ABSTRACT
In 2020, the number of deaths caused by lung cancer worldwide reached 1,796,144, making it the leading cause of cancer-related deaths. Cyclooxygenase-2/prostaglandin endoperoxide synthase 2 (COX-2/PTGS2) is overexpressed in lung cancer, which promotes tumor proliferation, invasion, angiogenesis, and resistance to apoptosis. Here, we report that the oligonucleotide drug HQi-sRNA-2 from Traditional Chinese Medicine Huangqin targeting COX-2/PTGS2 significantly inhibited proliferation, migration, and invasion and induced apoptosis in the human lung cancer cell line NCI-H460. Oral delivery of HQi-sRNA-2 bencaosomes prolonged survival, reduced tumor burden, and maintained weight in a spontaneous mouse lung cancer model. Compared with paclitaxel, HQi-sRNA-2 may be less toxic and have approximately equal efficacy in reducing tumor burden. Our previous studies reported that herbal small RNAs (sRNAs) are functional medical components. Our data suggest that sphingosine (d18:1)-HQi-sRNA-2 bencaosomes, targeting COX-2/PTGS2 and downregulating the PI3K and AKT signaling pathways, may provide novel therapeutics for lung cancer.
ABSTRACT
The isatin group is widespread in nature and is considered to be a privileged building block for drug discovery. In order to develop novel SHP1 inhibitors with fluorescent properties as tools for SHP1 biology research, this work designed and synthesized a series of isatin derivatives. The presentive compound 5a showed good inhibitory activity against SHP1PTP with IC50 of 11 ± 3 µM, displayed about 92% inhibitory rate against MV-4-11 cell proliferation at the concentration of 20 µM, exhibited suitable fluorescent properties with a long emission wavelength and a large Stokes shift, and presented blue fluorescent imaging in HeLa cells with low cytotoxicity. This study could offer chemical tool to further understand SHP1 biology and develop novel SHP1 inhibitors in therapy.
Subject(s)
Cell Proliferation , Isatin , Isatin/chemistry , Isatin/pharmacology , Isatin/chemical synthesis , Humans , HeLa Cells , Cell Proliferation/drug effects , Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 6/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Structure-Activity Relationship , Molecular Structure , Fluorescent Dyes/chemistry , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/pharmacology , Cell Line, Tumor , FluorescenceABSTRACT
Type 2 diabetes mellitus is a prevalent metabolic disease, posing a considerable threat to public health. Oligonucleotide drugs have proven to be a promising field of therapy for the diseases. In this study, we reported that a herbal small RNA (sRNA), JGL-sRNA-h7 (B34735529, F1439.L002444.A11), could exhibit potent hypoglycemic effects by targeting glucose-6-phosphatase. Oral administration of sphingosine (d18:1)-JGL-sRNA-h7 bencaosomes ameliorated hyperglycemia and diabetic kidney injury better than metformin in db/db mice. Furthermore, glucose tolerance was also improved in sphingosine (d18:1)-JGL-sRNA-h7 bencaosomes-treated beagle dogs. Our study indicates that JGL-sRNA-h7 could be a promising hypoglycemic oligonucleotide drug.
ABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Bu-Zhong-Yi-Qi Decoction(BZYQD) is a traditional formula commonly used in China, known for its effects in tonifying Qi and raising Yang. It can relieve symptoms of cognitive impairment such as forgetfulness and lack of concentration caused by qi deficiency, which is common in aging and debilitating. However, much of the current research on BZYQD has been focused on its impact on the digestive system, leaving its molecular mechanisms in improving cognitive function largely unexplored. AIM OF THE STUDY: Cognitive decline in the aging central nervous system is intrinsically linked to oxidative damage. This study aims to investigate the therapeutic mechanism of BZYQD in treating mild cognitive impairment caused by qi deficiency, particularly through repair of mitochondrial oxidative damage. MATERIALS AND METHODS: A rat model of mild cognitive impairment (MCI) was established by administering reserpine subcutaneously for two weeks, followed by a two-week treatment with BZYQD/GBE. In vitro experiments were conducted to assess the effects of BZYQD on neuronal cells using a H2O2-induced oxidative damage model in PC12 cells. The open field test and the Morris water maze test evaluated the cognitive and learning memory abilities of the rats. HE staining and TEM were employed to observe morphological changes in the hippocampus and its mitochondria. Mitochondrial activity, ATP levels, and cellular viability were measured using assay kits. Protein expression in the SIRT3/MnSOD/OGG1 pathway was analyzed in tissues and cells through western blotting. Levels of 8-OH-dG in mitochondria extracted from tissues and cells were quantified using ELISA. Mitochondrial morphology in PC12 cells was visualized using Mito Red, and mitochondrial membrane potential was assessed using the JC-1 kit. RESULTS: BZYQD treatment significantly improved cognitive decline caused by reserpine in rats, as well as enhanced mitochondrial morphology and function in the hippocampus. Our findings indicate that BZYQD mitigates mtDNA oxidative damage in rats by modulating the SIRT3/MnSOD/OGG1 pathway. In PC12 cells, BZYQD reduced oxidative damage to mitochondria and mtDNA in H2O2-induced conditions and was associated with changes in the SIRT3/MnSOD/OGG1 pathway. CONCLUSION: BZYQD effectively counteracts reserpine-induced mild cognitive impairment and ameliorates mitochondrial oxidative stress damage through the SIRT3/MnSOD/OGG1 pathway.
Subject(s)
Cognitive Dysfunction , Drugs, Chinese Herbal , Mitochondria , Oxidative Stress , Rats, Sprague-Dawley , Sirtuin 3 , Superoxide Dismutase , Animals , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/metabolism , Oxidative Stress/drug effects , Drugs, Chinese Herbal/pharmacology , Mitochondria/drug effects , Mitochondria/metabolism , Rats , PC12 Cells , Male , Sirtuin 3/metabolism , Superoxide Dismutase/metabolism , Signal Transduction/drug effects , Disease Models, Animal , Hippocampus/drug effects , Hippocampus/metabolism , Neuroprotective Agents/pharmacology , SirtuinsABSTRACT
Rhizoma Panacis Japonici (RPJ) is an ancient herbal medicine from China that has long been employed for its medicinal benefits in relieving arthritis physical debility and diverse afflictions. The primary bioactive constituents found in RPJ are triterpene saponins, which exhibit numerous pharmacological actions, including anti-inflammatory, antioxidant, and immunomodulating effects. The present study established a straightforward and effective approach for characterizing triterpene saponins in RPJ. An offline HILIC × RP LC/QTOF-MS method was developed, along with a self-constructed in-house database containing 612 saponins reported in the Panax genus and 228 predicted metabolites. The approach achieved good chromatographic performance in isolating triterpene saponins of RPJ, with the HILIC column as the first dimension (1D) and the BEH C18 column as the second dimension (2D). The developed two-dimensional liquid chromatography system exhibited an orthogonality of 0.61 and a peak capacity of 1249. Detection was performed using a QTOF mass spectrometer in a data-independent manner (MSE) in a negative ion mode. Using the in-house database, the collected MS data were processed by an automatic workflow on UNIFI 1.8.2 software, which included data correction, matching of precursor and product ions, and peak annotation. In this study, 307 saponins were characterized from RPJ and 76 saponins were identified for the first time in Panax japonicus. This research not only enhances our understanding of the chemical characteristics of RPJ but also offers a simple and efficient method for analyzing the complex composition of herbal medicine.
Subject(s)
Drugs, Chinese Herbal , Panax , Plants, Medicinal , Saponins , Triterpenes , Saponins/chemistry , Triterpenes/chemistry , Chromatography, High Pressure Liquid/methods , Plant Extracts/chemistry , Mass Spectrometry , Plants, Medicinal/chemistryABSTRACT
The expanding growth of shale gas development has sparked global concern over water-related environmental issues. However, research on groundwater contamination in shale gas areas in China remains limited, impeding environmentally friendly industry practices. To address this gap, we investigated the Wufeng-Longmaxi shale region in the Sichuan Basin, encompassing both operational and prospective shale gas extraction sites, to assess the effects of shale gas operations on shallow groundwater quality. We found there was no significant correlation between groundwater quality and the minimum distance from the shale gas well pads, and some groundwater samples located far from shale gas well pads, rather than those close to pads, were salinized. These findings suggest minimal impacts from shale gas drilling and hydraulic fracturing. The salinized groundwater samples are characterized by high salinity levels and ion concentrations, and are located near fault zones. The primary source of shallow groundwater salinization was derived from the Triassic formation brines confirmed through the assessment of the sensitivity and conservative mixing models. Faults in the study area were identified as pathways for the upward migration of Triassic brines, evidenced by the proximity of salinized samples to fault zones. However, further investigation is required to ascertain whether shale gas extraction activities have induced the migration of formation brines. The occurrence and reactivation of faults, induced by microseismic activities, may pose an increased risk of groundwater contamination in tectonically complex fault zones during shale gas extraction. Therefore, it is imperative to enhance extraction strategies and technologies, particularly in shale regions with well-developed faults, such as optimizing well placement regulation, controlling hydraulic fracturing scale, and strengthening environmental monitoring. By shedding light on potential environmental ramifications of shale gas extraction, especially in fault-rich regions, our study informs water protection strategies and the sustainable advancement of the shale gas industry.
ABSTRACT
Truncated transforming growth factor ß receptor type II (tTßRII), serving as a trap for binding excessive transforming growth factor ß1 (TGF-ß1) by means of competing with wild-type TßRII, is a promising strategy for the treatment of kidney fibrosis. Platelet-derived growth factor ß receptor (PDGFßR) is highly expressed in interstitial myofibroblasts in kidney fibrosis. This study identified the interaction between a novel tTßRII variant Z-tTßRII (PDGFßR-specific affibody ZPDGFßR fused to the N-terminus of tTßRII) and TGF-ß1. Moreover, Z-tTßRII highly targeted to TGF-ß1-activated NIH3T3 cells and UUO-induced fibrotic kidney, but less to normal cells, tissues, and organs. Furthermore, Z-tTßRII significantly inhibited cell proliferation and migration, and reduced fibrosis markers expression and phosphorylation level of Smad2/3 in activated NIH3T3 cells. Meanwhile, Z-tTßRII markedly alleviated the kidney histopathology and fibrotic responses, and inhibited the TGF-ß1/Smad signaling pathway in UUO mice. Besides, Z-tTßRII showed good safety performance in the treatment of UUO mice. In conclusion, these results demonstrated that Z-tTßRII may be a potential candidate for a targeting therapy on renal fibrosis due to the high potential of fibrotic kidney-targeting and strong anti-renal fibrosis activity.
Subject(s)
Kidney Diseases , Transforming Growth Factor beta1 , Mice , Animals , Transforming Growth Factor beta1/metabolism , Receptor, Platelet-Derived Growth Factor beta/metabolism , NIH 3T3 Cells , Signal Transduction , Kidney Diseases/pathology , FibrosisABSTRACT
Human Hox genes (Homeobox) play a crucial role in embryonic development and cancer. The HOXC10 gene, a member of the HOX family, has been reported abnormally expressed in several cancers. However, the association between HOXC10 and hepatocellular carcinoma (HCC) remains to be elucidated. In the present study, tissue microarray cohort data showed that high levels of HOXC10 expression predicted a poor survival in HCC patients. Meanwhile, HOXC10 was significantly upregulated in the Huh7 cell line compared with the well differentiated cell line HepG2 and human normal liver cells. Functionally, silencing HOXC10 in Huh7 cells inhibited cell proliferation, increased apoptosis, and inhibited invasion and migration of HCC cells. HOXC10 overexpression in HepG2 cells increased cell proliferation, decreased apoptosis, and increased invasion and migration of HCC cells. In the HepG2 xenograft models, HOXC10 increased the tumor volume and weight compared with control. Mechanistically, the m6A modification of HOXC10 by METTL3 enhanced its expression by enhancing its mRNA stability. Both the in vitro and in vivo results showed that overexpressed HOXC10 activated the PTEN/AKT/mTOR pathway. In summary, the findings highlight the importance of HOXC10 in the regulation of HCC progression. HOXC10 is potentially a future therapeutic target for HCC treatment.
ABSTRACT
Excessive production of transforming growth factor ß1 (TGF-ß1) in activated hepatic stellate cells (aHSCs) promotes liver fibrosis by activating the TGF-ß1/Smad signaling pathway. Thus, specifically inhibiting the pro-fibrotic activity of TGF-ß1 in aHSCs is an ideal strategy for treating liver fibrosis. Overexpression of platelet-derived growth factor ß receptor (PDGFßR) has been demonstrated on the surface of aHSCs relative to normal cells in liver fibrosis. Interferon-gamma peptidomimetic (mIFNγ) and truncated TGF-ß receptor type II (tTßRII) inhibit the TGF-ß1/Smad signaling pathway by different mechanisms. In this study, we designed a chimeric protein by the conjugation of (1) mIFNγ and tTßRII coupled via plasma protease-cleavable linker sequences (FNPKTP) to (2) PDGFßR-recognizing peptide (BiPPB), namely BiPPB-mIFNγ-tTßRII. This novel protein BiPPB-mIFNγ-tTßRII was effectively prepared using Escherichia coli expression system. The active components BiPPB-mIFNγ and tTßRII were slowly released from BiPPB-mIFNγ-tTßRII by hydrolysis using the plasma protease thrombin in vitro. Moreover, BiPPB-mIFNγ-tTßRII highly targeted to fibrotic liver tissues, markedly ameliorated liver morphology and fibrotic responses in chronic liver fibrosis mice by both inhibiting the phosphorylation of Smad2/3 and inducing the expression of Smad7. Meanwhile, BiPPB-mIFNγ-tTßRII markedly reduced the deposition of collagen fibrils and expression of fibrosis-related proteins in acute liver fibrosis mice. Furthermore, BiPPB-mIFNγ-tTßRII showed a good safety performance in both liver fibrosis mice. Taken together, BiPPB-mIFNγ-tTßRII improved the in vivo anti-liver fibrotic activity due to its high fibrotic liver-targeting potential and the dual inhibition of the TGF-ß1/Smad signaling pathway, which may be a potential candidate for targeting therapy on liver fibrosis.
ABSTRACT
Acute lung injury (ALI) and its extreme manifestation, acute respiratory distress syndrome (ARDS), are life-threatening diseases in intensive care units. LncRNA THRIL plays a crucial role in regulating the inflammatory response; however, the potential function of THRIL in ALI/ARDS and the associated mechanism remain unclear. In our study, we found that THRIL was upregulated in the serum of ALI/ARDS patients, and its increased expression was positively correlated with the inflammatory cytokines IL-17. In LPS-induced A549 cells, knockdown of THRIL inhibited the release of the proinflammatory cytokines TNF-α, IL-1ß, IL-17, and IL-6, decreased the number of monodansylcadaverine-positive cells and LC3-II with immunofluorescence staining, decreased the expression of autophagy marker ATG7 and Beclin1, and increased expression of p62. Mechanistically, the transcription factor AP-1 bound directly to the THRIL promoter region and activated its transcription by c-Jun upon LPS exposure. Moreover, m6A modification of THRIL was increased in LPS-treated A549 cells, and METTL14 knockdown significantly abolished m6A modification and reduced stabilization of THRIL mRNA. In conclusion, our findings reveal that THRIL, transcriptionally activated by AP-1 and modified by METTL14-mediated m6A modification, induces autophagy in LPS-treated A549 cells, suggesting the potential application of THRIL for ALI/ARDS therapy.
Subject(s)
RNA, Long Noncoding , Respiratory Distress Syndrome , Humans , Alveolar Epithelial Cells , Cytokines/metabolism , Interleukin-17/metabolism , Lipopolysaccharides/metabolism , Methyltransferases/metabolism , Respiratory Distress Syndrome/genetics , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Transcription Factor AP-1/genetics , Transcription Factor AP-1/metabolism , RNA Processing, Post-Transcriptional/geneticsABSTRACT
Wide-bandgap perovskites play a key role in high-performance tandem solar cells, which have the potential to break the Schockley-Queisser limit. Here, a 2D/3D hybrid wide-bandgap perovskite was developed using octane-1,8-diaminium (ODA) as spacer. The incorporation of the ODA spacer can not only significantly reduce charge carrier nonradiative recombination loss but also inhibit phase separation. Moreover, with a synergy effect using butylammonium iodide (BAI) as a surface defect passivator, both the phase stability and device performance were further improved. Compared to the control inverted device with a VOC of 1.16 V and a PCE of 18.50%, the optimized PSCs based on a surface processed 2D/3D perovskite exhibit a superior high VOC of 1.26 V and a champion PCE of 22.19%, which is a record efficiency for wide-bandgap PSCs (Eg > 1.65 eV). This work provides a very effective strategy to suppress phase separation in wide-bandgap perovskites for highly efficient and stable solar cells.
ABSTRACT
The combination of phototherapy and chemotherapy has become attractive and effective cancer treatment. However, the accurate delivery of both chemo-phototherapy drugs to the target site as well as the development of high-efficient phototherapy and chemotherapy drugs remain major challenges. In this study, indocyanine green (ICG) and paclitaxel (PTX)-loaded aptamer ferritin (HAS1411-PTX-ICG) was developed as a biocompatible nanoplatform for combined chemo/photothermal/photodynamic (PTT/PDT) therapy that was safe and highly effective against tumors. HAS1411 was prepared by coupling aptamer AS1411 to the surface of human H chain ferritin (HFtn) by the carbon diimide method to further enhance the targeting of HFtn. Both ICG and PTX were effectively encapsulated in the HAS1411 by incubation at 60 â. Moreover, under near-infrared (NIR) light irradiation, HAS1411 enhanced the photothermal effect and cell internalization of ICG, as well as the production of reactive oxygen species in cancer cells. HAS1411-PTX-ICG displayed effective cytotoxicity and a significant tumor spheroids inhibitory effect owning to the improved internalization of PTX and ICG mediated by TfR1 and nucleolin dual receptors. Co-loaded PTX combined with ICG can produce chemo/PTT/PDT under near-infrared (NIR) light irradiation, enhancing the anti-tumor effect. The dual-targeting HAS1411 nanocarrier developed in this study can be a promising delivery system for cancer therapy and the fabricated HAS1411-PTX-ICG possesses potential application in chemo-phototherapy.
Subject(s)
Antineoplastic Agents , Hyperthermia, Induced , Nanoparticles , Neoplasms , Humans , Paclitaxel/pharmacology , Indocyanine Green/pharmacology , Ferritins , Phototherapy/methods , Antineoplastic Agents/pharmacology , Cell Line, TumorABSTRACT
Cross-kingdom herbal miRNA was first reported in 2012. Using a modified herbal extraction protocol, we obtained 73,677,287 sequences by RNA-seq from 245 traditional Chinese Medicine (TCM), of which 20,758,257 were unique sequences. We constructed a Bencao (herbal) small RNA (sRNA) Atlas ( http://bencao.bmicc.cn ), annotated the sequences by sequence-based clustering, and created a nomenclature system for Bencao sRNAs. The profiles of 21,757 miRNAs in the Atlas were highly consistent with those of plant miRNAs in miRBase. Using software tools, our results demonstrated that all human genes might be regulated by sRNAs from the Bencao sRNA Atlas, part of the predicted human target genes were experimentally validated, suggesting that Bencao sRNAs might be one of the main bioactive components of herbal medicines. We established roadmaps for oligonucleotide drugs development and optimization of TCM prescriptions. Moreover, the decoctosome, a lipo-nano particle consisting of 0.5%-2.5% of the decoction, demonstrated potent medical effects. We propose a Bencao (herbal) Index, including small-molecule compounds (SM), protein peptides (P), nucleic acid (N), non-nucleic and non-proteinogenic large-molecule compounds (LM) and elements from Mendeleev's periodic table (E), to quantitatively measure the medical effects of botanic medicine. The Bencao sRNA Atlas is a resource for developing gene-targeting oligonucleotide drugs and optimizing botanical medicine, and may provide potential remedies for the theory and practice of one medicine.
Subject(s)
Drugs, Chinese Herbal , MicroRNAs , RNA, Small Untranslated , Humans , Medicine, Chinese Traditional , MicroRNAs/genetics , Drugs, Chinese Herbal/chemistry , RNA, Small Untranslated/genetics , OligonucleotidesABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Rhizomes of Panax japonicus (RPJ), a traditional herbal medicine, was used for treating arthritis and physical weakness in China from the Ming dynasty. Triterpene saponins are the main bioactive components of RPJ. In this work, for the first time, we evaluate the therapeutic effect of the total saponin from RPJ (TSPJ) on experimental autoimmune encephalomyelitis (EAE) mice induced by myelin oligodendrocyte glycoprotein (MOG) 35-55, a commonly used animal model of Multiple sclerosis (MS). AIM OF THE STUDY: To evaluate the therapeutic effect of TSPJ on EAE and explored its possible underlying mechanisms. MATERIALS AND METHODS: EAE was induced by MOG 35-55. Mice were administrated with TSPJ (36.5 mg/kg, 73 mg/kg) and prednisone acetate (positive control) orally once daily up to 28 days postimmunization, and their neurological deficit was scored. Hematoxylin and Eosin (HE), Luxol Fast Blue (LFB), and transmission electron microscopy (TEM) were carried out to evaluate the EAE-induced pathological changes in the brain and spinal cord. IL-17a and Foxp3 levels in central nervous system (CNS)were evaluated by immunohistochemical staining. The changes in IL-1ß, IL-6, and TNF-α levels in serum and CNS were measured with ELISA. Quantitative reverse transcription PCR (qRT-PCR) was used to access mRNA expression in CNS of the above indices. The percentages of Th1, Th2, Th17and Treg cells in spleen were determined by Flow Cytometry (FCM). Furthermore, 16S rDNA sequencing was used to detect the intestinal flora of mice in each group. In vitro studies, lipopolysaccharides (LPS)-induced BV2 microglia cells were used and the expression of TLR4, MyD88, p65, and p-p65 in cells was detected by Western blot. RESULTS: TSPJ treatment significantly alleviated neurological impairment caused by EAE. Histological examination confirmed the protective effects of TSPJ on myelin sheath and the reduction of inflammatory cell infiltration in the brain and spinal cord of EAE mice. TSPJ notably downregulated the ratio of IL-17a/Foxp3 at protein and mRNA levels in CNS, as well as Th17/Treg and Th1/Th2 cell ratios in the spleen of EAE mice. The levels of TNF-α, IL-6, and IL-1ß in CNS and peripheral serum also decreased post-TSPJ treatment. In vitro, TSPJ suppressed LPS-induced production of inflammatory factors in BV2 cells via TLR4-MyD88-NF-κB signaling pathway. More importantly, TSPJ interventions altered the composition of gut microbiota and restored the ratio of Firmicutes to Bacteroidetes in EAE mice. Furthermore, Spearman's correlation analysis revealed that a relationship existed between statistically significantly altered genera and CNS inflammatory indices. CONCLUSION: Our results demonstrated TSPJ had therapeutic effects on EAE. Its anti-neuroinflammation property in EAE was related to modulating gut microbiota and inhibiting TLR4-MyD88-NF-κB signaling pathway. Our study indicated that TSPJ may be a potential candidate for the treatment of MS.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Gastrointestinal Microbiome , Mice , Animals , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Encephalomyelitis, Autoimmune, Experimental/metabolism , Interleukin-17/metabolism , Tumor Necrosis Factor-alpha/metabolism , Interleukin-6/metabolism , NF-kappa B/metabolism , Lipopolysaccharides , Myeloid Differentiation Factor 88/metabolism , Toll-Like Receptor 4/metabolism , Cytokines/metabolism , Inflammation/pathology , Myelin-Oligodendrocyte Glycoprotein/metabolism , Myelin-Oligodendrocyte Glycoprotein/therapeutic use , Forkhead Transcription Factors/metabolism , RNA, Messenger , Mice, Inbred C57BLABSTRACT
The biocompatible protein nanocarrier with homogeneous particle size is a promising candidate material for the delivery of targeted drugs to tumors. Doxorubicin (DOX) is a commonly prescribed anthracycline antitumor drug, although it may cause nephrotoxicity and cardiotoxicity. The Chinese herbal remedy ursolic acid (UA), a pentacyclic triterpenoid with anticancer action, has been used as a potential drug sensitizer to increase the effectiveness of chemotherapy and pharmacological therapy. Therefore, the dose of DOX can be reduced by compatibility with UA to lower its side effects. Ferritin binds to tumor cells through an interaction with the transferrin receptor 1 (TfR1), which is overexpressed in human cancer cells. In this study, the hydrophobic drug UA and the hydrophilic drug DOX were successfully encapsulated into the ferritin inner cavity using the thermal treatment method incubated at 60 °C for 4 h. The results demonstrated that loaded ferritin could specifically enter breast cancer cells MCF-7 and non-small-cell lung cancer cells A549 in comparison with free UA and DOX, enhancing their therapeutic effects. The loading ratio of two drugs was optimized in the constructed nanocarriers, and the effectiveness of the constructed nanodrugs in inhibiting tumor proliferation was verified by cell apoptosis and three-dimensional (3D) tumor spheroids studies. For the first time, the hydrophilic and hydrophobic drugs were loaded simultaneously within unmodified ferritin without other addition of additives, which would reduce the toxic side effects of DOX and enhance its therapeutic effect. This study also showed that the ferritin-based nanocarrier has potential for drug delivery to tumors.
Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Pharmaceutical Preparations , Carcinoma, Non-Small-Cell Lung/drug therapy , Apoferritins , Lung Neoplasms/drug therapy , Antineoplastic Agents/pharmacology , Doxorubicin/pharmacologyABSTRACT
The application of drug delivery systems based on ferritin nanocarrier has been developed as a potential strategy in cancer therapy. The limited permeability of ferritin remains a challenge for drug penetration into the deeper tumor tissues. CendR peptides have been reported to bear tumor-specific penetration by recognizing neuropilin (NRP-1) receptor that overexpressed on a wide range of cancer cells. Herein, we modified CendR peptide L(RGERPPR), its retro-inverso peptide D(RPPREGR), and inverso peptide D(RGERPPR) on the outer surface of human H chain ferritin by sulfhydryl-maleimide coupling reaction. Approximately 45 paclitaxel (PTX) molecules could be loaded into each ferritin inner cavity by a thermal-triggered method at a specific ionic strength. The penetration ability of three peptide-modified ferritin constructs showed that D(RGERPPR)-modified HFtn was able to be engulfed by A549 and MCF-7 tumor cells and spheroids at the highest level. Due to the dual-targeting effect of ferritin and modified peptides, the PTX-loaded nanocomposites could effectively enter the cells with high expression of TfR1 and NRP-1 receptors and enhanced the cytotoxicity against tumor cells. Remarkably, H-D(RGE)-PTX displayed a superior tumor growth suppression efficacy in A549 tumor-bearing nude mice. The inverso CendR peptide-modified HFtn nanocarrier was first generated and could provide an effective dual-targeting platform for treatment of cancers.
Subject(s)
Neoplasms , Paclitaxel , Mice , Animals , Humans , Paclitaxel/pharmacology , Paclitaxel/therapeutic use , Paclitaxel/chemistry , Ferritins , Mice, Nude , Cell Line, Tumor , Peptides/chemistry , Drug Delivery Systems , Mice, Inbred BALB C , Neoplasms/drug therapyABSTRACT
2D Dion-Jacobson (DJ) perovskites have become emerging photovoltaic materials owing to their intrinsic structure stability. However, as insulating aliphatic cations are widely used as spacers, the interactions between the spacers and inorganic layers in DJ perovskites have rarely been studied. Here, an organic semiconductor spacer with two covalently connected thiophene rings, namely bithiophene dimethylammonium (BThDMA), is successfully developed for 2D DJ perovskite solar cells (PSCs). An important finding is that there are strong orbital interactions between the conjugated organic spacer and adjacent inorganic layers, whereas no such interactions exist in DJ perovskite using an aliphatic octane-1,8-diaminium (ODA) spacer with similar length. The BThDMA spacer with multiple conjugated aromatic rings can also induce crystal growth with large grain size and preferred vertical orientation, resulting in reduced trap density and improved charge-carrier mobility. As a result, the optimized device based on (BThDMA)MAn -1 Pbn I3 n +1 (nominal n = 5) shows an excellent PCE of 18.1% with negligible hysteresis, which is a record efficiency for 2D DJ PSCs using a spacer with two or more covalently linked aromatic rings. These findings provide a novel and important insight on achieving efficient and stable 2D DJ perovskite solar cells by developing organic semiconductor spacers.
ABSTRACT
Respiratory infection is the main route for the transmission of coronavirus pneumonia, and the results have shown that the urban spatial environment significantly influences the risk of infection. Based on the Wells-Riley model of respiratory infection probability, the study determined the human respiratory-related parameters and the effective influence range; extracted urban morphological parameters, assessed the ventilation effects of different spatial environments, and, combined with population flow monitoring data, constructed a method for assessing the risk of Covid-19 respiratory infection in urban-scale grid cells. In the empirical study in Shenyang city, a severe cold region, urban morphological parameters, population size, background wind speed, and individual behavior patterns were used to calculate the distribution characteristics of temporal and spatial concomitant risks in urban areas grids under different scenarios. The results showed that the correlation between the risk of respiratory infection in urban public spaces and the above variables was significant. The exposure time had the greatest degree of influence on the probability of respiratory infection risk among the variables. At the same time, the change in human body spacing beyond 1 m had a minor influence on the risk of infection. Among the urban morphological parameters, building height had the highest correlation with the risk of infection, while building density had the lowest correlation. The actual point distribution of the epidemic in Shenyang from March to April 2022 was used to verify the evaluation results. The overlap rate between medium or higher risk areas and actual cases was 78.55%. The planning strategies for epidemic prevention and control were proposed for the spatial differentiation characteristics of different risk elements. The research results can accurately classify the risk level of urban space and provide a scientific basis for the planning response of epidemic prevention and control and the safety of public activities.
ABSTRACT
In our previous GWAS of Chinese and Nordic dairy cattle, genes CACNB2, SLC39A12, and ZEB1 locating on BTA 13 were suggested as candidate genes for reproduction. In this study, validation of these associations was performed in an independent population with records of nine reproductive traits. More importantly, functions of these genes in the reproductive process were verified by employing the expression data of ovarian follicles. The potential variants within the three genes were firstly detected in 68 Chinese Holstein bulls, and then screened in 1,588 Chinese Holstein cows using the KASP (Kompetitive allele-specific PCR) method. There were nine variants with polymorphisms in CACNB2, five in SLC39A12, and four in ZEB1, respectively, of which one SNP was in the upstream regulatory region, two in exon region, four in downstream regulatory region, and 11 SNPs in intronic regions. Amongst the 18 variants, g.33267056T/G in CACNB2 explained the largest phenotypic variance for age at first calving (0.011%), interval from first to last insemination (0.004%), and calving ease (0.002%), while g.32751518G/A in SLC39A12 contributed the most to stillbirth in heifers (0.038%). Two haplotype blocks were constructed for CACNB2 while one each for SLC39A12 and ZEB1, which were significantly associated with five reproductive traits, including age at the first service, age at the first calving, calving ease in heifers and cows, and the interval from calving to the first insemination. We then studied the profile of gene expression in granulosa cells isolated from four developmental stages of ovarian follicles from eight dairy cows. All three genes were differentially expressed between ovarian follicles with different sizes (p < 0.05), indicating their potential roles in the reproductive process of dairy cows. This study successfully demonstrated the associations of three BTA 13 genes CACNB2, SLC39A12, and ZEB1 with reproduction and further examined their expression levels in ovarian follicles directly. These findings can be beneficial for the ongoing genomic selection program for reproductive traits which have long been considered as traits that are difficult to achieve genetic improvement due to the lack of efficient genetic markers.
ABSTRACT
High-crystalline-quality wide-bandgap metal halide perovskite materials that achieve superior performance in perovskite solar cells (PSCs) have been widely explored. Precursor concentration plays a crucial role in the wide-bandgap perovskite crystallization process. Herein, we investigated the influence of precursor concentration on the morphology, crystallinity, optical property, and defect density of perovskite materials and the photoelectric performance of solar cells. We found that the precursor concentration was the key factor for accurately controlling the nucleation and crystal growth process, which determines the crystallization of perovskite materials. The precursor concentration based on Cs0.05FA0.8MA0.15Pb(I0.84Br0.16)3 perovskite was controlled from 0.8 M to 2.3 M. The perovskite grains grow larger with the increase in concentration, while the grain boundary and bulk defect decrease. After regulation and optimization, the champion PSC with the 2.0 M precursor concentration exhibits a power conversion efficiency (PCE) of 21.13%. The management of precursor concentration provides an effective way for obtaining high-crystalline-quality wide-bandgap perovskite materials and high-performance PSCs.