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1.
J Mater Chem B ; 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31912081

RESUMO

Angiogenesis plays an important role in the occurrence and development of skin tumors and vascular anomalies (VAs). Many drugs have been adopted for the inhibition of angiogenesis, among which rapamycin (RAPA) possesses good application prospects. However, the clinical potential of RAPA for VAs is limited by its poor solubility, low bioavailability, and high cytotoxicity. To extend its application prospect for VAs treatment, in this study, we develop RAPA-loaded dissolving polymeric microneedles (RAPA DMNs) made of polyvinylpyrrolidone (PVP) due to its excellent solubilizing ability. RAPA DMNs are shown to have sufficient mechanical strength to overcome the skin barrier of the stratum corneum and could deliver RAPA to a depth of 200 µm. The microneedle shafts completely dissolve and 80% of the drug could be released within 10 min after insertion ex vivo. The DMNs-penetrated mice skin could repair itself within 4 h after the application of RAPA DMNs. RAPA DMNs also show good anti-angiogenic effect by inhibiting the growth of human umbilical vein endothelial cells (HUVECs) and decreasing the secretion of vascular endothelial growth factor (VEGF). Therefore, RAPA DMNs promisingly provide a safe and efficient approach for VAs treatment.

2.
Chem Commun (Camb) ; 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31897459

RESUMO

Correction for 'Discovery, biosynthesis and antifungal mechanism of the polyene-polyol meijiemycin' by Zhen Jie Low et al., Chem. Commun., 2020, DOI: 10.1039/c9cc08908j.

3.
Proc Natl Acad Sci U S A ; 117(1): 238-242, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31852824

RESUMO

With the recent discovery of the quantum anomalous Hall insulator (QAHI), which exhibits the conductive quantum Hall edge states without external magnetic field, it becomes possible to create a topological superconductor (SC) by introducing superconductivity into these edge states. In this case, 2 distinct topological superconducting phases with 1 or 2 chiral Majorana edge modes were theoretically predicted, characterized by Chern numbers (N) of 1 and 2, respectively. We present spectroscopic evidence from Andreev reflection experiments for the presence of chiral Majorana modes in an Nb/(Cr0.12Bi0.26Sb0.62)2Te3 heterostructure with distinct signatures attributed to 2 different topological superconducting phases. The results are in qualitatively good agreement with the theoretical predictions.

4.
Nanoscale ; 12(2): 1100-1108, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31845949

RESUMO

The hybrid perovskite CH3NH3PbX3 (X = Cl, Br, I) is a promising material for developing novel optoelectronic devices. Due to its intrinsic non-layered crystal structure, it remains challenging to synthesize two-dimensional (2D) single-crystalline CH3NH3PbX3 with nanoscale thickness. Here, we report a bottom-up approach to fabricate large CH3NH3PbX3 2D crystals via liquid-phase growth on a mica substrate. The strong potassium-halogen interactions at the perovskite/mica interface decrease the interface energy, driving the striking in-plane growth of the perovskite. The grown 2D CH3NH3PbBr3 crystal was characterized as 8 nm in thickness and hundreds of micrometers in lateral size. Weak exciton binding energy was crucial for improving the photoelectric performance of 2D CH3NH3PbBr3. A visible-light photodetector with a metal/insulator/perovskite configuration was finally achieved with a photoresponsivity of 126 A W-1 and a bandwidth exceeding 80 kHz. Our work proves that the liquid-phase growth on mica is a controllable method to grow 2D hybrid CH3NH3PbX3 perovskites, which can facilitate both device applications and fundamental investigations.

5.
J Infect Dis ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31793629

RESUMO

BACKGROUND: Clostridium difficile infection (CDI) causes diarrhea and colitis. We aimed at finding a common pathogenic pathway in CDI among humans and mice by comparing toxin-mediated effects in human and mouse colonic tissues. METHOD: We determined the cytokine secretion of toxin A- and B-treated human and mouse colonic explants using multiplex ELISA. RESULTS: Toxin A and toxin B exposure to fresh human and mouse colonic explants caused different patterns of cytokine secretion. Toxin A induced macrophage inflammatory protein 1 alpha (MIP-1α) secretion in both human and mouse explants. Toxin A reduced chloride anion exchanger SLC26A3 expression in mouse colonic explants and human colonic epithelial cells. C. difficile-infected patients had increased colonic MIP-1α expression and reduced colonic SLC26A3 expression compared to controls. Anti-MIP-1α neutralizing antibody prevented mortality, ameliorated colonic injury, reduced colonic IL-1beta mRNA expression, and restored colonic Slc26a3 expression in C. difficile-infected mice. The anti-MIP-1α neutralizing antibody prevented CDI recurrence. Slc26a3 inhibition augmented colonic IL-1ß mRNA expression and abolished the protective effect of anti-MIP-1α neutralizing antibody in C. difficile-infected mice. CONCLUSION: MIP-1α is a common toxin A-dependent chemokine in human and mouse colon. MIP-1α mediates detrimental effects by reducing Slc26a3 and enhancing IL-1ß expression in the colon.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31863720

RESUMO

Even though transition metal phosphides (TMPs) have been developed as one of the most promising alternatives to Pt catalyst for hydrogen evolution reaction (HER), further improvement of their performance requires fine regulation over TMP sites at the local atomic level and profound insight of the catalytic mechanisms related to their specific electronic structure. Herein, for the first time, boron (B)-modulated electrocatalytic characteristics in CoP anchored on the carbon nanotubes (B-CoP/CNT) with impressive HER activities over a wide pH range were reported. The superior HER performance of B-CoP/CNT even surpass commercial Pt/C in both neutral and alkaline media at large current density (> 100 mA cm-2). A combined experimental and theoretical study clearly identified that low-electronegative B dopant could reform the local electronic configuration and atomic arrangement of bonded Co and adjacent P atoms, enhance the electrons' delocalization capacity of Co atoms for high electrical conductivity, and optimize the free energy of H adsorption and H2 desorption on the active sites for better HER kinetics. This work enlightens a feasible strategy to explore efficient electrocatalysts by the electronic structure refinement using non-metal as modulator.

7.
Int J Mol Sci ; 21(1)2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31878055

RESUMO

According to the theories of traditional Chinese medicine, spleen deficiency often leads to diarrhea, and deep-fried Atractylodis Rhizoma (DAR) is commonly used for the treatment. However, the association between spleen deficiency and diarrhea remains unclear. The present study aimed to investigate the therapeutic effect of DAR for the treatment of diarrhea caused by spleen deficiency and analyze the related mechanisms. It was found that a high dose group of an ethanolic extract of deep-fried Atractylodis Rhizoma (EEDAR-H) significantly inhibited weight loss, diarrhea, and pathological changes in colon tissue induced by rhubarb. EEDAR-H was found to significantly reduce the level of intestinal inflammatory cytokines and increase the expression of gastrointestinal motility hormones. In addition, EEDAR-H significantly increased the expression of aquaporin 3 (AQP3) and aquaporin 8 (AQP8) and restored abnormal water metabolism; Shen-Ling-Bai-Zhu-San (SLBZS) induced the same effect as EEDAR-H. Additional tests on the mechanism found that EEDAR-H and SLBZS promoted the integrity of the intestinal barrier. Both significantly increased the expression of the tight junction protein ZO-1 and Occludin, inhibited the phosphorylation of p38MAPK and MLC, and significantly reduced the expression levels of PAR-2. Analysis of the gut microbiota indicated that overall changes in its structure were reversed after treatment with EEDAR-H or SLBZS, in addition to significant modulation of the abundance of different phyla. At the genus level, EEDAR-H or SLBZS significantly reduced the levels of potential pathogens and increased those of beneficial bacteria.

8.
Phytomedicine ; 67: 153141, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31884406

RESUMO

BACKGROUND: Nobiletin (N), a polymethoxylated flavone from citrus fruits, enhanced anti-cancer effects of paclitaxel (PTX) in multi-drug resistance (MDR) cancer cells via inhibiting P-glycoprotein (P-gp) in our previous report. But the in vivo chemo-sensitizing effect of nobiletin is unknown. Moreover, considering the nonlinear pharmacokinetics and narrow therapeutic window of PTX, drug-drug interaction should be explored for using nobiletin with PTX together. PURPOSE: In this study, we wanted to explore whether nobiletin could affect the pharmacokinetic (PK) behavior of PTX and reverse drug resistance in vivo as well as the corresponding mechanisms. STUDY DESIGN AND METHODS: Accurate and sensitive UPLC-MS/MS method was developed for the detection of PTX, and was applied to the pharmacokinetic study in rats. In vivo anti-MDR tumor study was carried out with A549/T xenograft nude mice model. Immunohistochemistry and western blot analysis were used for evaluating the levels of P-gp, Nrf2, and AKT/ERK pathways in MDR tumors. RESULTS: Nobiletin significantly enhanced the therapeutic effects of PTX, and inhibited the MDR tumor sizes in the A549/T xenograft model, while PTX or nobiletin alone did not. We found that nobiletin increased the PTX concentrations in tumor tissues but did not affect the PK behavior of PTX. Notably, Nrf2 and phosphorylation of AKT/ERK expression in MDR tumor tissues were significantly inhibited by giving nobiletin and PTX together. However, nobiletin did not affect the expression of P-gp. CONCLUSION: Nobiletin reversed PTX resistance in MDR tumor via increasing the PTX content in the MDR tumor and inhibiting AKT/ERK/Nrf2 pathways, but without affecting the systematic exposure of PTX, indicating that nobiletin may be an effective and safe MDR tumor reversal agent.

9.
Toxicol Lett ; 321: 131-137, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31877331

RESUMO

Prior exposures to chemicals/agents may alter epigenome in such a way that subsequent exposure to the same or different xenobiotic would produce different responses. Understanding the mechanism for this "priming" effect is of clinical significance in avoiding adverse drug-drug interactions. Here we reported a dramatic priming effect of dimethyl sulfoxide (DMSO) on pregnane X receptor (PXR)-mediated gene regulations and analyzed the underpinning epigenetic mechanism. We showed that DMSO (1.25-2.5 %) pretreatment has a profound effect in enhancing the expression of PXR target genes. This priming effect persisted up to 48 h. Mechanistically, DMSO pretreatment reduced H4K12 acetylation and therefore enhanced the subsequent rifampicin stimulated histone H4R3 methylation on the regulatory region of PXR target gene CYP3A4. We showed that protein arginine methyltransferase 1 (PRMT1), which methylates H4R3, was important for priming by DMSO. Inhibition of methyltransferase by the pharmacological inhibitor adenosine dialehyde (AdoX), or RNAi knockdown of PRMT1, abolished the DMSO priming effects. On the other hand, Trichostation A (TSA) pretreatment, which increases histone acetylation and therefore suppresses H4R3 methylation, also abolished the DMSO priming effects. Based on the above observation, we proposed a model of sequential order of histone methylation and acetylation on the transcription "relay".

10.
Chem Commun (Camb) ; 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31848534

RESUMO

Produced by a newly isolated Streptomycetes strain, meijiemycin is a gigantic linear polyene-polyol that exhibits structural features not seen in other members of the polyene-polyol family. We propose a biosynthetic mechanism and demonstrate that meijiemycin inhibits hyphal growth by inducing the aggregation of ergosterol and restructuring of the fungal plasma membrane.

11.
Pharmacol Res ; 151: 104519, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31706011

RESUMO

Silybin (SB) is widely used to treat chronic liver diseases, especially this compound is much efficient for the treatments of alcoholic and non-alcoholic steatohepatitis (NASH). However, low bioavailability seriously limits wide-application of SB in biomedical niche. Prior to this study, we found that tangeretin (TG) could remarkably increase the bioavailability of SB by the inhibition of efflux transporters, which encourges us to therapeutical discovery of SB and TG combitional use against NASH. Here, we revealed that TG is capable of improving hepatic-protective activity of SB in mice with NASH by interfering liver oxidative stress, inflammation, and lipid accumulation. In addition, TG was observed to enhance the exposural level of SB in the plasma and liver of mice. Our metabolome assay confirmed that amino acid metabolism and lipid biosynthesis mostly accounted for combitional use of SB and TG to teat NASH in mice, basically biosynthesis of unsaturated fatty acids was mostly affected. Notably, significant inhibitions in fatty acid generating and transporting proteins such as G6PD, FABP4, LPL and CD36/FAT, and cholesterol metabolism enzyme CYP27A1 as well as nuclear transcription factors FXR, PPAR-γ, and LXR were illustrated to decipher therapeutic mechanisms of SB and TG against experimental NASH. Taken together, the strategy based combitional use of SB and TG has a potential-capacity to treat NASH.

12.
Toxicol Appl Pharmacol ; 384: 114789, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31669811

RESUMO

Previous studies showed that dopamine (DA) significantly reduces the frequency of cancer stem-like cells (CSC) and enhances the efficacy of sunitinib (SUN) in the treatment of breast cancer and non-small cell lung cancer (NSCLC). To overcome the shortcomings of DA in clinical practice, the purpose of this study was to investigate the efficacy as well as the underlying mechanism of an orally available, N-arylpiperazine-containing compound C2, in the treatment of pancreatic cancer when used alone or in combination with SUN. Our results showed that C2 and SUN exerted synergistic effects on inhibiting the growth of SW1990 and PANC-1 pancreatic cancer cells. C2 significantly inhibited colony formation and migration of both cells. SW1990 xenograft and patient-derived xenograft (PDX) models were utilized for pharmacodynamic investigation in vivo. C2 alone showed little inhibition effect on tumor growth but increased the anti-tumor efficacy of SUN in both xenografts. Moreover, C2 down-regulated CSC markers (CD133 and ALDH) of both cancer cells and up-regulated the expression of dopamine receptor D1 (D1DR) in tumor. Besides, the SW1990 tumor growth was dose-dependently inhibited when the cells were pretreated with C2 before implantation. C2 increased intratumoral cAMP level, and the combination with D1DR specific antagonist SCH23390 reversed the above-mentioned effects of C2 both in vitro and in vivo, indicating the activation of D1DR may be involved in the underlying mechanism of C2 action. In summary, C2 could reduce the CSC frequency and enhance the anti-cancer effect of SUN in the treatment of pancreatic cancer, demonstrating its potential in cancer therapy.

13.
Nat Commun ; 10(1): 5078, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31699995

RESUMO

A multiprotein complex polarisome nucleates actin cables for polarized cell growth in budding yeast and filamentous fungi. However, the dynamic regulations of polarisome proteins in polymerizing actin under physiological and stress conditions remains unknown. We identify a previously functionally unknown polarisome member, actin-interacting-protein 5 (Aip5), which promotes actin assembly synergistically with formin Bni1. Aip5-C terminus is responsible for its activities by interacting with G-actin and Bni1. Through N-terminal intrinsically disordered region, Aip5 forms high-order oligomers and generate cytoplasmic condensates under the stresses conditions. The molecular dynamics and reversibility of Aip5 condensates are regulated by scaffolding protein Spa2 via liquid-liquid phase separation both in vitro and in vivo. In the absence of Spa2, Aip5 condensates hamper cell growth and actin cable structures under stress treatment. The present study reveals the mechanisms of actin assembly for polarity establishment and the adaptation in stress conditions to protect actin assembly by protein phase separation.

14.
Sci Rep ; 9(1): 16088, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31695091

RESUMO

Fencing for grazing exclusion has been widely found to have an impact on grassland soil organic carbon (SOC) and total nitrogen (TN), but little is known about the impact of fenced grassland on the changes in deep soil carbon (C) and nitrogen (N) stocks in temperate grasslands. We studied the influence of 30 years fencing on vegetation and deep soil characteristics (0-500 cm) in the semi-arid grasslands of northern China. The results showed that fencing significantly increased the aboveground biomass (AGB), litter biomass (LB), total biomass, vegetation coverage and height, and soil water content and the SOC and TN in the deep soil. The belowground biomass (BGB) did not significantly differ between the fenced and grazed grassland. However, fencing significantly decreased the root/shoot ratio, forbs biomass, pH, and soil bulk density. Meanwhile, fencing has significantly increased the C and N stocks in the AGB and LB but not in the BGB. After 30 years of fencing, the C and N stocks significantly increased in the 0-500 cm soil layer. The accumulation of SOC mainly occurred in the deep layers (30-180 cm), and the accumulation of TN occurred in the soil layers of 0 to 60 cm and 160 to 500 cm. Our results indicate that fencing is an effective way to improve deep soil C and N stocks in temperate grassland of northwest China. There were large C and N stocks in the soil layers of 100 to 500 cm in the fenced grasslands, and their dynamics should not be ignored.

15.
Artigo em Inglês | MEDLINE | ID: mdl-31727367

RESUMO

Helicobacter pylori (H. pylori) infection can promote the development of gastric cancer (GC); however, the underlying mechanism is not clear. FAM60A has been found showing high levels in some cancer cells, including lung cancer (A549), and pancreatic cancer (Capan-2) cell lines. Data in oncomine showed that FAM60A overexpression was an critical prognostic factor in GC. In this study, we showed that knockdown of FAM60A could revert the increase of proliferation and the decrease of apoptosis caused by H.pylori infection in HGC-27 and AGS cells. Conversely, FAM60A upregulation promoted proliferation and inhibited apoptosis in HGC-27 and AGS cells. We also found that the PI3K/AKT pathway inhibitor LY294002 could revert the changes caused by FAM60A upregulation in HGC-27 and AGS cells. Thus, our study provides evidence that FAM60A act as a carcinogen and suggests that H. pylori-induced upregulation of FAM60A may contribute to the development of gastric cancer.

16.
J Mater Chem B ; 7(42): 6604-6611, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31589215

RESUMO

Hypertrophic scarring is a widespread skin disorder that affects a patient's confidence and quality of life. Intralesional injection of bleomycin is one of the most commonly employed treatments for hypertrophic scars, which, however, always brings pain and requires long-term treatment. To overcome these limitations, new methods for bleomycin delivery enabling painlessness, self-administration, the fast onset of action, and good bioavailability are urgently needed. In this study, we developed bleomycin-loaded dissolving microneedles (BMN) made up of hyaluronic acid (HA) with excellent aqueous solubility and enhanced efficacy for inhibiting hypertrophic scars. The as-obtained BMN possesses sufficient mechanical strength to pierce porcine skin ex vivo with an insertion depth of over 300 µm. Moreover, BMN can dissolve rapidly and release 20% of loaded bleomycin within 1 min and 52% within 10 min, and the BMN-treated skin could recover to its original status within 3 h, demonstrating good biocompatibility. Besides, the HA matrix also maintains the stability and activity of bleomycin. Furthermore, we show that BMN consisting of HA and bleomycin can inhibit the proliferation of human hypertrophic scar fibroblasts (hHSFs) and the secretion of transforming growth factor-ß (TGF-ß1) in vitro. Therefore, bleomycin-loaded dissolving HA microneedles provide a potential route to treat hypertrophic scars in a convenient, efficient, and minimally invasive manner.

17.
Chem Biol Interact ; 315: 108851, 2019 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-31614129

RESUMO

BACKGROUND: Currently, few herbal pharmacokinetic (PK) parameters have been applied successfully for therapeutic monitoring because of the complexity of consistency when there are multiple chemicals and efficacies. PURPOSE: The present study aims to evaluate the herbal PK properties by investigating the PK parameters of the 8 absorbed bioactive compounds (ABCs), which can represent its parent herbal holistic efficacy, to achieve a PK therapeutic monitoring of herbs. METHOD: First, we tested the hypothesis that the antidepressant and prokinetic effects and related anti-inflammation and anti-oxidation activity (APIO) by Fructus aurantii-Magnolia Bark (FM) formula are related to 8 compounds according to the absorbable evidence and the determined contents. Subsequently, stable and representative APIO from 8ABCs allowed us to develop a sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of 8 compounds following the oral administration of FM decoction (20 g/kg) in rats. RESULT: 8 compounds either including Meranzin hydrate (MH) or MH alone almost identically (8 compounds: 91.62-108.82%)or nearly(MH: 65.38-88.41%) replicated the parent formula FM in terms of efficacy for inducing APIO. CONCLUSION: This unifying strategy shows how multi-herb formulas pharmacokinetic therapeutic monitoring can be achieved by the method we established.

18.
Molecules ; 24(20)2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31615114

RESUMO

Silymarin, the extract of milk thistle, and its major active flavonolignan silybin, are common products widely used in the phytotherapy of liver diseases. They also have promising effects in protecting the pancreas, kidney, myocardium, and the central nervous system. However, inconsistent results are noted in the different clinical studies due to the low bioavailability of silymarin. Extensive studies were conducted to explore the metabolism and transport of silymarin/silybin as well as the impact of its consumption on the pharmacokinetics of other clinical drugs. Here, we aimed to summarize and highlight the current knowledge of the metabolism and transport of silymarin. It was concluded that the major efflux transporters of silybin are multidrug resistance-associated protein (MRP2) and breast cancer resistance protein (BCRP) based on results from the transporter-overexpressing cell lines and MRP2-deficient (TR-) rats. Nevertheless, compounds that inhibit the efflux transporters MRP2 and BCRP can enhance the absorption and activity of silybin. Although silymarin does inhibit certain drug-metabolizing enzymes and drug transporters, such effects are unlikely to manifest in clinical settings. Overall, silymarin is a safe and well-tolerated phytomedicine.

19.
Lipids ; 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31574567

RESUMO

Oxidized low-density lipoprotein (Ox-LDL) may induce apoptosis and dysfunction of vascular endothelial cells, contributing to the initiation and development of atherosclerosis and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) plays a central role in Ox-LDL uptake in the course of atherogenesis. Humanin (HN), a mitochondrial-derived peptide, was recently demonstrated to exert a protective role against endothelial dysfunction and Ox-LDL-induced progression of atherosclerosis. The HN analog HNGF6A (HNG) modulates cholesterol metabolism in macrophage RAW 264.7 cells. However, whether HNG affects Ox-LDL metabolism in endothelial cells is unknown. In this study, we investigated the effect of HNG on Ox-LDL accumulation in human umbilical vein endothelial cell (HUVEC) and its underlying mechanisms. HUVEC were preincubated with HNG for 1 h before addition of Ox-LDL. Total cholesterol content was measured by using a tissue total cholesterol assay kit and flow cytometry. Cell viability was measured by CCK8 assay. Protein content was examined by Western blot assays. Flow cytometry was used to identify apoptotic cells. Flow cytometry and tissue total cholesterol assays showed that HNG reduced Ox-LDL accumulation in HUVEC. In addition, HNG inhibited Ox-LDL-induced apoptosis of HUVEC. Western blot results showed that HNG reduced LOX-1 protein content. However, when LOX-1 was knocked down or inhibited, the effect of HNG in reducing Ox-LDL aggregation and apoptosis in HUVEC disappeared. Our study demonstrated that HNG reduces lipid aggregation and apoptosis in HUVEC in a LOX-1-dependent manner.

20.
Oncogene ; 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31576013

RESUMO

Multiple myeloma (MM) is still incurable despite the successful application of proteasome inhibitors in clinic. Bortezomib represents the most common chemotherapy for MM, whereas acquired drug resistance and eventually developed relapse remain the major obstruction. In the current study, we established bortezomib-resistant myeloma cell lines and screened gene expression profiles using single cell RNA-sequencing. Resistant MM cells exhibited increased clonogenic potential, specific metabolic, and epigenetic signatures, along with the self-renewal signaling characteristic of MM stem-like cells. Aberrant activation of hedgehog (Hh) signaling was correlated with drug resistance and stem cell-like transcriptional program. The key transcriptional factor GLI2 of the Hh pathway was restricted in the high acetylation and low ubiquitination states in bortezomib-resistant myeloma cells. Further investigation revealed that SIRT1 deacetylates and stabilizes GLI2 protein at lysine 757 and consequentially activates the Hh signaling, and itself serves as a direct target of Hh signaling to format a positive regulating loop. Using combination screening with an epigenetic compound library, we identified the SIRT1 specific inhibitor S1541 and S2804 had very obvious synergetic antimyeloma effect. Sirt1 inhibition could partially impeded the Hh pathway and conferred bortezomib sensitivity in vitro and in vivo. Notably, elevated SIRT1 level was also a prominent hallmark for the resistant myeloma cells, and this expression pattern was confirmed in myeloma patients, but independent of RAS/RAF mutations. Clinically, SIRT1 expression in patients with complete response was suppressed but elevated in relapsed patients, and retrospective analysis showed patients with higher SIRT1 expression had poorer outcomes. In conclusion, the cooperation of SIRT1 and Hh is an important mechanism of drug resistance in myeloma, and therapeutics combining SIRT1 inhibitors will sensitize myeloma cells to proteasome inhibitors.

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