Targeted delivery of celastrol to mesangial cells is effective against mesangioproliferative glomerulonephritis

Guo, Litao; Luo, Shuang; Du, Zhengwu; Zhou, Meiling; Li, Peiwen; Fu, Yao; Sun, Xun; Huang, Yuan; Zhang, Zhirong

doi:10.1038/s41467-017-00834-8

Cited by 156 publications

(138 citation statements)

References 54 publications

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“…Similar to previous reported poor solubility and pharmacokinetics of celastrol [24], pristimerin in solution did not induce significant tumor growth inhibition in our preliminary study in PDX mouse model of endometrial cancer (data not shown). We therefore used a nanoparticle-based delivery approach to improve the pharmacokinetics and therapeutic efficacy of pristimerin.…”

Section: Quantification and Characterization Of Pristimerin-loaded Plsupporting

confidence: 90%

MTDH/AEG-1 downregulation using pristimerin-loaded nanoparticles inhibits Fanconi anemia proteins and increases sensitivity to platinum-based chemotherapy

Areecheewakul

et al. 2019

Gynecologic Oncology

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h i g h l i g h t sEndometrial cancer patients with high copy number of MTDH show poor outcome.Inhibition MTDH increases DNA damage induced g-H2Ax foci formation and sensitivity to cisplatin.MTDH binds with mRNAs encoding for FANCD2 and FANCI. Pristimerin-loaded nanoparticles inhibit MTDH, FANCD2 and FANCI to increase sensitivity to cisplatin. a b s t r a c tObjective: Platinum compounds have been widely used as a primary treatment for many types of cancer. However, resistance is the major cause of therapeutic failure for patients with metastatic or recurrent disease, thus highlighting the need to identify novel factors driving resistance to Platinum compounds. Metadherin (MTDH, also known as AEG-1 and LYRIC), located in a frequently amplified region of chromosome 8, has been consistently associated with resistance to chemotherapeutic agents, though the precise mechanisms remain incompletely defined.Methods: The mRNA of FANCD2 and FANCI was pulled down by RNA-binding protein immunoprecipitation. Pristimerin-loaded nanoparticles were prepared using the nanoprecipitation method. Immunocompromised mice bearing patient-derived xenograft tumors were treated with pristimerinloaded nanoparticles, cisplatin and a combination of the two.Results: MTDH, through its recently discovered role as an RNA binding protein, regulates expression of FANCD2 and FANCI, two components of the Fanconi anemia complementation group (FA) that play critical roles in interstrand crosslink damage induced by platinum compounds. Pristimerin, a quinonemethide triterpenoid extract from members of the Celastraceae family used to treat inflammation in traditional Chinese medicine, significantly decreased MTDH, FANCD2 and FANCI levels in cancer cells, thereby restoring sensitivity to platinum-based chemotherapy. Using a patient-derived xenograft model of endometrial cancer, we discovered that treatment with pristimerin in a novel nanoparticle formulation markedly inhibited tumor growth when combined with cisplatin.Conclusions: MTDH is involved in post-transcriptional regulation of FANCD2 and FANCI. Pristimerin can increase sensitivity to platinum-based agents in tumors with MTDH overexpression by inhibiting the FA pathway.

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Section: Quantification and Characterization Of Pristimerin-loaded Plsupporting

confidence: 90%

MTDH/AEG-1 downregulation using pristimerin-loaded nanoparticles inhibits Fanconi anemia proteins and increases sensitivity to platinum-based chemotherapy

Areecheewakul

et al. 2019

Gynecologic Oncology

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“…Celastrol is a triterpene compound obtained from the roots of the Tripterygium Wilfordi (thunder god vine) (17). Celastrol represented a promising treatment option for mesangioproliferative glomerulonephritis and other glomerular diseases (26). Celastrol improved obesity and metabolic dysfunction via the activation of heat shock factor 1-peroxisome proliferatoractivated ␥ coactivator-1␣ axis in mice (27).…”

Section: Discussionmentioning

confidence: 99%

Celastrol Protects From Cholestatic Liver Injury Through Modulation of SIRT1-FXR Signaling

Zhao

Liu

Cheng

et al. 2019

Molecular & Cellular Proteomics

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The present study used metabolomics, transcriptomics, protein analysis by immunoblots, chemical inhibition and gene knockout mice to determine the effects of celastrol on cholestasis and its mechanisms. Samples from patients were used to validate our findings, and the data supported the conclusions that celastrol protected against cholestatic liver injury through modulation of the SIRT1 and FXR. Graphical Abstract Highlights• 1. Celastrol alleviated cholestatic liver injury.• 2. Celastrol inhibited the decrease of SIRT1 induced by deoxycholic acid.• 3. SIRT1-FXR signaling pathway mediated the effect of celastrol.Celastrol, derived from the roots of the Tripterygium Wilfordi, shows a striking effect on obesity. In the present study, the role of celastrol in cholestasis was investigated using metabolomics and transcriptomics. Celastrol treatment significantly alleviated cholestatic liver injury in mice induced by ␣-naphthyl isothiocyanate (ANIT) and thioacetamide (TAA). Celastrol was found to activate sirtuin 1 (SIRT1), increase farnesoid X receptor (FXR) signaling and inhibit nuclear factor-kappa B and P53 signaling. The protective role of celastrol in cholestatic liver injury was diminished in mice on co-administration of SIRT1 inhibitors. Further, the effects of celastrol on cholestatic liver injury were dramatically decreased in Fxr-null mice, suggesting that the SIRT1-FXR signaling pathway mediates the protective effects of celastrol. These observations demonstrated a novel role for celastrol in protecting against cholestatic liver injury through modulation of the SIRT1 and FXR.

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“…30 Moreover, a type of albumin nanoparticle with defined sizes of ~95 nm to deliver celastrol selectively to mesangial cells has been recently reported. 35 Hence, as shown in the real-time biodistribution in DN model mice, controlling particle size is an effective approach to realize renal target delivery. However, accumulation in peritubular capillaries does not seem to correlate with the size of nanoparticles, showing conspicuous accumulation characteristics in different portions of the kidney.…”

Section: Discussionmentioning

confidence: 99%

“…34 Most other kidney therapy studies based on size demonstrated that the accumulation of nanoparticles is restricted to the glomerular mesangium and the kidney's extracellular matrix, reaching the maximal glomerular deposition by using ~80 nm nanoparticles. 31,35 In addition, charge selectivity is also an important criterion for kidney targeting. Nanoparticles with a surface charge of ,15 mV have minimal macrophage uptake and long circulation time.…”

Section: Introductionmentioning

confidence: 99%

Kidney-targeted drug delivery via rhein-loaded polyethyleneglycol-<em>co</em>-polycaprolactone-<em>co</em>-polyethyleneimine nanoparticles for diabetic nephropathy therapy

Chen¹,

Han²,

Zhu³

et al. 2018

IJN

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IntroductionDiabetic nephropathy (DN) is the primary root of morbidity and mortality in diabetic patients. Unfortunately, currently, no effective therapeutic strategies are available to ameliorate and reverse the progression of DN. Rhein (RH) is an anthraquinone derivative extracted from herbal medicines with various pharmacological effects on DN. However, its clinical administration is limited by its poor solubility, low bioavailability, reduced distribution into the kidney and adverse effects.Methods and resultsTo improve the delivery of RH into kidney and the therapeutic effect on DN, we synthesized and utilized polyethyleneglycol-co-polycaprolactone-co-polyethylenimine triblock amphiphilic polymers to prepare RH-loaded polyethyleneglycol-co-polycaprolactone-co-polyethylenimine nanoparticles (PPP-RH-NPs). PPP-RH-NP size was optimized to 75 ± 25 nm for kidney-targeted drug delivery; the positive zeta potential allowed an effective cellular uptake and the polyethylenimine amine groups facilitate the endosomal escape quickly. The distribution and pharmacodynamics of PPP-RH-NPs were studied in a streptozocin-induced DN model, which explicitly demonstrated kidney-targeted distribution and improved the therapeutic effects of RH on DN by ameliorating several pathological indicators.ConclusionTherefore, this study not only stimulates further clinical research on RH but also, more importantly, proposes a promising DN therapy consisting of an effective kidney-targeted drug delivery.

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Targeted delivery of celastrol to mesangial cells is effective against mesangioproliferative glomerulonephritis

Cited by 156 publications

References 54 publications

MTDH/AEG-1 downregulation using pristimerin-loaded nanoparticles inhibits Fanconi anemia proteins and increases sensitivity to platinum-based chemotherapy

MTDH/AEG-1 downregulation using pristimerin-loaded nanoparticles inhibits Fanconi anemia proteins and increases sensitivity to platinum-based chemotherapy

Celastrol Protects From Cholestatic Liver Injury Through Modulation of SIRT1-FXR Signaling

Kidney-targeted drug delivery via rhein-loaded polyethyleneglycol-<em>co</em>-polycaprolactone-<em>co</em>-polyethyleneimine nanoparticles for diabetic nephropathy therapy

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