilanthus tithymaloides as multidrug resistance modulators.

Three new diterpenoids with an unusual carbon skeleton, pedilanins A-C (1-3), and nine new jatrophane diterpenoids, pedilanins D-L (4-12), along with five known ones (13-17), were isolated from Pedilanthus tithymaloides. Compounds 1-3 characterize an unprecedented tricyclo[10.3.0.02,9]pentadecane skeleton. Compounds 4-8 are rare examples of the jatrophanes bearing a cyclic hemiketal substructure. Their structures were determined by an extensive analysis of HRESIMS, NMR, quantum-chemical calculation, DP4+ probability, and X-ray crystallographic data. In the bioassay, compounds 1-12 dramatically reversed multidrug resistance in cancer cells with the fold-reversals ranging from 17.9 to 396.8 at the noncytotoxic concentration of 10 µM. The mechanism results indicated that compounds 2 and 3 inhibited the P-glycoprotein (Pgp) transporter function, thus reversing the drug resistance.