Soybean ethylene response factors GmENS1 and GmENS2 promote nodule senescence.

The final phase in root nodule development is nodule senescence. The mechanism underlying the initiation of nodule senescence requires further elucidation. Here, we investigated the intrinsic signals governing soybean (Glycine max L. Merr.) nodule senescence, uncovering ethylene as a key signal in this intricate mechanism. Two AP2/ERF transcription factor genes, GmENS1 and GmENS2 (Ethylene-responsive transcription factors required for Nodule Senescence), exhibit heightened expression levels in both aged nodules and nodules treated with ethylene. Overexpression of either GmENS1 or GmENS2 accelerated senescence in soybean nodules, whereas the knockout or knockdown of both genes delayed senescence and enhanced nitrogenase activity. Furthermore, our findings indicated that GmENS1 and GmENS2 directly bind to the promoters of GmNAC039, GmNAC018, and GmNAC030, encoding three NAC transcription factors essential for activating soybean nodule senescence. Notably, the nodule senescence process mediated by GmENS1 or GmENS2 overexpression was suppressed in the soybean nac039/018/030 triple mutant compared with the wild-type control. These data indicate GmENS1 and GmENS2 as pivotal transcription factors mediating ethylene-induced nodule senescence through the direct activation of GmNAC039/GmNAC018/GmNAC030 expression in soybean.

Targeting the DNA repair pathway for breast cancer therapy: Beyond the molecular subtypes.

DNA repair is a vital mechanism in cells that protects against DNA damage caused by internal and external factors. It involves a network of signaling pathways that monitor and transmit damage signals, activating various cellular activities to repair DNA damage and maintain genomic integrity. Dysfunctions in this repair pathway are strongly associated with the development and progression of cancer. However, they also present an opportunity for targeted therapy in breast cancer. Extensive research has focused on developing inhibitors that play a crucial role in the signaling pathway of DNA repair, particularly due to the remarkable success of PARP1 inhibitors (PARPis) in treating breast cancer patients with BRCA1/2 mutations. In this review, we summarize the current research progress and clinical implementation of BRCA and BRCAness in targeted treatments for the DNA repair pathway. Additionally, we present advancements in diverse inhibitors of DNA repair, both as individual and combined approaches, for treating breast cancer. We also discuss the clinical application of DNA repair-targeted therapy for breast cancer, including the rationale, indications, and summarized clinical data for patients with different breast cancer subtypes. We assess their influence on cancer progression, survival rates, and major adverse reactions. Last, we anticipate forthcoming advancements in targeted therapy for cancer treatment and emphasize prospective areas of development.

Small cytosolic double-stranded DNA represses cyclic GMP-AMP synthase activation and induces autophagy.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a major mediator of inflammation following stimulation with >45 bp double-stranded DNA (dsDNA). Herein, we identify a class of ∼20-40 bp small cytosolic dsDNA (scDNA) molecules that compete with long dsDNA (200-1,500 bp herring testis [HT]-DNA) for binding to cGAS, thus repressing HT-DNA-induced cGAS activation. The scDNA promotes cGAS and Beclin-1 interaction, releasing Rubicon, a negative regulator of phosphatidylinositol 3-kinase class III (PI3KC3), from the Beclin-1-PI3KC3 complex. This leads to PI3KC3 activation and induces autophagy, causing degradation of STING and long cytosolic dsDNA. Moreover, DNA damage decreases, and autophagy inducers increase scDNA levels. scDNA transfection and treatment with autophagy inducers attenuate DNA damage-induced cGAS activation. Thus, scDNA molecules serve as effective brakes for cGAS activation, preventing excessive inflammatory cytokine production following DNA damage. Our findings may have therapeutic implications for cytosolic DNA-associated inflammatory diseases.

Erratum: Dual-Targeted Gold Nanoprism for Recognition of Early Apoptosis, Dual-Model Imaging and Precise Cancer Photothermal Therapy: Erratum.

[This corrects the article DOI: 10.7150/thno.34755.].

Light-triggered photosynthetic engineered bacteria for enhanced-photodynamic therapy by relieving tumor hypoxic microenvironment.

Background: Singlet oxygen (1O2) has received considerable research attention in photodynamic therapy (PDT) due to its cytotoxic solid features. However, the inherent hypoxic state of the tumor microenvironment (TME) leads to the meager 1O2 quantum yield of inorganic PDT reagents, and their application in vivo remains elusive. Methods: We developed a novel strategy to fabricate active photosynthetic bacteria/photosensitizer/photothermal agent hybrids for photosynthetic tumor oxygenation and PDT and PTT tumor therapy under different laser irradiation sources. Photosynthetic bacteria combined with Ce6 photosensitizer and Au NPs photothermal agent, the obtained Bac@Au-Ce6 effectively targets tumor tissues and further enhances the tumor accumulation of Au-Ce6. Results: The results showed that the Au-Ce6-loaded engineered bacteria (Bac@Au-Ce6) maintained the photosynthetic properties of Syne. After i.v. injection, Bac@Au-Ce6 efficiently aggregates at tumor sites due to the tumor-targeting ability of active Syne. With 660 nm laser irradiation at the tumor site, the photoautotrophic Syne undergoes sustained photosynthetic O2 release and immediately activates O2 to 1O2 via a loaded photosensitizer. PTT was subsequently imparted by 808 laser irradiations to enhance tumor killing further. Conclusions: This work provides a new platform for engineering bacteria-mediated photosynthesis to promote PDT combined with PTT multi-faceted anti-tumor.

Targeting macrophage polarization as a promising therapeutic strategy for the treatment of osteoarthritis.

Osteoarthritis (OA) is a chronic osteoarthropathy characterized by the progressive degeneration of articular cartilage and synovial inflammation. Early OA clinical treatments involve intra-articular injection of glucocorticoids, oral acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs), which are used for anti-inflammation and pain relief. However, long-term use of these agents will lead to inevitable side effects, even aggravate cartilage loss. At present, there are no disease-modifying OA drugs (DMOADs) yet approved by regulatory agencies. Polarization regulation of synovial macrophages is a new target for OA treatment. Inhibiting M1 polarization and promoting M2 polarization of synovial macrophages can alleviate synovial inflammation, relieve joint pain and inhibit articular cartilage degradation, which is a promising strategy for OA treatment. In this study, we describe the molecular mechanisms of macrophage polarization and its key role in the development of OA. Subsequently, we summarize the latest progress of strategies for OA treatment through macrophage reprogramming, including small molecule compounds (conventional western medicine and synthetic compounds, monomer compounds of traditional Chinese medicine), biomacromolecules, metal/metal oxides, cells, and cell derivatives, and interprets the molecular mechanisms, hoping to provide some information for DMOADs development.

Live bio-nano-sonosensitizer targets malignant tumors in synergistic therapy.

Sonosensitizers that can increase the concentration of reactive oxygen species (ROS) within a tumor microenvironment is a high priority for sonodynamic therapy (SDT). In this study, a functionalized, smart nanosonosensitizer based on Au-RuO2 nanoparticles (NPs) and selenium nanoparticles (Se NPs) that were electrostatically self-assembled onto the surface of Listeria innocua (LI) was used to create Bac@ARS. Au NPs provided the core in which RuO2 was deposited to form Au-RuO2 NPs. Additionally, the underlying properties of the Au NPs and Se NPs were used to optimize the sonosensitivity performance. Compared with pristine RuO2 NPs, Bac@ARS exhibits highly efficient ROS-producing activity. Furthermore, Bac@ARS remodeled the hypoxic tumor microenvironment, enabling overproduction of ROS. Importantly, Bac@ARS exploits the natural tropism of LI to selectively accumulate in tumors, which improved the treatment precision at hypoxic tumor sites after sonodynamic activation. However, the activity of LI was greatly reduced after ultrasound (US) irradiation, ensuring the biosafety of Bac@ARS. Bac@ARS was also used to monitor tumors, in real time, using photoacoustic imaging of the gold-based nanoparticles. Therefore, Bac@ARS is a promising microbial sonosensitizer providing a new platform for the optimization of sonosensitizers for tumor treatment. STATEMENT OF SIGNIFICANCE: A bio-nano-sonosensitizer was designed using a Au nanoparticle (NP) core modified with RuO2 NPs. The Au-RuO2 NPs together with Se-NPs are attached via electrostatic adsorption to a live bacterium Listeria innocua (LI), creating Bac@ARS. The role of the NPs was to optimize the sonosensitivity performance at the target tumor site. Bac@ARS reshaped the tumor microenvironment and overcame tumor hypoxia leading to ROS overproduction. This activated a potent ICD-mediated cellular immunity and anti-tumor activity. Importantly, Bac@ARS exploited the natural tropism of LI to selectively accumulate in tumors, resulting in more precise delivery of the therapeutic effect while exhibiting reduced effects on healthy tissues.

Assessment of heavy metals contamination and human health risk assessment of the commonly consumed medicinal herbs in China.

This study investigates heavy metal contamination of commonly consumed medicinal herbs and human health risks to the Chinese population arising from the consumption of herbs that contain potentially harmful elements. Food safety standards for Chinese residents are becoming stricter, and much work in this field needs to be performed. This study examines Co, Ba, Fe, Cr, Mn, Ni, Zn, As, Cd, Pb, Cu, Be, Sb, and Bi concentrations in four regularly consumed Chinese herb species: Radix Paeoniae Alba (RPA), Radix Angelicae Dahuricae (RAD), Rhizoma Atractylodis Macrocephalae (RAM), and Radix Puerariae (RP). A pollution status examination and evaluation of heavy metals in RPA, RAD, RAM, and RP were performed. The human health risk assessment associated with the intake of potentially harmful elements in herbs was calculated in terms of the estimated daily intake (EDI), the target hazard quotient (THQ), the estimated hazard index (HI), and the lifetime cancer risk (CR). The mean single-factor pollution index (PI) showed that in the RPA, RAD, RAM, and RP samples, approximately 10.0%, 10.0%, 30.0%, and 10.0%, respectively, were polluted by Cd. The present study indicated that the pattern of consumption of the studied herbs in China does not seem to suggest an excessive health hazard associated with any of the toxic elements studied.

Multiple responses optimization of antioxidative components extracted from Fenugreek seeds using response surface methodology to identify their chemical compositions.

Fenugreek seeds (Trigonella foenum-graecum L.), one kind of traditional Chinese medicine, are reported to be of great potential as a new alternative in terms of their bioactive components. In our present study, an ultrasonic-assisted method was applied in the extraction of antioxidative components from fenugreek seeds. Four factors: ethanol concentration, liquid-solid ratio, sonication time, and sonication power were selected and multiple responses were studied using the response surface methodology (RSM). The effects of factors along with the correlation between all responses (flavonoids content, 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, OH- assay) were studied. The regression model indicated that all four factors are of significant effect on all responses. The model predicted that the ethanol concentration of 72%, solvent-to-material ratio of 35 ml/g, ultrasonic time of 41 min, and 500 W of power would provide a flavonoid yield of 9.10 mg/g, DPPH clearance of 80.33%, and OH- clearance of 24.28%, respectively. The confirmation test showed the closeness of the predicted results with those of experimental values. And AB-8 resin was successfully used to purify the fenuellus hulusi seed extract, and the flavonoid concentration of 78.14% was obtained. Six flavonoids (Swertisin, Puerarin apioside, Jasminoside B, Astragalin, Apigenin-7-O-beta-D-glucoside, and Apiin) were successfully identified by the liquid chromatography-mass spectrometry (LC-MS) analysis.

N6-methyladenosine modification-mediated mRNA metabolism is essential for human pancreatic lineage specification and islet organogenesis.

Pancreatic differentiation from human pluripotent stem cells (hPSCs) provides promising avenues for investigating development and treating diseases. N6-methyladenosine (m6A) is the most prevalent internal messenger RNA (mRNA) modification and plays pivotal roles in regulation of mRNA metabolism, while its functions remain elusive. Here, we profile the dynamic landscapes of m6A transcriptome-wide during pancreatic differentiation. Next, we generate knockout hPSC lines of the major m6A demethylase ALKBH5, and find that ALKBH5 plays significant regulatory roles in pancreatic organogenesis. Mechanistic studies reveal that ALKBH5 deficiency reduces the mRNA stability of key pancreatic transcription factors in an m6A and YTHDF2-dependent manner. We further identify that ALKBH5 cofactor α-ketoglutarate can be applied to enhance differentiation. Collectively, our findings identify ALKBH5 as an essential regulator of pancreatic differentiation and highlight that m6A modification-mediated mRNA metabolism presents an important layer of regulation during cell-fate specification and holds great potentials for translational applications.

Role of an FNIP Repeat Domain-Containing Protein Encoded by Megavirus Baoshan during Viral Infection.

FNIP repeat domain-containing protein (FNIP protein) is a little-studied atypical leucine-rich repeat domain-containing protein found in social amoebae and mimiviruses. Here, a recently reported mimivirus of lineage C, Megavirus baoshan, was analyzed for FNIP protein genes. A total of 82 FNIP protein genes were identified, each containing up to 26 copies of the FNIP repeat, and mostly having an F-box domain at the N terminus. Both nucleotide and amino acid sequences of FNIP repeat were highly conserved. Most of the FNIP protein genes clustered together tandemly in groups of two to 14 genes. Nearly all FNIP protein genes shared similar expression patterns and were expressed 4 to 9 h postinfection. A typical viral FNIP protein, Mb0983, was selected for functional analysis. Protein interactome analysis identified two small GTPases, Rap1B and Rab7A, that interacted with Mb0983 in cytoplasm. The overexpression of Mb0983 in Acanthamoeba castellanii accelerated the degradation of Rap1B and Rab7A during viral infection. Mb0983 also interacted with host SKP1 and cullin-1, which were conserved components of the SKP1-cullin-1-F-box protein (SCF)-type ubiquitin E3 ligase complex. Deletion of the F-box domain of Mb0983 not only abolished its interaction with SKP1 and cullin-1 but also returned the speed of Rap1B and Rab7A degradation to normal in infected A. castellanii. These results suggested that Mb0983 is a part of the SCF-type ubiquitin E3 ligase complex and plays a role in the degradation of Rap1B and Rab7A. They also implied that other viral F-box-containing FNIP proteins might have similar effects on various host proteins. IMPORTANCE Megavirus baoshan encodes 82 FNIP proteins, more than any other reported mimiviruses. Their genetic and transcriptional features suggest that they are important for virus infection and adaption. Since most mimiviral FNIP proteins have the F-box domain, they were predicted to be involved in protein ubiquitylation. FNIP protein Mb0983 interacted with host SKP1 and cullin-1 through the F-box domain, supporting the idea that it is a part of the SCF-type ubiquitin E3 ligase complex. The substrates of Mb0983 for degradation were identified as the host small GTPases Rap1B and Rab7A. Combining the facts of the presence of a large number of FNIP genes in megavirus genomes, the extremely high expression level of the viral ubiquitin gene, and the reported observation that 35% of megavirus-infected amoeba cells died without productive infection, it is likely that megavirus actively explores the host ubiquitin-proteasome pathway in infection and that viral FNIP proteins play roles in the process.

Rhizobium cremeum sp. nov., isolated from sewage and capable of acquisition of heavy metal and aromatic compounds resistance genes.

Two strains of Rhizobia isolated from sewage collected from the Chinese Baijiu distillery were characterized using a polyphasic approach. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strains W15T and W16 were grouped as a separate clade closely related to Rhizobium daejeonense L61T (98.6%). Multilocus sequence analysis (MLSA) with three housekeeping genes (recA, glnII and rpoA) also showed that strains W15T and W16 belonged to the genus Rhizobium. Average nucleotide identity and digital DNA-DNA hybridization values between genome sequences of strain W15T and the closely related species ranged from 77.0% to 87.8% and from 23.9% to 30.9%. The DNA G + C content of strain W15T was 61.6 mol%. Strain W15T contained Q-10 as the major ubiquinone and the dominant fatty acids were summed feature 8 (C 18:1ω7c and/or C 18:1ω6c; 73.1%) and C18:0 (7.6%). The main polar lipids are phosphatidylcholine, phosphatidylmethylethanolamine, phosphatidylethanolamine and phosphatidylglycerol. On the basis of the evidences presented in this study, strains W15T and W16 represents a novel species of the genus Rhizobium, for which the name Rhizobium cremeum sp. nov. is proposed. The type strain is W15T (= CGMCC 1.18731T = KACC 22344T).

Human expandable pancreatic progenitor-derived ß cells ameliorate diabetes.

An unlimited source of human pancreatic ß cells is in high demand. Even with recent advances in pancreatic differentiation from human pluripotent stem cells, major hurdles remain in large-scale and cost-effective production of functional ß cells. Here, through chemical screening, we demonstrate that the bromodomain and extraterminal domain (BET) inhibitor I-BET151 can robustly promote the expansion of PDX1+NKX6.1+ pancreatic progenitors (PPs). These expandable PPs (ePPs) maintain pancreatic progenitor cell status in the long term and can efficiently differentiate into functional pancreatic ß (ePP-ß) cells. Notably, transplantation of ePP-ß cells rapidly ameliorated diabetes in mice, suggesting strong potential for cell replacement therapy. Mechanistically, I-BET151 activates Notch signaling and promotes the expression of key PP-associated genes, underscoring the importance of epigenetic and transcriptional modulations for lineage-specific progenitor self-renewal. In summary, our studies achieve the long-term goal of robust expansion of PPs and represent a substantial step toward unlimited supplies of functional ß cells for biomedical research and regenerative medicine.

The Prevalence and Factors Associated with the Prescription of Opioids for Head/Neck Pain after Elective Craniotomy for Tumor Resection/Vascular Repair: A Retrospective Cohort Study.

Background and objective: There is no report of the rate of opioid prescription at the time of hospital discharge, which may be associated with various patient and procedure-related factors. This study examined the prevalence and factors associated with prescribing opioids for head/neck pain after elective craniotomy for tumor resection/vascular repair. Methods: We performed a retrospective cohort study on adults undergoing elective craniotomy for tumor resection/vascular repair at a large quaternary-care hospital. We used univariable and multivariable analysis to examine the prevalence and factors (pre-operative, intraoperative, and postoperative) associated with prescribing opioids at the time of hospital discharge. We also examined the factors associated with discharge oral morphine equivalent use. Results: The study sample comprised 273 patients with a median age of 54 years [IQR 41,65], 173 females (63%), 174 (63.7%) tumor resections, and 99 (36.2%) vascular repairs. The majority (n = 264, 96.7%) received opioids postoperatively. The opiate prescription rates were 72% (n = 196/273) at hospital discharge, 23% (19/83) at neurosurgical clinical visits within 30 days of the procedure, and 2.4% (2/83) after 30 days from the procedure. The median oral morphine equivalent (OME) at discharge use was 300 [IQR 175,600]. Patients were discharged with a median supply of 5 days [IQR 3,7]. On multivariable analysis, opioid prescription at hospital discharge was associated with pre-existent chronic pain (adjusted odds ratio, aOR 1.87 [1.06,3.29], p = 0.03) and time from surgery to hospital discharge (compared to patients discharged within days 1−4 postoperatively, patients discharged between days 5−12 (aOR 0.3, 95% CI [0.15; 0.59], p = 0.0005), discharged at 12 days and later (aOR 0.17, 95% CI [0.07; 0.39], p < 0.001)). There was a linear relationship between the first 24 h OME (p < 0.001), daily OME (p < 0.001), hospital OME (p < 0.001), and discharge OME. Conclusions: This single-center study finds that at the time of hospital discharge, opioids are prescribed for head/neck pain in as many as seven out of ten patients after elective craniotomy. A history of chronic pain and time from surgery to discharge may be associated with opiate prescriptions. Discharge OME may be associated with first 24-h, daily OME, and hospital OME use. Findings need further evaluation in a large multicenter sample. The findings are important to consider as there is growing interest in an early discharge after elective craniotomy.

Crystalline ruthenium polypyridine nanoparticles: a targeted treatment of bacterial infection with multifunctional antibacterial, adhesion and surface-anchoring photosensitizer properties.

Photodynamic antibacterial therapy employs nanocomposites as an alternative to traditional antibiotics for the treatment of bacterial infections. However, many of these antibacterial materials are less effective towards bacteria than traditional drugs, either due to poor specificity or antibacterial activity. This can result in needless and excessive drug use in treatments. This paper describes a multifunctional drug delivery nanoparticle (MDD-NP), Sph-Ru-MMT@PZ, based on the nanostructured-form of [Ru(bpy)2dppz] (PF6)2 (Sph-Ru), which has adhesive properties towards its microbial targets as well as surface-anchoring photosensitizer effects. The design and construction of MDD-NP is based on the adhesive properties of the outer layers of montmorillonite (MMT), which allows Sph-Ru-MMT@PZ to successfully reach its bacterial target; the outer layer of the E. coli. In addition, under 670 nm red irradiation therapy (R-IT), the surface-anchoring properties use the photosensitizer phthalocyanine zinc (PZ) to destroy the bacteria by producing reactive oxygen species (ROS) which causes cell lysis of E. coli. More importantly, Sph-Ru-MMT@PZ has no fluorescence response to live E. coli with intact cell membranes but selectively stained and demonstrated fluorescence during membrane damage of early-stage cells as well as exposure of nuclear materials at late-stage of cell lysis. Sph-Ru-MMT@PZ showed beneficial and synergistic anti-infective effects in vivo by inhibiting the E. coli infection-induced inflammatory response and eventually promoting wound healing in mice. This new strategy for high precision antibacterial therapy towards specific targets, provides an exciting opportunity for the application of multifunctional nanocomposites towards microbial infections.

The VANGL1 P384R variant cause both neural tube defect and Klippel-Feil syndrome.

BACKGROUND: Neural tube defect (NTD) is a common birth defect causing much death in the world. Variants in VANGL1 lead to NTD and caudal regression syndrome. NTD displays a complex phenotype encompassing both genetic and environmental factors. METHODS: The fetus was diagnosed by prenatal ultrasound examination. Postnatal CT and autopsy were performed. Genetic testing was conducted in the family and Sanger sequencing was validated. Multiple prediction soft-wares were used to predict the pathogenicity of the variant. RESULTS: The VANGL1 gene variant c.1151C>G (P384R) was detected in a fetus diagnosed with tethered spinal cord and sacrococcygeal lipoma. The VANGL1 variant c.1151C>G (P384R) was reported in a Klippel-Feil syndrome patient. The VANGL1 variant was validated in the trio-family but the mother showed no abnormalities. CONCLUSION: Overall, this study presents fetal NTD caused by the same VANGL1 variant found in a Klippel-Feil syndrome patient with complete clinical information of prenatal ultrasound, postnatal CT, and genetic results as early as 25 GW. Our study not only expands the VANGL1 mutational spectrum but also sheds light on the important role of the VANGL1 P384R variant in human development.

Inhibition of Syk promotes chemical reprogramming of fibroblasts via metabolic rewiring and H2 S production.

Chemical compounds have recently been introduced as alternative and non-integrating inducers of pluripotent stem cell fate. However, chemical reprogramming is hampered by low efficiency and the molecular mechanisms remain poorly characterized. Here, we show that inhibition of spleen tyrosine kinase (Syk) by R406 significantly promotes mouse chemical reprogramming. Mechanistically, R406 alleviates Syk / calcineurin (Cn) / nuclear factor of activated T cells (NFAT) signaling-mediated suppression of glycine, serine, and threonine metabolic genes and dependent metabolites. Syk inhibition upregulates glycine level and downstream transsulfuration cysteine biosynthesis, promoting cysteine metabolism and cellular hydrogen sulfide (H2 S) production. This metabolic rewiring decreased oxidative phosphorylation and ROS levels, enhancing chemical reprogramming. In sum, our study identifies Syk-Cn-NFAT signaling axis as a new barrier of chemical reprogramming and suggests metabolic rewiring and redox homeostasis as important opportunities for controlling cell fates.

Ruthenium-loaded mesoporous silica as tumor microenvironment-response nano-fenton reactors for precise cancer therapy.

BACKGROUND: Nano-Fenton reactors as novel strategy to selectively convert hydrogen peroxide (H2O2) into active hydroxyl radicals in tumor microenvironment for cancer therapy had attracted much attention. However, side effects and low efficiency remain the main drawbacks for cancer precise therapy. RESULTS: Here, ruthenium-loaded palmitoyl ascorbate (PA)-modified mesoporous silica (Ru@SiO2-PA) was successfully fabricated and characterized. The results indicated that Ru@SiO2-PA under pH6.0 environment displayed enhanced growth inhibition against human cancer cells than that of pH7.4, which indicated the super selectivity between cancer cells and normal cells. Ru@SiO2-PA also induced enhanced cancer cells apoptosis, followed by caspase-3 activation and cytochrome-c release. Mechanism investigation revealed that Ru@SiO2-PA caused enhanced generation of superoxide anion, which subsequently triggered DNA damage and dysfunction of MAPKs and PI3K/AKT pathways. Moreover, Ru@SiO2-PA effectively inhibited tumor spheroids and tumor xenografts growth in vivo by induction of apoptosis. The real-time imaging by monitoring Ru fluorescence in vitro and in vivo revealed that Ru@SiO2-PA mainly accumulated in cell nucleus and tumor xenografts. Importantly, Ru@SiO2-PA showed no side effects in vivo, predicting the safety and potential application in clinic. CONCLUSIONS: Our findings validated the rational design that Ru@SiO2-PA can act as novel tumor microenvironment-response nano-Fenton reactors for cancer precise therapy.

Human small intestine cancer cell membrane-camouflaged quercetin-melanin for antibacterial and antitumor activity.

E. coli has become an important factor that can lead to cancer because of its ability to cause diverse intestinal changes. Nano-polymer materials provide ideal drug delivery systems for preparing antibacterial and anti-cancer drugs because of their unique structure, easy modification, and high drug loading. The modified natural melanin has the potential to be an excellent nano-carrier. By improving the water-solubility and biocompatibility of the loaded natural drug quercetin, the antibacterial effect of quercetin can be fully played. Here, natural melanin was extracted from frozen squid to synthesize carrier polydopamine (PDA) nanoparticles, and the natural drug quercetin (Q) was modified on the surface of PDA by π-π bond and covalent bond action to produce melanin-quercetin (PDA-Q). We also developed human small intestinal cancer cells (HIC) membrane-camouflaged melanin-Quercetin (PDA-Q) nanoparticles as an anti-cancer platform in vivo. The potential bacteriostatic mechanism was likely driven by the penetration of PDA-Q in E. coli cells, damaging the integrity of the membranes of E. coli and inducing cell death. The mice wound experiment and bacteremia model experiment revealed that C@PDA-Q had a strong inhibitory effect on E. coli in vivo. In addition, the results of the in vitro tumor test also revealed that C@PDA-Q had strong anti-tumor activity against HIC cells of human small intestinal cancer, and the IC50 value was 12.3 ± 0.7 µg/ml, which was slightly better than that for cisplatin. As both melanin nanoparticles and HIC membrane are natural biomaterials, the synthesized C@PDA-Q nano-polymer material shows great potential for use in anti-cancer nano-drug loading.

Mesoporous silica integrated with Fe3O4 and palmitoyl ascorbate as a new nano-Fenton reactor for amplified tumor oxidation therapy.

Co-delivery of H2O2-generating agent and catalyst via a nano-Fenton reactor to the tumor acidic microenvironment for amplified tumor oxidation therapy has been widely studied. However, high side effects and low efficiency remain the limitations of the design and development of this process. Herein, a new nano-Fenton reactor in which mesoporous silica is integrated with Fe3O4 and palmitoyl ascorbate (Fe3O4@SiO2-PA) was designed, with the product exhibiting good dispersion, stability, uniformity and consistent spectral characteristics. The results show that Fe3O4@mSiO2-PA successfully enters cancer cells, significantly inhibits HeLa cells and 3D tumor spheroid growth in vitro via the induction of apoptosis. Meanwhile, Fe3O4@mSiO2-PA administration in vivo markedly suppresses HeLa tumor xenografts growth via the induction of apoptosis, followed by caspase-3 activation and cytochrome C release. Further investigation revealed that Fe3O4@mSiO2-PA causes enhanced production of reactive oxygen species (ROS), which subsequently triggers DNA damage and causes dysfunction of the MAPK and PI3K/AKT pathways. Importantly, Fe3O4@mSiO2-PA shows few side effects and good biocompatibility in vivo. Taken together, these results suggest that Fe3O4@mSiO2-PA inhibits HeLa cell growth in vitro and in vivo by triggering enhanced oxidative damage and regulating multiple signal pathways. Our findings validate the rational design that mesoporous silica integrated with Fe3O4 and palmitoyl ascorbate can act as a new nano-Fenton reactor for amplified tumor oxidation therapy.