Combination of monensin and erlotinib synergistically inhibited the growth and cancer stem cell properties of triple-negative breast cancer by simultaneously inhibiting EGFR and PI3K signaling pathways.

BACKGROUND: Cancer stem cells (CSCs) in triple-negative breast cancer (TNBC) are recognized as a highly challenging subset of cells, renowned for their heightened propensity for relapse and unfavorable prognosis. Monensin, an ionophoric antibiotic, has been reported to exhibit significant therapeutic efficacy against various cancers, especially CSCs. Erlotinib is classified as one of the EGFR-TKIs and has been previously identified as a promising therapeutic target for TNBC. Our research aims to assess the effectiveness of combination of monensin and erlotinib as a potential treatment strategy for TNBC. METHODS: The combination of monensin and erlotinib was assessed for its potential anticancer activity through various in vitro assays, including cytotoxicity assay, colony formation assay, wound healing assay, transwell assay, mammosphere formation assay, and proportion of CSCs assay. Additionally, an in vivo study using tumor-bearing nude mice was conducted to evaluate the inhibitory effect of the monensin and erlotinib combination on tumor growth. RESULTS: The results indicated that combination of monensin with erlotinib synergistically inhibited cell proliferation, the migration rate, the invasion ability and decreased the CSCs proportion, and CSC markers SOX2 and CD133 in vivo and in vitro. Furthermore, the primary proteins involved in the signaling pathways of the EGFR/ERK and PI3K/AKT are simultaneously inhibited by the combination treatment of monensin and erlotinib in vivo and in vitro. CONCLUSIONS: The simultaneous inhibition of the EGFR/ERK and PI3K/AKT/mTOR signaling pathways by the combination of monensin and erlotinib exhibited a synergistic effect on suppressing tumor proliferation and cancer cell stemness in TNBC.

EDA Complex-Enabled Annulation to Access CF2-Containing Tetralones and Quinazolinones Using Persulfates as Electron Donors.

A photocatalyst-free and EDA complex-enabled radical cascade cyclization reaction of inactive alkenes with bromodifluoroacetamides was reported for the divergent synthesis of fluorine-containing tetralones and quinazolinones. In this transformation, persulfates as electron donors and difluoro bromamide as electron acceptors generate the EDA complex. This is a promising photochemical method with advantages such as mild reaction conditions, simple operation, being metal-free, and excellent functional group tolerance.

New stenurothripid thrips from mid-Cretaceous Kachin amber (Thysanoptera, Stenurothripidae).

Hitherto, only two species of the thysanopteran suborder Terebrantia have been reported from mid-Cretaceous Kachin amber (Myanmar). This is here expanded through the discovery of two new genera and species, described and figured as Parallelothripsseparatusgen. et sp. nov. and Didymothripsabdominalisgen. et sp. nov., both of the family Stenurothripidae. Both taxa have key apomorphies of the Stenurothripidae, allowing for a confident assignment as to family. Both species have characteristic comb-like anteromarginal setae, which are discussed along with structural differences between the two sexes. Cycad pollen was found on the thrips' bodies, providing further evidence that Thysanoptera were pollinators of gymnosperms during the mid-Cretaceous.

Antibiofilm activity of polyethylene glycol-quercetin nanoparticles-loaded gelatin-N,O-carboxymethyl chitosan composite nanogels against Staphylococcus epidermidis.

BACKGROUND: Biofilms, such as those from Staphylococcus epidermidis, are generally insensitive to traditional antimicrobial agents, making it difficult to inhibit their formation. Although quercetin has excellent antibiofilm effects, its clinical applications are limited by the lack of sustained and targeted release at the site of S. epidermidis infection. OBJECTIVES: Polyethylene glycol-quercetin nanoparticles (PQ-NPs)-loaded gelatin-N,O-carboxymethyl chitosan (N,O-CMCS) composite nanogels were prepared and assessed for the on-demand release potential for reducing S. epidermidis biofilm formation. METHODS: The formation mechanism, physicochemical characterization, and antibiofilm activity of PQ-nanogels against S. epidermidis were studied. RESULTS: Physicochemical characterization confirmed that PQ-nanogels had been prepared by the electrostatic interactions between gelatin and N,O-CMCS with sodium tripolyphosphate. The PQ-nanogels exhibited obvious pH and gelatinase-responsive to achieve on-demand release in the micro-environment (pH 5.5 and gelatinase) of S. epidermidis. In addition, PQ-nanogels had excellent antibiofilm activity, and the potential antibiofilm mechanism may enhance its antibiofilm activity by reducing its relative biofilm formation, surface hydrophobicity, exopolysaccharides production, and eDNA production. CONCLUSIONS: This study will guide the development of the dual responsiveness (pH and gelatinase) of nanogels to achieve on-demand release for reducing S. epidermidis biofilm formation.

Using halofuginone-silver thermosensitive nanohydrogels with antibacterial and anti-inflammatory properties for healing wounds infected with Staphylococcus aureus.

Contamination by pathogens, such as bacteria, can irritate a wound and prevent its healing, which may affect the physical fitness of the infected person. As such, the development of more novel nano-biomaterials able to cope with the inflammatory reaction to bacterial infection during the wound healing process to accelerate wound healing is required. Herein, a halofuginone­silver nano thermosensitive hydrogel (HTPM&AgNPs-gel) was prepared via a physical swelling method. HTPM&AgNPs-gel was characterized based on thermogravimetric analysis, differential scanning calorimetry, morphology, injectability, and rheological mechanics that reflected its exemplary nature. Moreover, HTPM&AgNPs-gel was further tested for its ability to facilitate healing of skin fibroblasts and exert antibacterial activity. Finally, HTPM&AgNPs-gel was tested for its capacity to accelerate general wound healing and treat bacterially induced wound damage. HTPM&AgNPs-gel appeared spherical under a transmission electron microscope and showed a grid structure under a scanning electron microscope. Additionally, HTPM&AgNPs-gel demonstrated excellent properties, including injectability, temperature-dependent swelling behavior, low loss at high temperatures, and appropriate rheological properties. Further, HTPM&AgNPs-gel was found to effectively promote healing of skin fibroblasts and inhibit the proliferation of Escherichia coli and Staphylococcus aureus. An evaluation of the wound healing efficacy demonstrated that HTPM&AgNPs-gel had a more pronounced ability to facilitate wound repair and antibacterial effects than HTPM-gel or AgNPs-gel alone, and exhibited ideal biocompatibility. Notably, HTPM&AgNPs-gel also inhibited inflammatory responses in the healing process. HTPM&AgNPs-gel exhibited antibacterial, anti-inflammatory, and scar repair features, which remarkably promoted wound healing. These findings indicated that HTPM&AgNPs-gel holds great clinical potential as a promising and valuable wound healing treatment.

Maduramicin-guided nanotherapy: A polymeric micelles for targeted drug delivery in canine mammary tumors.

Canine mammary tumors (CMT) can severely compromise the life quality of the affected dogs through local recurrence, distant metastases and ultimately succumb to death. Recently, more attention has been given to the potential antimetastatic effect of maduramicin (MAD) on breast cancer. However, its poor aqueous solubility and toxicity to normal tissues limit its clinical application. Therefore, to address the drawbacks of MAD and enhance its anticancer and antimetastatic effects, MAD-loaded TPGS polymeric micelles (MAD-TPGS) were prepared by a thin-film hydration technique. The optimized MAD-TPGS exhibited excellent size distribution, stability and improved water solubility. Cellular uptake assays showed that TPGS polymer micelles could enhance drug internalization. Moreover, TPGS synergistically improved the cytotoxicity of MAD by targeting mitochondrial organelles, improving reactive oxygen species levels and reducing the mitochondrial transmembrane potential. More importantly, MAD-TPGS significantly impeded the metastasis of tumor cells. In vivo results further confirmed that, in addition to exhibiting excellent biocompatibility, MAD-TPGS exhibited greater antitumor efficacy than free MAD. Interestingly, MAD-TPGS displayed superior suppression of CMT metastasis via tail vein injection compared to oral administration, indicating its suitability for intravenous delivery. Overall, MAD-TPGS could be applied as a potential antimetastatic cancer agent for CMT.

Enhanced In Vitro Antiviral Activity of Ivermectin-Loaded Nanostructured Lipid Carriers against Porcine Epidemic Diarrhea Virus via Improved Intracellular Delivery.

Porcine epidemic diarrhea virus (PEDV) is an acute enteric coronavirus, inducing watery diarrhea and high mortality in piglets, leading to huge economic losses in global pig industry. Ivermectin (IVM), an FDA-approved antiparasitic agent, is characterized by high efficacy and wide applicability. However, the poor bioavailability limits its application. Since the virus is parasitized inside the host cells, increasing the intracellular drug uptake can improve antiviral efficacy. Hence, we aimed to develop nanostructured lipid carriers (NLCs) to enhance the antiviral efficacy of IVM. The findings first revealed the capacity of IVM to inhibit the infectivity of PEDV by reducing viral replication with a certain direct inactivation effect. The as-prepared IVM-NLCs possessed hydrodynamic diameter of 153.5 nm with a zeta potential of -31.5 mV and high encapsulation efficiency (95.72%) and drug loading (11.17%). IVM interacted with lipids and was enveloped in lipid carriers with an amorphous state. Furthermore, its encapsulation in NLCs could enhance drug internalization. Meanwhile, IVM-NLCs inhibited PEDV proliferation by up to three orders of magnitude in terms of viral RNA copies, impeding the accumulation of reactive oxygen species and mitigating the mitochondrial dysfunction caused by PEDV infection. Moreover, IVM-NLCs markedly decreased the apoptosis rate of PEDV-induced Vero cells. Hence, IVM-NLCs showed superior inhibitory effect against PEDV compared to free IVM. Together, these results implied that NLCs is an efficient delivery system for IVM to improve its antiviral efficacy against PEDV via enhanced intracellular uptake.

YOLO-Granada: a lightweight attentioned Yolo for pomegranates fruit detection.

Pomegranate is an important fruit crop that is usually managed manually through experience. Intelligent management systems for pomegranate orchards can improve yields and address labor shortages. Fast and accurate detection of pomegranates is one of the key technologies of this management system, crucial for yield and scientific management. Currently, most solutions use deep learning to achieve pomegranate detection, but deep learning is not effective in detecting small targets and large parameters, and the computation speed is slow; therefore, there is room for improving the pomegranate detection task. Based on the improved You Only Look Once version 5 (YOLOv5) algorithm, a lightweight pomegranate growth period detection algorithm YOLO-Granada is proposed. A lightweight ShuffleNetv2 network is used as the backbone to extract pomegranate features. Using grouped convolution reduces the computational effort of ordinary convolution, and using channel shuffle increases the interaction between different channels. In addition, the attention mechanism can help the neural network suppress less significant features in the channels or space, and the Convolutional Block Attention Module attention mechanism can improve the effect of attention and optimize the object detection accuracy by using the contribution factor of weights. The average accuracy of the improved network reaches 0.922. It is only less than 1% lower than the original YOLOv5s model (0.929) but brings a speed increase and a compression of the model size. and the detection speed is 17.3% faster than the original network. The parameters, floating-point operations, and model size of this network are compressed to 54.7%, 51.3%, and 56.3% of the original network, respectively. In addition, the algorithm detects 8.66 images per second, achieving real-time results. In this study, the Nihui convolutional neural network framework was further utilized to develop an Android-based application for real-time pomegranate detection. The method provides a more accurate and lightweight solution for intelligent management devices in pomegranate orchards, which can provide a reference for the design of neural networks in agricultural applications.

Injectable nano-in situ-thermosensitive-hydrogels based on halofuginone and silver for postoperative treatment against triple-negative breast cancer.

Postoperative distant metastasis and high recurrence rate causes a dilemma in treating triple-negative breast cancer (TNBC) owing to its unforeseeable invasion into various organs or tissues. The wealth of nutrition provided by vascular may facilitate the proliferation and angiogenesis of cancer cells, which further enhance the rates of postoperative metastasis and recurrence. Chemotherapy, as a systemic postoperative adjuvant therapy, is generally applied to diminish recurrence and metastasis of TNBC. Herein, an halofuginone-silver nano thermosensitive hydrogel (HTPM&AgNPs-gel) was prepared via a physical swelling method. The in vitro anticancer efficacy of HTPM&AgNPs-gel was analyzed by investigating cell proliferation, migration, invasion, and angiogenesis capacity. Furthermore, the in vivo anti-cancer activity of HTPM&AgNPs-gel was further appraised through the tumor suppression, anti-metastatic, anti-angiogenic, and anti-inflammatory ability. The optimized HTPM&AgNPs-gel, a thermosensitive hydrogel, showed excellent properties, including syringeability, swelling behavior, and a sustained release effect without hemolysis. In addition, HTPM&AgNPs-gel was confirmed to effectively inhibit the proliferation, migration, invasion, and angiogenesis of MDA-MB-231 cells. An evaluation of the in vivo anti-tumor efficacy demonstrated that HTPM&AgNPs-gel showed a stronger tumor inhibition rate (68.17%) than did HTPM-gel or AgNPs-gel used alone and exhibited outstanding biocompatibility. Notably, HTPM&AgNPs-gel also inhibited lung metastasis induced by residual tumor tissue after surgery and further blocked angiogenesis-related inflammatory responses. Taken together, the suppression of inflammation by interdicting the blood vessels adjoining the tumor and inhibiting angiogenesis is a potential strategy to attenuate the recurrence and metastasis of TNBC. HTPM&AgNPs-gel is a promising anticancer agent for TNBC as a local postoperative treatment.